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Alman, Benjamin Aaron

Positions:

James R. Urbaniak, M.D., Professor of Orthopedic Surgery

Orthopaedics
School of Medicine

Professor of Orthopaedic Surgery

Orthopaedics
School of Medicine

Professor in Cell Biology

Cell Biology
School of Medicine

Professor in the Department of Pathology

Pathology
School of Medicine

Professor in Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chair of Orthopaedic Surgery

Orthopaedics
School of Medicine

Education:

M.D. 1986

M.D. — Jefferson Medical College of Thomas Jefferson University

News:

Grants:

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

Rejuvenating fracture repair: The role of the macrophage and Beta-catenin

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 15, 2016
End Date
March 31, 2021

Targeting Tumor Initiating Cell in Undifferentiated Pleomorphic Sarcoma

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2019

Molecular Etiology of Enchondromatosis: Hedgehog Regulation in Chondrocytes

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 23, 2014
End Date
August 31, 2019

Collaboration for a Cure: Identifying new Therapeutic Targets for Desmoid Tumors

Administered By
Orthopaedics
AwardedBy
Desmoid Tumor Research Foundation, Inc.
Role
Principal Investigator
Start Date
November 01, 2013
End Date
October 31, 2017

Training Program in Developmental and Stem Cell Biology

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 01, 2001
End Date
October 31, 2017
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Publications:

Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair.

Patients with Neurofibromatosis type 1 display delayed fracture healing and the increased deposition of fibrous tissue at the fracture site. Severe cases can lead to non-union and even congenital pseudarthrosis. Neurofibromatosis type 1 is caused by a mutation in the NF1 gene and mice lacking the Nf1 gene show a fracture repair phenotype similar to that seen in patients. Tissue from the fracture site of patients with Neurofibromatosis type 1 and from mice deficient in the Nf1 gene both show elevated levels of β-catenin protein and activation of β-catenin mediated signaling. Constitutively elevated β-catenin leads to a delayed and fibrous fracture repair process, and (RS)-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine (Nefopam, a centrally-acting, non-narcotic analgesic agent) inhibits β-catenin mediated signaling during skin wound repair. Here we investigate Nefopam's potential as a modulator of bone repair in mice deficient in Nf1. Mice were treated with Nefopam and investigated for bone fracture repair. Bone marrow stromal cells flushed from the long bones of unfractured mice were treated with Nefopam and investigated for osteogenic potential. Treatment with Nefopam was able to lower the β-catenin level and the Axin2 transcript level in the fracture calluses of Nf1 deficient mice. Cultures from the bone marrow of Nf1-/- mice had significantly lower osteoblastic colonies and mineralized nodules, which was increased when cells were cultured in the presence of Nefopam. Fracture calluses were harvested and analyzed 14days and 21days after injury. Nf1-/- calluses had less bone, less cartilage, and higher fibrous tissue content than control calluses. Treatment with Nefopam increased the bone and cartilage content and decreased the fibrous tissue content in Nf1-/- calluses. These findings present a potential treatment for patients with Neurofibromatosis 1 in the context of bone repair. Since Nefopam is already in use in patient care, it could be rapidly translated to the clinical setting.

Authors
Baht, GS; Nadesan, P; Silkstone, D; Alman, BA
MLA Citation
Baht, GS, Nadesan, P, Silkstone, D, and Alman, BA. "Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair." Bone 98 (May 2017): 31-36.
PMID
28254468
Source
epmc
Published In
BONE
Volume
98
Publish Date
2017
Start Page
31
End Page
36
DOI
10.1016/j.bone.2017.02.012

Mechanism of hard-nanomaterial clearance by the liver.

The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

Authors
Tsoi, KM; MacParland, SA; Ma, X-Z; Spetzler, VN; Echeverri, J; Ouyang, B; Fadel, SM; Sykes, EA; Goldaracena, N; Kaths, JM; Conneely, JB; Alman, BA; Selzner, M; Ostrowski, MA; Adeyi, OA; Zilman, A; McGilvray, ID; Chan, WCW
MLA Citation
Tsoi, KM, MacParland, SA, Ma, X-Z, Spetzler, VN, Echeverri, J, Ouyang, B, Fadel, SM, Sykes, EA, Goldaracena, N, Kaths, JM, Conneely, JB, Alman, BA, Selzner, M, Ostrowski, MA, Adeyi, OA, Zilman, A, McGilvray, ID, and Chan, WCW. "Mechanism of hard-nanomaterial clearance by the liver." Nature materials 15.11 (November 2016): 1212-1221.
PMID
27525571
Source
epmc
Published In
Nature Materials
Volume
15
Issue
11
Publish Date
2016
Start Page
1212
End Page
1221
DOI
10.1038/nmat4718

β-Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.

Tibial pseudarthrosis causes substantial morbidity in patients with neurofibromatosis type 1 (NF1). We studied tibial pseudarthrosis tissue from patients with NF1 and found elevated levels of β-catenin compared to unaffected bone. To elucidate the role of β-catenin in fracture healing, we used a surgically induced tibial fracture model in conditional knockout (KO) Nfl (Nf1(flox/flox)) mice. When treated with a Cre-expressing adenovirus (Ad-Cre), there was a localized knockdown of Nf1 in the healing fracture and a subsequent development of a fibrous pseudarthrosis. Consistent with human data, elevated β-catenin levels were found in the murine fracture sites. The increased fibrous tissue at the fracture site was rescued by local treatment with a Wingless-type MMTV integration site (Wnt) antagonist, Dickkopf-1 (Dkk1). The murine pseudarthrosis phenotype was also rescued by conditional β-catenin gene inactivation. The number of colony-forming unit osteoblasts (CFU-Os), a surrogate marker of undifferentiated mesenchymal cells able to differentiate to osteoblasts, correlated with the capacity to form bone at the fracture site. Our findings indicate that the protein level of β-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of β-catenin in NF1 causes a shift away from osteoblastic differentiation resulting in a pseudarthrosis in vivo These results support the notion that pharmacological modulation of β-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. β-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.

Authors
Ghadakzadeh, S; Kannu, P; Whetstone, H; Howard, A; Alman, BA
MLA Citation
Ghadakzadeh, S, Kannu, P, Whetstone, H, Howard, A, and Alman, BA. "β-Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30.9 (September 2016): 3227-3237.
PMID
27306335
Source
epmc
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
30
Issue
9
Publish Date
2016
Start Page
3227
End Page
3237
DOI
10.1096/fj.201500190rr

Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype.

The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype.

Authors
Sato, S; Tang, YJ; Wei, Q; Hirata, M; Weng, A; Han, I; Okawa, A; Takeda, S; Whetstone, H; Nadesan, P; Kirsch, DG; Wunder, JS; Alman, BA
MLA Citation
Sato, S, Tang, YJ, Wei, Q, Hirata, M, Weng, A, Han, I, Okawa, A, Takeda, S, Whetstone, H, Nadesan, P, Kirsch, DG, Wunder, JS, and Alman, BA. "Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype." Cell reports 16.4 (July 13, 2016): 917-927.
PMID
27425618
Source
epmc
Published In
Cell Reports
Volume
16
Issue
4
Publish Date
2016
Start Page
917
End Page
927
DOI
10.1016/j.celrep.2016.06.058

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis.

Both the WNT/β-catenin and hedgehog signaling pathways are important in the regulation of limb development, chondrocyte differentiation, and degeneration of articular cartilage in osteoarthritis (OA). It is not clear how these signaling pathways interact in interzone cell differentiation and synovial joint morphogenesis. Here, we determined that constitutive activation of hedgehog signaling specifically within interzone cells induces joint morphological changes by selectively inhibiting β-catenin-induced Fgf18 expression. Stabilization of β-catenin or treatment with FGF18 rescued hedgehog-induced phenotypes. Hedgehog signaling induced expression of a dominant negative isoform of TCF7L2 (dnTCF7L2) in interzone progeny, which may account for the selective regulation of β-catenin target genes observed. Knockdown of TCF7L2 isoforms in mouse chondrocytes rescued hedgehog signaling-induced Fgf18 downregulation, while overexpression of the human dnTCF7L2 orthologue (dnTCF4) in human chondrocytes promoted the expression of catabolic enzymes associated with OA. Similarly, expression of dnTCF4 in human chondrocytes positively correlated with the aggrecanase ADAMTS4. Consistent with our developmental findings, activation of β-catenin also attenuated hedgehog-induced or surgically induced articular cartilage degeneration in mouse models of OA. Thus, our results demonstrate that hedgehog inhibits selective β-catenin target gene expression to direct interzone progeny fates and articular cartilage development and disease. Moreover, agents that increase β-catenin activity have the potential to therapeutically attenuate articular cartilage degeneration as part of OA.

Authors
Rockel, JS; Yu, C; Whetstone, H; Craft, AM; Reilly, K; Ma, H; Tsushima, H; Puviindran, V; Al-Jazrawe, M; Keller, GM; Alman, BA
MLA Citation
Rockel, JS, Yu, C, Whetstone, H, Craft, AM, Reilly, K, Ma, H, Tsushima, H, Puviindran, V, Al-Jazrawe, M, Keller, GM, and Alman, BA. "Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis." The Journal of clinical investigation 126.5 (May 2016): 1649-1663.
PMID
27018594
Source
epmc
Published In
Journal of Clinical Investigation
Volume
126
Issue
5
Publish Date
2016
Start Page
1649
End Page
1663
DOI
10.1172/jci80205

Simulation for Teaching Orthopaedic Residents in a Competency-based Curriculum: Do the Benefits Justify the Increased Costs?

Authors
Nousiainen, MT; McQueen, SA; Ferguson, P; Alman, B; Kraemer, W; Safir, O; Reznick, R; Sonnadara, R
MLA Citation
Nousiainen, MT, McQueen, SA, Ferguson, P, Alman, B, Kraemer, W, Safir, O, Reznick, R, and Sonnadara, R. "Simulation for Teaching Orthopaedic Residents in a Competency-based Curriculum: Do the Benefits Justify the Increased Costs?." Clinical Orthopaedics and Related Research® 474.4 (April 2016): 935-944.
Source
crossref
Published In
Clinical Orthopaedics and Related Research ®
Volume
474
Issue
4
Publish Date
2016
Start Page
935
End Page
944
DOI
10.1007/s11999-015-4512-6

Adynamic Bone Decreases Bone Toughness During Aging by Affecting Mineral and Matrix.

Adynamic bone is the most frequent type of bone lesion in patients with chronic kidney disease; long-term use of antiresorptive therapy may also lead to the adynamic bone condition. The hallmark of adynamic bone is a loss of bone turnover, and a major clinical concern of adynamic bone is diminished bone quality and an increase in fracture risk. Our current study aims to investigate how bone quality changes with age in our previously established mouse model of adynamic bone. Young and old mice (4 months old and 16 months old, respectively) were used in this study. Col2.3Δtk (DTK) mice were treated with ganciclovir and pamidronate to create the adynamic bone condition. Bone quality was evaluated using established techniques including bone histomorphometry, microcomputed tomography, quantitative backscattered electron imaging, and biomechanical testing. Changes in mineral and matrix properties were examined by powder X-ray diffraction and Raman spectroscopy. Aging controls had a natural decline in bone formation and resorption with a corresponding deterioration in trabecular bone structure. Bone turnover was severely blunted at all ages in adynamic animals, which preserved trabecular bone loss normally associated with aging. However, the preservation of trabecular bone mass and structure in old adynamic mice did not rescue deterioration of bone mechanical properties. There was also a decrease in cortical bone toughness in old adynamic mice that was accompanied by a more mature collagen matrix and longer bone crystals. Little is known about the effects of metabolic bone disease on bone fracture resistance. We observed an age-related decrease in bone toughness that was worsened by the adynamic condition, and this decrease may be due to material level changes at the tissue level. Our mouse model may be useful in the investigation of the mechanisms involved in fractures occurring in elderly patients on antiresorptive therapy who have very low bone turnover.

Authors
Ng, AH; Omelon, S; Variola, F; Allo, B; Willett, TL; Alman, BA; Grynpas, MD
MLA Citation
Ng, AH, Omelon, S, Variola, F, Allo, B, Willett, TL, Alman, BA, and Grynpas, MD. "Adynamic Bone Decreases Bone Toughness During Aging by Affecting Mineral and Matrix." Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 31.2 (February 2016): 369-379.
PMID
26332924
Source
epmc
Published In
Journal of Bone and Mineral Research
Volume
31
Issue
2
Publish Date
2016
Start Page
369
End Page
379
DOI
10.1002/jbmr.2702

Regulation of Cholesterol Homeostasis by Hedgehog Signaling in Osteoarthritic Cartilage.

With no effective therapies to attenuate cartilage degeneration in osteoarthritis (OA), the result is pain and disability. Activation of hedgehog (HH) signaling causes changes related to the progression of OA, with higher levels of Gli-mediated transcriptional activation associated with increased disease severity. To elucidate the mechanism through which this occurs, this study sought to identify genes regulated by HH signaling in human OA chondrocytes.Using human OA cartilage samples, microarray analyses were performed to detect changes in gene expression when the HH pathway was modulated. Results were analyzed for differentially expressed genes, grouped into functional networks, and validated in independent samples. To investigate the effects of chondrocyte-specific sterol accumulation, we generated mice lacking Insig1 and Insig2, which are major negative regulators of cholesterol homeostasis, under Col2a1 regulatory elements.HH signaling was found to regulate genes that govern cholesterol homeostasis, and this led to alterations in cholesterol accumulation in chondrocytes. A higher level of Gli-mediated transcription resulted in accumulation of intracellular cholesterol. In genetically modified mice, chondrocyte-specific cholesterol accumulation was associated with an OA phenotype. Reducing cholesterol accumulation attenuated the severity of OA in mice in vivo and decreased the expression of proteases in human OA cartilage in vitro.HH signaling regulates cholesterol homeostasis in chondrocytes, and intracellular cholesterol accumulation contributes to the severity of OA. Our findings have therapeutic implications, since reduction of HH signaling reversed cholesterol accumulation and statin treatment attenuated cartilage degeneration.

Authors
Ali, SA; Al-Jazrawe, M; Ma, H; Whetstone, H; Poon, R; Farr, S; Naples, M; Adeli, K; Alman, BA
MLA Citation
Ali, SA, Al-Jazrawe, M, Ma, H, Whetstone, H, Poon, R, Farr, S, Naples, M, Adeli, K, and Alman, BA. "Regulation of Cholesterol Homeostasis by Hedgehog Signaling in Osteoarthritic Cartilage." Arthritis & rheumatology (Hoboken, N.J.) 68.1 (January 2016): 127-137.
PMID
26315393
Source
epmc
Published In
Arthritis and Rheumatology
Volume
68
Issue
1
Publish Date
2016
Start Page
127
End Page
137
DOI
10.1002/art.39337

Construct validity and reliability of a real-time multidimensional smartphone app to assess pain in children and adolescents with cancer.

We evaluated the construct validity (including responsiveness), reliability, and feasibility of the Pain Squad multidimensional smartphone-based pain assessment application (app) in children and adolescents with cancer, using 2 descriptive studies with repeated measures. Participants (8-18 years) undergoing cancer treatment were drawn from 4 pediatric cancer centers. In study 1, 92 participants self-reported their level of pain twice daily for 2 weeks using the Pain Squad app to assess app construct validity and reliability. In study 2, 14 participants recorded their level of pain twice a day for 1 week before and 2 weeks after cancer-related surgery to determine app responsiveness. Participants in both studies completed multiple measures to determine the construct validity and feasibility of the Pain Squad app. Correlations between average weekly pain ratings on the Pain Squad app and recalled least, average, and worst weekly pain were moderate to high (0.43-0.68). Correlations with health-related quality of life and pain coping (measured with PedsQL Inventory 4.0, PedsQL Cancer Module, and Pain Coping Questionnaire) were -0.46 to 0.29. The app showed excellent internal consistency (α = 0.96). Pain ratings changed because of surgery with large effect sizes between baseline and the first week postsurgery (>0.85) and small effect sizes between baseline and the second week postsurgery (0.13-0.32). These findings provide evidence of the construct validity, reliability, and feasibility of the Pain Squad app in children and adolescents with cancer. Use of real-time data capture approaches should be considered in future studies of childhood cancer pain. A video accompanying this abstract is available online as Supplemental Digital Content at http://links.lww.com/PAIN/A169.

Authors
Stinson, JN; Jibb, LA; Nguyen, C; Nathan, PC; Maloney, AM; Dupuis, LL; Gerstle, JT; Hopyan, S; Alman, BA; Strahlendorf, C; Portwine, C; Johnston, DL
MLA Citation
Stinson, JN, Jibb, LA, Nguyen, C, Nathan, PC, Maloney, AM, Dupuis, LL, Gerstle, JT, Hopyan, S, Alman, BA, Strahlendorf, C, Portwine, C, and Johnston, DL. "Construct validity and reliability of a real-time multidimensional smartphone app to assess pain in children and adolescents with cancer." Pain 156.12 (December 2015): 2607-2615.
PMID
26580680
Source
epmc
Published In
PAIN
Volume
156
Issue
12
Publish Date
2015
Start Page
2607
End Page
2615
DOI
10.1097/j.pain.0000000000000385

Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia

Authors
Gray, MJ; Kannu, P; Sharma, S; Neyt, C; Zhang, D; Paria, N; Daniel, PB; Whetstone, H; Sprenger, H-G; Hammerschmidt, P; Weng, A; Dupuis, L; Jobling, R; Mendoza-Londono, R; Dray, M; Su, P; Wilson, MJ; Kapur, RP; McCarthy, EF; Alman, BA; Howard, A; Somers, GR; Marshall, CR; Manners, S; Flanagan, AM; Rathjen, KE; Karol, LA; Crawford, H; Markie, DM; Rios, JJ; Wise, CA; Robertson, SP
MLA Citation
Gray, MJ, Kannu, P, Sharma, S, Neyt, C, Zhang, D, Paria, N, Daniel, PB, Whetstone, H, Sprenger, H-G, Hammerschmidt, P, Weng, A, Dupuis, L, Jobling, R, Mendoza-Londono, R, Dray, M, Su, P, Wilson, MJ, Kapur, RP, McCarthy, EF, Alman, BA, Howard, A, Somers, GR, Marshall, CR, Manners, S, Flanagan, AM, Rathjen, KE, Karol, LA, Crawford, H, Markie, DM, Rios, JJ, Wise, CA, and Robertson, SP. "Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia." The American Journal of Human Genetics 97.6 (December 2015): 837-847.
Source
crossref
Published In
The American Journal of Human Genetics
Volume
97
Issue
6
Publish Date
2015
Start Page
837
End Page
847
DOI
10.1016/j.ajhg.2015.11.001

Bone Marrow Stress Decreases Osteogenic Progenitors.

Age-related bone loss may be a result of declining levels of stem cells in the bone marrow. Using the Col2.3Δtk (DTK) transgenic mouse, osteoblast depletion was used as a source of marrow stress in order to investigate the effects of aging on osteogenic progenitors which reside in the marrow space. Five-month-old DTK mice were treated with one or two cycles of ganciclovir to conditionally ablate differentiated osteoblasts, whereas controls were saline-treated. Treatment cycles were two weeks in length followed by four weeks of recovery. All animals were sacrificed at 8 months of age; bone marrow stromal cells (BMSCs) were harvested for cell culture and whole bones were excised for bone quality assessment. Colony-forming unit (CFU) assays were conducted to investigate the osteogenic potential of BMSC in vitro, and RNA was extracted to assess the expression of osteoblastic genes. Bone quality assessments included bone histomorphometry, TRAP staining, microcomputed tomography, and biomechanical testing. Osteoblast depletion decreased CFU-F (fibroblast), CFU-ALP (alkaline phosphatase), and CFU-VK (von Kossa) counts and BMSC osteogenic capacity in cell culture. Ex vivo, there were no differences in bone mineral density of vertebrae or femurs between treatment groups. Histology showed a decrease in bone volume and bone connectivity with repeated osteoblast depletion; however, this was accompanied by an increase in bone formation rate. There were no notable differences in osteoclast parameters or observed bone marrow adiposity. We have developed a model that uses bone marrow stress to mimic age-related decrease in osteogenic progenitors. Our data suggest that the number of healthy BMSCs and their osteogenic potential decline with repeated osteoblast depletion. However, activity of the remaining osteoblasts increases to compensate for this loss in progenitor osteogenic potential.

Authors
Ng, AH; Baht, GS; Alman, BA; Grynpas, MD
MLA Citation
Ng, AH, Baht, GS, Alman, BA, and Grynpas, MD. "Bone Marrow Stress Decreases Osteogenic Progenitors." Calcified tissue international 97.5 (November 2015): 476-486.
PMID
26220824
Source
epmc
Published In
Calcified Tissue International
Volume
97
Issue
5
Publish Date
2015
Start Page
476
End Page
486
DOI
10.1007/s00223-015-0032-3

Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma.

Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma.

Authors
Wei, Q; Tang, YJ; Voisin, V; Sato, S; Hirata, M; Whetstone, H; Han, I; Ailles, L; Bader, GD; Wunder, J; Alman, BA
MLA Citation
Wei, Q, Tang, YJ, Voisin, V, Sato, S, Hirata, M, Whetstone, H, Han, I, Ailles, L, Bader, GD, Wunder, J, and Alman, BA. "Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma." Oncotarget 6.37 (November 2015): 40283-40294.
PMID
26517673
Source
epmc
Published In
Oncotarget
Volume
6
Issue
37
Publish Date
2015
Start Page
40283
End Page
40294
DOI
10.18632/oncotarget.5375

The role of hedgehog signalling in skeletal health and disease.

Hedgehog ligands bind to protein patched homologue 1 (PTC), a conserved receptor that activates the GLI family of transcription factors, which are involved in development, disease and skeletal repair processes. During embryonic development, hedgehog signalling helps to pattern the limbs and plays a critical part in regulating chondrocyte differentiation and osteogenesis during the longitudinal growth of long bones. This signalling pathway also regulates mesenchymal cell differentiation during skeletal repair and regeneration. In pathologic and degenerative processes, such as osteoarthritis or cartilaginous tumour formation, hedgehog signalling is dysregulated. Several pharmacologic strategies can modulate hedgehog signalling, and targeting this pathway could lead to the development of novel therapeutic approaches. For example, by precisely regulating the level of activity of the hedgehog signalling pathway, the pace of degeneration in osteoarthritis could be slowed, bone repair could be enhanced, and cartilaginous tumour cell viability could be inhibited. As such, regulation of hedgehog signalling could be manipulated to safeguard skeletal health.

Authors
Alman, BA
MLA Citation
Alman, BA. "The role of hedgehog signalling in skeletal health and disease." Nature reviews. Rheumatology 11.9 (September 2015): 552-560.
PMID
26077918
Source
epmc
Published In
Nature Reviews Rheumatology
Volume
11
Issue
9
Publish Date
2015
Start Page
552
End Page
560
DOI
10.1038/nrrheum.2015.84

Macrophages promote osteoblastic differentiation in-vivo: implications in fracture repair and bone homeostasis.

Macrophages are activated in inflammation and during early phases of repair processes. Interestingly, they are also present in bone during development, but their function during this process is unclear. Here, we explore the function of macrophages in bone development, growth, and repair using transgenic mice to constitutively or conditionally deplete macrophages. Depletion of macrophages led to early skeletal growth retardation and progressive osteoporosis. By 3 months of age, macrophage-deficient mice displayed a 25% reduction in bone mineral density and a 70% reduction in the number of trabecular bone compared to control littermates. Despite depletion of macrophages, functional osteoclasts were still present in bones, lining trabecular bone and the endosteal surface of the cortical bone. Furthermore, ablation of macrophages led to a 60% reduction in the number of bone marrow mesenchymal progenitor cells and a decrease in the ability of these cells to differentiate to osteoblasts. When macrophages were depleted during fracture repair, bone union was impaired. Calluses from macrophage-deficient animals were smaller, and contained less bone and more fibrotic tissue deposition. Taken together, this shows that macrophages are crucial for maintaining bone homeostasis and promoting fracture repair by enhancing the differentiation of mesenchymal progenitors.

Authors
Vi, L; Baht, GS; Whetstone, H; Ng, A; Wei, Q; Poon, R; Mylvaganam, S; Grynpas, M; Alman, BA
MLA Citation
Vi, L, Baht, GS, Whetstone, H, Ng, A, Wei, Q, Poon, R, Mylvaganam, S, Grynpas, M, and Alman, BA. "Macrophages promote osteoblastic differentiation in-vivo: implications in fracture repair and bone homeostasis." Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 30.6 (June 2015): 1090-1102.
PMID
25487241
Source
epmc
Published In
Journal of Bone and Mineral Research
Volume
30
Issue
6
Publish Date
2015
Start Page
1090
End Page
1102
DOI
10.1002/jbmr.2422

Generation of articular chondrocytes from human pluripotent stem cells.

The replacement of articular cartilage through transplantation of chondrogenic cells or preformed cartilage tissue represents a potential new avenue for the treatment of degenerative joint diseases. Although many studies have described differentiation of human pluripotent stem cells (hPSCs) to the chondrogenic lineage, the generation of chondrocytes able to produce stable articular cartilage in vivo has not been demonstrated. Here we show that activation of the TGFβ pathway in hPSC-derived chondrogenic progenitors promotes the efficient development of articular chondrocytes that can form stable cartilage tissue in vitro and in vivo. In contrast, chondrocytes specified by BMP4 signaling display characteristics of hypertrophy and give rise to cartilage tissues that initiate the endochondral ossification process in vivo. These findings provide a simple serum-free and efficient approach for the routine generation of hPSC-derived articular chondrocytes for modeling diseases of the joint and developing cell therapy approaches to treat them.

Authors
Craft, AM; Rockel, JS; Nartiss, Y; Kandel, RA; Alman, BA; Keller, GM
MLA Citation
Craft, AM, Rockel, JS, Nartiss, Y, Kandel, RA, Alman, BA, and Keller, GM. "Generation of articular chondrocytes from human pluripotent stem cells." Nature biotechnology 33.6 (June 2015): 638-645.
PMID
25961409
Source
epmc
Published In
Nature Biotechnology
Volume
33
Issue
6
Publish Date
2015
Start Page
638
End Page
645
DOI
10.10.38/nbt.3210

Exposure to a youthful circulaton rejuvenates bone repair through modulation of β-catenin.

The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals. This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.

Authors
Baht, GS; Silkstone, D; Vi, L; Nadesan, P; Amani, Y; Whetstone, H; Wei, Q; Alman, BA
MLA Citation
Baht, GS, Silkstone, D, Vi, L, Nadesan, P, Amani, Y, Whetstone, H, Wei, Q, and Alman, BA. "Exposure to a youthful circulaton rejuvenates bone repair through modulation of β-catenin." Nature communications 6 (May 19, 2015): 7131-.
PMID
25988592
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
7131
DOI
10.1038/ncomms8131

Macrophage-secreted Factors that Rejuvenate Delayed Fracture Healing Characteristic of Aging

Authors
Sekar, M; Alman, BA
MLA Citation
Sekar, M, and Alman, BA. "Macrophage-secreted Factors that Rejuvenate Delayed Fracture Healing Characteristic of Aging." April 2015.
Source
wos-lite
Published In
Journal of American Geriatrics Society
Volume
63
Publish Date
2015
Start Page
S149
End Page
S149

Mutant IDH is sufficient to initiate enchondromatosis in mice.

Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

Authors
Hirata, M; Sasaki, M; Cairns, RA; Inoue, S; Puviindran, V; Li, WY; Snow, BE; Jones, LD; Wei, Q; Sato, S; Tang, YJ; Nadesan, P; Rockel, J; Whetstone, H; Poon, R; Weng, A; Gross, S; Straley, K; Gliser, C; Xu, Y; Wunder, J; Mak, TW; Alman, BA
MLA Citation
Hirata, M, Sasaki, M, Cairns, RA, Inoue, S, Puviindran, V, Li, WY, Snow, BE, Jones, LD, Wei, Q, Sato, S, Tang, YJ, Nadesan, P, Rockel, J, Whetstone, H, Poon, R, Weng, A, Gross, S, Straley, K, Gliser, C, Xu, Y, Wunder, J, Mak, TW, and Alman, BA. "Mutant IDH is sufficient to initiate enchondromatosis in mice." Proceedings of the National Academy of Sciences of the United States of America 112.9 (March 2015): 2829-2834.
PMID
25730874
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
9
Publish Date
2015
Start Page
2829
End Page
2834
DOI
10.1073/pnas.1424400112

Erratum: Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin.

Authors
Baht, GS; Silkstone, D; Vi, L; Nadesan, P; Amani, Y; Whetstone, H; Wei, Q; Alman, BA
MLA Citation
Baht, GS, Silkstone, D, Vi, L, Nadesan, P, Amani, Y, Whetstone, H, Wei, Q, and Alman, BA. "Erratum: Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin." Nature communications 6 (January 2015): 7761-.
PMID
26307670
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
7761
DOI
10.1038/ncomms8761

Student-led learning: a new teaching paradigm for surgical skills.

BACKGROUND: Competency-based education and simulation are being used more frequently in surgical skills curricula. We explored a novel student-led learning paradigm, which allows trainees to become more active participants in the learning process while maintaining expert guidance and supervision. METHODS: Twelve first-year orthopedic residents were randomized to either a student-led (SL) or a traditional instructor-led group during an intensive, month-long, laboratory-based technical skills training course. A rigorous qualitative-description approach was used for analysis. RESULTS: Four prominent themes emerged: instructional style, feedback, peer and instructor collaboration, and self-efficacy. Compared with the instructor-led group, there was more peer assistance, feedback, collaboration, and hands-on and active learning observed in the SL group. CONCLUSIONS: The flexible and socially rich nature of the SL learning environment may aid in development of both technical and nontechnical skills early in residency and ultimately privilege later clinical learning.

Authors
Hoogenes, J; Mironova, P; Safir, O; McQueen, SA; Abdelbary, H; Drexler, M; Nousiainen, M; Ferguson, P; Kraemer, W; Alman, B; Reznick, RK; Sonnadara, RR
MLA Citation
Hoogenes, J, Mironova, P, Safir, O, McQueen, SA, Abdelbary, H, Drexler, M, Nousiainen, M, Ferguson, P, Kraemer, W, Alman, B, Reznick, RK, and Sonnadara, RR. "Student-led learning: a new teaching paradigm for surgical skills." American journal of surgery 209.1 (January 2015): 107-114.
PMID
25454965
Source
epmc
Published In
The American Journal of Surgery
Volume
209
Issue
1
Publish Date
2015
Start Page
107
End Page
114
DOI
10.1016/j.amjsurg.2014.08.037

Optimal therapy for desmoid tumors: current options and challenges for the future.

Desmoid tumors, or aggressive fibromatosis, are rare, locally infiltrative neoplasms caused by mutations that activate β-catenin. Although these tumors do not metastasize, they are difficult to manage due to variability in tumor presentation and behavior. A variety of treatment options exist, including surgery, radiotherapy, chemotherapy, hormone therapy, isolated limb perfusion, cryoablation and tyrosine kinase inhibitors. Treatment-induced morbidity and poor local control rates, combined with spontaneous stabilization of some desmoid tumors, have allowed watchful waiting to recently emerge as a front-line management option. This has emphasized the need to better understand tumor behavior in order to differentiate between tumors that may stabilize and those that may progress. Here, we review the most recent findings in desmoid tumor biology and treatment options for this enigmatic disease.

Authors
Al-Jazrawe, M; Au, M; Alman, B
MLA Citation
Al-Jazrawe, M, Au, M, and Alman, B. "Optimal therapy for desmoid tumors: current options and challenges for the future." Expert review of anticancer therapy 15.12 (January 2015): 1443-1458.
PMID
26472625
Source
epmc
Published In
Expert Review of Anticancer Therapy
Volume
15
Issue
12
Publish Date
2015
Start Page
1443
End Page
1458
DOI
10.1586/14737140.2015.1096203

Bone Marrow Stress Decreases Osteogenic Progenitors

© 2015, Springer Science+Business Media New York.Age-related bone loss may be a result of declining levels of stem cells in the bone marrow. Using the Col2.3Δtk (DTK) transgenic mouse, osteoblast depletion was used as a source of marrow stress in order to investigate the effects of aging on osteogenic progenitors which reside in the marrow space. Five-month-old DTK mice were treated with one or two cycles of ganciclovir to conditionally ablate differentiated osteoblasts, whereas controls were saline-treated. Treatment cycles were two weeks in length followed by four weeks of recovery. All animals were sacrificed at 8 months of age; bone marrow stromal cells (BMSCs) were harvested for cell culture and whole bones were excised for bone quality assessment. Colony-forming unit (CFU) assays were conducted to investigate the osteogenic potential of BMSC in vitro, and RNA was extracted to assess the expression of osteoblastic genes. Bone quality assessments included bone histomorphometry, TRAP staining, microcomputed tomography, and biomechanical testing. Osteoblast depletion decreased CFU-F (fibroblast), CFU-ALP (alkaline phosphatase), and CFU-VK (von Kossa) counts and BMSC osteogenic capacity in cell culture. Ex vivo, there were no differences in bone mineral density of vertebrae or femurs between treatment groups. Histology showed a decrease in bone volume and bone connectivity with repeated osteoblast depletion; however, this was accompanied by an increase in bone formation rate. There were no notable differences in osteoclast parameters or observed bone marrow adiposity. We have developed a model that uses bone marrow stress to mimic age-related decrease in osteogenic progenitors. Our data suggest that the number of healthy BMSCs and their osteogenic potential decline with repeated osteoblast depletion. However, activity of the remaining osteoblasts increases to compensate for this loss in progenitor osteogenic potential.

Authors
Ng, AH; Baht, GS; Alman, BA; Grynpas, MD
MLA Citation
Ng, AH, Baht, GS, Alman, BA, and Grynpas, MD. "Bone Marrow Stress Decreases Osteogenic Progenitors." Calcified Tissue International 97.5 (2015): 476-486.
Source
scival
Published In
Calcified Tissue International
Volume
97
Issue
5
Publish Date
2015
Start Page
476
End Page
486
DOI
10.1007/s00223-015-0032-3

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

Authors
Zhukova, N; Ramaswamy, V; Remke, M; Martin, DC; Castelo-Branco, P; Zhang, CH; Fraser, M; Tse, K; Poon, R; Shih, DJH; Baskin, B; Ray, PN; Bouffet, E; Dirks, P; von Bueren, AO; Pfaff, E; Korshunov, A; Jones, DTW; Northcott, PA; Kool, M; Pugh, TJ; Pomeroy, SL; Cho, Y-J; Pietsch, T; Gessi, M; Rutkowski, S; Bognár, L; Cho, B-K; Eberhart, CG; Conter, CF; Fouladi, M; French, PJ; Grajkowska, WA; Gupta, N; Hauser, P; Jabado, N; Vasiljevic, A; Jung, S; Kim, S-K; Klekner, A; Kumabe, T; Lach, B et al.
MLA Citation
Zhukova, N, Ramaswamy, V, Remke, M, Martin, DC, Castelo-Branco, P, Zhang, CH, Fraser, M, Tse, K, Poon, R, Shih, DJH, Baskin, B, Ray, PN, Bouffet, E, Dirks, P, von Bueren, AO, Pfaff, E, Korshunov, A, Jones, DTW, Northcott, PA, Kool, M, Pugh, TJ, Pomeroy, SL, Cho, Y-J, Pietsch, T, Gessi, M, Rutkowski, S, Bognár, L, Cho, B-K, Eberhart, CG, Conter, CF, Fouladi, M, French, PJ, Grajkowska, WA, Gupta, N, Hauser, P, Jabado, N, Vasiljevic, A, Jung, S, Kim, S-K, Klekner, A, Kumabe, T, and Lach, B et al. "WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma." Acta neuropathologica communications 2 (December 24, 2014): 174-.
PMID
25539912
Source
epmc
Published In
Acta Neuropathologica Communications
Volume
2
Publish Date
2014
Start Page
174
DOI
10.1186/s40478-014-0174-y

The immature skeleton

Authors
Alman, BA
MLA Citation
Alman, BA. "The immature skeleton." Rockwood and Wilkins' Fractures in Children: Eighth Edition. December 3, 2014.
Source
scopus
Publish Date
2014

Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease.

Skeletal metastasis is a serious complication of many primary cancers. A common feature of tumor cells that metastasize to the bone marrow microenvironment is that they initiate a cascade of events, recruiting and presumably/potentially altering the phenotype of bone marrow mesenchymal stromal cells (MSC) to produce an environment that allows for tumor growth and in some cases, drug-resistant dormancy of latent cancer cells. Consequently the MSC population can contribute to metastatic disease through several distinct mechanisms by differentiating into cancer-associated fibroblasts (CAFs). Understanding the expression and epigenetic changes that occur as normal MSCs become associated with metastatic tumors would reveal possible therapeutic targets for treating skeletal metastasis.

Authors
Gordon, JAR; Lisle, JW; Alman, BA; Lian, JB
MLA Citation
Gordon, JAR, Lisle, JW, Alman, BA, and Lian, JB. "Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease." Journal of cellular physiology 229.12 (December 2014): 1884-1886.
PMID
24905746
Source
epmc
Published In
Journal of Cellular Physiology
Volume
229
Issue
12
Publish Date
2014
Start Page
1884
End Page
1886
DOI
10.1002/jcp.24692

Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents.

Lithium, a treatment for bipolar disorder, is not clinically indicated for use in fracture management but has been reported to positively influence bone biology. It is hypothesized that lithium dosing for beneficial effects on bone health may be much lower than the dosing required for psychotropic benefits in patients with bipolar disorder. A preclinical study with a rodent fracture model was utilized to best define the lowest effective dose, best timing of treatment onset, and optimal treatment duration for the use of lithium as a new treatment in fracture care.A design-of-experiments approach was used to assess the parameters of dose, timing of treatment onset, and treatment duration. Closed femoral shaft fractures were generated and analyzed with use of destructive torsional mechanical testing and microcomputed tomography-based image analysis. Eleven different outcome measures were quantified, with maximum yield torque as the primary study outcome, to assess the quality of long-bone fracture-healing.Fracture-healing was maximized with a lithium treatment combination of a low dose (twenty milligrams per kilogram of body weight per day), later onset of lithium treatment (seven days after fracture), and longer treatment duration (two weeks), with maximum yield torque displaying a 46% increase compared with nontreated and sham-treated controls (481.1 ± 104.0 N-mm compared with 329.9 ± 135.8 N-mm; p = 0.04). Design-of-experiments analysis determined the timing of treatment onset to be the most influential parameter for improving fracture-healing, with femora treated at a later onset (seven days after fracture) showing a significant (21%) increase in maximum yield torque compared with those treated at an earlier onset (three days after fracture) (p = 0.01).A later onset of lithium administration significantly improved femoral fracture-healing. Trends indicated that a lower dose and longer treatment duration also had a positive effect on fracture repair.Orally administered low-dose lithium therapy with a large postfracture administration window has the potential to yield a safe, reliable, and cost-effective treatment to enhance bone-healing and restore earlier function and mobility pending appropriate large-animal proof-of-concept models, safety data, and U.S. Food and Drug Administration clinical trials approval.

Authors
Bernick, J; Wang, Y; Sigal, IA; Alman, BA; Whyne, CM; Nam, D
MLA Citation
Bernick, J, Wang, Y, Sigal, IA, Alman, BA, Whyne, CM, and Nam, D. "Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents." The Journal of bone and joint surgery. American volume 96.23 (December 2014): 1990-1998.
PMID
25471914
Source
epmc
Published In
The Journal of Bone and Joint Surgery
Volume
96
Issue
23
Publish Date
2014
Start Page
1990
End Page
1998
DOI
10.2106/jbjs.n.00057

Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD).

The etiology of Adynamic Bone Disease (ABD) is poorly understood but the hallmark of ABD is a lack of bone turnover. ABD occurs in renal osteodystrophy (ROD) and is suspected to occur in elderly patients on long-term anti-resorptive therapy. A major clinical concern of ABD is diminished bone quality and an increased fracture risk. To our knowledge, experimental animal models for ABD other than ROD-ABD have not been developed or studied. The objectives of this study were to develop a mouse model of ABD without the complications of renal ablation, and to characterize changes in bone quality in ABD relative to controls. To re-create the adynamic bone condition, 4-month old female Col2.3Δtk mice were treated with ganciclovir to specifically ablate osteoblasts, and pamidronate was used to inhibit osteoclastic resorption. Four groups of animals were used to characterize bone quality in ABD: Normal bone controls, No Formation controls, No Resorption controls, and an Adynamic group. After a 6-week treatment period, the animals were sacrificed and the bones were harvested for analyses. Bone quality assessments were conducted using established techniques including bone histology, quantitative backscattered electron imaging (qBEI), dual energy X-ray absorptiometry (DXA), microcomputed tomography (microCT), and biomechanical testing. Histomorphometry confirmed osteoblast-related hallmarks of ABD in our mouse model. Bone formation was near complete suppression in the No Formation and Adynamic specimens. Inhibition of bone resorption in the Adynamic group was confirmed by tartrate-resistant acid phosphatase (TRAP) stain. Normal bone mineral density and architecture were maintained in the Adynamic group, whereas the No Formation group showed a reduction in bone mineral content and trabecular thickness relative to the Adynamic group. As expected, the No Formation group had a more hypomineralized profile and the Adynamic group had a higher mean mineralization profile that is similar to suppressed bone turnover in human. This data confirms successful replication of the adynamic bone condition in a mouse without the complication of renal ablation. Our approach is the first model of ABD that uses pharmacological manipulation in a transgenic mouse to mimic the bone cellular dynamics observed in the human ABD condition. We plan to use our mouse model to investigate the adynamic bone condition in aging and to study changes to bone quality and fracture risk as a consequence of over-suppressed bone turnover.

Authors
Ng, AH; Willett, TL; Alman, BA; Grynpas, MD
MLA Citation
Ng, AH, Willett, TL, Alman, BA, and Grynpas, MD. "Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD)." Bone 68 (November 2014): 57-66.
PMID
25111968
Source
epmc
Published In
BONE
Volume
68
Publish Date
2014
Start Page
57
End Page
66
DOI
10.1016/j.bone.2014.07.037

The immature skeleton

Authors
Alman, BA
MLA Citation
Alman, BA. "The immature skeleton." Rockwood, Green, and Wilkins Fractures in Adults and Children: Eighth Edition. October 23, 2014.
Source
scopus
Volume
2-2
Publish Date
2014

Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation.

Integrin-mediated force application induces a conformational change in latent TGF-β1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical activation of TGF-β1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-β1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-β1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-β1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer.

Authors
Klingberg, F; Chow, ML; Koehler, A; Boo, S; Buscemi, L; Quinn, TM; Costell, M; Alman, BA; Genot, E; Hinz, B
MLA Citation
Klingberg, F, Chow, ML, Koehler, A, Boo, S, Buscemi, L, Quinn, TM, Costell, M, Alman, BA, Genot, E, and Hinz, B. "Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation." The Journal of cell biology 207.2 (October 20, 2014): 283-297.
PMID
25332161
Source
epmc
Published In
The Journal of Cell Biology
Volume
207
Issue
2
Publish Date
2014
Start Page
283
End Page
297
DOI
10.1083/jcb.201402006

The immature skeleton

Authors
Alman, BA
MLA Citation
Alman, BA. "The immature skeleton." Rockwood & Wilkins Fractures in Children: Eighth Edition. September 9, 2014.
Source
scopus
Publish Date
2014

Letter to the editor response.

Authors
Sonnadara, RR; Mui, C; McQueen, S; Mironova, P; Nousiainen, M; Safir, O; Kraemer, W; Ferguson, P; Alman, B; Reznick, R
MLA Citation
Sonnadara, RR, Mui, C, McQueen, S, Mironova, P, Nousiainen, M, Safir, O, Kraemer, W, Ferguson, P, Alman, B, and Reznick, R. "Letter to the editor response." Journal of surgical education 71.5 (September 2014): 652-653.
PMID
25123907
Source
epmc
Published In
Journal of Surgical Education
Volume
71
Issue
5
Publish Date
2014
Start Page
652
End Page
653
DOI
10.1016/j.jsurg.2014.05.018

On the shoulders of giants: The future of the Journal of Orthopaedic Research

Authors
Alman, B; Evans, C
MLA Citation
Alman, B, and Evans, C. "On the shoulders of giants: The future of the Journal of Orthopaedic Research." Journal of Orthopaedic Research 32.9 (September 2014): 1095-1096.
Source
crossref
Published In
Journal of Orthopaedic Research
Volume
32
Issue
9
Publish Date
2014
Start Page
1095
End Page
1096
DOI
10.1002/jor.22689

Patient outcomes in the operative and nonoperative management of high-grade spondylolisthesis in children.

BACKGROUND: The optimal management of high-grade spondylolisthesis in the growing child is controversial. Some authors have advocated for surgery in all cases regardless of symptoms. Surgical intervention results in a >10% risk of complications with increased risk of neurological injury associated with slip reduction maneuvers. There is a paucity of literature regarding nonoperative management in this setting. This study sought to obtain outcome measures in pediatric patients with high-grade spondylolisthesis managed either operatively or nonoperatively. METHODS: Database review was performed to identify patients with a high-grade (Meyerding grade III to V) spondylolisthesis managed either operatively or nonoperatively. Retrospective radiographic and chart review was performed. Patients were then contacted by phone to obtain current quality-of-life measurements using the Scoliosis Research Society (SRS)-30 questionnaire. RESULTS: Fifty-three patients were identified for inclusion in the study and 49 were contacted for 92% follow-up. Twenty-four patients were treated with operative intervention, and 25 patients were initially treated nonoperatively, but 10 went on to require surgical intervention. Mean age at presentation was 12.6 years (range, 8 to 17 y) and mean age at follow-up was 20.1 years (range, 10 to 29 y). There were no outcome differences between the groups. A more kyphotic slip angle was associated with worse SRS-30 outcome scores across all groups. In the nonoperative group, the slip angle was significantly larger in patients who failed conservative treatment (34 ± 17 degrees) than in those who remained nonsurgical at final follow-up (20 ± 14 degrees). Slip angle in the operative group was 27 ± 14 degrees. In surgical patients, an older age at surgery was associated with better SRS-30 outcome scores. CONCLUSIONS: Nonoperative management or "watchful waiting" of the minimally symptomatic or asymptomatic child with a high-grade spondylolisthesis is safe and does not lead to significant problems. Operative intervention for the symptomatic patient achieves similar long-term results compared with patients whose minimal symptoms do not warrant surgery. Delayed surgical intervention does not result in worse outcomes. Regardless of treatment modality, patients with a more kyphotic slip angle tend to have a poorer prognosis. LEVEL OF EVIDENCE: Level III.

Authors
Lundine, KM; Lewis, SJ; Al-Aubaidi, Z; Alman, B; Howard, AW
MLA Citation
Lundine, KM, Lewis, SJ, Al-Aubaidi, Z, Alman, B, and Howard, AW. "Patient outcomes in the operative and nonoperative management of high-grade spondylolisthesis in children." Journal of pediatric orthopedics 34.5 (July 2014): 483-489.
PMID
24590330
Source
epmc
Published In
Journal of Pediatric Orthopaedics
Volume
34
Issue
5
Publish Date
2014
Start Page
483
End Page
489
DOI
10.1097/bpo.0000000000000133

β-Catenin-regulated myeloid cell adhesion and migration determine wound healing.

A β-catenin/T cell factor-dependent transcriptional program is critical during cutaneous wound repair for the regulation of scar size; however, the relative contribution of β-catenin activity and function in specific cell types in the granulation tissue during the healing process is unknown. Here, cell lineage tracing revealed that cells in which β-catenin is transcriptionally active express a gene profile that is characteristic of the myeloid lineage. Mice harboring a macrophage-specific deletion of the gene encoding β-catenin exhibited insufficient skin wound healing due to macrophage-specific defects in migration, adhesion to fibroblasts, and ability to produce TGF-β1. In irradiated mice, only macrophages expressing β-catenin were able to rescue wound-healing deficiency. Evaluation of scar tissue collected from patients with hypertrophic and normal scars revealed a correlation between the number of macrophages within the wound, β-catenin levels, and cellularity. Our data indicate that β-catenin regulates myeloid cell motility and adhesion and that β-catenin-mediated macrophage motility contributes to the number of mesenchymal cells and ultimate scar size following cutaneous injury.

Authors
Amini-Nik, S; Cambridge, E; Yu, W; Guo, A; Whetstone, H; Nadesan, P; Poon, R; Hinz, B; Alman, BA
MLA Citation
Amini-Nik, S, Cambridge, E, Yu, W, Guo, A, Whetstone, H, Nadesan, P, Poon, R, Hinz, B, and Alman, BA. "β-Catenin-regulated myeloid cell adhesion and migration determine wound healing." The Journal of clinical investigation 124.6 (June 2014): 2599-2610.
PMID
24837430
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
6
Publish Date
2014
Start Page
2599
End Page
2610
DOI
10.1172/jci62059

Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.

Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand-dependent settings, where Hh signaling occurs either directly within the cancer cells or within the nonmalignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand-dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI-926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926-treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in downmodulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling, and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathologic changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma.

Authors
Campbell, VT; Nadesan, P; Ali, SA; Wang, CYY; Whetstone, H; Poon, R; Wei, Q; Keilty, J; Proctor, J; Wang, LW; Apte, SS; McGovern, K; Alman, BA; Wunder, JS
MLA Citation
Campbell, VT, Nadesan, P, Ali, SA, Wang, CYY, Whetstone, H, Poon, R, Wei, Q, Keilty, J, Proctor, J, Wang, LW, Apte, SS, McGovern, K, Alman, BA, and Wunder, JS. "Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth." Molecular cancer therapeutics 13.5 (May 2014): 1259-1269.
PMID
24634412
Source
epmc
Published In
Molecular cancer therapeutics
Volume
13
Issue
5
Publish Date
2014
Start Page
1259
End Page
1269
DOI
10.1158/1535-7163.mct-13-0731

Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation

Fracture repair is a well orchestrated process involving various cell types and signaling molecules. The hedgehog signaling pathway is activated in chondrocytes during fracture repair and is known to regulate chondrogenesis however, its role in osteoblasts during injury is yet unknown. In this study we observed tibial fracture repair in mice in which hedgehog signaling was modulated through genetic alterations of the pathway activator, smoothened. Levels of the hedgehog target genes Gli1 and Ptch1 in wildtype mice were upregulated in fracture calluses throughout the repair process. Forced activation of the hedgehog pathway in ubiquitous fashion resulted in increased matrix deposition in the fracture callus. Interestingly, inhibition in chondrocytes did not alter the fracture repair phenotype, while activation of hedgehog in osteoblasts was a requirement for normal fracture repair. In vitro, transcript levels of Gli1 and Ptch1 were elevated during osteoblastogenesis. Activation of hedgehog signaling positively affected osteoblastic differentiation and mineralization as detected using alkaline phosphatase and Von Kossa staining and Alp and Col1 expression. Here we show that the hedgehog signaling pathway plays a critical role in osteoblasts during fracture repair: inhibition of the pathway in osteoblasts leads to decreased matrix at the fracture site while activation increased matrix deposition.© 2013 The Authors. Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res J Orthop Res 32:581-586, 2014. © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society.

Authors
Baht, GS; Silkstone, D; Nadesan, P; Whetstone, H; Alman, BA
MLA Citation
Baht, GS, Silkstone, D, Nadesan, P, Whetstone, H, and Alman, BA. "Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation." Journal of Orthopaedic Research 32.4 (April 1, 2014): 581-586.
Source
scopus
Published In
Journal of Orthopaedic Research
Volume
32
Issue
4
Publish Date
2014
Start Page
581
End Page
586
DOI
10.1002/jor.22562

Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation.

Fracture repair is a well orchestrated process involving various cell types and signaling molecules. The hedgehog signaling pathway is activated in chondrocytes during fracture repair and is known to regulate chondrogenesis however, its role in osteoblasts during injury is yet unknown. In this study we observed tibial fracture repair in mice in which hedgehog signaling was modulated through genetic alterations of the pathway activator, smoothened. Levels of the hedgehog target genes Gli1 and Ptch1 in wildtype mice were upregulated in fracture calluses throughout the repair process. Forced activation of the hedgehog pathway in ubiquitous fashion resulted in increased matrix deposition in the fracture callus. Interestingly, inhibition in chondrocytes did not alter the fracture repair phenotype, while activation of hedgehog in osteoblasts was a requirement for normal fracture repair. In vitro, transcript levels of Gli1 and Ptch1 were elevated during osteoblastogenesis. Activation of hedgehog signaling positively affected osteoblastic differentiation and mineralization as detected using alkaline phosphatase and Von Kossa staining and Alp and Col1 expression. Here we show that the hedgehog signaling pathway plays a critical role in osteoblasts during fracture repair: inhibition of the pathway in osteoblasts leads to decreased matrix at the fracture site while activation increased matrix deposition.

Authors
Baht, GS; Silkstone, D; Nadesan, P; Whetstone, H; Alman, BA
MLA Citation
Baht, GS, Silkstone, D, Nadesan, P, Whetstone, H, and Alman, BA. "Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation." Journal of orthopaedic research : official publication of the Orthopaedic Research Society 32.4 (April 2014): 581-586.
PMID
24347536
Source
epmc
Published In
Journal of Orthopaedic Research
Volume
32
Issue
4
Publish Date
2014
Start Page
581
End Page
586
DOI
10.1002/jor.22562

HEDGEHOG SIGNALING REGULATES CHOLESTEROL HOMEOSTASIS IN OSTEOARTHRITIS

Authors
Ali, SA; Whetstone, HC; Alman, BA
MLA Citation
Ali, SA, Whetstone, HC, and Alman, BA. "HEDGEHOG SIGNALING REGULATES CHOLESTEROL HOMEOSTASIS IN OSTEOARTHRITIS." April 2014.
Source
wos-lite
Published In
Osteoarthritis and Cartilage
Volume
22
Publish Date
2014
Start Page
S160
End Page
S160

Percutaneous screw fixation promotes healing of lateral condyle nonunion in children.

BACKGROUND: This retrospective study examined whether pediatric lateral condyle nonunions could be successfully managed by percutaneous screw fixation. We report the outcome of this minimally invasive technique avoiding open reduction and bone grafting associated with the risk of avascular necrosis (AVN), infection, and stiffness. METHODS: The hospital radiology database was searched between 1998 and 2008. This identified 16 consecutive patients aged 2 to 10 years, with lateral condyle nonunions treated with percutaneous screw fixation. We assessed clinical and radiographic outcomes from presentation to final follow-up. Potential risk factors for recalcitrant nonunion were identified. Categorical variables are presented as proportions and percentages. Continuous variables were assessed for normality with the d'Agostino-Pearson test. Normally distributed variables are presented as means with 1 SD. Non-normally distributed data are presented as medians with interquartile range. RESULTS: Outcome was defined as successful if radiologic and clinical union was achieved. Twelve patients (75%) united after surgery, at a mean of 16.2 weeks (±6.74). Four (25%) failed to unite. The failures presented with nonunion later (median of 225.5 wk from initial injury). This was significantly different (P=0.039) from presentation in the successful group (median time 15.7 wk).Median age at injury was 5.1 years (range, 3.2 to 7.2) in the successful and 2.8 years (range, 2.1 to 4.7) in the unsuccessful group (P=0.18). Overall, mean time from nonunion diagnosis to percutaneous surgery was 5.2 weeks (±4.11). Forty-four percent had implant removal once union was achieved and no cases of AVN were reported. CONCLUSIONS: We demonstrate this technique to be successful in nonunions addressed within 16 weeks from initial injury to diagnosis. Our 4 failures occurred in nonunions diagnosed >31 weeks from the injury (31, 68, 383, 427 wk). All had been managed nonoperatively as their primary treatment plan.Percutaneous fixation is feasible and safe. Patients not achieving union were diagnosed after a greater delay. There was a trend toward successfully treated patients being younger. There were no cases of AVN, infection, or elbow stiffness. LEVEL OF EVIDENCE: Level 4.

Authors
Knight, DM; Alves, C; Alman, B; Howard, A
MLA Citation
Knight, DM, Alves, C, Alman, B, and Howard, A. "Percutaneous screw fixation promotes healing of lateral condyle nonunion in children." Journal of pediatric orthopedics 34.2 (March 2014): 155-160.
PMID
25028799
Source
epmc
Published In
Journal of Pediatric Orthopaedics
Volume
34
Issue
2
Publish Date
2014
Start Page
155
End Page
160
DOI
10.1097/bpo.0000000000000077

Involvement and targeted intervention of dysregulated hedgehog signaling in osteosarcoma

BACKGROUND During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma. METHODS Small-molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small-molecule Smoothened (SMO) antagonist, IPI-926 (saridegib), also was examined in patient-derived xenograft models. RESULTS An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma-associated oncogene 2 (GLI2) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand-independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand-dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand-dependent Hedgehog signaling was identified. IPI-926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand-dependent models. CONCLUSIONS The current results indicate that both ligand-dependent and ligand-independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI-926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma. Cancer 2014;120:537-547. © 2013 American Cancer Society. Dysregulated Hedgehog signaling is investigated as a targeted intervention for osteosarcoma using small-molecule modulators of the Hedgehog pathway in cell lines and IPI-926 (saridegib), a specific Smoothened inhibitor, in patient-derived xenograft models. Ligand-dependent and ligand-independent dysregulation and signaling crosstalk between the tumor and the stroma is identified and is supported by specific blockage of signaling exerted by the inhibitors. © 2013 American Cancer Society.

Authors
Lo, WW; Wunder, JS; Dickson, BC; Campbell, V; McGovern, K; Alman, BA; Andrulis, IL
MLA Citation
Lo, WW, Wunder, JS, Dickson, BC, Campbell, V, McGovern, K, Alman, BA, and Andrulis, IL. "Involvement and targeted intervention of dysregulated hedgehog signaling in osteosarcoma." Cancer 120.4 (February 15, 2014): 537-547.
Source
scopus
Published In
Cancer
Volume
120
Issue
4
Publish Date
2014
Start Page
537
End Page
547
DOI
10.1002/cncr.28439

Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma.

BACKGROUND: During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma. METHODS: Small-molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small-molecule Smoothened (SMO) antagonist, IPI-926 (saridegib), also was examined in patient-derived xenograft models. RESULTS: An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma-associated oncogene 2 (GLI2) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand-independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand-dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand-dependent Hedgehog signaling was identified. IPI-926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand-dependent models. CONCLUSIONS: The current results indicate that both ligand-dependent and ligand-independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI-926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma.

Authors
Lo, WW; Wunder, JS; Dickson, BC; Campbell, V; McGovern, K; Alman, BA; Andrulis, IL
MLA Citation
Lo, WW, Wunder, JS, Dickson, BC, Campbell, V, McGovern, K, Alman, BA, and Andrulis, IL. "Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma." Cancer 120.4 (February 15, 2014): 537-547.
PMID
24151134
Source
pubmed
Published In
Cancer
Volume
120
Issue
4
Publish Date
2014
Start Page
537
End Page
547
DOI
10.1002/cncr.28439

Reflections on competency-based education and training for surgical residents

Authors
Sonnadara, RR; Mui, C; McQueen, S; Mironova, P; Nousiainen, M; Safir, O; Kraemer, W; Ferguson, P; Alman, B; Reznick, R
MLA Citation
Sonnadara, RR, Mui, C, McQueen, S, Mironova, P, Nousiainen, M, Safir, O, Kraemer, W, Ferguson, P, Alman, B, and Reznick, R. "Reflections on competency-based education and training for surgical residents." Journal of Surgical Education 71.1 (2014): 151-158.
Source
scival
Published In
Journal of Surgical Education
Volume
71
Issue
1
Publish Date
2014
Start Page
151
End Page
158
DOI
10.1016/j.jsurg.2013.06.020

Patient outcomes in the operative and nonoperative management of high-grade spondylolisthesis in children

Background: The optimal management of high-grade spondylolisthesis in the growing child is controversial. Some authors have advocated for surgery in all cases regardless of symptoms. Surgical intervention results in a >10% risk of complications with increased risk of neurological injury associated with slip reduction maneuvers. There is a paucity of literature regarding nonoperative management in this setting. This study sought to obtain outcome measures in pediatric patients with high-grade spondylolisthesis managed either operatively or nonoperatively. Methods: Database review was performed to identify patients with a high-grade (Meyerding grade III to V) spondylolisthesis managed either operatively or nonoperatively. Retrospective radiographic and chart review was performed. Patients were then contacted by phone to obtain current quality-of-life measurements using the Scoliosis Research Society (SRS)-30 questionnaire. Results: Fifty-three patients were identified for inclusion in the study and 49 were contacted for 92% follow-up. Twenty-four patients were treated with operative intervention, and 25 patients were initially treated nonoperatively, but 10 went on to require surgical intervention. Mean age at presentation was 12.6 years (range, 8 to 17 y) and mean age at follow-up was 20.1 years (range, 10 to 29 y). There were no outcome differences between the groups. A more kyphotic slip angle was associated with worse SRS-30 outcome scores across all groups. In the nonoperative group, the slip angle was significantly larger in patients who failed conservative treatment (34±17 degrees) than in those who remained nonsurgical at final follow-up (20±14 degrees). Slip angle in the operative group was 27±14 degrees. In surgical patients, an older age at surgery was associated with better SRS-30 outcome scores. Conclusions: Nonoperative management or "watchful waiting" of the minimally symptomatic or asymptomatic child with a high-grade spondylolisthesis is safe and does not lead to significant problems. Operative intervention for the symptomatic patient achieves similar long-term results compared with patients whose minimal symptoms do not warrant surgery. Delayed surgical intervention does not result in worse outcomes. Regardless of treatment modality, patients with a more kyphotic slip angle tend to have a poorer prognosis. Level of evidence: Level III. Copyright © 2014 by Lippincott Williams & Wilkins.

Authors
Lundine, KM; Lewis, SJ; Al-Aubaidi, Z; Alman, B; Howard, AW
MLA Citation
Lundine, KM, Lewis, SJ, Al-Aubaidi, Z, Alman, B, and Howard, AW. "Patient outcomes in the operative and nonoperative management of high-grade spondylolisthesis in children." Journal of Pediatric Orthopaedics 34.5 (2014): 483-489.
Source
scival
Published In
Journal of Pediatric Orthopaedics
Volume
34
Issue
5
Publish Date
2014
Start Page
483
End Page
489
DOI
10.1097/BPO.0000000000000133

Reduced beta-catenin Expression in Mouse Cardiomyocytes Increases Matrix Metalloproteinase Activation and Apoptosis, Producing Greater Post-Infarction Ventricular Dysfunction

Authors
Singh, K; Mihic, A; Hatta, K; Amini-Nik, S; Wu, J; Li, S-H; Sun, L; Alman, BA; Brunt, KR; Weisel, RD; Li, R-K
MLA Citation
Singh, K, Mihic, A, Hatta, K, Amini-Nik, S, Wu, J, Li, S-H, Sun, L, Alman, BA, Brunt, KR, Weisel, RD, and Li, R-K. "Reduced beta-catenin Expression in Mouse Cardiomyocytes Increases Matrix Metalloproteinase Activation and Apoptosis, Producing Greater Post-Infarction Ventricular Dysfunction." November 26, 2013.
Source
wos-lite
Published In
Circulation
Volume
128
Issue
22
Publish Date
2013

Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes.

Primary cilia can act as either a negative or positive regulator of the hedgehog (Hh) signaling pathway. Many cartilage tumors are characterized by abnormal activation of the Hh pathway. Here, we report that the presence of primary cilia occurs at a low frequency (12.4%) in neoplastic chondrocytes from malignant human chondrosarcomas, compared with chondrocytes from normal articular cartilage (67.7%). To determine the function of primary cilia in cartilaginous neoplasia, we studied benign cartilage tumors that are formed in mice by chondrocyte-specific overexpression of Gli2, a downstream transcriptional activator of the Hh pathway. Col2A1-Gli2 mice were crossed with Ift88+/- mice, which display a partial loss of ciliogenesis. Surprisingly, cartilage tumors developed in Ift88+/- mice that were phenotypically similar to those that arise in Col2A1-Gli2 mice. Further activation of the Hh pathway was observed in Col2A1-Gli2; Ift88+/- mice compared with either Col2A1-Gli2 or Ift88+/- mice, which was associated with an increased incidence of cartilage tumors. Chondrosarcomas were established in explant cultures, and treated with choral hydrate, which disrupts the functional primary cilia. Thus, treatment resulted in hyperactivity of the Hh signaling pathway, as well as cellular changes that could promote tumor growth. Primary cilia functions to inhibit Hh signaling in neoplastic chondrocytes. The activation of Hh signaling is sufficient to induce benign cartilage tumors without another oncogenic initiating event. Moreover, as primary cilia suppress Hh pathway activation in chondrosarcoma, cellular mechanisms inhibiting proper cilia function may be important in maintaining the neoplastic phenotype.

Authors
Ho, L; Ali, SA; Al-Jazrawe, M; Kandel, R; Wunder, JS; Alman, BA
MLA Citation
Ho, L, Ali, SA, Al-Jazrawe, M, Kandel, R, Wunder, JS, and Alman, BA. "Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes." Oncogene 32.47 (November 21, 2013): 5388-5396.
PMID
23246966
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
32
Issue
47
Publish Date
2013
Start Page
5388
End Page
5396
DOI
10.1038/onc.2012.588

Three-year experience with an innovative, modular competency-based curriculum for orthopaedic training

Authors
Ferguson, PC; Kraemer, W; Nousiainen, M; Safir, O; Sonnadara, R; Alman, B; Reznick, R
MLA Citation
Ferguson, PC, Kraemer, W, Nousiainen, M, Safir, O, Sonnadara, R, Alman, B, and Reznick, R. "Three-year experience with an innovative, modular competency-based curriculum for orthopaedic training." Journal of Bone and Joint Surgery - Series A 95.21 (November 6, 2013).
Source
scopus
Published In
The Journal of Bone and Joint Surgery
Volume
95
Issue
21
Publish Date
2013
DOI
10.2106/JBJS.M.00314

Three-Year Experience with an Innovative, Modular Competency-Based Curriculum for Orthopaedic Training

Authors
Ferguson, PC; Kraemer, W; Nousiainen, M; Safir, O; Sonnadara, R; Alman, B; Reznick, R
MLA Citation
Ferguson, PC, Kraemer, W, Nousiainen, M, Safir, O, Sonnadara, R, Alman, B, and Reznick, R. "Three-Year Experience with an Innovative, Modular Competency-Based Curriculum for Orthopaedic Training." The Journal of Bone and Joint Surgery-American Volume 95.21 (November 2013): e166-1-6.
Source
crossref
Published In
The Journal of Bone and Joint Surgery
Volume
95
Issue
21
Publish Date
2013
Start Page
e166
End Page
1-6
DOI
10.2106/JBJS.M.00314

Three-year experience with an innovative, modular competency-based curriculum for orthopaedic training.

Authors
Ferguson, PC; Kraemer, W; Nousiainen, M; Safir, O; Sonnadara, R; Alman, B; Reznick, R
MLA Citation
Ferguson, PC, Kraemer, W, Nousiainen, M, Safir, O, Sonnadara, R, Alman, B, and Reznick, R. "Three-year experience with an innovative, modular competency-based curriculum for orthopaedic training." The Journal of bone and joint surgery. American volume 95.21 (November 2013): e166-.
PMID
24196478
Source
epmc
Published In
The Journal of Bone and Joint Surgery
Volume
95
Issue
21
Publish Date
2013
Start Page
e166
DOI
10.2106/jbjs.m.00314

Targeting stem cell behavior in desmoid tumors (aggressive fibromatosis) by inhibiting hedgehog signaling.

Desmoid tumor (also called aggressive fibromatosis) is a lesion of mesenchymal origin that can occur as a sporadic tumor or a manifestation of the preneoplastic syndrome, familial adenomatous polyposis caused by a mutation in adenomatous polyposis coli (APC). This tumor type is characterized by the stabilization of β-catenin and activation of Tcf-mediated transcription. Cell transplantation data suggest that desmoid tumors are derived from mesenchymal progenitor cells (MSCs). As such, modulating cell signaling pathways that regulate MSC differentiation or proliferation, such as hedgehog (Hh) signaling, could alter the tumor phenotype. Here, we found that Hh signaling is activated in human and murine desmoid tumors. Inhibiting Hh signaling in human cell cultures decreased cell proliferation and β-catenin protein levels. Apc(+)/Apc(1638N) mice, which develop desmoid tumors, develop smaller and fewer tumors when Hh signaling was inhibited either genetically (by crossing Apc(+)/Apc(1638N) mice with mice lacking one copy of a Hh-activated transcription factor, Gli2 (+/-) mice) or using a pharmacologic inhibitor. Both in mice and in human tumor cell cultures, β-catenin and Hh-mediated signaling positively regulate each other's activity. These data show that targeting a pathway that regulates MSC differentiation influences desmoid tumor behavior, providing functional evidence supporting the notion that these tumors are derived from mesenchymal progenitors. It also suggests Hh blockade as a therapeutic approach for this tumor type.

Authors
Ghanbari-Azarnier, R; Sato, S; Wei, Q; Al-Jazrawe, M; Alman, BA
MLA Citation
Ghanbari-Azarnier, R, Sato, S, Wei, Q, Al-Jazrawe, M, and Alman, BA. "Targeting stem cell behavior in desmoid tumors (aggressive fibromatosis) by inhibiting hedgehog signaling." Neoplasia 15.7 (July 2013): 712-719.
PMID
23814483
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
15
Issue
7
Publish Date
2013
Start Page
712
End Page
719

Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up.

BACKGROUND: Duchenne muscular dystrophy, a progressive muscle disorder that occurs in males, causes a gradual decline in muscle strength. This progressive decline is associated with the development of scoliosis. Previous studies have shown that the use of glucocorticoids slows the progression of scoliosis, but it is unknown if the spine remains straight in the long term. We examined if glucocorticoid treatment has a long-term effect on the prevalence of scoliosis. METHODS: Fifty-four boys who had been diagnosed with Duchenne muscular dystrophy while they were still walking were enrolled in a non-randomized comparative study of the glucocorticoid deflazacort. The families of thirty boys elected for them to use glucocorticoid treatment and the families of twenty-four boys elected for them not to have this treatment. The boys were matched for important baseline characteristics including age and pulmonary function. Every four to six months, they were examined for the development of scoliosis, and the duration of follow-up for surviving patients was fifteen years. Because surgery was recommended for spinal curves measuring >20° on sitting posteroanterior radiographs, a curve of this magnitude was used as the definition for a patient developing scoliosis. RESULTS: Five boys (21%) in the non-treatment group and one boy (3%) in the glucocorticoid treatment group died. At the most recent follow-up, of the boys who survived, six (20%) in the glucocorticoid treatment group and twenty-two (92%) in the non-treatment group developed scoliosis and underwent spinal surgery. After fifteen years of follow-up, the survivorship analysis (avoiding surgery) was 78% (95% confidence interval, 57% to 89%) in the treatment group and 8.3% (95% confidence interval, 0.8% to 28%) in the non-treatment group. Significance (p = 5.8 × 10(-7)) was calculated with log-rank and chi-square tests. None of the patients in the glucocorticoid group developed scoliosis after ten years of deflazacort treatment. CONCLUSION: The long-term use of the glucocorticoid results in a substantial decreased need for spinal surgery to treat scoliosis.

Authors
Lebel, DE; Corston, JA; McAdam, LC; Biggar, WD; Alman, BA
MLA Citation
Lebel, DE, Corston, JA, McAdam, LC, Biggar, WD, and Alman, BA. "Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up." J Bone Joint Surg Am 95.12 (June 19, 2013): 1057-1061.
PMID
23783200
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
95
Issue
12
Publish Date
2013
Start Page
1057
End Page
1061
DOI
10.2106/JBJS.L.01577

Cutaneous wound healing: recruiting developmental pathways for regeneration.

Following a skin injury, the damaged tissue is repaired through the coordinated biological actions that constitute the cutaneous healing response. In mammals, repaired skin is not identical to intact uninjured skin, however, and this disparity may be caused by differences in the mechanisms that regulate postnatal cutaneous wound repair compared to embryonic skin development. Improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for wound healing complications. Here we focus on the roles of several key developmental signaling pathways (Wnt/β-catenin, TGF-β, Hedgehog, Notch) in mammalian cutaneous wound repair, and compare this to their function in skin development. We discuss the varying responses to cutaneous injury across the taxa, ranging from complete regeneration to scar tissue formation. Finally, we outline how research into the role of developmental pathways during skin repair has contributed to current wound therapies, and holds potential for the development of more effective treatments.

Authors
Bielefeld, KA; Amini-Nik, S; Alman, BA
MLA Citation
Bielefeld, KA, Amini-Nik, S, and Alman, BA. "Cutaneous wound healing: recruiting developmental pathways for regeneration." Cell Mol Life Sci 70.12 (June 2013): 2059-2081. (Review)
PMID
23052205
Source
pubmed
Published In
Cellular and Molecular Life Sciences
Volume
70
Issue
12
Publish Date
2013
Start Page
2059
End Page
2081
DOI
10.1007/s00018-012-1152-9

Specification of chondrocytes and cartilage tissues from embryonic stem cells.

Osteoarthritis primarily affects the articular cartilage of synovial joints. Cell and/or cartilage replacement is a promising therapy, provided there is access to appropriate tissue and sufficient numbers of articular chondrocytes. Embryonic stem cells (ESCs) represent a potentially unlimited source of chondrocytes and tissues as they can generate a broad spectrum of cell types under appropriate conditions in vitro. Here, we demonstrate that mouse ESC-derived chondrogenic mesoderm arises from a Flk-1(-)/Pdgfrα(+) (F(-)P(+)) population that emerges in a defined temporal pattern following the development of an early cardiogenic F(-)P(+) population. Specification of the late-arising F(-)P(+) population with BMP4 generated a highly enriched population of chondrocytes expressing genes associated with growth plate hypertrophic chondrocytes. By contrast, specification with Gdf5, together with inhibition of hedgehog and BMP signaling pathways, generated a population of non-hypertrophic chondrocytes that displayed properties of articular chondrocytes. The two chondrocyte populations retained their hypertrophic and non-hypertrophic properties when induced to generate spatially organized proteoglycan-rich cartilage-like tissue in vitro. Transplantation of either type of chondrocyte, or tissue generated from them, into immunodeficient recipients resulted in the development of cartilage tissue and bone within an 8-week period. Significant ossification was not observed when the tissue was transplanted into osteoblast-depleted mice or into diffusion chambers that prevent vascularization. Thus, through stage-specific manipulation of appropriate signaling pathways it is possible to efficiently and reproducibly derive hypertrophic and non-hypertrophic chondrocyte populations from mouse ESCs that are able to generate distinct cartilage-like tissue in vitro and maintain a cartilage tissue phenotype within an avascular and/or osteoblast-free niche in vivo.

Authors
Craft, AM; Ahmed, N; Rockel, JS; Baht, GS; Alman, BA; Kandel, RA; Grigoriadis, AE; Keller, GM
MLA Citation
Craft, AM, Ahmed, N, Rockel, JS, Baht, GS, Alman, BA, Kandel, RA, Grigoriadis, AE, and Keller, GM. "Specification of chondrocytes and cartilage tissues from embryonic stem cells." Development (Cambridge, England) 140.12 (June 2013): 2597-2610.
PMID
23715552
Source
epmc
Published In
Development (Cambridge)
Volume
140
Issue
12
Publish Date
2013
Start Page
2597
End Page
2610
DOI
10.1242/dev.087890

Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies.

Despite significant interest in developing quantum dots (QDs) for biomedical applications, many researchers are convinced that QDs will never be used for treating patients because of their potential toxicity. The perception that QDs are toxic is rooted in two assumptions. Cadmium-containing QDs can kill cells in culture. Many researchers then assume that because QDs are toxic to cells, they must be toxic to humans. In addition, many researchers classify QDs as a homogeneous group of materials. Therefore, if CdSe QDs are harmful, they extrapolate this result to all QDs. Though unsubstantiated, these assumptions continue to drive QD research. When dosing is physiologically appropriate, QD toxicity has not been demonstrated in animal models. In addition, QDs are not uniform: each design is a unique combination of physicochemical properties that influence biological activity and toxicity. In this Account, we summarize key findings from in vitro and in vivo studies, explore the causes of the discrepancy in QD toxicological data, and provide our view of the future direction of the field. In vitro and in vivo QD studies have advanced our knowledge of cellular transport kinetics, mechanisms of QD toxicity, and biodistribution following animal injection. Cell culture experiments have shown that QDs undergo design-dependent intracellular localization and they can cause cytotoxicity by releasing free cadmium into solution and by generating free radical species. In animal experiments, QDs preferentially enter the liver and spleen following intravascular injection, undergo minimal excretion if larger than 6 nm, and appear to be safe to the animal. In vitro and in vivo studies show an apparent discrepancy with regard to toxicity. Dosing provides one explanation for these findings. Under culture conditions, a cell experiences a constant QD dose, but the in vivo QD concentration can vary, and the organ-specific dose may not be high enough to induce detectable toxicity. Because QDs are retained within animals, long-term toxicity may be a problem but has not been established. Future QD toxicity studies should be standardized and systematized because methodological variability in the current body of literature makes it difficult to compare and contrast results. We advocate the following steps for consistent, comparable toxicology data: (a) standardize dose metrics, (b) characterize QD uptake concentration, (c) identify in vitro models that reflect the cells QDs interact with in vivo, and (d) use multiple assays to determine sublethal toxicity and biocompatibility. Finally, we should ask more specific toxicological questions. For example: "At what dose are 5 nm CdSe QDs that are stabilized with mercaptoacetic acid and conjugated to the antibody herceptin toxic to HeLa cells?" rather than "Are QDs toxic?" QDs are still a long way from realizing their potential as a medical technology. Modifying the current QD toxicological research paradigm, investigating toxicity in a case-by-case manner, and improving study quality are important steps in identifying a QD formulation that is safe for human use.

Authors
Tsoi, KM; Dai, Q; Alman, BA; Chan, WCW
MLA Citation
Tsoi, KM, Dai, Q, Alman, BA, and Chan, WCW. "Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies." Acc Chem Res 46.3 (March 19, 2013): 662-671.
PMID
22853558
Source
pubmed
Published In
Accounts of Chemical Research
Volume
46
Issue
3
Publish Date
2013
Start Page
662
End Page
671
DOI
10.1021/ar300040z

Patients' views on surgeons' financial conflicts of interest.

BACKGROUND: The U.S. Department of Justice's investigations into financial relationships between surgical device manufacturers and orthopaedic surgeons have raised the question as to whether surgeons can continue to collaborate with industry and maintain public trust. We explored postoperative patients' views on financial relationships between surgeons and surgical device manufacturers, their views on disclosure as a method to manage these relationships, and their opinions on oversight. METHODS: From November 2010 to March 2011, we surveyed 251 postoperative patients in the U.S. (an 88% response rate) and 252 postoperative patients in Canada (a 92% response rate) in follow-up hip and knee arthroplasty clinics with use of self-administered questionnaires. Patients were eligible to complete the questionnaire if their surgery (primary or revision hip or knee arthroplasty) had occurred at least three months earlier. RESULTS: Few patients are worried about possible financial relationships between their surgeon and industry (6% of surveyed patients in the U.S. and 6% of surveyed patients in Canada). Most patients thought that it is appropriate for surgeons to receive payments from manufacturers for activities that can benefit patients, such as royalties for inventions (U.S., 69%; Canada, 66%) and consultancy (U.S., 48%; Canada, 53%). Most patients felt that it is not appropriate for their surgeon to receive gifts from industry (U.S., 63%; Canada, 59%). A majority felt that their surgeon would hold patients' interests paramount, regardless of any financial relationship with a manufacturer (U.S., 76%; Canada, 74%). A majority of patients wanted their surgeon's professional organization to ensure that financial relationships are appropriate (U.S., 83%; Canada, 83%); a minority endorsed government oversight of these relationships (U.S., 26%; Canada, 35%). CONCLUSIONS: Most patients are not worried about possible financial relationships between their surgeon and industry. They clearly distinguish financial relationships that benefit current or future patients from those that benefit the surgeon or device manufacturer. They favor disclosure with professional oversight as a method of managing financial relationships between surgeons and manufacturers.

Authors
Camp, MW; Mattingly, DA; Gross, AE; Nousiainen, MT; Alman, BA; McKneally, MF
MLA Citation
Camp, MW, Mattingly, DA, Gross, AE, Nousiainen, MT, Alman, BA, and McKneally, MF. "Patients' views on surgeons' financial conflicts of interest." J Bone Joint Surg Am 95.2 (January 16, 2013): e9 1-8-.
PMID
23324970
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
95
Issue
2
Publish Date
2013
Start Page
e9 1-8
DOI
10.2106/JBJS.L.00270

Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes

Primary cilia can act as either a negative or positive regulator of the hedgehog (Hh) signaling pathway. Many cartilage tumors are characterized by abnormal activation of the Hh pathway. Here, we report that the presence of primary cilia occurs at a low frequency (12.4%) in neoplastic chondrocytes from malignant human chondrosarcomas, compared with chondrocytes from normal articular cartilage (67.7%). To determine the function of primary cilia in cartilaginous neoplasia, we studied benign cartilage tumors that are formed in mice by chondrocyte-specific overexpression of Gli2, a downstream transcriptional activator of the Hh pathway. Col2A1-Gli2 mice were crossed with Ift88+/- mice, which display a partial loss of ciliogenesis. Surprisingly, cartilage tumors developed in Ift88+/- mice that were phenotypically similar to those that arise in Col2A1-Gli2 mice. Further activation of the Hh pathway was observed in Col2A1-Gli2; Ift88+/- mice compared with either Col2A1-Gli2 or Ift88+/- mice, which was associated with an increased incidence of cartilage tumors. Chondrosarcomas were established in explant cultures, and treated with choral hydrate, which disrupts the functional primary cilia. Thus, treatment resulted in hyperactivity of the Hh signaling pathway, as well as cellular changes that could promote tumor growth. Primary cilia functions to inhibit Hh signaling in neoplastic chondrocytes. The activation of Hh signaling is sufficient to induce benign cartilage tumors without another oncogenic initiating event. Moreover, as primary cilia suppress Hh pathway activation in chondrosarcoma, cellular mechanisms inhibiting proper cilia function may be important in maintaining the neoplastic phenotype. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Ho, L; Ali, SA; Al-Jazrawe, M; Kandel, R; Wunder, JS; Alman, BA
MLA Citation
Ho, L, Ali, SA, Al-Jazrawe, M, Kandel, R, Wunder, JS, and Alman, BA. "Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes." Oncogene 32.47 (January 1, 2013): 5388-5396.
Source
scopus
Published In
Oncogene: Including Oncogene Reviews
Volume
32
Issue
47
Publish Date
2013
Start Page
5388
End Page
5396
DOI
10.1038/onc.2012.588

Toronto orthopaedic boot camp III: examining the efficacy of student-regulated learning during an intensive, laboratory-based surgical skills course.

Previous studies have presented compelling data that a 1-month "boot-camp"-style course can be a highly effective mechanism for teaching and developing targeted technical skills. In the current study, we examine whether performance of these targeted skills is improved when residents are trained using directed, student-led (SL) learning methods compared with traditional instructor-led (IL) learning methods. Twelve first-year orthopedic residents began their training with a 1-month, intensive skills course. Six residents were taught basic surgical skills using a format that focused on deliberate, SL exploration and practice of the skills under instructor supervision (SL group). The remaining residents were taught the same surgical skills using more traditional IL methods that included complete demonstration of the surgical task by an orthopedic surgeon, followed by an extended period of instruction (IL group). Performance on 4 targeted technical skills (sawing, bone drilling, suturing, and plaster splint application) was tested using an objective, structured assessment of technical skills examination for the 2 groups at the beginning and the end of the skills course. Before the start of the skills course, there were no differences in performance scores between the 2 groups. On completion of the skills course, mean global rating scores for the 4 surgical skills tasks were greater for the SL group compared with the IL group: SL, 3.95 ± 0.1; IL, 3.42 ± 0.1; F(1,10) = 7.66 P < .02. A similar pattern of results was revealed by the checklists scores, with the SL group outperforming the IL group: SL, 94.9 ± 2.1; IL, 86.4 ± 2.1; F(1,10) = 8.512; P < .02. Previous work has demonstrated the effectiveness of teaching basic surgical skills through an intensive course at the onset of residency. The present study shows that allowing surgical trainees to take a directed, student-regulated approach to learning basic surgical skills can further improve performance of these skills. Copyright © 2013. Published by Mosby, Inc.

Authors
Sonnadara, RR; Garbedian, S; Safir, O; Mui, C; Mironova, P; Nousiainen, M; Ferguson, P; Alman, B; Kraemer, W; Reznick, R
MLA Citation
Sonnadara, RR, Garbedian, S, Safir, O, Mui, C, Mironova, P, Nousiainen, M, Ferguson, P, Alman, B, Kraemer, W, and Reznick, R. "Toronto orthopaedic boot camp III: examining the efficacy of student-regulated learning during an intensive, laboratory-based surgical skills course." Surgery 154.1 (2013): 29-33.
PMID
23809482
Source
scival
Published In
Surgery
Volume
154
Issue
1
Publish Date
2013
Start Page
29
End Page
33
DOI
10.1016/j.surg.2013.05.003

Reflections on Competency-Based Education and Training for Surgical Residents

Authors
Sonnadara, RR; Mui, C; McQueen, S; Mironova, P; Nousiainen, M; Safir, O; Kraemer, W; Ferguson, P; Alman, B; Reznick, R
MLA Citation
Sonnadara, RR, Mui, C, McQueen, S, Mironova, P, Nousiainen, M, Safir, O, Kraemer, W, Ferguson, P, Alman, B, and Reznick, R. "Reflections on Competency-Based Education and Training for Surgical Residents." Journal of Surgical Education (2013).
PMID
24411437
Source
scival
Published In
Journal of Surgical Education
Publish Date
2013
DOI
10.1016/j.jsurg.2013.06.020

Reflections on current methods for evaluating skills during joint replacement surgery: A scoping review

Valid and reliable techniques for assessing performance are essential to surgical education, especially with the emergence of competency-based frameworks. Despite this, there is a paucity of adequate tools for the evaluation of skills required during joint replacement surgery. In this scoping review, we examine current methods for assessing surgeons' competency in joint replacement procedures in both simulated and clinical environments. The ability of many of the tools currently in use to make valid, reliable and comprehensive assessments of performance is unclear. Furthermore, many simulation-based assessments have been criticised for a lack of transferability to the clinical setting. It is imperative that more effective methods of assessment are developed and implemented in order to improve our ability to evaluate the performance of skills relating to total joint replacement. This will enable educators to provide formative feedback to learners throughout the training process to ensure that they have attained core competencies upon completion of their training. This should help ensure positive patient outcomes as the surgical trainees enter independent practice. © 2013 The British Editorial Society of Bone & Joint Surgery.

Authors
Sonnadara, R; McQueen, S; Mironova, P; Safir, O; Nousiainen, M; Ferguson, P; Alman, B; Kraemer, W; Reznick, R
MLA Citation
Sonnadara, R, McQueen, S, Mironova, P, Safir, O, Nousiainen, M, Ferguson, P, Alman, B, Kraemer, W, and Reznick, R. "Reflections on current methods for evaluating skills during joint replacement surgery: A scoping review." Bone and Joint Journal 95 B.11 (2013): 1445-1449.
PMID
24151260
Source
scival
Published In
Bone and Joint Journal
Volume
95 B
Issue
11
Publish Date
2013
Start Page
1445
End Page
1449
DOI
10.1302/0301-620X.95B11.30732

Competency-based education: a new model for teaching orthopaedics.

The current methods used to train residents to become orthopaedic surgeons are based on tradition, not evidence-based models. Educators have only a limited ability to assess trainees for competency using validated tests in various domains. The reduction in resident work hours limits the time available for clinical training, which has resulted in some calls for lengthening the training process. Another approach to address limited training hours is to focus training in a program that allows residents to graduate from a rotation based on demonstrated competency rather than on time on a service. A pilot orthopaedic residency curriculum, which uses a competency-based framework of resident training and maximizes the use of available training hours, has been designed and is being implemented.

Authors
Alman, BA; Ferguson, P; Kraemer, W; Nousiainen, MT; Reznick, RK
MLA Citation
Alman, BA, Ferguson, P, Kraemer, W, Nousiainen, MT, and Reznick, RK. "Competency-based education: a new model for teaching orthopaedics." Instr Course Lect 62 (2013): 565-569.
PMID
23395058
Source
pubmed
Published In
Instructional course lectures
Volume
62
Publish Date
2013
Start Page
565
End Page
569

Development and testing of a multidimensional iphone pain assessment application for adolescents with cancer

Background: Pain is one of the most common and distressing symptoms reported by adolescents with cancer. Despite advancements in pain assessment and management research, pain due to cancer and/or its treatments continues to be poorly managed. Our research group has developed a native iPhone application (app) called Pain Squad to tackle the problem of poorly managed pain in the adolescent with cancer group. The app functions as an electronic pain diary and is unique in its ability to collect data on pain intensity, duration, location, and the impact pain has on an adolescent's life (ie, relationships, school work, sleep, mood). It also evaluates medications and other physical and psychological pain management strategies used. Users are prompted twice daily at configurable times to complete 20 questions characterizing their pain and the app transmits results to a database for aggregate reporting through a Web interface. Each diary entry represents a pain case filed by an adolescent with cancer and a reward system (ie, moving up through law-enforcement team ranks, built-in videotaped acknowledgements from fictitious officers) encourages consistent use of the diary. Objective: Our objective was to design, develop, and test the usability, feasibility, compliance, and satisfaction of a game-based smartphone pain assessment tool for adolescents with cancer. Methods: We used both low- and high-fidelity qualitative usability testing with qualitative semi-structured, audio-taped interviews and iterative cycles to design and refine the iPhone based Pain Squad app. Qualitative thematic analysis of interviews using constant comparative methodology captured emergent themes related to app usability. Content validity was assessed using question importance-rating surveys completed by participants. Compliance and satisfaction data were collected following a 2-week feasibility trial where users were alarmed to record their pain twice daily on the app. Results: Thematic analysis of usability interviews showed the app to be appealing overall to adolescents. Analyses of both lowand high-fidelity testing resulted in minor revisions to the app to refine the theme and improve its usability. Adolescents resoundingly endorsed the game-based nature of the app and its virtual reward system. The importance of app pain diary questions was established by content validity analysis. Compliance with the app, assessed during feasibility testing, was high (mean 81%, SD 22%) and adolescents from this phase of the study found the app likeable, easy to use, and not bothersome to complete. Conclusions: A multifaceted usability approach demonstrated how the Pain Squad app could be made more appealing to children and adolescents with cancer. The game-based nature and built-in reward system of the app was appealing to adolescents and may have resulted in the high compliance rates and satisfaction ratings observed during clinical feasibility testing.

Authors
Stinson, JN; Jibb, LA; Nguyen, C; Nathan, PC; Maloney, AM; Dupuis, LL; Gerstle, JT; Alman, B; Hopyan, S; Strahlendorf, C; Portwine, C; Johnston, DL; Orr, M
MLA Citation
Stinson, JN, Jibb, LA, Nguyen, C, Nathan, PC, Maloney, AM, Dupuis, LL, Gerstle, JT, Alman, B, Hopyan, S, Strahlendorf, C, Portwine, C, Johnston, DL, and Orr, M. "Development and testing of a multidimensional iphone pain assessment application for adolescents with cancer." Journal of Medical Internet Research 15.3 (2013): e51-.
PMID
23475457
Source
scival
Published In
Journal of medical Internet research
Volume
15
Issue
3
Publish Date
2013
Start Page
e51
DOI
10.2196/jmir.2350

Suppressor of fused (Sufu) mediates the effect of parathyroid hormone-like hormone (Pthlh) on chondrocyte differentiation in the growth plate.

Growth plate chondrocytes undergo a coordinated process of differentiation, regulating long bone growth. Parathyroid hormone-like hormone (Pthlh) inhibits hypertrophic differentiation in the growth plate chondrocytes and reduces Hedgehog (Hh) signaling. In mice lacking the Hh mediator Suppressor of fused (Sufu), Pthlh treatment resulted in the up-regulation of Hh activity and an increased number of hypertrophic chondrocytes. Furthermore, Pthlh increased Sufu protein levels, and in chondrocytes lacking Sufu, it was unable to process Hh-regulated Gli transcription factors. Pthlh regulates chondrocyte differentiation and Gli activity in a Sufu-dependent manner, with Sufu acting as a molecular switch in its regulation of differentiation.

Authors
Hsu, S-HC; Zhang, X; Cheng, S; Wunder, JS; Hui, C-C; Alman, BA
MLA Citation
Hsu, S-HC, Zhang, X, Cheng, S, Wunder, JS, Hui, C-C, and Alman, BA. "Suppressor of fused (Sufu) mediates the effect of parathyroid hormone-like hormone (Pthlh) on chondrocyte differentiation in the growth plate." J Biol Chem 287.43 (October 19, 2012): 36222-36228.
PMID
22930757
Source
pubmed
Published In
The Journal of biological chemistry
Volume
287
Issue
43
Publish Date
2012
Start Page
36222
End Page
36228
DOI
10.1074/jbc.M112.382275

Abnormal fatty acid metabolism in spinal muscular atrophy may predispose to perioperative risks.

A 15 year old boy with SMA type II underwent spinal fusion and suffered a mitochondrial Reye-like catabolic crisis 4 days postop with hypoketotic hypoglycemia, lactic acidaemia, hyperammonemia and liver failure, with 90% coagulative necrosis and diffuse macro- and microvesicular steatosis, requiring orthotopic liver transplantation. This crisis responded in part to mitochondrial therapy and anabolic rescue. He made a dramatic sustained neurological recovery, though his post-transplant liver biopsies revealed micro- and macrosteatosis. We hypothesize that a combination of surgical stress-catecholamine induced lipolysis, prolonged general anaesthesia with propofol and sevoflurane, and perioperative fasting on a background of decreased β-oxidation were potential risk factors for the mitochondrial decompensation.

Authors
Zolkipli, Z; Sherlock, M; Biggar, WD; Taylor, G; Hutchison, JS; Peliowski, A; Alman, BA; Ling, SC; Tein, I
MLA Citation
Zolkipli, Z, Sherlock, M, Biggar, WD, Taylor, G, Hutchison, JS, Peliowski, A, Alman, BA, Ling, SC, and Tein, I. "Abnormal fatty acid metabolism in spinal muscular atrophy may predispose to perioperative risks." Eur J Paediatr Neurol 16.5 (September 2012): 549-553.
PMID
22264649
Source
pubmed
Published In
European Journal of Paediatric Neurology
Volume
16
Issue
5
Publish Date
2012
Start Page
549
End Page
553
DOI
10.1016/j.ejpn.2012.01.004

Orthopaedic resident education--it's a whole new game: "If I'm going to be a spine surgeon, why do I need to learn how to reconstruct an anterior cruciate ligament?": AOA critical issues.

Authors
Black, KP; Alman, BA; Levine, WN; Nestler, SP; Pinney, SJ
MLA Citation
Black, KP, Alman, BA, Levine, WN, Nestler, SP, and Pinney, SJ. "Orthopaedic resident education--it's a whole new game: "If I'm going to be a spine surgeon, why do I need to learn how to reconstruct an anterior cruciate ligament?": AOA critical issues." J Bone Joint Surg Am 94.13 (July 3, 2012): e96-.
PMID
22760397
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
94
Issue
13
Publish Date
2012
Start Page
e96
DOI
10.2106/JBJS.K.01214

The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy.

Deflazacort is the most commonly prescribed corticosteroid for the treatment of Duchenne muscular dystrophy in Canada. We review the long-term experience with deflazacort treatment at two centers in Canada; Montreal and Toronto. Deflazacort has benefitted both cohorts by prolonged ambulation, preserved cardiac and respiratory function, less scoliosis and improved survival. Common side effects in both cohorts include weight gain, decreased height and cataract formation. The Canadian experience supports the use of deflazacort in treating boys with Duchenne muscular dystrophy.

Authors
McAdam, LC; Mayo, AL; Alman, BA; Biggar, WD
MLA Citation
McAdam, LC, Mayo, AL, Alman, BA, and Biggar, WD. "The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy." Acta Myol 31.1 (May 2012): 16-20.
PMID
22655512
Source
pubmed
Published In
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases
Volume
31
Issue
1
Publish Date
2012
Start Page
16
End Page
20

A mechanism for gene-environment interaction in the etiology of congenital scoliosis.

Congenital scoliosis, a lateral curvature of the spine caused by vertebral defects, occurs in approximately 1 in 1,000 live births. Here we demonstrate that haploinsufficiency of Notch signaling pathway genes in humans can cause this congenital abnormality. We also show that in a mouse model, the combination of this genetic risk factor with an environmental condition (short-term gestational hypoxia) significantly increases the penetrance and severity of vertebral defects. We demonstrate that hypoxia disrupts FGF signaling, leading to a temporary failure of embryonic somitogenesis. Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction.

Authors
Sparrow, DB; Chapman, G; Smith, AJ; Mattar, MZ; Major, JA; O'Reilly, VC; Saga, Y; Zackai, EH; Dormans, JP; Alman, BA; McGregor, L; Kageyama, R; Kusumi, K; Dunwoodie, SL
MLA Citation
Sparrow, DB, Chapman, G, Smith, AJ, Mattar, MZ, Major, JA, O'Reilly, VC, Saga, Y, Zackai, EH, Dormans, JP, Alman, BA, McGregor, L, Kageyama, R, Kusumi, K, and Dunwoodie, SL. "A mechanism for gene-environment interaction in the etiology of congenital scoliosis." Cell 149.2 (April 13, 2012): 295-306.
PMID
22484060
Source
pubmed
Published In
Cell
Volume
149
Issue
2
Publish Date
2012
Start Page
295
End Page
306
DOI
10.1016/j.cell.2012.02.054

Hedgehog and Notch signaling regulate self-renewal of undifferentiated pleomorphic sarcomas.

Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self-renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial.

Authors
Wang, CYY; Wei, Q; Han, I; Sato, S; Ghanbari-Azarnier, R; Whetstone, H; Poon, R; Hu, J; Zheng, F; Zhang, P; Wang, W; Wunder, JS; Alman, BA
MLA Citation
Wang, CYY, Wei, Q, Han, I, Sato, S, Ghanbari-Azarnier, R, Whetstone, H, Poon, R, Hu, J, Zheng, F, Zhang, P, Wang, W, Wunder, JS, and Alman, BA. "Hedgehog and Notch signaling regulate self-renewal of undifferentiated pleomorphic sarcomas." Cancer Res 72.4 (February 15, 2012): 1013-1022.
PMID
22232736
Source
pubmed
Published In
Cancer Research
Volume
72
Issue
4
Publish Date
2012
Start Page
1013
End Page
1022
DOI
10.1158/0008-5472.CAN-11-2531

Desmoid tumors: Are they benign or malignant?

© Springer Science+Business Media B.V. 2012.The distinction between benign and malignant tumors is classically based on the metastatic potential of a tumor type. While desmoid tumors do not metastasize and as such are classified as benign lesions, their clinical behavior, cellular biology, and molecular etiology all share more characteristics with malignancies than benign processes. Research into these aspects of desmoid tumor biology has the potential not only to develop better treatments for desmoid tumors, but also to shed light into fundamental aspects of tumor biology that will have broad ranging applications. Its classification as a benign process could have implications hampering research, advocacy, and management progress.

Authors
Alman, B
MLA Citation
Alman, B. "Desmoid tumors: Are they benign or malignant?." Desmoid Tumors. January 1, 2012. 195-203.
Source
scopus
Publish Date
2012
Start Page
195
End Page
203
DOI
10.1007/978-94-007-1685-8_13

A high throughput screen identifies Nefopam as targeting cell proliferation in β-catenin driven neoplastic and reactive fibroproliferative disorders.

Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of β-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and β-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42% of baseline in cell cultures from β-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and β-catenin protein level to 50% of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment. Nefopam caused a 45% decline in tumor number, 33% decline in tumor volume, and a 40% decline in scar size when tested in mice. There was also a 50% decline in β-catenin level in-vivo. Nefopam targets β-catenin protein level in mesenchymal cells in-vitro and in-vivo, and may be an effective therapy for neoplastic and reactive processes driven by β-catenin mediated signaling.

Authors
Poon, R; Hong, H; Wei, X; Pan, J; Alman, BA
MLA Citation
Poon, R, Hong, H, Wei, X, Pan, J, and Alman, BA. "A high throughput screen identifies Nefopam as targeting cell proliferation in β-catenin driven neoplastic and reactive fibroproliferative disorders." PLoS One 7.5 (2012): e37940-.
PMID
22666417
Source
pubmed
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e37940
DOI
10.1371/journal.pone.0037940

Plagiarism: An assault on the integrity of scientific research

Authors
Buckwalter, JA; Wright, T; Mogoanta, L; Alman, B
MLA Citation
Buckwalter, JA, Wright, T, Mogoanta, L, and Alman, B. "Plagiarism: An assault on the integrity of scientific research." Journal of Orthopaedic Research 30.12 (2012): 1867-1868.
PMID
22912339
Source
scival
Published In
Journal of Orthopaedic Research
Volume
30
Issue
12
Publish Date
2012
Start Page
1867
End Page
1868
DOI
10.1002/jor.22198

RNA extraction from human articular cartilage by chondrocyte isolation

We report an optimized method for RNA extraction from human articular cartilage that does not require the use of specialized equipment or column purification. To maximize RNA yield while minimizing degradation and contamination, chondrocytes are isolated from the extracellular matrix and the traditional TRIzol protocol is modified to include two RNA-DNA-protein phase separations. We compared RNA extracted using this modified method with the traditional TRIzol method by spectrophotometry, Bioanalyzer, and real-time polymerase chain reaction (PCR). With the modified method, RNA recovery is increased by nearly 1 μg per 100 mg of cartilage, and RNA integrity number (RIN) is improved from 2.0 to 7.5. © 2012 Elsevier Inc. All rights reserved.

Authors
Ali, SA; Alman, B
MLA Citation
Ali, SA, and Alman, B. "RNA extraction from human articular cartilage by chondrocyte isolation." Analytical Biochemistry 429.1 (2012): 39-41.
PMID
22776092
Source
scival
Published In
Analytical Biochemistry
Volume
429
Issue
1
Publish Date
2012
Start Page
39
End Page
41
DOI
10.1016/j.ab.2012.06.028

Open reduction and internal fixation of unstable slipped capital femoral epiphysis by means of surgical dislocation does not decrease the rate of avascular necrosis: A preliminary study

Purpose: The treatment of unstable slipped capital femoral epiphysis (SCFE) remains controversial. Surgical dislocation and open reduction has the potential to significantly reduce the rate of avascular necrosis (AVN) by allowing direct preservation of the femoral head blood supply. The purpose of this study was to determine if open reduction of the unstable SCFE by means of surgical hip dislocation reduced the risk of AVN compared with closed reduction and percutaneous pinning. Methods: We reviewed the medical records and radiographs of patients treated at our institution between the years 2000 and 2008. Sex, age, side of slip, precipitating event, pre- and post-operative anterior physeal separation (APS) and slip angle, slip severity, time between inciting event and surgical treatment, number of screws used, development of AVN, and need for subsequent surgery were evaluated. Statistical analysis was performed to compare risk factors and occurrence of AVN. Results: From 2004 to 2008, we treated 12 patients with unstable SCFEs: six had closed reduction and percutaneous pinning and six underwent open reduction by means of surgical hip dislocation. There were no statistically significant differences between the two groups regarding sex, age, slip angle, APS, time to surgery, and AVN rate. At follow-up, 4 (66.7 %) patients had AVN in the group which had open reduction, while 2 (33.3 %) patients had AVN in the group which underwent closed reduction. (p = 0.57). Conclusions: Open reduction of the unstable SCFE by means of surgical dislocation of the hip does not decrease the rate of AVN when compared to closed reduction. © 2012 EPOS.

Authors
Alves, C; Steele, M; Narayanan, U; Howard, A; Alman, B; Wright, JG
MLA Citation
Alves, C, Steele, M, Narayanan, U, Howard, A, Alman, B, and Wright, JG. "Open reduction and internal fixation of unstable slipped capital femoral epiphysis by means of surgical dislocation does not decrease the rate of avascular necrosis: A preliminary study." Journal of Children's Orthopaedics 6.4 (2012): 277-283.
Source
scival
Published In
Journal of Children's Orthopaedics
Volume
6
Issue
4
Publish Date
2012
Start Page
277
End Page
283
DOI
10.1007/s11832-012-0423-1

A new Cre driver mouse line, Tcf21/Pod1-Cre, targets metanephric mesenchyme

Conditional gene targeting in mice has provided great insight into the role of gene function in kidney development and disease. Although a number of Cre-driver mouse strains already exist for the kidney, development of additional strains with unique expression patterns is needed. Here we report the generation and validation of a Tcf21/Pod1-Cre driver strain that expresses Cre recombinase throughout the condensing and stromal mesenchyme of developing kidneys and in their derivatives including epithelial components of the nephron and interstitial cells. To test the efficiency of this line, we crossed it to mice transgenic for either loss or gain of function β-catenin conditional alleles. Mice with deletion of β-catenin from Tcf21-expressing cells are born with hypoplastic kidneys, hydroureters and hydronephrosis. By contrast, Tcf21-Cre driven gain of function for β-catenin in mice results in fused midline kidneys and hypoplastic kidneys. Finally, we report the first renal mesenchymal deletion of Patched1 (Ptch1), the receptor for sonic hedgehog (Shh), which results in renal cysts demonstrating a functional role of Shh signaling pathway in renal cystogensis. In summary, we report the generation and validation of a new Cre driver strain that provides robust excision in metanephric mesenchyme. © 2012 Maezawa et al.

Authors
Maezawa, Y; Binnie, M; Li, C; Thorner, P; Hui, C-C; Alman, B; Taketo, MM; Quaggin, SE
MLA Citation
Maezawa, Y, Binnie, M, Li, C, Thorner, P, Hui, C-C, Alman, B, Taketo, MM, and Quaggin, SE. "A new Cre driver mouse line, Tcf21/Pod1-Cre, targets metanephric mesenchyme." PLoS ONE 7.7 (2012).
PMID
22792366
Source
scival
Published In
PloS one
Volume
7
Issue
7
Publish Date
2012
DOI
10.1371/journal.pone.0040547

T-lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair

While it is well known that the presence of lymphocytes and cytokines are important for fracture healing, the exact role of the various cytokines expressed by cells of the immune system on osteoblast biology remains unclear. To study the role of inflammatory cytokines in fracture repair, we studied tibial bone healing in wild-type and Rag1-/- mice. Histological analysis, μCT stereology, biomechanical testing, calcein staining and quantitative RNA gene expression studies were performed on healing tibial fractures. These data provide support for Rag1-/- mice as a model of impaired fracture healing compared to wild-type. Moreover, the pro-inflammatory cytokine, IL-17F, was found to be a key mediator in the cellular response of the immune system in osteogenesis. In vitro studies showed that IL-17F alone stimulated osteoblast maturation. We propose a model in which the Th17 subset of T-lymphocytes produces IL-17F to stimulate bone healing. This is a pivotal link in advancing our current understanding of the molecular and cellular basis of fracture healing, which in turn may aid in optimizing fracture management and in the treatment of impaired bone healing. © 2012 Nam et al.

Authors
Nam, D; Mau, E; Wang, Y; Wright, D; Silkstone, D; Whetstone, H; Whyne, C; Alman, B
MLA Citation
Nam, D, Mau, E, Wang, Y, Wright, D, Silkstone, D, Whetstone, H, Whyne, C, and Alman, B. "T-lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair." PLoS ONE 7.6 (2012).
PMID
22768215
Source
scival
Published In
PloS one
Volume
7
Issue
6
Publish Date
2012
DOI
10.1371/journal.pone.0040044

Orthopaedic Boot Camp II: Examining the retention rates of an intensive surgical skills course

Background: We examined retention rates for basic surgical skills taught through a 1-month intensive laboratory boot camp-style course at the onset of residency. Methods: We present data from 3 groups, each composed of 6 residents. The first group consisted of residents from a new competency-based curriculum (CBC). They started residency training with the Toronto Orthopaedic Boot Camp course. The other 2 groups were junior (JR) and senior (SR) residents from a traditional program whose residency training included no such course. Performance on targeted technical skills was tested using an objective structured assessment of technical skills examination 7 months after the onset of training for the CBC and JR groups and at least 43 months after the onset of training for the SR group. Results: The mean global rating scale score for the CBC group immediately after the skills course was 4.3, which was maintained 6 months later. There were no significant performance differences between the CBC and SR groups. Both the CBC and SR groups performed significantly better than the JR group (mean global rating scale 3.7; F[2, 15] = 12.269, P <.001). Conclusion: We conclude that a surgical skills course at the onset of residency is an effective mechanism for teaching targeted technical skills and that skills taught in this manner can have excellent retention rates. Furthermore, an early focus on technical skills allows junior residents to perform at the same level as senior residents for certain tasks and may privilege later learning. © 2012 Mosby, Inc. All rights reserved.

Authors
Sonnadara, RR; Garbedian, S; Safir, O; Nousiainen, M; Alman, B; Ferguson, P; Kraemer, W; Reznick, R
MLA Citation
Sonnadara, RR, Garbedian, S, Safir, O, Nousiainen, M, Alman, B, Ferguson, P, Kraemer, W, and Reznick, R. "Orthopaedic Boot Camp II: Examining the retention rates of an intensive surgical skills course." Surgery (United States) 151.6 (2012): 803-807.
PMID
22652121
Source
scival
Published In
Surgery
Volume
151
Issue
6
Publish Date
2012
Start Page
803
End Page
807
DOI
10.1016/j.surg.2012.03.017

The Canadian experience with long term deflazacort treatment in Duchenne muscular dystrophy

Deflazacort is the most commonly prescribed corticosteroid for the treatment of Duchenne muscular dystrophy in Canada. We review the long term experience with deflazacort treatment at two centers in Canada; Montreal and Toronto. Deflazacort has benefitted both cohorts by prolonged ambulation, preserved cardiac and respiratory function, less scoliosis and improved survival. Common side effects in both cohorts include weight gain, decreased height and cataract formation. The Canadian experience supports the use of deflazacort in treating boys with Duchenne muscular dystrophy.

Authors
McAdam, LC; Mayo, AL; Alman, BA; Biggar, WD
MLA Citation
McAdam, LC, Mayo, AL, Alman, BA, and Biggar, WD. "The Canadian experience with long term deflazacort treatment in Duchenne muscular dystrophy." Acta Myologica 31.MAY (2012): 16-20.
Source
scival
Published In
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases
Volume
31
Issue
MAY
Publish Date
2012
Start Page
16
End Page
20

The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity.

Vascularized composite allotransplantation as a viable reconstructive option is gaining recognition and new cases are being reported with increasing frequency including hand, face and laryngeal transplantation. However, only one successful complete lower limb transplantation has been reported to date, in which a functioning limb from one ischiopagus twin with a lethal cardiac anomaly was transplanted to the other. Six years later, the patient is mobilizing well and engaging in sporting activities with her peers in a mainstream school. Clinical evaluation of motor and sensory modalities demonstrated a good functional result. Quality of life was assessed using the short form-36 health survey and lower extremity functional scale disclosing a high level of social and physical capacity. Functional magnetic resonance imaging was performed and showed cortical integration of the limb; the implications of cortical plasticity and vascularized composite allotransplantation for the correction of congenital limb anomalies are presented.

Authors
Fattah, A; Cypel, T; Donner, EJ; Wang, F; Alman, BA; Zuker, RM
MLA Citation
Fattah, A, Cypel, T, Donner, EJ, Wang, F, Alman, BA, and Zuker, RM. "The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity." Am J Transplant 11.12 (December 2011): 2762-2767.
PMID
21991888
Source
pubmed
Published In
American Journal of Transplantation
Volume
11
Issue
12
Publish Date
2011
Start Page
2762
End Page
2767
DOI
10.1111/j.1600-6143.2011.03782.x

Heal thyself: using endogenous regeneration to repair bone.

Bone has the capacity to repair itself after an injury, and this occurs in normal fracture repair. This reparative process can be harnessed to regenerate segments of bone using distraction osteogenesis, in which the healing bone is slowly stretched. The use of animal models is identifying the important sources of cells for this endogenous bone regeneration, signaling molecules that regulate this reparative process, and the environmental cues important for success bone regeneration. A more complete understanding of the cells and pathways involved in this process can be applied to improve the outcome of distraction osteogenesis and to the development of methods to enhance endogenous bone regeneration.

Authors
Alman, BA; Kelley, SP; Nam, D
MLA Citation
Alman, BA, Kelley, SP, and Nam, D. "Heal thyself: using endogenous regeneration to repair bone." Tissue Eng Part B Rev 17.6 (December 2011): 431-436. (Review)
PMID
21682602
Source
pubmed
Published In
Tissue Engineering, Part B, Reviews
Volume
17
Issue
6
Publish Date
2011
Start Page
431
End Page
436
DOI
10.1089/ten.TEB.2011.0189

Osteoid osteoma and osteoblastoma.

Osteoid osteoma and osteoblastoma are commonly seen benign osteogenic bone neoplasms. Both tumors are typically seen in the second decade of life, with a notable predilection in males. Histologically, these tumors resemble each other, with characteristically increased osteoid tissue formation surrounded by vascular fibrous stroma and perilesional sclerosis. However, osteoblastomas are larger than osteoid osteomas, and they exhibit greater osteoid production and vascularity. Clinically, osteoid osteoma most commonly occurs in the long bones (eg, femur, tibia). The lesions cause night pain that is relieved with nonsteroidal anti-inflammatory drugs (NSAIDs). Osteoblastoma is most frequently located in the axial skeleton, and the pain is usually not worse at night and is less likely to be relieved with NSAIDs. Osteoblastoma can be locally aggressive; osteoid osteoma lacks growth potential. Osteoid osteoma may be managed nonsurgically with NSAIDs. When surgery is required, minimally invasive methods (eg, CT-guided excision, radiofrequency ablation) are preferred. Osteoblastoma has a higher rate of recurrence than does osteoid osteoma, and patients must be treated surgically with intralesional curettage or en bloc resection.

Authors
Atesok, KI; Alman, BA; Schemitsch, EH; Peyser, A; Mankin, H
MLA Citation
Atesok, KI, Alman, BA, Schemitsch, EH, Peyser, A, and Mankin, H. "Osteoid osteoma and osteoblastoma." J Am Acad Orthop Surg 19.11 (November 2011): 678-689. (Review)
PMID
22052644
Source
pubmed
Published In
The Journal of the American Academy of Orthopaedic Surgeons
Volume
19
Issue
11
Publish Date
2011
Start Page
678
End Page
689

Aggressive Fibromatosis (Desmoid Tumor) Is Derived from Mesenchymal Progenitor Cells (vol 70, pg 7690, 2010)

Authors
Wu, C; Amini-Nik, S; Nadesan, P; Stanford, WL; Alman, BA
MLA Citation
Wu, C, Amini-Nik, S, Nadesan, P, Stanford, WL, and Alman, BA. "Aggressive Fibromatosis (Desmoid Tumor) Is Derived from Mesenchymal Progenitor Cells (vol 70, pg 7690, 2010)." CANCER RESEARCH 71.18 (September 15, 2011): 6084-6084.
Source
wos-lite
Published In
Cancer Research
Volume
71
Issue
18
Publish Date
2011
Start Page
6084
End Page
6084
DOI
10.1158/0008-5472.CAN-11-2654

Pax7 expressing cells contribute to dermal wound repair, regulating scar size through a β-catenin mediated process.

During skin wound healing, fibroblast-like cells reconstitute the dermal compartment of the repaired skin filling the wound gap. A subset of these cells are transcriptionally active for β-catenin/T-cell factor (TCF) signaling during the proliferative phase of the repair process, and β-catenin levels control the size of the scar that ultimately forms by regulating the number of dermal fibroblasts. Here, we performed cell lineage studies to reveal a source of the dermal cells in which β-catenin signaling is activated during wound repair. Using a reporter mouse, we found that cells in the early wound in which TCF-dependent transcription is activated express genes involved in muscle development. Using mice in which cells express Pax7 (muscle progenitors) or Mck (differentiated myocytes) are permanently labeled, we showed that one quarter of dermal cells in the healing wound are Pax7 expressing progeny, but none are Mck progeny. Removing one allele of β-catenin in Pax7 expressing progeny resulted in a significantly smaller scar size with fewer Pax7 expressing progeny cell contributing to wound repair. During wound healing, β-catenin activation causes muscle satellite cells to adopt a fibrotic phenotype and this is a source of dermal cells in the repair process.

Authors
Amini-Nik, S; Glancy, D; Boimer, C; Whetstone, H; Keller, C; Alman, BA
MLA Citation
Amini-Nik, S, Glancy, D, Boimer, C, Whetstone, H, Keller, C, and Alman, BA. "Pax7 expressing cells contribute to dermal wound repair, regulating scar size through a β-catenin mediated process." Stem Cells 29.9 (September 2011): 1371-1379.
PMID
21739529
Source
pubmed
Published In
Stem Cells
Volume
29
Issue
9
Publish Date
2011
Start Page
1371
End Page
1379
DOI
10.1002/stem.688

Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu.

Proper regulation of Indian hedgehog (Ihh) signaling is vital for chondrocyte proliferation and differentiation in the growth plate. Its dysregulation causes skeletal dysplasia, osteoarthritis or cartilaginous neoplasia. Here, we show that Suppressor of fused (Sufu) and Kif7 are essential regulators of Ihh signaling. While Sufu acts as a negative regulator of Gli transcription factors, Kif7 functions both positively and negatively in chondrocytes. Kif7 plays a role in the turnover of Sufu and the exclusion of Sufu-Gli complexes from the primary cilium. Importantly, halving the dose of Sufu restores normal hedgehog pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory activity of Sufu. Furthermore, Kif7 also inhibits Gli transcriptional activity in the chondrocytes when Sufu function is absent. Therefore, Kif7 regulates the activity of Gli transcription factors through both Sufu-dependent and -independent mechanisms.

Authors
Hsu, S-HC; Zhang, X; Yu, C; Li, ZJ; Wunder, JS; Hui, C-C; Alman, BA
MLA Citation
Hsu, S-HC, Zhang, X, Yu, C, Li, ZJ, Wunder, JS, Hui, C-C, and Alman, BA. "Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu." Development 138.17 (September 2011): 3791-3801.
PMID
21795282
Source
pubmed
Published In
Development (Cambridge)
Volume
138
Issue
17
Publish Date
2011
Start Page
3791
End Page
3801
DOI
10.1242/dev.069492

Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing.

β-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate β-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating β-catenin and found an increase in β-catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3β-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased β-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of β-catenin signaling. Because fibronectin is a transcriptional target of β-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.

Authors
Bielefeld, KA; Amini-Nik, S; Whetstone, H; Poon, R; Youn, A; Wang, J; Alman, BA
MLA Citation
Bielefeld, KA, Amini-Nik, S, Whetstone, H, Poon, R, Youn, A, Wang, J, and Alman, BA. "Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing." J Biol Chem 286.31 (August 5, 2011): 27687-27697.
PMID
21652705
Source
pubmed
Published In
The Journal of biological chemistry
Volume
286
Issue
31
Publish Date
2011
Start Page
27687
End Page
27697
DOI
10.1074/jbc.M111.261677

Don't hedge your bets: hedgehog signaling as a central mediator of endochondral bone development and cartilage diseases.

Cell differentiation and patterning are vital processes in the development of the appendicular skeleton. The hedgehog (Hh) signaling pathway plays a central role in regulating the anterior-posterior axis of the distal limb as well as the length of endochondral bones. Ligand-induced Hh signaling inhibits the processing of the Gli transcription factors from activator to repressor isoforms. In the growth plate, Indian hedgehog inhibits Gli processing, resulting in accumulation of Gli activators that induce chondrocyte maturation and hypertrophic differentiation. Parathyroid hormone-like hormone promote and Gli processing to repressor forms, thus regulating the rate of hypertrophic differentiation. In cartilage diseases such as osteoarthritis and cartilage tumors, there is a recapitulation of developmental processes that involve increased Hh signaling. Studies have shown that pharmacological inhibitors of Hh signaling can attenuate the progression osteoarthritis and cartilage tumor growth. Thus, Hh blockade can serve as a potential therapy for the treatment of various cartilage diseases.

Authors
Rockel, JS; Alman, BA
MLA Citation
Rockel, JS, and Alman, BA. "Don't hedge your bets: hedgehog signaling as a central mediator of endochondral bone development and cartilage diseases." J Orthop Res 29.6 (June 2011): 810-815.
PMID
21308758
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
29
Issue
6
Publish Date
2011
Start Page
810
End Page
815
DOI
10.1002/jor.21372

Development of a mouse model of Adynamic Bone Disease (ABD)

Authors
Ng, AH; Alman, BA; Grynpas, MD
MLA Citation
Ng, AH, Alman, BA, and Grynpas, MD. "Development of a mouse model of Adynamic Bone Disease (ABD)." May 7, 2011.
Source
wos-lite
Published In
BONE
Volume
48
Publish Date
2011
Start Page
S174
End Page
S174
DOI
10.1016/j.bone.2011.03.398

Testosterone regulates cell proliferation in aggressive fibromatosis (desmoid tumour).

BACKGROUND: Aggressive fibromatosis (desmoid tumour) is a locally invasive tumour caused by mutations resulting in β-catenin protein stabilisation. Apc1638N mice are predisposed to developing aggressive fibromatosis tumours, and male mice develop greater numbers of tumours than female mice, suggesting a role for androgens in this tumour type. METHODS: Human aggressive fibromatosis tumours were examined for the expression of the androgen receptor, and primary human tumour cell cultures were treated with testosterone. Orchidectomised Apc1638N mice were investigated for the development of tumours, and were treated with testosterone to study the effect of tumour formation and the level of β-catenin. RESULTS: Androgen receptors are universally expressed in human aggressive fibromatosis tumours. Testosterone increased the proliferation rate and β-catenin protein level in a dose-dependent manner in human aggressive fibromatosis tumours. Orchiectomy reduced the number and size of tumours that formed in male Apc1638N mice to a similar level as observed in female mice. Testosterone treatment increased the number of tumours that formed in orchidectomised male mice, and resulted in a marked increase in β-catenin protein levels. CONCLUSION: Testosterone regulates β-catenin protein level and proliferation rate in this mesenchymal tumour. This work identifies the therapeutic use of testosterone blockade in aggressive fibromatosis as an area for further investigation.

Authors
Hong, H; Nadesan, P; Poon, R; Alman, BA
MLA Citation
Hong, H, Nadesan, P, Poon, R, and Alman, BA. "Testosterone regulates cell proliferation in aggressive fibromatosis (desmoid tumour)." Br J Cancer 104.9 (April 26, 2011): 1452-1458.
PMID
21468052
Source
pubmed
Published In
British Journal of Cancer
Volume
104
Issue
9
Publish Date
2011
Start Page
1452
End Page
1458
DOI
10.1038/bjc.2011.107

Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids.

Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression.

Authors
Robanus-Maandag, E; Bosch, C; Amini-Nik, S; Knijnenburg, J; Szuhai, K; Cervera, P; Poon, R; Eccles, D; Radice, P; Giovannini, M; Alman, BA; Tejpar, S; Devilee, P; Fodde, R
MLA Citation
Robanus-Maandag, E, Bosch, C, Amini-Nik, S, Knijnenburg, J, Szuhai, K, Cervera, P, Poon, R, Eccles, D, Radice, P, Giovannini, M, Alman, BA, Tejpar, S, Devilee, P, and Fodde, R. "Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids." PLoS One 6.9 (2011): e24354-.
PMID
21931686
Source
pubmed
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
Start Page
e24354
DOI
10.1371/journal.pone.0024354

Orthopedic boot camp: Examining the effectiveness of an intensive surgical skills course

Background: Changes in health care across the globe have had a profound impact on the number of hands-on surgical training opportunities that are available to residents. In the current study, we examine whether an intensive laboratory-based skills course at the start of orthopedic surgical training is an effective mechanism for teaching core technical skills. Methods: First-year residents were divided into 3 groups (on-service, n = 8; off-service, n = 8; and a new, competency-based program that has as a major element of the curriculum a focused, intensive skills laboratory-based experience, n = 6). Baseline surgical skills were assessed prior to commencing training. The intensive skills laboratory group was then given an intensive surgical skills course, whereas the other 2 groups embarked on traditional residency. After the surgical skills course, all the residents were assessed for core surgical skills using an objective structured assessment of technical skills (OSATS) procedure. Results: Pretraining scores revealed no differences between the groups of residents using both checklist (F[2,19] = 0.852, P = .442) and global rating scores (F[2,19] = 0.704, P = .507). Post-training scores revealed a significant difference, with residents from the intensive skills laboratory group performing better on both the checklists (on-service = 78.9, off-service = 78.6, intensive skills laboratory = 92.3; F[2,19] = 6.914, P < .01) and global rating scores (on-service = 3.4, off-service = 3.4, intensive skills laboratory = 4.3; F[2,19] = 5.722, P < .01), than the other groups who showed no differences between them. Conclusion: The intensive skills course used in this study was highly effective at teaching and developing targeted surgical skills in first-year orthopedic residents. We predict that allowing residents to acquire key technical skills at the start of their training will enhance learning opportunities at later stages of training. © 2011 Mosby, Inc. All rights reserved.

Authors
Sonnadara, RR; Vliet, AV; Safir, O; Alman, B; Ferguson, P; Kraemer, W; Reznick, R
MLA Citation
Sonnadara, RR, Vliet, AV, Safir, O, Alman, B, Ferguson, P, Kraemer, W, and Reznick, R. "Orthopedic boot camp: Examining the effectiveness of an intensive surgical skills course." Surgery 149.6 (2011): 745-749.
PMID
21236456
Source
scival
Published In
Surgery
Volume
149
Issue
6
Publish Date
2011
Start Page
745
End Page
749
DOI
10.1016/j.surg.2010.11.011

Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells.

The cellular origins from which most tumors arise are poorly defined, especially in mesenchymal neoplasms. Aggressive fibromatosis, also known as desmoid tumor, is a locally invasive soft tissue tumor that has mesenchymal characteristics. We found that aggressive fibromatosis tumors express genes and cell surface markers characteristic of mesenchymal stem cells (MSC). In mice that are genetically predisposed to develop aggressive fibromatosis tumors (Apc(wt/1638N)), we found that the number of tumors formed was proportional to the number of MSCs present. Sca-1(-/-) mice, which develop fewer MSCs, were crossed with Apc(wt/1638N) mice. Doubly mutant mice deficient in Sca-1 developed substantially fewer aggressive fibromatosis tumors than wild-type (WT) littermates, but Sca-1 deficiency had no effect on the formation of epithelial-derived intestinal polyps. MSCs isolated from Apc(wt/1638N) mice (or mice expressing a stabilized form of β-catenin) induced aberrant cellular growth reminiscent of aggressive fibromatosis tumors after engraftment to immunocompromised mice, but WT cells and mature fibroblasts from the same animals did not. Taken together, our findings indicate that aggressive fibromatosis is derived from MSCs, and that β-catenin supports tumorigenesis by maintaining mesenchymal progenitor cells in a less differentiated state. Protecting this progenitor cell population might prevent tumor formation in patients harboring a germline APC mutation, where fibromatosis is currently the leading cause of mortality.

Authors
Wu, C; Amini-Nik, S; Nadesan, P; Stanford, WL; Alman, BA
MLA Citation
Wu, C, Amini-Nik, S, Nadesan, P, Stanford, WL, and Alman, BA. "Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells." Cancer Res 70.19 (October 1, 2010): 7690-7698.
PMID
20841474
Source
pubmed
Published In
Cancer Research
Volume
70
Issue
19
Publish Date
2010
Start Page
7690
End Page
7698
DOI
10.1158/0008-5472.CAN-10-1656

Ultrafast mid-IR laser scalpel: protein signals of the fundamental limits to minimally invasive surgery.

Lasers have in principle the capability to cut at the level of a single cell, the fundamental limit to minimally invasive procedures and restructuring biological tissues. To date, this limit has not been achieved due to collateral damage on the macroscale that arises from thermal and shock wave induced collateral damage of surrounding tissue. Here, we report on a novel concept using a specifically designed Picosecond IR Laser (PIRL) that selectively energizes water molecules in the tissue to drive ablation or cutting process faster than thermal exchange of energy and shock wave propagation, without plasma formation or ionizing radiation effects. The targeted laser process imparts the least amount of energy in the remaining tissue without any of the deleterious photochemical or photothermal effects that accompanies other laser wavelengths and pulse parameters. Full thickness incisional and excisional wounds were generated in CD1 mice using the Picosecond IR Laser, a conventional surgical laser (DELight Er:YAG) or mechanical surgical tools. Transmission and scanning electron microscopy showed that the PIRL laser produced minimal tissue ablation with less damage of surrounding tissues than wounds formed using the other modalities. The width of scars formed by wounds made by the PIRL laser were half that of the scars produced using either a conventional surgical laser or a scalpel. Aniline blue staining showed higher levels of collagen in the early stage of the wounds produced using the PIRL laser, suggesting that these wounds mature faster. There were more viable cells extracted from skin using the PIRL laser, suggesting less cellular damage. β-catenin and TGF-β signalling, which are activated during the proliferative phase of wound healing, and whose level of activation correlates with the size of wounds was lower in wounds generated by the PIRL system. Wounds created with the PIRL systsem also showed a lower rate of cell proliferation. Direct comparison of wound healing responses to a conventional surgical laser, and standard mechanical instruments shows far less damage and near absence of scar formation by using PIRL laser. This new laser source appears to have achieved the long held promise of lasers in minimally invasive surgery.

Authors
Amini-Nik, S; Kraemer, D; Cowan, ML; Gunaratne, K; Nadesan, P; Alman, BA; Miller, RJD
MLA Citation
Amini-Nik, S, Kraemer, D, Cowan, ML, Gunaratne, K, Nadesan, P, Alman, BA, and Miller, RJD. "Ultrafast mid-IR laser scalpel: protein signals of the fundamental limits to minimally invasive surgery. (Published online)" PLoS One 5.9 (September 28, 2010).
PMID
20927391
Source
pubmed
Published In
PloS one
Volume
5
Issue
9
Publish Date
2010
DOI
10.1371/journal.pone.0013053

Cartilage tumours and bone development: molecular pathology and possible therapeutic targets.

As a group, cartilage tumours are the most common primary bone lesions. They range from benign lesions, such as enchondromas and osteochondromas, to malignant chondrosarcoma. The benign lesions result from the deregulation of the hedgehog signalling pathway, which is involved in normal bone development. These lesions can be the precursors of malignant chondrosarcomas, which are notoriously resistant to conventional chemotherapy and radiotherapy. Cytogenetic studies and mouse models are beginning to identify genes and signalling pathways that have roles in tumour progression, such as hedgehog, p53, insulin-like growth factor, cyclin-dependent kinase 4, hypoxia-inducible factor, matrix metalloproteinases, SRC and AKT, suggesting potential new therapeutic approaches.

Authors
Bovée, JVMG; Hogendoorn, PCW; Wunder, JS; Alman, BA
MLA Citation
Bovée, JVMG, Hogendoorn, PCW, Wunder, JS, and Alman, BA. "Cartilage tumours and bone development: molecular pathology and possible therapeutic targets." Nat Rev Cancer 10.7 (July 2010): 481-488. (Review)
PMID
20535132
Source
pubmed
Published In
Nature Reviews Cancer
Volume
10
Issue
7
Publish Date
2010
Start Page
481
End Page
488
DOI
10.1038/nrc2869

Pathogenesis of radiation-induced capsular contracture in tissue expander and implant breast reconstruction.

BACKGROUND: Capsular contracture is the main complication in postmastectomy tissue expander and implant breast reconstruction in patients requiring radiotherapy. There is evidence that the wingless signaling pathway plays a central role in the pathogenesis of fibroproliferation in fibromatosis and hyperplastic skin wounds, involving multiple linked events leading to up-regulation of target genes and fibroproliferation. Here, the authors tested their hypothesis that the wingless signaling pathway may also regulate radiotherapy-induced fibroproliferation in capsular tissue around expanders/implants in breast reconstruction. METHODS: Biopsies of the periprosthetic capsule were obtained from patients undergoing bilateral expander breast reconstruction in which one side was radiated and the other side was not radiated. Capsular biopsies were snap-frozen and stored at -80 degrees C for Western blot assays to determine protein content of phospho-glycogen-synthase-kinase-3beta (phospho-GSK-3beta), total GSK-3beta, beta-catenin, cyclooxygenase-2 (COX-2), and collagen types I and III (n = three to five patients), normalized to beta-actin. Immunostaining for beta-catenin in radiated and nonradiated capsular tissue was also performed. Slides were scanned and analyzed using Zeiss Mirax Scan. RESULTS: The following protein content levels were significantly (p < 0.01) increased in radiated capsule compared with nonradiated capsule: phospho-GSK-3beta (6.7-fold), total GSK-3beta (3.0-fold), beta-catenin (2.3-fold), COX-2 (2.8-fold), and collagen type I (1.6-fold) and type III (1.8-fold). Immunohistochemical staining demonstrated increased fibroblast cytosolic beta-catenin staining and evidence of beta-catenin nuclear translocation in radiated compared with nonradiated capsular tissue. CONCLUSION: Results from this study highlight the importance of the wingless signaling pathway in the pathogenesis of radiation-induced fibroproliferation associated with capsular contracture in expander/implant breast reconstruction.

Authors
Lipa, JE; Qiu, W; Huang, N; Alman, BA; Pang, CY
MLA Citation
Lipa, JE, Qiu, W, Huang, N, Alman, BA, and Pang, CY. "Pathogenesis of radiation-induced capsular contracture in tissue expander and implant breast reconstruction." Plast Reconstr Surg 125.2 (February 2010): 437-445.
PMID
20124829
Source
pubmed
Published In
Plastic and Reconstructive Surgery
Volume
125
Issue
2
Publish Date
2010
Start Page
437
End Page
445
DOI
10.1097/PRS.0b013e3181c82d05

Overview and comparison of idiopathic, neuromuscular, and congenital forms of scoliosis

© Springer Science+Business Media, LLC 2010. All rights reserved.Scoliosis is really a physical finding, a lateral curvature of the spine. There are a number of potential causes, not all of which are related to a primary spinal deformity. For instance, if a patient has one leg longer than another, they will display a curved spine; otherwise their trunk would leave the pelvis at an angle, causing the individual to always look like they are leaning to one side. In a similar way, if an individual leans their back to one side, they will also show a scoliosis on a radiograph.

Authors
Alman, B
MLA Citation
Alman, B. "Overview and comparison of idiopathic, neuromuscular, and congenital forms of scoliosis." (January 1, 2010): 73-79. (Chapter)
Source
scopus
Publish Date
2010
Start Page
73
End Page
79
DOI
10.1007/978-1-4419-1406-4_4

Modulating hedgehog signaling can attenuate the severity of osteoarthritis (vol 15, pg 1421, 2009)

Authors
Lin, AC; Seeto, BL; Bartoszko, JM; Khoury, MA; Whetstone, H; Ho, L; Hsu, C; Ali, AS; Alman, BA
MLA Citation
Lin, AC, Seeto, BL, Bartoszko, JM, Khoury, MA, Whetstone, H, Ho, L, Hsu, C, Ali, AS, and Alman, BA. "Modulating hedgehog signaling can attenuate the severity of osteoarthritis (vol 15, pg 1421, 2009)." NATURE MEDICINE 16.1 (January 2010): 129-129.
Source
wos-lite
Published In
Nature Medicine
Volume
16
Issue
1
Publish Date
2010
Start Page
129
End Page
129
DOI
10.1038/nm0110-129b

A novel fibrotic disorder associated with increased dermal fibroblast proliferation and downregulation of genes of the microfibrillar network

Clinical evaluation of a young woman with subcutaneous fibrotic nodules, progressive distal joint contractures and marfanoid stature revealed a previously unrecognized fibrotic disorder characterized by several unique phenotypic features and some features overlapping with known disorders. Mutational analysis of the FBN1 and FBN2 genes excluded Marfan syndrome and congenital contractural arachnodactyly. MMP2 gene sequence analysis excluded multicentric osteolysis, nodulosis and arthropathy. The lack of mutations within the MAGP2 gene also excluded an MAGP2-associated disorder. In order to establish the mechanistic basis for the severe skin pathology noted in this patient, we performed transcriptional profiling of dermal fibroblasts, and candidate gene expression studies in conjunction with immunocytochemistry and cell-based and functional assays. Data from these experiments have further excluded any previously recognized fibrotic disorder and identified a unique pattern of gene expression in this patient consistent with progressive fibrosis. The pathogenic mechanisms included persistent proliferation of dermal fibroblasts in coexistence with a disarray of the microfibrillar network. Collagen accumulation, moreover, could be linked to extensive crosslinking resulting from increased activities of lysyl oxidases (LOX and LOXL), and lack of remodelling due to deficiencies in collagenolytic matrix metalloproteinases. The disorder may represent a novel syndrome in which transforming growth factor-β1-independent dermal fibrosis, unlike known microfibrillar disorders caused by single gene deficiencies, associates with a disarray of the microfibrillar network. © 2010 British Association of Dermatologists.

Authors
Szauter, KM; Ordas, A; Laxer, RM; Pope, E; Wherrett, D; Alman, B; Mink, M; Boyd, CD; Csiszar, K; Hinek, A
MLA Citation
Szauter, KM, Ordas, A, Laxer, RM, Pope, E, Wherrett, D, Alman, B, Mink, M, Boyd, CD, Csiszar, K, and Hinek, A. "A novel fibrotic disorder associated with increased dermal fibroblast proliferation and downregulation of genes of the microfibrillar network." British Journal of Dermatology 163.5 (2010): 1102-1115.
PMID
20560960
Source
scival
Published In
British Journal of Dermatology
Volume
163
Issue
5
Publish Date
2010
Start Page
1102
End Page
1115
DOI
10.1111/j.1365-2133.2010.09911.x

Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae

Existing nomenclature systems for describing and reporting congenital segmentation defects of the vertebrae (SDV) are confusing, inconsistently applied, and lack molecular genetic advances. Our aim was to develop and assess a new classification system for SDV. A multidisciplinary group of the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) developed a new classification system for SDV, and 5 members group (Group 1) independently classified 10 previously unseen cases using this system. Inter-observer reliability was assessed using kappa, which compares observed agreement with that expected by chance. Seven independent general radiologists unaffiliated with the ICVAS (Group 2) classified the same 10 cases (total, 70 scores) before and after the ICVAS system was explained. We demonstrated the following: Inter-observer reliability for Group 1 yielded a kappa value of 0.21 (95% confidence intervals (CI) 0.052, 0.366, P=0.0046); A consensus diagnosis was established for the 10 cases. For Group 2, before the ICVAS system was explained, 1 of 70 scores (1.4%) agreed with the Group 1 consensus diagnoses; Group 2 offered 12 different diagnoses, but 38 of 70 (54.3%) responses were "Don't Know." After the ICVAS system was explained, 47 of 70 responses (67.1%; 95% CI 55.5, 77.0) agreed with the Group 1 consensus, an improvement of 65.7% (95% CI 52.5, 75.6, P - < 0.00005), with no "Don't Know" responses. Group 2 average reporting times, before and after explanation of the ICVAS system, were 148 and 48 min, respectively. We conclude that the ICVAS radiological classification system was found to be reliable and applicable for 10 SDV phenotypes. © 2010 Wiley-Liss, Inc.

Authors
Offiah, A; Alman, B; Cornier, AS; Giampietro, PF; Tassy, O; Wade, A; Turnpenny, PD
MLA Citation
Offiah, A, Alman, B, Cornier, AS, Giampietro, PF, Tassy, O, Wade, A, and Turnpenny, PD. "Pilot assessment of a radiologic classification system for segmentation defects of the vertebrae." American Journal of Medical Genetics, Part A 152.6 (2010): 1357-1371.
PMID
20503308
Source
scival
Published In
American Journal of Medical Genetics Part A
Volume
152
Issue
6
Publish Date
2010
Start Page
1357
End Page
1371
DOI
10.1002/ajmg.a.33361

Protecting the hedgerow: p53 and hedgehog pathway interactions

A common environment for the Hedgehog (Subfamily: Erinaceinae) is a row of shrubs and trees often used on farms for enclosing or separating fields, called a hedgerow. Maintenance of a continuous shrub border is important for shielding crops from weather damage, but also provides an ideal protective habitat for the hedgehog. Similar to its mammalian counterpart, the Hedgehog (Hh) signalling pathway requires a controlled environment to regulate proper functioning of the cell. When allowed to run wild, constitutive activation of the Hh pathway results in tumorigenesis in different tissues types, including brain, skin and cartilage. With an additional loss of p53 tumor suppressor activity, an increase in tumor incidence, size and metastasis have been observed. p53 has a number of functions that can suppress tumor formation and growth in most, if not all Hh-related cancers, such as the inhibition of cell cycle progression and cell survival. Furthermore, increasing evidence of an interaction between p53 and Hedgehog signalling pathways suggests a critical role for the tumor suppressor activity of p53 in "protecting the hedgerow". © 2010 Landes Bioscience.

Authors
Ho, L; Alman, B
MLA Citation
Ho, L, and Alman, B. "Protecting the hedgerow: p53 and hedgehog pathway interactions." Cell Cycle 9.3 (2010): 506-511.
PMID
20081367
Source
scival
Published In
Cell Cycle
Volume
9
Issue
3
Publish Date
2010
Start Page
506
End Page
511

Genetic Diagnosis of Skeletal Dysplasias

This chapter discusses the molecular genetic diagnosis of skeletal dysplasia. Skeletal dysplasias are mentioned to be a distinct group of disorders in which the skeletal abnormalities are caused by an intrinsic derangement in bone development. Among the large number of these disorders are single gene heritable disorders that are relatively rare. Skeletal dysplasia are broadly classified by the function of the defective gene product disorders into genes that encode for proteins, that regulates the normal developmental processes of growth plate chondrocytes and those that encode the matrix components. The classification of skeletal dysplasias according to the gene product of the causative gene helps to narrow down the dysplasias into limited number of working diagnosis. The mutated genes in skeletal dysplasias encode proteins that play a critical role in the growth plate and understanding the role in growth plate function gives important information into the molecular pathology of skeletal dysplasia. This information make it easy to understand the mutation that causes a particular mutation as well as gives clues to the type of genes that might be mutated to cause a skeletal dysplasia phenotype. © 2010 Elsevier Inc. All rights reserved.

Authors
Alman, B
MLA Citation
Alman, B. "Genetic Diagnosis of Skeletal Dysplasias." Genetic Diagnosis of Endocrine Disorders (2010): 149-154.
Source
scival
Published In
Genetic Diagnosis of Endocrine Disorders
Publish Date
2010
Start Page
149
End Page
154
DOI
10.1016/B978-0-12-374430-2.00013-4

Robert Bruce Salter, C.C., MD, FRCSC. Dec 15, 1924-May 10, 2010

Authors
Alman, B; Wedge, J
MLA Citation
Alman, B, and Wedge, J. "Robert Bruce Salter, C.C., MD, FRCSC. Dec 15, 1924-May 10, 2010." Journal of Children's Orthopaedics (2010): 1-2.
Source
scival
Published In
Journal of Children's Orthopaedics
Publish Date
2010
Start Page
1
End Page
2
DOI
10.1007/s11832-010-0272-8

Modulating hedgehog signaling can attenuate the severity of osteoarthritis.

Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.

Authors
Lin, AC; Seeto, BL; Bartoszko, JM; Khoury, MA; Whetstone, H; Ho, L; Hsu, C; Ali, SA; Alman, BA
MLA Citation
Lin, AC, Seeto, BL, Bartoszko, JM, Khoury, MA, Whetstone, H, Ho, L, Hsu, C, Ali, SA, and Alman, BA. "Modulating hedgehog signaling can attenuate the severity of osteoarthritis." Nat Med 15.12 (December 2009): 1421-1425.
PMID
19915594
Source
pubmed
Published In
Nature Medicine
Volume
15
Issue
12
Publish Date
2009
Start Page
1421
End Page
1425
DOI
10.1038/nm.2055

Multiple hereditary exostosis and hedgehog signaling: implications for novel therapies.

Authors
Alman, BA
MLA Citation
Alman, BA. "Multiple hereditary exostosis and hedgehog signaling: implications for novel therapies." J Bone Joint Surg Am 91 Suppl 4 (July 2009): 63-67.
PMID
19571070
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
91 Suppl 4
Publish Date
2009
Start Page
63
End Page
67
DOI
10.2106/JBJS.I.00301

Beta-catenin and transforming growth factor beta have distinct roles regulating fibroblast cell motility and the induction of collagen lattice contraction.

BACKGROUND: beta-catenin and transforming growth factor beta signaling are activated in fibroblasts during wound healing. Both signaling pathways positively regulate fibroblast proliferation during this reparative process, and the effect of transforming growth factor beta is partially mediated by beta-catenin. Other cellular processes, such as cell motility and the induction of extracellular matrix contraction, also play important roles during wound repair. We examined the function of beta-catenin and its interaction with transforming growth factor beta in cell motility and the induction of collagen lattice contraction. RESULTS: Floating three dimensional collagen lattices seeded with cells expressing conditional null and stabilized beta-catenin alleles, showed a modest negative relationship between beta-catenin level and the degree of lattice contraction. Transforming growth factor beta had a more dramatic effect, positively regulating lattice contraction. In contrast to the situation in the regulation of cell proliferation, this effect of transforming growth factor beta was not mediated by beta-catenin. Treating wild-type cells or primary human fibroblasts with dickkopf-1, which inhibits beta-catenin, or lithium, which stimulates beta-catenin produced similar results. Scratch wound assays and Boyden chamber motility studies using these same cells found that beta-catenin positively regulated cell motility, while transforming growth factor beta had little effect. CONCLUSION: This data demonstrates the complexity of the interaction of various signaling pathways in the regulation of cell behavior during wound repair. Cell motility and the induction of collagen lattice contraction are not always coupled, and are likely regulated by different intracellular mechanisms. There is unlikely to be a single signaling pathway that acts as master regulator of fibroblast behavior in wound repair. beta-catenin plays dominant role regulating cell motility, while transforming growth factor beta plays a dominant role regulating the induction of collagen lattice contraction.

Authors
Poon, R; Nik, SA; Ahn, J; Slade, L; Alman, BA
MLA Citation
Poon, R, Nik, SA, Ahn, J, Slade, L, and Alman, BA. "Beta-catenin and transforming growth factor beta have distinct roles regulating fibroblast cell motility and the induction of collagen lattice contraction. (Published online)" BMC Cell Biol 10 (May 11, 2009): 38-.
PMID
19432963
Source
pubmed
Published In
BMC Cell Biology
Volume
10
Publish Date
2009
Start Page
38
DOI
10.1186/1471-2121-10-38

Beta-catenin mediates soft tissue contracture in clubfoot.

The contracted tissues from clubfeet resemble tissues from other fibroproliferative disorders such as palmar fibromatosis. Beta-catenin-mediated signaling is a crucial pathway controlling the fibroproliferative response in many fibroproliferative disorders. To determine if beta-catenin signaling plays a role in clubfoot, contracted and less contracted tissues from clubfeet were studied using Western analysis to determine the protein level of beta-catenin. Primary cell cultures were established from these tissues, and they were treated with either lithium to increase beta-catenin or Dickkopf-1 to inhibit beta-catenin. RNA was extracted from the cells and analyzed to determine how beta-catenin regulates expression of Type III collagen, an extracellular matrix protein upregulated in contracted clubfoot tissue. There was a more than twofold increase in beta-catenin protein in the contracted tissues. Treatment with either lithium or Dickkopf-1 showed Type III collagen RNA expression positively correlated with the protein level of beta-catenin. These data support the concept that beta-catenin-mediated signaling plays an important role regulating contracture in clubfeet. Because pharmacologic agents are under development to block this signaling pathway, such drugs could be used in cases of severe stiffness to improve range of motion or to decrease the need for radical surgical approaches.

Authors
Poon, R; Li, C; Alman, BA
MLA Citation
Poon, R, Li, C, and Alman, BA. "Beta-catenin mediates soft tissue contracture in clubfoot." Clin Orthop Relat Res 467.5 (May 2009): 1180-1185.
PMID
19169765
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Volume
467
Issue
5
Publish Date
2009
Start Page
1180
End Page
1185
DOI
10.1007/s11999-008-0692-7

Wnt pathway, an essential role in bone regeneration.

Fracture repair is a complex regenerative process initiated in response to injury, resulting in optimal restoration of skeletal function. Although histology characteristics at various phases of fracture repair are clear and well established, much remains to be understood about the process of bone healing, particularly at the molecular signaling level. During the past decade, secreted signaling molecules of the Wnt family have been widely investigated and found to play a central role in controlling embryonic development processes. Wnt signaling pathway also plays a pivotal role in the regulation of bone mass. Recent published data reveal that Wnt signaling pathway is activated during postnatal bone regenerative events, such as ectopic endochondral bone formation and fracture repair. Dysregulation of this pathway greatly inhibits bone formation and healing process. Interestingly, activation of Wnt pathway has potential to improve bone healing, but only utilized after mesenchymal cells have become committed to the osteoblast lineage. These advances suggest an essential role of Wnt pathway in bone regeneration.

Authors
Chen, Y; Alman, BA
MLA Citation
Chen, Y, and Alman, BA. "Wnt pathway, an essential role in bone regeneration." J Cell Biochem 106.3 (February 15, 2009): 353-362. (Review)
PMID
19127541
Source
pubmed
Published In
Journal of Cellular Biochemistry
Volume
106
Issue
3
Publish Date
2009
Start Page
353
End Page
362
DOI
10.1002/jcb.22020

Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans.

Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.

Authors
Giampietro, PF; Dunwoodie, SL; Kusumi, K; Pourquié, O; Tassy, O; Offiah, AC; Cornier, AS; Alman, BA; Blank, RD; Raggio, CL; Glurich, I; Turnpenny, PD
MLA Citation
Giampietro, PF, Dunwoodie, SL, Kusumi, K, Pourquié, O, Tassy, O, Offiah, AC, Cornier, AS, Alman, BA, Blank, RD, Raggio, CL, Glurich, I, and Turnpenny, PD. "Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans." Ann N Y Acad Sci 1151 (January 2009): 38-67. (Review)
PMID
19154516
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1151
Publish Date
2009
Start Page
38
End Page
67
DOI
10.1111/j.1749-6632.2008.03452.x

Beta-catenin is a mediator of the response of fibroblasts to irradiation.

Radiation causes soft tissue complications that include fibrosis and deficient wound healing. beta-Catenin, a key component in the canonical Wnt-signaling pathway, is activated in fibrotic processes and wound repair and, as such, could play a role in mediating cellular responses to irradiation. beta-Catenin can form a transcriptionally active complex with members of the Tcf family. A reporter mouse model, in addition to human cell cultures, was used to demonstrate that ionizing radiation activates beta-catenin-mediated, Tcf-dependent transcription both in vitro and in vivo. Furthermore, radiation activates beta-catenin via a Wnt-mediated mechanism, as in the presence of dickkopf-1, an inhibitor of Wnt receptor activation, beta-catenin levels did not increase after irradiation. Fibroblast cell cultures were derived from mice expressing either null or stabilized beta-catenin alleles. Cells expressing stabilized beta-catenin alleles had a higher proliferation rate and formed more colony-forming units than wild-type or null cells after irradiation. Wound healing was studied in these same mice after irradiation. There was a positive correlation between the tensile strength of the wound, the expression levels of type 1 collagen in the skin, and beta-catenin levels. Mice treated with lithium showed increased beta-catenin levels and increased wound strength. beta-Catenin mediates the effects of ionizing radiation in fibroblasts, and its modulation has the potential to decrease the severity of radiation-induced soft tissue complications.

Authors
Gurung, A; Uddin, F; Hill, RP; Ferguson, PC; Alman, BA
MLA Citation
Gurung, A, Uddin, F, Hill, RP, Ferguson, PC, and Alman, BA. "Beta-catenin is a mediator of the response of fibroblasts to irradiation." Am J Pathol 174.1 (January 2009): 248-255.
PMID
19036807
Source
pubmed
Published In
The American journal of pathology
Volume
174
Issue
1
Publish Date
2009
Start Page
248
End Page
255
DOI
10.2353/ajpath.2009.080576

Erratum: Patched-one or smoothened gene mutations are infrequent in chondrosarcoma (Clinical Orthopaedics and Related Research DOI: 10.1007/s11999-008-0332-2)

Authors
Yan, T; Angelini, M; Alman, BA; Andrulis, IL; Wunder, JS
MLA Citation
Yan, T, Angelini, M, Alman, BA, Andrulis, IL, and Wunder, JS. "Erratum: Patched-one or smoothened gene mutations are infrequent in chondrosarcoma (Clinical Orthopaedics and Related Research DOI: 10.1007/s11999-008-0332-2)." Clinical Orthopaedics and Related Research 467.12 (2009): 3356--.
Source
scival
Published In
Clinical Orthopaedics and Related Research ®
Volume
467
Issue
12
Publish Date
2009
Start Page
3356-
DOI
10.1007/s11999-009-1134-x

Gli2 and p53 Cooperate to Regulate IGFBP-3- Mediated Chondrocyte Apoptosis in the Progression from Benign to Malignant Cartilage Tumors

Clinical evidence suggests that benign cartilage lesions can progress to malignant chondrosarcoma, but the molecular events in this progression are unknown. Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed lesions similar to chondrosarcomas when they were also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and insulin-like growth factor (IGF) signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limb explants with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when they were also deficient for Igf2. IGF signaling-meditated apoptosis regulates the progression to malignant chondrosarcoma. © 2009 Elsevier Inc. All rights reserved.

Authors
Ho, L; Stojanovski, A; Whetstone, H; Wei, QX; Mau, E; Wunder, JS; Alman, B
MLA Citation
Ho, L, Stojanovski, A, Whetstone, H, Wei, QX, Mau, E, Wunder, JS, and Alman, B. "Gli2 and p53 Cooperate to Regulate IGFBP-3- Mediated Chondrocyte Apoptosis in the Progression from Benign to Malignant Cartilage Tumors." Cancer Cell 16.2 (2009): 126-136.
PMID
19647223
Source
scival
Published In
Cancer Cell
Volume
16
Issue
2
Publish Date
2009
Start Page
126
End Page
136
DOI
10.1016/j.ccr.2009.05.013

Skin-derived precursors differentiate into skeletogenic cell types and contribute to bone repair

Skin-derived precursors (SKPs) are multipotent dermal precursors that share similarities with neural crest stem cells and that can give rise to peripheral neural and some mesodermal cell types, such as adipocytes. Here, we have asked whether rodent or human SKPs can generate other mesenchymally derived cell types, with a particular focus on osteocytes and chondrocytes. In culture, rodent and human foreskin-derived SKPs differentiated into alkaline-positive, collagen type-1-positive, mineralizing osteocytes, and into collagen type-II-positive chondrocytes that secreted chondrocyte-specific proteoglycans. Clonal analysis demonstrated that SKPs efficiently generated these skeletogenic cell types, and that they were multipotent with regard to the osteogenic and chondrogenic lineages. To ask if SKPs could generate these same lineages in vivo, genetically tagged, undifferentiated rat SKPs were transplanted into a tibial bone fracture model. Over the ensuing 6 weeks, many of the transplanted cells survived within the bone callus, where they were morphologically and phenotypically similar to the endogenous mesenchymal/osteogenic cells. Moreover, some transplanted cells adopted a mature osteocyte phenotype and integrated into the newly formed bone. Some transplanted cells also differentiated into chondrocytes and into smooth muscle cells and/or pericytes that were associated with blood vessels. Thus, both rodent and human SKPs generate skeletogenic cell types in culture, and the injured bone environment is sufficient to instruct SKPs to differentiate down an osteogenic lineage, in a fashion similar to the endogenous mesenchymal precursors. © Mary Ann Liebert, Inc.

Authors
Lavoie, J-F; Biernaskie, JA; Chen, Y; Bagli, D; Alman, B; Kaplan, DR; Miller, FD
MLA Citation
Lavoie, J-F, Biernaskie, JA, Chen, Y, Bagli, D, Alman, B, Kaplan, DR, and Miller, FD. "Skin-derived precursors differentiate into skeletogenic cell types and contribute to bone repair." Stem Cells and Development 18.6 (2009): 893-905.
PMID
18834279
Source
scival
Published In
Stem Cells and Development
Volume
18
Issue
6
Publish Date
2009
Start Page
893
End Page
905
DOI
10.1089/scd.2008.0260

Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3

We have identified a consanguineous Pakistani family where oligodontia is inherited along with short stature in an autosomal-recessive fashion. Increased bone density was present in the spine and at the base of the skull. Using high-density single-nucleotide polymorphism microarrays for homozygosity mapping, we identified a 28 Mb homozygous stretch shared between affected individuals on chromosome 11q13. Screening selected candidate genes within this region, we identified a homozygous nonsense mutation, Y774X, within LTBP3, the gene for the latent TGF-β binding protein 3, an extracellular matrix protein believed to be required for osteoclast function. © 2009 The American Society of Human Genetics.

Authors
Noor, A; Windpassinger, C; Vitcu, I; Orlic, M; Rafiq, MA; Khalid, M; Malik, MN; Ayub, M; Alman, B; Vincent, JB
MLA Citation
Noor, A, Windpassinger, C, Vitcu, I, Orlic, M, Rafiq, MA, Khalid, M, Malik, MN, Ayub, M, Alman, B, and Vincent, JB. "Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3." American Journal of Human Genetics 84.4 (2009): 519-523.
PMID
19344874
Source
scival
Published In
The American Journal of Human Genetics
Volume
84
Issue
4
Publish Date
2009
Start Page
519
End Page
523
DOI
10.1016/j.ajhg.2009.03.007

Parathyroid hormone-related protein regulates glioma-associated oncogene transcriptional activation: lessons learned from bone development and cartilage neoplasia.

Hedgehog and parathyroid hormone-related protein (PTHrP) signaling play important roles regulating the differentiation of chondrocytes, which form the template for growing bone. By studying the interaction of the pathways in normal and neoplastic growth-plate chondrocytes (from enchondromas, a benign cartilage tumor), an unexpected direct regulation of hedgehog-mediated transcriptional activation by parathyroid hormone-related protein was uncovered. This regulation acts through the processing of the hedgehog-activated transcription factor, glioma-associated oncogene-three (Gli3). When PTHrP activates its receptor, Gli3 is processed to its repressor form though a protein kinase A (PKA) -dependent mechanism. Thus, activation of a G protein-coupled receptor can negatively regulate hedgehog-mediated transcription independent of hedgehog ligand activity, raising intriguing therapeutic possibilities.

Authors
Alman, BA; Wunder, JS
MLA Citation
Alman, BA, and Wunder, JS. "Parathyroid hormone-related protein regulates glioma-associated oncogene transcriptional activation: lessons learned from bone development and cartilage neoplasia." Ann N Y Acad Sci 1144 (November 2008): 36-41. (Review)
PMID
19076361
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1144
Publish Date
2008
Start Page
36
End Page
41
DOI
10.1196/annals.1418.006

Radiation effects and radioprotection in MC3T3-E1 mouse calvarial osteoblastic cells.

BACKGROUND: Little is known about the mechanisms and treatment of radiation-induced inhibition of craniofacial bone growth. In an earlier study, the radioprotector amifostine (WR-2721) administered to rabbits before irradiation radioprotected cultured orbitozygomatic complex periosteal osteoblast-like cells. This study assessed the effects of amifostine and its active metabolite on the radiation survival, function, and phenotype of mouse calvarial osteoblast-like cells in a cell culture model. METHODS: MC3T3-E1 newborn mouse calvarial osteoblast-like cells underwent gamma-radiation (0 to 10 Gy) in the presence or absence of either WR-2721 or WR-1065, its active metabolite (10 to 10 M). The effects of radiation with and without drugs were assessed using endpoints of colony-forming ability, cell viability, alkaline phosphatase activity, and expression of osteoblastic phenotype genes (alkaline phosphatase, collagen type I, osteocalcin, and osteopontin). All experiments were replicated at least in triplicate. RESULTS: Irradiation resulted in a dose-dependent inhibition of clonogenic cell survival. Pretreatment with WR-1065, but not WR-2721, resulted in a significant improvement of osteoblast-like cell survival. Specifically, maximum radioprotection was observed with 10 M WR-1065 at a clinically relevant 2-Gy dose of irradiation. No significant radioprotection was observed at the lower (5 x 10 M) concentration of WR-1065. Furthermore, radiation seemed to suppress the expression of osteoblastic phenotype-related genes in a dose-dependent manner. CONCLUSIONS: This study reveals improved survival after irradiation in osteoblast-like cells treated with WR-1065 in vitro and corroborates previous findings from animal models. Further studies using this agent and similar drugs are important for devising strategies to prevent radiation-induced inhibition of craniofacial bone growth.

Authors
Gevorgyan, A; Sukhu, B; Alman, BA; Bristow, RG; Pang, CY; Forrest, CR
MLA Citation
Gevorgyan, A, Sukhu, B, Alman, BA, Bristow, RG, Pang, CY, and Forrest, CR. "Radiation effects and radioprotection in MC3T3-E1 mouse calvarial osteoblastic cells." Plast Reconstr Surg 122.4 (October 2008): 1025-1035.
PMID
18827633
Source
pubmed
Published In
Plastic and Reconstructive Surgery
Volume
122
Issue
4
Publish Date
2008
Start Page
1025
End Page
1035
DOI
10.1097/PRS.0b013e3181845931

Molecular diagnosis of vertebral segmentation disorders in humans.

BACKGROUND: Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement and functional distress. OBJECTIVE: To provide an overview of the current understanding of vertebral malformations, at both the clinical level and the molecular level, and factors that contribute to their occurrence. METHODS: The literature related to the following was reviewed: recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformations; and complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and non-syndromic congenital vertebral malformations. RESULTS/CONCLUSION: Expert opinions extend to discussion of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.

Authors
Giampietro, PF; Dunwoodie, SL; Kusumi, K; Pourquié, O; Tassy, O; Offiah, AC; Cornier, AS; Alman, BA; Blank, RD; Raggio, CL; Glurich, I; Turnpenny, PD
MLA Citation
Giampietro, PF, Dunwoodie, SL, Kusumi, K, Pourquié, O, Tassy, O, Offiah, AC, Cornier, AS, Alman, BA, Blank, RD, Raggio, CL, Glurich, I, and Turnpenny, PD. "Molecular diagnosis of vertebral segmentation disorders in humans." Expert Opin Med Diagn 2.10 (October 2008): 1107-1121.
PMID
23496422
Source
pubmed
Published In
Expert Opinion on Medical Diagnostics
Volume
2
Issue
10
Publish Date
2008
Start Page
1107
End Page
1121
DOI
10.1517/17530059.2.10.1107

Side population cells in human cancers.

Cancer stem cells (CSCs) are found in multiple tumor types. While the presence of surface markers selectively expressed on CSCs are used to isolate these cells, no marker or pattern of makers are known to prospectively identify CSCs in many tumor types. In such cases exploitation of stem cell characteristics can be used to identify CSCs and one such characteristic is the capacity to extrude dyes such as Hoechst 33342. Cell that exclude this dye are referred to as side population (SP) cells. These cells share characteristics of CSCs, specifically, they are enriched for tumor initiating capacity, they express stem-like genes, and they are resistant to chemotherapeutic drugs. Dye exclusion is a valuable technique as it identifies a unique population of cells with stem-like characteristics.

Authors
Wu, C; Alman, BA
MLA Citation
Wu, C, and Alman, BA. "Side population cells in human cancers." Cancer Lett 268.1 (September 8, 2008): 1-9. (Review)
PMID
18487012
Source
pubmed
Published In
Cancer Letters
Volume
268
Issue
1
Publish Date
2008
Start Page
1
End Page
9
DOI
10.1016/j.canlet.2008.03.048

Patched-one or smoothened gene mutations are infrequent in chondrosarcoma.

Constitutive hedgehog signaling has been implicated in the tumorigenesis of cartilaginous neoplasia; however, a common mutational mechanism remains unknown. Some tumors exhibiting hedgehog pathway activation such as basal cell cancer frequently harbor PATCHED-ONE (PTCH-1) or SMOOTHENED (SMO) gene mutations. We therefore asked whether mutations of the hedgehog receptor genes PTCH-1 or SMO occur in cartilage tumors. Singlestrand conformation polymorphism (SSCP) analysis with subsequent manual sequencing was performed to detect alterations of PTCH-1 and SMO in 46 cartilage tumors. SSCP detected five shifts in the PTCH-1 gene and two shifts in SMO. Direct DNA sequencing revealed the five shifts in PTCH-1 were caused by silent nucleotide alterations. The two SMO shifts were the result of the same missense mutation (783G>A) and occurred in one dedifferentiated chondrosarcoma and a synovial chondromatosis. The patient with chondromatosis also carried this same mutation in the germline. However, this mutation was also identified in leukocyte DNA from three of 127 (2.4%) control subjects without cartilage tumors, suggesting it may represent a rare SMO variant. Constitutive activation of the hedgehog signaling pathway in chondrosarcoma is rarely caused by PTCH-1 or SMO mutations. [corrected]

Authors
Yan, T; Angelini, M; Alman, BA; Andrulis, IL; Wunder, JS
MLA Citation
Yan, T, Angelini, M, Alman, BA, Andrulis, IL, and Wunder, JS. "Patched-one or smoothened gene mutations are infrequent in chondrosarcoma." Clin Orthop Relat Res 466.9 (September 2008): 2184-2189.
PMID
18543049
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Volume
466
Issue
9
Publish Date
2008
Start Page
2184
End Page
2189
DOI
10.1007/s11999-008-0332-2

Beta-catenin in the race to fracture repair: in it to Wnt.

The Wnt/beta-catenin pathway regulates multiple biological events during embryonic development, including bone formation. Fracture repair recapitulates some of the processes of normal bone development, such as the formation of bone from a cartilaginous template, and many cell-signaling pathways that underlie bone development are activated during the repair process. The Wnt/beta-catenin signaling pathway is activated during fracture repair, and dysregulation of this pathway alters the normal bone-healing response. In early pluripotent mesenchymal stem cells, Wnt/beta-catenin signaling needs to be precisely regulated to facilitate the differentiation of osteoblasts; by contrast, beta-catenin is not needed for chondrocyte differentiation. Once mesenchymal stem cells are committed to the osteoblast lineage, activation of Wnt/beta-catenin signaling enhances bone formation. This activity suggests that the Wnt/beta-catenin pathway is a therapeutic target during bone repair. Indeed, treatments that activate Wnt/beta-catenin signaling, such as lithium, increase bone density and also enhance healing.

Authors
Silkstone, D; Hong, H; Alman, BA
MLA Citation
Silkstone, D, Hong, H, and Alman, BA. "Beta-catenin in the race to fracture repair: in it to Wnt." Nat Clin Pract Rheumatol 4.8 (August 2008): 413-419. (Review)
PMID
18560386
Source
pubmed
Published In
Nature Clinical Practice Rheumatology
Volume
4
Issue
8
Publish Date
2008
Start Page
413
End Page
419
DOI
10.1038/ncprheum0838

Allograft airway fibrosis in the pulmonary milieu: a disorder of tissue remodeling.

Obliterative bronchiolitis (OB) is thought to be a form of chronic allograft rejection. However, immunosuppressive therapy is not effective once fibrosis has developed. We hypothesize that disordered tissue remodeling is a mechanism for the pathogenesis of OB. We examined allograft airway fibrosis in an intrapulmonary tracheal transplant model of OB. Allograft airways were completely obliterated at day 21 by fibrotic tissue; however, tissue remodeling continued thereafter, as demonstrated by the change of collagen deposition density, shift from type I to type III collagen, shift from fibroblasts to myofibroblasts and shift of expression profiles and activities of matrix metalloproteinases (MMPs). We then used a broad-spectrum MMP inhibitor, SC080, to attempt to manipulate tissue remodeling. Administration of the MMP inhibitor from day 0 to day 28 reduced airway obliteration, without inhibiting T-cell activation. MMP inhibition from day 14 to day 28 showed similar effects on airway obliteration. MMP inhibition from day 21 to day 35 did not reverse the airway obliteration, but significantly reduced the collagen deposition, type III collagen and myofibroblasts in the lumen. We conclude that tissue remodeling plays a critical role in the development and maintenance of fibrosis after transplantation.

Authors
Sato, M; Liu, M; Anraku, M; Ogura, T; D'Cruz, G; Alman, BA; Waddell, TK; Kim, E; Zhang, L; Keshavjee, S
MLA Citation
Sato, M, Liu, M, Anraku, M, Ogura, T, D'Cruz, G, Alman, BA, Waddell, TK, Kim, E, Zhang, L, and Keshavjee, S. "Allograft airway fibrosis in the pulmonary milieu: a disorder of tissue remodeling." Am J Transplant 8.3 (March 2008): 517-528.
PMID
18294148
Source
pubmed
Published In
American Journal of Transplantation
Volume
8
Issue
3
Publish Date
2008
Start Page
517
End Page
528
DOI
10.1111/j.1600-6143.2007.02106.x

Skeletal dysplasias and the growth plate.

Skeletal dysplasias are disorders in which there is derangement in the growth or shape of the skeleton. Long bone grows from cartilage that persists near the ends until skeletal maturity as the growth plate. Developmental biology work has identified the major regulatory proteins in growth plate chondroyte function. There are hundreds of skeletal dysplasias, and the molecular genetic etiology of many was defined in the past decade and a half. Now that the causative genes for these disorders have been identified, they can be broadly classified by the function of the protein that these genes encode for into disorders caused by extracellular structural proteins, proteins that regulate normal growth plate chondrocyte differentiation and patterning, and enzymes that process these proteins. There are clinical similarities within each group, and the phenotype can be predicted based on the role of the mutated protein in normal growth plate function. As such, this framework to classify the skeletal dysplasias has practical clinical implications.

Authors
Alman, BA
MLA Citation
Alman, BA. "Skeletal dysplasias and the growth plate." Clin Genet 73.1 (January 2008): 24-30. (Review)
PMID
18070126
Source
pubmed
Published In
Clinical Genetics
Volume
73
Issue
1
Publish Date
2008
Start Page
24
End Page
30
DOI
10.1111/j.1399-0004.2007.00933.x

Diagnosis of limb-girdle muscular dystrophy 2A by immunohistochemical techniques

The Western blot technique is currently the standard detection method for suspected limb girdle muscular dystrophy (LGMD) 2A (calpainopathy). This is the first report in the English literature of the successful application of immunohistochemical techniques to support a diagnosis of LGMD 2A. This approach is straightforward and appears to be reasonably specific. We propose that immunohistochemical methods should be re-evaluated for the screening of undiagnosed patients with suspected LGMD 2A. © 2007 Japanese Society of Neuropathology.

Authors
Kolski, HK; Hawkins, C; Zatz, M; Paula, FD; Biggar, D; Alman, B; Vajsar, J
MLA Citation
Kolski, HK, Hawkins, C, Zatz, M, Paula, FD, Biggar, D, Alman, B, and Vajsar, J. "Diagnosis of limb-girdle muscular dystrophy 2A by immunohistochemical techniques." Neuropathology 28.3 (2008): 264-268.
PMID
18031465
Source
scival
Published In
Neuropathology
Volume
28
Issue
3
Publish Date
2008
Start Page
264
End Page
268
DOI
10.1111/j.1440-1789.2007.00871.x

IFN-β signaling positively regulates tumorigenesis in aggressive fibromatosis, potentially by modulating mesenchymal progenitors (Cancer Research (August 1, 2007) 67 (7124-7131))

Authors
Goh, YI; Tjandra, SS; Hsu, C; Goh, YI; Gurung, A; Poon, R; Nadesan, P; Alman, BA
MLA Citation
Goh, YI, Tjandra, SS, Hsu, C, Goh, YI, Gurung, A, Poon, R, Nadesan, P, and Alman, BA. "IFN-β signaling positively regulates tumorigenesis in aggressive fibromatosis, potentially by modulating mesenchymal progenitors (Cancer Research (August 1, 2007) 67 (7124-7131))." Cancer Research 68.3 (2008): 956--.
Source
scival
Published In
Cancer Research
Volume
68
Issue
3
Publish Date
2008
Start Page
956-
DOI
10.1158/0008-5472.CAN-68-3-COR2

Side population cells isolated from mesenchymal neoplasms have tumor initiating potential.

Although many cancers are maintained by tumor-initiating cells, this has not been shown for mesenchymal tumors, in part due to the lack of unique surface markers that identify mesenchymal progenitors. An alternative technique to isolate stem-like cells is to isolate side population (SP) cells based on efflux of Hoechst 33342 dye. We examined 29 mesenchymal tumors ranging from benign to high-grade sarcomas and identified SP cells in all but six samples. There was a positive correlation between the percentage of SP cells and the grade of the tumor. SP cells preferentially formed tumors when grafted into immunodeficient mice, and only cells from tumors that developed from the SP cells had the ability to initiate tumor formation upon serial transplantation. Although SP cells are able to efflux rhodamine dye in addition to Hoechst 33342, we found that the ability to efflux rhodamine dye did not identify a population of cells enriched for tumor-initiating capacity. Here, we identify a subpopulation of cells within a broad range of benign and malignant mesenchymal tumors with tumor-initiating capacity. In addition, our data suggest that the proportion of SP cells could be used as a prognostic factor and that therapeutically targeting this subpopulation of cells could be used to improve patient outcome.

Authors
Wu, C; Wei, Q; Utomo, V; Nadesan, P; Whetstone, H; Kandel, R; Wunder, JS; Alman, BA
MLA Citation
Wu, C, Wei, Q, Utomo, V, Nadesan, P, Whetstone, H, Kandel, R, Wunder, JS, and Alman, BA. "Side population cells isolated from mesenchymal neoplasms have tumor initiating potential." Cancer Res 67.17 (September 1, 2007): 8216-8222.
PMID
17804735
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
17
Publish Date
2007
Start Page
8216
End Page
8222
DOI
10.1158/0008-5472.CAN-07-0999

IFN-{beta} signaling positively regulates tumorigenesis in aggressive fibromatosis, potentially by modulating mesenchymal progenitors.

Aggressive fibromatosis (also called desmoid tumor) is a benign, locally invasive, soft tissue tumor composed of cells with mesenchymal characteristics. These tumors are characterized by increased levels of beta-catenin-mediated T-cell factor (TCF)-dependent transcriptional activation. We found that type 1 IFN signaling is activated in human and murine aggressive fibromatosis tumors and that the expression of associated response genes is regulated by beta-catenin. When mice deficient for the type 1 IFN receptor (Ifnar1-/-) were crossed with mice predisposed to developing aggressive fibromatosis tumors (Apc/Apc1638N), a significant decrease in aggressive fibromatosis tumor formation was observed compared with littermate controls, showing a novel role for type 1 IFN signaling in promoting tumor formation. Type 1 IFN activation inhibits cell proliferation but does not alter cell apoptosis or the level of beta-catenin-mediated TCF-dependent transcriptional activation in aggressive fibromatosis cell cultures. Thus, these changes cannot explain our in vivo results. Intriguingly, Ifnar1-/- mice have smaller numbers of mesenchymal progenitor cells compared with littermate controls, and treatment of aggressive fibromatosis cell cultures with IFN increases the proportion of cells that exclude Hoechst dye and sort to the side population, raising the possibility that type 1 IFN signaling regulates the number of precursor cells present that drive aggressive fibromatosis tumor formation and maintenance. This study identified a novel role for IFN type 1 signaling as a positive regulator of neoplasia and suggests that IFN treatment is a less than optimal therapy for this tumor type.

Authors
Tjandra, SS; Hsu, C; Goh, YI; Gurung, A; Poon, R; Nadesan, P; Alman, BA
MLA Citation
Tjandra, SS, Hsu, C, Goh, YI, Gurung, A, Poon, R, Nadesan, P, and Alman, BA. "IFN-{beta} signaling positively regulates tumorigenesis in aggressive fibromatosis, potentially by modulating mesenchymal progenitors." Cancer Res 67.15 (August 1, 2007): 7124-7131.
PMID
17671179
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
15
Publish Date
2007
Start Page
7124
End Page
7131
DOI
10.1158/0008-5472.CAN-07-0686

CYP3A4/5 and pharmacogenetics in patients with sarcoma - Authors' reply.

Authors
Wunder, JS; Nielsen, TO; Maki, RG; O'sullivan, B; Alman, BA
MLA Citation
Wunder, JS, Nielsen, TO, Maki, RG, O'sullivan, B, and Alman, BA. "CYP3A4/5 and pharmacogenetics in patients with sarcoma - Authors' reply." Lancet Oncol 8.8 (August 2007): 668-669. (Letter)
PMID
17679079
Source
pubmed
Published In
The Lancet Oncology
Volume
8
Issue
8
Publish Date
2007
Start Page
668
End Page
669
DOI
10.1016/S1470-2045(07)70216-4

Opportunities for improving the therapeutic ratio for patients with sarcoma (vol 8, pg 513, 2007)

Authors
Wunder, T; Nielsen, TO; Maki, RG; O'Sullivan, B; Alman, BA
MLA Citation
Wunder, T, Nielsen, TO, Maki, RG, O'Sullivan, B, and Alman, BA. "Opportunities for improving the therapeutic ratio for patients with sarcoma (vol 8, pg 513, 2007)." LANCET ONCOLOGY 8.8 (August 2007): 670-670.
Source
wos-lite
Published In
The Lancet Oncology
Volume
8
Issue
8
Publish Date
2007
Start Page
670
End Page
670

Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing.

BACKGROUND: Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The beta-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of beta-catenin signaling in bone repair. METHODS AND FINDINGS: Western blot analysis showed significant up-regulation of beta-catenin during the bone healing process. Using a beta-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that beta-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/beta-catenin pathway) inhibited beta-catenin signaling and the healing process, suggesting that WNT ligands regulate beta-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized beta-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific beta-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of beta-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated beta-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. CONCLUSIONS: These results demonstrate that beta-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of beta-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, beta-catenin positively regulates osteoblasts. This is a different function for beta-catenin than has previously been reported during development. Activation of beta-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.

Authors
Chen, Y; Whetstone, HC; Lin, AC; Nadesan, P; Wei, Q; Poon, R; Alman, BA
MLA Citation
Chen, Y, Whetstone, HC, Lin, AC, Nadesan, P, Wei, Q, Poon, R, and Alman, BA. "Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing." PLoS Med 4.7 (July 31, 2007): e249-.
PMID
17676991
Source
pubmed
Published In
PLoS medicine
Volume
4
Issue
7
Publish Date
2007
Start Page
e249
DOI
10.1371/journal.pmed.0040249

Opportunities for improving the therapeutic ratio for patients with sarcoma.

Sarcomas are mesenchymal cancers, which, in many cases, have distinctive molecular features. Limb-sparing surgery delivered at specialised sarcoma centres as part of a multidisciplinary approach has become the standard treatment for most patients and usually provides excellent local control. Preoperative treatment with chemotherapy is most common for patients with bone sarcomas. The ideal sequence of surgery and radiation for local management of soft-tissue sarcoma remains controversial on the basis of early versus late treatment complications, although preoperative radiation can provide the best results for improved long-term function. New methods for radiation delivery and tumour sensitisation might provide further improvements. However, metastatic disease is common, and conventional chemotherapy provides for only a narrow therapeutic window outside of a few responsive pathological subtypes. Targeting underlying molecular events in specific sarcomas can provide for dramatic benefits, as has been seen with imatinib treatment for gastrointestinal stromal tumours and dermatofibrosarcoma protuberans. Trials of agents targeting the cell cycle and angiogenesis in soft-tissue sarcomas, and of those targeting osteoclasts in bone sarcomas, are currently underway. Biological data and preclinical studies support trials using inhibitors of hedgehog signalling in chondrosarcoma, inhibitors of wnt/beta-catenin in osteosarcoma and aggressive fibromatosis, and inhibitors of histone deacetylases in synovial sarcoma and Ewing sarcoma. Pharmacogenetic approaches will be needed to identify individual determinants of response and outcome in order to maximise the benefits of targeting specific molecular events and keep side-effects to a minimum. Research in stem-cell biology and nanotechnology holds promise for additional novel treatment options in the future.

Authors
Wunder, JS; Nielsen, TO; Maki, RG; O'Sullivan, B; Alman, BA
MLA Citation
Wunder, JS, Nielsen, TO, Maki, RG, O'Sullivan, B, and Alman, BA. "Opportunities for improving the therapeutic ratio for patients with sarcoma." Lancet Oncol 8.6 (June 2007): 513-524. (Review)
PMID
17540303
Source
pubmed
Published In
The Lancet Oncology
Volume
8
Issue
6
Publish Date
2007
Start Page
513
End Page
524
DOI
10.1016/S1470-2045(07)70169-9

PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms.

Growth plate chondrocytes undergo a tightly regulated process of differentiation, allowing for the longitudinal growth of bones. Although it is known that parathyroid hormone related protein (PTHrP) and Indian hedgehog regulate the differentiation of growth plate chondrocytes, how these pathways interact to regulate chondrocyte development is not fully elucidated. We examined how the interaction between PTHrP and the hedgehog activated transcription factors, Gli2 and Gli3, regulates growth plate chondrocyte differentiation and proliferation. Analysis of fetal limbs showed that Gli2 is a negative regulator and Gli3 a positive regulator of type X collagen expression. Limb explant cultures showed that PTHrP treatment inhibited type X collagen expression and increased chondrocyte proliferation. This effect was substantially enhanced in Gli2-/- limbs, was blocked in Gli3-/- limbs, and was only partially inhibited by hedgehog ligand blockade. PTHrP negatively regulated Gli mediated transcription in cell cultures, and regulated the level of the repressor form of Gli3 in a PKA dependent manner. These results show that PTHrP regulates growth plate chondrocyte proliferation and differentiation in part through the activity of Gli3, suggesting a crucial role for Gli3 in growth plate chondrocyte development.

Authors
Mau, E; Whetstone, H; Yu, C; Hopyan, S; Wunder, JS; Alman, BA
MLA Citation
Mau, E, Whetstone, H, Yu, C, Hopyan, S, Wunder, JS, and Alman, BA. "PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms." Dev Biol 305.1 (May 1, 2007): 28-39.
PMID
17328886
Source
pubmed
Published In
Developmental Biology
Volume
305
Issue
1
Publish Date
2007
Start Page
28
End Page
39
DOI
10.1016/j.ydbio.2007.01.031

Inhibition of notch signaling induces neural differentiation in Ewing sarcoma.

Cells from Ewing sarcoma exhibit cellular features and express markers, suggesting that the tumor is of neuroectodermal origin. Because Notch signaling regulates the differentiation of neuroectodermal cells during development, we examined the role of Notch signaling in Ewing sarcomas. We found that Ewing sarcomas express Notch receptors, ligands, and the Notch target gene HES1. To determine the functional implications of Notch signaling, we expressed tetracycline-regulated constitutively active, dominant-negative (DN), or wild-type Notch-1 receptors in two Ewing sarcoma cell lines, or we treated the cell lines with a gamma-secretase inhibitor. Expression of the constitutively active Notch-1 reduced proliferation and expression of the DN Notch-1 reduced apoptosis in vitro. However, there was only a small difference in the volume of tumors that formed when the cell lines expressing these constructs were implanted in nude mice. Xenograft tumors derived from the cell lines expressing DN Notch-1 exhibited a neural phenotype. Treatment with a gamma-secretase inhibitor caused similar changes as expression of the DN construct. Notch signaling plays a role in cell differentiation, proliferation, and apoptosis in Ewing sarcoma, but its inhibition is only associated with a small change in tumor growth potential.

Authors
Baliko, F; Bright, T; Poon, R; Cohen, B; Egan, SE; Alman, BA
MLA Citation
Baliko, F, Bright, T, Poon, R, Cohen, B, Egan, SE, and Alman, BA. "Inhibition of notch signaling induces neural differentiation in Ewing sarcoma." Am J Pathol 170.5 (May 2007): 1686-1694.
PMID
17456774
Source
pubmed
Published In
The American journal of pathology
Volume
170
Issue
5
Publish Date
2007
Start Page
1686
End Page
1694
DOI
10.2353/ajpath.2007.060971

Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.

BACKGROUND: Neoplasia can be driven by mutations resulting in dysregulation of transcription. In the mesenchymal neoplasm, aggressive fibromatosis, subtractive hybridization identified sterile alpha motif domain 9 (SAMD9) as a substantially down regulated gene in neoplasia. SAMD9 was recently found to be mutated in normophosphatemic familial tumoral calcinosis. In this study, we studied the gene structure and function of SAMD9, and its paralogous gene, SAMD9L, and examined these in a variety of species. RESULTS: SAMD9 is located on human chromosome 7q21.2 with a paralogous gene sterile alpha motif domain 9 like (SAMD9L) in the head-to-tail orientation. Although both genes are present in a variety of species, the orthologue for SAMD9 is lost in the mouse lineage due to a unique genomic rearrangement. Both SAMD9 and SAMD9L are ubiquitously expressed in human tissues. SAMD9 is expressed at a lower level in a variety of neoplasms associated with beta-catenin stabilization, such as aggressive fibromatosis, breast, and colon cancers. SAMD9 and SAMD9L contain an amino-terminal SAM domain, but the remainder of the predicted protein structure does not exhibit substantial homology to other known protein motifs. The putative protein product of SAMD9 localizes to the cytoplasm. In vitro data shows that SAMD9 negatively regulates cell proliferation. Over expression of SAMD9 in the colon cancer cell line, SW480, reduces the volume of tumors formed when transplanted into immune-deficient mice. CONCLUSION: SAMD9 and SAMD9L are a novel family of genes, which play a role regulating cell proliferation and suppressing the neoplastic phenotype. This is the first report as far as we know about a human gene that exists in rat, but is lost in mouse, due to a mouse specific rearrangement, resulting in the loss of the SAMD9 gene.

Authors
Li, CF; MacDonald, JR; Wei, RY; Ray, J; Lau, K; Kandel, C; Koffman, R; Bell, S; Scherer, SW; Alman, BA
MLA Citation
Li, CF, MacDonald, JR, Wei, RY, Ray, J, Lau, K, Kandel, C, Koffman, R, Bell, S, Scherer, SW, and Alman, BA. "Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. (Published online)" BMC Genomics 8 (April 3, 2007): 92-.
PMID
17407603
Source
pubmed
Published In
BMC Genomics
Volume
8
Publish Date
2007
Start Page
92
DOI
10.1186/1471-2164-8-92

Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse

Authors
Li, CF; MacDonald, JR; Wei, RY; Ray, J; Lau, K; Kandel, C; Koffman, R; Bell, S; Scherer, SW; Alman, BA
MLA Citation
Li, CF, MacDonald, JR, Wei, RY, Ray, J, Lau, K, Kandel, C, Koffman, R, Bell, S, Scherer, SW, and Alman, BA. "Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse." BMC GENOMICS 8 (April 3, 2007).
Source
wos-lite
Published In
BMC Genomics
Volume
8
Publish Date
2007
DOI
10.1186/1471-2164-8-94

Developmental biology in orthopaedics. Summary of the 2006 AAOS research symposium.

Authors
Alman, BA; Horton, WA
MLA Citation
Alman, BA, and Horton, WA. "Developmental biology in orthopaedics. Summary of the 2006 AAOS research symposium." J Bone Joint Surg Am 89.3 (March 2007): 668-671.
PMID
17332117
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
89
Issue
3
Publish Date
2007
Start Page
668
End Page
671
DOI
10.2106/JBJS.F.01609

Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation.

Endochondral ossification is recapitulated during bone morphogenetic protein (BMP)-induced ectopic bone formation. Although BMP and beta-catenin have been investigated in bone development and in mesenchymal cells, how they interact in this process is not clear. We implanted recombinant BMP-2 into the muscle of mice to investigate the effect of beta-catenin signaling on BMP-induced in vivo endochondral bone formation. BMP-2 induced expression of several Wnt ligands and their receptors and also activated beta-catenin-mediated T cell factor-dependent transcriptional activity. An adenovirus expressing Dickkopf-1 (Dkk-1, an inhibitor of canonical Wnt pathway) inhibited beta-catenin signaling and endochondral bone formation. Interestingly, Dkk-1 inhibited both chondrogenesis and osteogenesis. Likewise, mice expressing conditional beta-catenin null alleles also displayed an inhibition of BMP-induced chondrogenesis and osteogenesis. This is in contrast to studies of embryonic skeletogenesis, which demonstrate that beta-catenin is required for osteogenesis but is dispensable for chondrogenesis. These findings suggest that embryonic development pathways are not always recapitulated during post-natal regenerative processes, and the biochemical pathways utilized to regulate cell differentiation may be different. During in vivo ectopic bone formation, BMP-2 induces beta-catenin-mediated signaling through Wnt ligands, and beta-catenin is required for both chondrogenesis and osteogenesis.

Authors
Chen, Y; Whetstone, HC; Youn, A; Nadesan, P; Chow, ECY; Lin, AC; Alman, BA
MLA Citation
Chen, Y, Whetstone, HC, Youn, A, Nadesan, P, Chow, ECY, Lin, AC, and Alman, BA. "Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation." J Biol Chem 282.1 (January 5, 2007): 526-533.
PMID
17085452
Source
pubmed
Published In
The Journal of biological chemistry
Volume
282
Issue
1
Publish Date
2007
Start Page
526
End Page
533
DOI
10.1074/jbc.M602700200

An association between the 4G polymorphism in the PAI-1 promoter and the development of aggressive fibromatosis (desmoid tumor) in familial adenomatous polyposis patients.

Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations resulting in beta-catenin mediated transcriptional activation. Plasminogen activator inhibitor-1 (PAI-1) is expressed at a high level in aggressive fibromatosis, and using transgenic mice, we found that PAI-1 plays an important role in aggressive fibromatosis tumor formation. Familial adenomatous polyposis is associated with Adenomatous Polyposis Coli gene mutations resulting in beta-catenin mediated transcriptional activation, yet only some patients develop aggressive fibromatosis. Since PAI-1 expression is influenced by a promoter 4G/5G polymorphism, we investigated the incidence of this polymorphism in familial adenomatous polyposis patients who did and who did not develop aggressive fibromatosis, as well as sporadic aggressive fibromatosis patients. There was a trend towards association of the 4G allele (associated with high PAI-1 expression) with the development of aggressive fibromatosis in familial adenomatous polyposis patients (50% vs. 19%, P = 0.1). In familial adenomatous polyposis patients who did not develop aggressive fibromatosis, there was a significantly lower proportion of patients with a 4G allele compared to the healthy control (19% vs. 51%, P = 0.0286). The lower incidence of 4G polymorphism in the PAI-1 promoter may be preventive against the development of aggressive fibromatosis. This data provides additional evidence supporting an important role for PAI-1 in the pathogenesis of aggressive fibromatosis.

Authors
Li, CF; Wei, RY; Baliko, F; Bapat, B; Alman, BA
MLA Citation
Li, CF, Wei, RY, Baliko, F, Bapat, B, and Alman, BA. "An association between the 4G polymorphism in the PAI-1 promoter and the development of aggressive fibromatosis (desmoid tumor) in familial adenomatous polyposis patients." Fam Cancer 6.1 (2007): 89-95.
PMID
17160433
Source
pubmed
Published In
Familial Cancer
Volume
6
Issue
1
Publish Date
2007
Start Page
89
End Page
95
DOI
10.1007/s10689-006-9109-5

Are surgeons' preferences for instrumentation related to patient outcomes? A randomized clinical trial of two implants for idiopathic scoliosis

Background: Although many techniques for the surgical treatment of scoliosis have been described, we are not aware of any randomized trials that have compared implant systems. The relationship between surgeons' preferences for implants and patient outcomes is unknown. The purpose of the present study was to compare quality of life and curve correction associated with use of the Moss Miami system and the Universal Spine System for spinal fusion in patients with adolescent idiopathic scoliosis. Methods: The present study was a double-blind, randomized clinical trial. All adolescent patients with idiopathic scoliosis who were scheduled for posterior instrumentation and arthrodesis with or without anterior release were screened for eligibility. Patients were randomly allocated to treatment with either the Moss Miami system or the Universal Spine System. The primary outcome measure for this trial was Quality of Life Profile for Spinal Disorders. Results: Of the 129 subjects who were enrolled in the trial, sixty (95%) of sixty-three from the Universal Spine System group and sixty (91%) of sixty-six from the Moss Miami group were included in the final analysis. Two years postoperatively, the total Quality of Life score did not differ by the clinically important value of 5.5 between the two groups (difference, 1.07; 95% confidence interval, -3.67 to 5.82; p = 0.66). The percentage of Cobb angle correction was not significantly different for thoracic curves (55.1% ± 18.3% for the Moss Miami system group, compared with 54.1% ± 18.7% for the Universal Spine System group) (difference, -1%; 95% confidence interval, -7% to 5%; p = 0.77) or lumbar curves (45.4% ± 24.6% for the Moss Miami system group, compared with 41.9% ± 26.8% for the Universal Spine System group) (difference, -4%; 95% confidence interval, -16% to 11%; p = 0.57). Although surgeons were more satisfied with the Universal Spine System (difference, 42%; 95% confidence interval, 29% to 55%; p < 0.0001), satisfaction ratings were not related to any surgical outcomes. Conclusions: The Moss Miami system and the Universal Spine Systems provided similar quality of life and curve correction. Surgeon preference may be an unreliable means of selecting implants from the patient outcomes perspective. Levels of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2007 by The Journal of Bone and Joint Surgery, Incorporated.

Authors
Wright, JG; Donaldson, S; Howard, A; Stephens, D; Alman, B; Hedden, D
MLA Citation
Wright, JG, Donaldson, S, Howard, A, Stephens, D, Alman, B, and Hedden, D. "Are surgeons' preferences for instrumentation related to patient outcomes? A randomized clinical trial of two implants for idiopathic scoliosis." Journal of Bone and Joint Surgery - Series A 89 A.12 (2007): 2684-2693.
PMID
18056501
Source
scival
Published In
The Journal of Bone and Joint Surgery
Volume
89 A
Issue
12
Publish Date
2007
Start Page
2684
End Page
2693
DOI
10.2106/JBJS.F.00720

Scoliosis: Review of diagnosis and treatment

Scoliosis is a spinal deformity consisting of lateral curvature and rotation of the vertebrae. The causes of scoliosis vary and are classified broadly as congenital, neuromuscular, syndrome-related, idiopathic and spinal curvature due to secondary reasons. The majority of scoliosis cases encountered by the general practitioner will be idiopathic. The natural history relates to the etiology and age at presentation, and usually dictates the treatment. However, it is the patient's history, physical examination and radiographs that are critical in the initial evaluation of scoliosis, and in determining which patients need additional considerations. Scoliosis with a primary diagnosis (nonidiopathic) must be recognized by the physician to identify the causes, which may require intervention. Patients with congenital scoliosis must be evaluated for cardiac and renal abnormalities. School screening for scoliosis is controversial and is falling out of favour. The treatment for idiopathic scoliosis is based on age, curve magnitude and risk of progression, and includes observation, orthotic management and surgical correction with fusion. A child should be referred to a specialist if the curve is greater than 10° in a patient younger than 10 years of age, is greater than 20° in a patient 10 years of age or older, has atypical features or is associated with back pain or neurological abnormalities. ©2007 Pulsus Group Inc. All rights reserved.

Authors
Janicki, JA; Alman, B
MLA Citation
Janicki, JA, and Alman, B. "Scoliosis: Review of diagnosis and treatment." Paediatrics and Child Health 12.9 (2007): 771-776.
Source
scival
Published In
Paediatrics and Child Health: the journal of the Canadian Paediatric Society
Volume
12
Issue
9
Publish Date
2007
Start Page
771
End Page
776

Improvement in quality of life following surgery for adolescent idiopathic scoliosis

STUDY DESIGN. We used the Climent Quality of Life for Spinal Deformities Scale prospectively in a nonrandomized prospective comparative cohort of operative versus observational management of adolescent idiopathic scoliosis. OBJECTIVE. To compare the change in disease-specific quality of life associated with operating on adolescents with idiopathic scoliosis, to the change in disease-specific quality of life among observed scoliosis patients with a similar 2-year follow-up period. SUMMARY OF BACKGROUND DATA. The immediate effect of scoliosis surgery on quality of life from a patient perspective has not been properly documented but should play a role in the patient's decision to operate. METHODS. At a single tertiary referral children's hospital spinal clinic, 119 patients undergoing scoliosis surgery and 42 patients undergoing observation only for scoliosis were enrolled in a prospective study, including preoperative and postoperative spine-specific quality of life. Change in quality of life after 2 years of follow-up among operated versus observed patients (adjusted for baseline quality of life) was used to estimate the short-term benefit of scoliosis surgery. RESULTS. The operated group experienced an increase in quality of life of 4.3 points (95% confidence interval, 0.69-7.88) on the 115-point Climent scale. Although statistically significant, this increase was lower than the 5.5-point cutoff we had defined a priori as clinically significant. CONCLUSION. Scoliosis surgery results in a small increase in spine-related quality of life at 2 years. This increase is of questionable clinical significance. Decisions to operate on adolescents with scoliosis should acknowledge modest expectations about short-term gains in quality of life. © 2007 Lippincott Williams & Wilkins, Inc.

Authors
Howard, A; Donaldson, S; Hedden, D; Stephens, D; Alman, B; Wright, J
MLA Citation
Howard, A, Donaldson, S, Hedden, D, Stephens, D, Alman, B, and Wright, J. "Improvement in quality of life following surgery for adolescent idiopathic scoliosis." Spine 32.24 (2007): 2715-2718.
PMID
18007250
Source
scival
Published In
Spine
Volume
32
Issue
24
Publish Date
2007
Start Page
2715
End Page
2718
DOI
10.1097/BRS.0b013e31815a51cd

Does spinal fusion influence quality of life in neuromuscular scoliosis?

STUDY DESIGN. Systematic literature review of articles pertaining to quality of life (QOL) in neuromuscular scoliosis patients that underwent spinal fusion. OBJECTIVE. To determine if QOL is improved by scoliosis surgery in neuromuscular patients. SUMMARY OF BACKGROUND DATA. The primary focus of most prior studies on neuromuscular scoliosis has been on the technical correction of spinal deformities, and not the child's postoperative performance and function in activities of daily living. METHODS. Computer-based English literature search of Google and PubMed databases. RESULTS. A total of 198 publications in the English literature between 1980 and 2006 were identified from a PubMed and Google Scholar search of QOL in neuromuscular scoliosis patients that underwent spinal fusion. CONCLUSION. Spinal fusion improves QOL in CP (Grade C recommendation). Spinal fusion improves QOL in muscular dystrophy (Grade C recommendation). Spinal fusion does not improve QOL in spina bifida (Grade C recommendation). © 2007 Lippincott Williams & Wilkins, Inc.

Authors
Mercado, E; Alman, B; Wright, JG
MLA Citation
Mercado, E, Alman, B, and Wright, JG. "Does spinal fusion influence quality of life in neuromuscular scoliosis?." Spine 32.19 SUPPL. (2007): S120-S125.
PMID
17728678
Source
scival
Published In
Spine
Volume
32
Issue
19 SUPPL.
Publish Date
2007
Start Page
S120
End Page
S125
DOI
10.1097/BRS.0b013e318134eabe

Abnormal vertebral segmentation and the notch signaling pathway in man

Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes - DLL3, MESP2, and LNFG - have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing. © 2007 Wiley-Liss, Inc.

Authors
Turnpenny, PD; Alman, B; Cornier, AS; Giampietro, PF; Offiah, A; Tassy, O; Pourquié, O; Kusumi, K; Dunwoodie, S
MLA Citation
Turnpenny, PD, Alman, B, Cornier, AS, Giampietro, PF, Offiah, A, Tassy, O, Pourquié, O, Kusumi, K, and Dunwoodie, S. "Abnormal vertebral segmentation and the notch signaling pathway in man." Developmental Dynamics 236.6 (2007): 1456-1474.
PMID
17497699
Source
scival
Published In
Developmental Dynamics
Volume
236
Issue
6
Publish Date
2007
Start Page
1456
End Page
1474
DOI
10.1002/dvdy.21182

Surgical decision making in adolescent idiopathic scoliosis

STUDY DESIGN. Cross-sectional survey. OBJECTIVE. The objective of this paper was to assess the reliability of surgeons' decision-making in adolescent idiopathic scoliosis (AIS) based on patient photographs and clinical and radiographic data. SUMMARY OF BACKGROUND DATA. Orthopedic spine surgeons rated severity of deformity as the most important surgical consideration in AIS. However, studies have shown that surgeon reliability is highly variable when rating physical deformity. Surgeons' unreliable ratings of patients' physical deformity may lead to inconsistent decision-making. METHODS. Four pediatric spine surgeons viewed 40 patients with varying severity of AIS on three occasions, 2 weeks apart. In the first viewing, surgeons viewed only patient photos and body image scores. In the second viewing, surgeons viewed patient photos, body image scores, and clinical data. In the third viewing, surgeons viewed patient photos, body image scores, a 3-ft anteroposterior spinal radiograph, and corresponding radiographic data. After viewing each patient, surgeons were asked if: 1) spinal fusion with or without thoracoplasty would improve the patient's appearance; and 2) whether they would recommend this patient for spinal fusion with or without thoracoplasty. RESULTS. Surgeons' concordance in recommending patients for surgery and if they thought it would improve their appearance varied widely with kappa scores ranging from poor (0.34) to good (0.76). Recommendations for surgery were more consistent with the addition of radiographs but were not influenced by patients' body image perceptions. Surgeons' recommendations for surgery were also inconsistent with treatment actually received with overall kappa scores ranging from poor (0.32) to good (0.73). CONCLUSION. Surgical decision-making for AIS is inconsistent. © 2007 Lippincott Williams & Wilkins, Inc.

Authors
Donaldson, S; Stephens, D; Howard, A; Alman, B; Narayanan, U; Wright, JG
MLA Citation
Donaldson, S, Stephens, D, Howard, A, Alman, B, Narayanan, U, and Wright, JG. "Surgical decision making in adolescent idiopathic scoliosis." Spine 32.14 (2007): 1526-1532.
PMID
17572623
Source
scival
Published In
Spine
Volume
32
Issue
14
Publish Date
2007
Start Page
1526
End Page
1532
DOI
10.1097/BRS.0b013e318067dc75

A randomized, controlled trial of a removable brace versus casting in children with low-risk ankle fractures

OBJECTIVES. Isolated distal fibular ankle fractures in children are very common and at very low risk for future complications. Nevertheless, standard therapy for these fractures still consists of casting, a practice that carries risks, inconveniences, and use of subspecialty health care resources. Therefore, the main objective of this study was to determine whether children who have these low-risk ankle fractures that are treated with a removable ankle brace have at least as effective a recovery of physical function as those that are treated with a cast. METHODS. This was a noninferiority, randomized, single-blind trial in which children who were 5 to 18 years of age and treated in a pediatric emergency department for low-risk ankle fractures were randomly assigned to a removable ankle brace or a below-knee walking cast. The primary outcome at 4 weeks was physical function, measured by using the modified Activities Scale for Kids. Additional outcomes included patient preferences and costs. RESULTS. The mean activity score at 4 weeks was 91.3% in the brace group (n = 54), and this was significantly higher than the mean of 85.3% in the cast group (n = 50). Significantly more children who were treated with a brace had returned to baseline activities by 4 weeks compared with those who were casted (80.8% vs 59.5%). Fifty-four percent of the casted children would have preferred the brace, but only 5.7% of children who received the brace would have preferred the cast. The cost-effectiveness acceptability curve was always >80%; therefore, the brace was cost-effective compared with the cast. CONCLUSIONS. The removable ankle brace is more effective than the cast with respect to recovery of physical function, is associated with a faster return to baseline activities, is superior with respect to patient preferences, and is also cost-effective. Copyright © 2007 by the American Academy of Pediatrics.

Authors
Boutis, K; Willan, AR; Babyn, P; Narayanan, UG; Alman, B; Schuh, S
MLA Citation
Boutis, K, Willan, AR, Babyn, P, Narayanan, UG, Alman, B, and Schuh, S. "A randomized, controlled trial of a removable brace versus casting in children with low-risk ankle fractures." Pediatrics 119.6 (2007): e1256-e1263.
PMID
17545357
Source
scival
Published In
Pediatrics
Volume
119
Issue
6
Publish Date
2007
Start Page
e1256
End Page
e1263
DOI
10.1542/peds.2006-2958

Surgeon reliability in rating physical deformity in adolescent idiopathic scoliosis

STUDY DESIGN. Cross sectional survey. OBJECTIVES. To compare pediatric spine surgeons' relative rankings of the importance of surgical considerations, and their reliability of ratings of the physical deformity of patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA. Adolescents' appearance is a factor in surgical decision-making. Although the reliability of the Cobb angle has been extensively studied, less attention has been directed toward the reliability of surgeons' assessment of physical appearance. METHODS. Five surgeons ranked the relative importance of 13 surgical considerations. While viewing clinical photographs of 40 patients, surgeons rated the following: shoulder blades, shoulders, waist asymmetry, and the "overall appearance" of the back. RESULTS. "Severity of deformity" was consistently ranked the most important surgical consideration. Surgeons, however, varied widely in their reliability of their ratings of physical appearance: shoulder blades (κ = 0.34), shoulders (κ = 0.22), waist (κ = 0.24), and overall appearance (κ = 0.40). CONCLUSION. Because patients' physical appearance is an important element of surgical decision-making, differences among surgeons could be contributing to inconsistent recommendations. © 2007 Lippincott Williams & Wilkins, Inc.

Authors
Donaldson, S; Hedden, D; Stephens, D; Alman, B; Howard, A; Narayanan, U; Wright, JG
MLA Citation
Donaldson, S, Hedden, D, Stephens, D, Alman, B, Howard, A, Narayanan, U, and Wright, JG. "Surgeon reliability in rating physical deformity in adolescent idiopathic scoliosis." Spine 32.3 (2007): 363-367.
PMID
17268269
Source
scival
Published In
Spine
Volume
32
Issue
3
Publish Date
2007
Start Page
363
End Page
367
DOI
10.1097/01.brs.0000253605.71168.2e

Does deflazacort treatment impact the surgical outcomes for boys with Duchenne muscular dystrophy?

Authors
Biggar, WD; Harris, VA; Alman, BA
MLA Citation
Biggar, WD, Harris, VA, and Alman, BA. "Does deflazacort treatment impact the surgical outcomes for boys with Duchenne muscular dystrophy?." October 2006.
Source
wos-lite
Published In
Neuromuscular Disorders
Volume
16
Issue
9-10
Publish Date
2006
Start Page
719
End Page
720
DOI
10.1016/j.nmd.2006.05.240

Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing.

After cutaneous injury, a variety of cell types are activated to reconstitute the epithelial and dermal components of the skin. beta-Catenin plays disparate roles in keratinocytes and fibroblasts, inhibiting keratinocyte migration and activating fibroblast proliferation, suggesting that beta-catenin could either inhibit or enhance the healing process. How beta-catenin functions in concert with other signaling pathways important in the healing process is unknown. Wound size was examined in mice expressing conditional null or conditional stabilized alleles of beta-catenin, regulated by an adenovirus expressing cre-recombinase. The size of the wounds in the mice correlated with the protein level of beta-catenin. Using mice expressing these conditional alleles, we found that the wound phenotype imparted by Smad3 deficiency and by the injection of TGFbeta before wounding is mediated in part by beta-catenin. TGFbeta was not able to regulate proliferation in beta-catenin null fibroblasts, whereas keratinocyte proliferation rate was independent of beta-catenin. When mice are treated with lithium, beta-catenin-mediated signaling was activated in cutaneous wounds, which healed with a larger size. These results demonstrate a crucial role for beta-catenin in regulating cutaneous wound size. Furthermore, these data implicate mesenchymal cells as playing a critical role regulating wound size.

Authors
Cheon, SS; Wei, Q; Gurung, A; Youn, A; Bright, T; Poon, R; Whetstone, H; Guha, A; Alman, BA
MLA Citation
Cheon, SS, Wei, Q, Gurung, A, Youn, A, Bright, T, Poon, R, Whetstone, H, Guha, A, and Alman, BA. "Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing." FASEB J 20.6 (April 2006): 692-701.
PMID
16581977
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
20
Issue
6
Publish Date
2006
Start Page
692
End Page
701
DOI
10.1096/fj.05-4759com

Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation.

Chondrosarcoma is a malignant cartilage tumor that may arise from benign precursor lesions, such as enchondromas. Some cases of multiple enchondromas are caused by a mutation that results in constitutive activation of Hedgehog-mediated signaling. We found that chondrosarcomas expressed high levels of the Hedgehog target genes PTCH1 and GLI1. Treatment with parathyroid hormone-related protein down-regulated Indian Hedgehog (IHH) expression in normal growth plates but not in chondrosarcoma or enchondroma organ cultures. Treatment of the chondrosarcoma organ cultures with Hedgehog protein increased cell proliferation rate, whereas addition of chemical inhibitors of Hedgehog signaling decreased the proliferation rate. Chondrosarcoma xenografts from 12 different human tumors were established in NOD-SCID mice. Treatment with triparanol, an inhibitor of Hedgehog signaling, resulted in a 60% decrease in tumor volume, a 30% decrease in cellularity, and a 20% reduction in proliferation rate. These results show that Hedgehog signaling is active in chondrosarcoma and benign cartilage tumors and regulates tumor cell proliferation. Our data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.

Authors
Tiet, TD; Hopyan, S; Nadesan, P; Gokgoz, N; Poon, R; Lin, AC; Yan, T; Andrulis, IL; Alman, BA; Wunder, JS
MLA Citation
Tiet, TD, Hopyan, S, Nadesan, P, Gokgoz, N, Poon, R, Lin, AC, Yan, T, Andrulis, IL, Alman, BA, and Wunder, JS. "Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation." Am J Pathol 168.1 (January 2006): 321-330.
PMID
16400033
Source
pubmed
Published In
The American journal of pathology
Volume
168
Issue
1
Publish Date
2006
Start Page
321
End Page
330
DOI
10.2353/ajpath.2006.050001

First successful lower-extremity transplantation: Technique and functional result

Composite tissue transplantation has emerged as a viable alternative to prosthetics and complex reconstructive surgery. Thus far it is reserved for cases which cannot be effectively reconstructed and where it offers some benefits over prostheses. It has been used in the upper extremity with encouraging results and, most recently, in the face. This report outlines what is believed to be the first such use in the lower extremity. A normal lower limb in a 3-month-old ischiopagus twin who was not going to survive was transplanted to the appropriate pelvic position, revascularized, and reinnervated in an otherwise healthy sister. The limb survived and, because of the immune compatibility, did not require immune suppressive therapy. The return of muscle function in the transplanted limb is encouraging. The transplanted limb appears to be fully sensate. In addition to reinnervation, the limb is now spontaneously under the cortical control of the recipient. Copyright © 2006 by Thieme Medical Publishers, Inc.

Authors
Zuker, RM; Redett, R; Alman, B; Coles, JG; Timoney, N; Ein, SH
MLA Citation
Zuker, RM, Redett, R, Alman, B, Coles, JG, Timoney, N, and Ein, SH. "First successful lower-extremity transplantation: Technique and functional result." Journal of Reconstructive Microsurgery 22.4 (2006): 239-244.
PMID
16783680
Source
scival
Published In
Journal of Reconstructive Microsurgery
Volume
22
Issue
4
Publish Date
2006
Start Page
239
End Page
244
DOI
10.1055/s-2006-939928

Parents' and patients' perceptions of postoperative appearance in adolescent idiopathic scoliosis

STUDY DESIGN. A cross-sectional evaluation of patients after surgery for adolescent idiopathic scoliosis (AIS). OBJECTIVES. To determine the agreement between patients' and parents' perceptions of the patient's postoperative appearance and to compare those perceptions with physical and radiographic measures of deformity. SUMMARY OF BACKGROUND DATA. Improving cosmesis is an important aim of surgery. Patients' appearances may influence their evaluation of its outcome. METHODS. Physical and radiographic data were collected 2 years after surgery for 128 patients with AIS. Patients and parents independently rated shoulder blades, shoulders, waist, and overall appearance. Additionally, patients completed the Quality of Life Profile for Spinal Disorders (QLPSD). Agreement was evaluated with the weighted kappa statistic ranging between 0 and 1 where higher values indicate better agreement. RESULTS. Fair to moderate agreement was found between patient and parent ratings of the patient's shoulder blades (kappa = 0.39; 95% confidence interval [CI], 0.29-0.48), shoulders (kappa = 0.38; 95% CI, 0.26-0.50), waist (kappa = 0.45; 95% CI, 0.25-0.55), and overall appearance (kappa = 0.22; 95% CI, 0.04-0.40). Patients rated the appearance of their waist (P = 0.013) and overall appearance (P = 0.039) significantly worse than their parents. Patients' perceptions of their overall appearance had higher correlations with the body image subscale score (r = 0.45, P = 0.000) and the total quality of life score on the QLPSD (r = 0.37, P = 0.000) than did parents' perceptions of those same measures (r = 0.21, P = 0.025; and r = 0.08, P = 0.369, respectively). CONCLUSIONS. Radiographic and physical measures of deformity do not correlate well with patients' and parents' perceptions of appearance. Patients and parents do not strongly agree on the cosmetic outcome of AIS surgery. Therefore, given that the adolescents themselves undergo the surgery, patients' assessments of their deformity, rather than radiographic measures or parents' assessments, should play a major role in the evaluation of surgical success. ©2006, Lippincott Williams & Wilkins, Inc.

Authors
Smith, PL; Donaldson, S; Hedden, D; Alman, B; Howard, A; Stephens, D; Wright, JG
MLA Citation
Smith, PL, Donaldson, S, Hedden, D, Alman, B, Howard, A, Stephens, D, and Wright, JG. "Parents' and patients' perceptions of postoperative appearance in adolescent idiopathic scoliosis." Spine 31.20 (2006): 2367-2374.
PMID
16985466
Source
scival
Published In
Spine
Volume
31
Issue
20
Publish Date
2006
Start Page
2367
End Page
2374
DOI
10.1097/01.brs.0000240204.98960.dd

Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade

We compare the clinical course of 74 boys 10-18 years of age with Duchenne muscular dystrophy (DMD) treated (40) and not treated (34) with deflazacort. Treated boys were able to rise from supine to standing, climb stairs and walk 10 m without aids, 3-5 years longer than boys not treated. After 10 years of age, treated boys had significantly better pulmonary function than boys not treated and after15 years of age, 8 of 17 boys not treated required nocturnal ventilation compared with none of the 40 treated boys. For boys over 15 years of age, 11 of 17 boys not treated required assistance with feeding compared to none of the treated boys. By 18 years, 30 of 34 boys not treated had a spinal curve greater than 20° compared to 4 of 40 treated boys. By 18 years, 7 of 34 boys not treated had lost 25% or more of their body weight (treated 0 of 40) and 4 of those 7 boys required a gastric feeding tube. By 18 years, 20 of 34 boys not treated had cardiac left ventricular ejection fractions less than 45% compared to 4 of 40 treated boys and 12 of 34 died in their second decade (mean 17.6±1.7 years) primarily of cardiorespiratory complications. Two of 40 boys treated with deflazacort died at 13 and 18 years of age from cardiac failure. The treated boys were significantly shorter, did not have excessive weight gain and 22 of 40 had asymptomatic cataracts. Long bone fractures occurred in 25% of boys in both the treated and not treated groups. This longer-term study demonstrates that deflazacort has a very significant impact on health, quality of life and health care costs for boys with DMD and their families, and is associated with few side effects. © 2006 Elsevier B.V. All rights reserved.

Authors
Biggar, WD; Harris, VA; Eliasoph, L; Alman, B
MLA Citation
Biggar, WD, Harris, VA, Eliasoph, L, and Alman, B. "Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade." Neuromuscular Disorders 16.4 (2006): 249-255.
PMID
16545568
Source
scival
Published In
Neuromuscular Disorders
Volume
16
Issue
4
Publish Date
2006
Start Page
249
End Page
255
DOI
10.1016/j.nmd.2006.01.010

Duchenne muscular dystrophy and steroids: pharmacologic treatment in the absence of effective gene therapy.

Authors
Alman, BA
MLA Citation
Alman, BA. "Duchenne muscular dystrophy and steroids: pharmacologic treatment in the absence of effective gene therapy." J Pediatr Orthop 25.4 (July 2005): 554-556. (Review)
PMID
15958914
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
25
Issue
4
Publish Date
2005
Start Page
554
End Page
556

Dysregulation of hedgehog signalling predisposes to synovial chondromatosis.

Synovial chondromatosis is a condition affecting joints in which metaplastic cartilage nodules arise from the synovium, causing pain, joint dysfunction, and ultimately joint destruction. Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis. Significantly higher expression levels were found in synovial chondromatosis than in the synovium, from which it arises. To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied. The extra-toes mutant mouse has a phenotype consistent with overactive hedgehog signalling, suggesting that Gli3 acts as a transcriptional repressor of limb development. Eighty-five per cent of Gli3 mutant mice developed synovial chondromatosis at 18 months of age, compared with 30% of wild-type littermates (p < 0.05). Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice. These data demonstrate that hedgehog signalling plays an important role in the development of synovial chondromatosis and suggest that blockade of hedgehog signalling may be a potential treatment for this disorder.

Authors
Hopyan, S; Nadesan, P; Yu, C; Wunder, J; Alman, BA
MLA Citation
Hopyan, S, Nadesan, P, Yu, C, Wunder, J, and Alman, BA. "Dysregulation of hedgehog signalling predisposes to synovial chondromatosis." J Pathol 206.2 (June 2005): 143-150.
PMID
15834844
Source
pubmed
Published In
The Journal of Pathology
Volume
206
Issue
2
Publish Date
2005
Start Page
143
End Page
150
DOI
10.1002/path.1761

Prolonged beta-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds.

Mesenchymal cells that accumulate during the proliferative phase of wound healing and that are present in hyperplastic wounds share cytologic similarities with the cells from fibroproliferative lesions in which there is activation of beta-catenin-mediated transcription. Re-excision wounds from a previous biopsy and samples from hyperplastic cutaneous wounds were studied along with normal tissues. During normal wound healing, there was an increase in beta-catenin protein level, peaking 4 weeks following the insult and returning towards baseline level by 12 weeks. Hyperplastic wounds exhibited a prolonged duration of elevated beta-catenin, lasting more than 2 years following the initial injury. The level of expression of genes known to be upregulated in the proliferative phase of wound healing (alpha-smooth muscle actin and type three collagen), correlated with beta-catenin protein level. The phosphorylation level of glycogen synthase kinase-3-beta, a kinase important for beta-catenin protein destabilization, correlated with beta-catenin protein level. Beta-catenin was transcriptionally active in these wounds as demonstrated by the expression of the beta-catenin target genes (MMP-7 and FN) and by activation of a tcf-reporter in primary cell cultures. Beta-catenin stabilization increases cell proliferation and motility in fibroblasts in vitro, and likely has a similar function during its transient elevation in the proliferative phase of normal wound healing. In hyperplastic wounds, there is dysregulation of beta-catenin, maintaining the mesenchymal cells in a prolonged proliferative state. As such, beta-catenin likely plays a central role in mesenchymal cells during the healing process, and is an appealing therapeutic target for disorders of wound healing.

Authors
Cheon, S; Poon, R; Yu, C; Khoury, M; Shenker, R; Fish, J; Alman, BA
MLA Citation
Cheon, S, Poon, R, Yu, C, Khoury, M, Shenker, R, Fish, J, and Alman, BA. "Prolonged beta-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds." Lab Invest 85.3 (March 2005): 416-425.
PMID
15654359
Source
pubmed
Published In
Laboratory Investigation
Volume
85
Issue
3
Publish Date
2005
Start Page
416
End Page
425
DOI
10.1038/labinvest.3700237

Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations, resulting in beta-catenin-mediated transcriptional activation. We found that plasminogen activator inhibitor-1 (PAI-1) was upregulated fourfold in aggressive fibromatosis. We investigated the ability of beta-catenin to regulate a PAI-1 reporter, and found that PAI-1 is an indirect target. To determine the role of PAI-1 in vivo, a mouse containing a targeted deletion in Pai-1 was crossed with a mouse that develops aggressive fibromatosis and gastrointestinal tumors (Apc/Apc1638N mouse). Pai-1 deficiency reduced the number of aggressive fibromatosis tumors formed, but not the number of gastrointestinal tumors. Deficiency of Pai-1 reduced tumor cell proliferation and motility rate. Although PAI-1 can alter cell motility by competing for a common binding site on vitronectin, blocking this site did not alter the motility rate. The number of cells moving through matrigel (invasion rate) did not change with Pai-1 deficiency, but because of the low motility rate the invasion index (invasion rate/motility) was increased in Pai-1-deficient cells. This suggests a proteolytic effect for PAI-1 regulating cell invasiveness. Our study found that, although PAI-1 has cellular effects that could inhibit or enhance tumor growth, on balance, it acts as a tumor enhancer in aggressive fibromatosis.

Authors
Fen Li, C; Kandel, C; Baliko, F; Nadesan, P; Brünner, N; Alman, BA
MLA Citation
Fen Li, C, Kandel, C, Baliko, F, Nadesan, P, Brünner, N, and Alman, BA. "Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor)." Oncogene 24.9 (February 24, 2005): 1615-1624.
PMID
15674349
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
24
Issue
9
Publish Date
2005
Start Page
1615
End Page
1624
DOI
10.1038/sj.onc.1208193

Should foot surgery be performed for children with duchenne muscular dystrophy?

Authors
Leitch, KK; Raza, N; Biggar, D; Stephen, D; Wright, JG; Alman, BA
MLA Citation
Leitch, KK, Raza, N, Biggar, D, Stephen, D, Wright, JG, and Alman, BA. "Should foot surgery be performed for children with duchenne muscular dystrophy?." JOURNAL OF PEDIATRIC ORTHOPAEDICS 25.1 (2005): 95-97.
PMID
15614068
Source
wos-lite
Published In
Journal of Pediatric Orthopaedics
Volume
25
Issue
1
Publish Date
2005
Start Page
95
End Page
97
DOI
10.1097/00004694-200501000-00021

The effect of surgical delay on acute infection following 554 open fractures in children

Background: Traditional recommendations hold that open fractures in both children and adults require urgent surgical débridement for a number of reasons, including the preservation of soft-tissue viability and vascular status as well as the prevention of infection. Following the widespread use of early administration of antibiotics, a number of single-institution studies challenged the belief that urgent surgical débridement decreases the risk of acute infection. Methods: We performed a retrospective, multicenter study of open fractures that had been treated at six tertiary pédiatric medical centers between 1989 and 2000. The standard protocol at each medical center was for all children to be given intravenous antibiotics upon arrival in the emergency department. The medical records of all children with open fractures were reviewed to identify the location of the fracture, the interval between the injury and the time of surgery, the Gustilo and Anderson classification, and the occurrence of acute infection. Results: The analysis included 554 open fractures in 536 consecutive patients who were eighteen years of age or younger. The overall infection rate was 3% (sixteen of 554). The infection rate was 3% (twelve of 344) for fractures that had been treated within six hours after the injury, compared with 2% (four of 210) for those that had been treated at least seven hours after the injury; this difference was not significant (p = 0.43). When the fractures were separated according to the Gustilo and Anderson classification system, there were no significant differences in the infection rate between those that had been treated within six hours after the injury and those that had been treated at least seven hours after the injury. Specifically, these infection rates were 2% (three of 173) and 2% (two of 129), respectively, for type-I fractures, 3% (three of 110) and 0% (zero of forty-four), respectively, for type-II fractures, and 10% (six of sixty-one) and 2% (two of thirty-seven), respectively, for type-III fractures (p > 0.05 for all three comparisons). Conclusions: In the present retrospective, multicenter study of children with Gustilo and Anderson type-I, II, and III open fractures, the rates of acute infection were similar regardless of whether surgery was performed within six hours after the injury or at least seven hours after the injury. The findings of the present study suggest that, in children who receive early antibiotic therapy following an open fracture, surgical débridement within six hours after the injury offers little benefit over débridement within twenty-four hours after the injury with regard to the prevention of acute infection.

Authors
Skaggs, DL; Friend, L; Alman, B; Chambers, HG; Schmitz, M; Leake, B; Kay, RM; Flynn, JM
MLA Citation
Skaggs, DL, Friend, L, Alman, B, Chambers, HG, Schmitz, M, Leake, B, Kay, RM, and Flynn, JM. "The effect of surgical delay on acute infection following 554 open fractures in children." Journal of Bone and Joint Surgery - Series A 87.1 (2005): 8-12.
PMID
15634809
Source
scival
Published In
The Journal of Bone and Joint Surgery
Volume
87
Issue
1
Publish Date
2005
Start Page
8
End Page
12
DOI
10.2106/JBJS.C.01561

Bone morphogenetic proteins are expressed by both bone-forming and non-bone-forming lesions.

CONTEXT: Bone morphogenetic proteins (BMPs) are thought to be responsible for bone formation; they cause bone to form in soft tissues and are clinically used in helping fracture union or tumor reconstructions. Skeletal metastases from epithelial tumors may be either bone-forming (blastic) or non-bone-forming (lytic). OBJECTIVE: We studied the expression of BMPs in a variety of primary and secondary lesions of bone (both bone-forming and non-bone-forming) to determine if there was a consistent relationship between bone formation and BMP expression. DESIGN: We compared a bone-forming lesion (fibrous dysplasia) with a non-bone-forming lesion (desmoid tumor), using reverse transcription-polymerase chain reaction, Northern blot analysis, and immunohistochemistry to detect BMPs. We also studied a number of non-bone-forming secondary lesions (carcinomas that formed lytic metastases to the skeleton) and found BMP production in most of these tumors. RESULTS: We found that BMPs were expressed in both bone-forming and non-bone-forming benign musculoskeletal lesions. In the first part of the study, BMPs were found in both fibrous dysplasia and desmoid tumors. Bone morphogenetic proteins were also expressed by several tumors. In the next part of the study (paraffin-embedded tissue), BMPs were expressed by a variety of tumors, irrespective of the radiological nature (blastic or lytic) of their metastases. CONCLUSIONS: We conclude that BMP production alone cannot explain bone formation, and other factors either alone or in combination may be responsible for blastic metastases to the skeleton and for bone formation by primary bone lesions, such as fibrous dysplasia.

Authors
Khurana, JS; Ogino, S; Shen, T; Parekh, H; Scherbel, U; DeLong, W; Feldman, MD; Zhang, PJ; Wolfe, HJ; Alman, BA
MLA Citation
Khurana, JS, Ogino, S, Shen, T, Parekh, H, Scherbel, U, DeLong, W, Feldman, MD, Zhang, PJ, Wolfe, HJ, and Alman, BA. "Bone morphogenetic proteins are expressed by both bone-forming and non-bone-forming lesions." Arch Pathol Lab Med 128.11 (November 2004): 1267-1269.
PMID
15508192
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
128
Issue
11
Publish Date
2004
Start Page
1267
End Page
1269

Bone Morphogenetic Proteins Are Expressed by Both Bone-Forming and Non-Bone-Forming Lesions.

Context.-Bone morphogenetic proteins (BMPs) are thought to be responsible for bone formation; they cause bone to form in soft tissues and are clinically used in helping fracture union or tumor reconstructions. Skeletal metastases from epithelial tumors may be either bone-forming (blastic) or non-bone-forming (lytic).Objective.-We studied the expression of BMPs in a variety of primary and secondary lesions of bone (both bone-forming and non-bone-forming) to determine if there was a consistent relationship between bone formation and BMP expression.Design.-We compared a bone-forming lesion (fibrous dysplasia) with a non-bone-forming lesion (desmoid tumor), using reverse transcription-polymerase chain reaction, Northern blot analysis, and immunohistochemistry to detect BMPs. We also studied a number of non-bone-forming secondary lesions (carcinomas that formed lytic metastases to the skeleton) and found BMP production in most of these tumors.Results.-We found that BMPs were expressed in both bone-forming and non-bone-forming benign musculoskeletal lesions. In the first part of the study, BMPs were found in both fibrous dysplasia and desmoid tumors. Bone morphogenetic proteins were also expressed by several tumors. In the next part of the study (paraffin-embedded tissue), BMPs were expressed by a variety of tumors, irrespective of the radiological nature (blastic or lytic) of their metastases.Conclusions.-We conclude that BMP production alone cannot explain bone formation, and other factors either alone or in combination may be responsible for blastic metastases to the skeleton and for bone formation by primary bone lesions, such as fibrous dysplasia.

Authors
Khurana, JS; Ogino, S; Shen, T; Parekh, H; Scherbel, U; Delong, W; Feldman, MD; Zhang, PJ; Wolfe, HJ; Alman, BA
MLA Citation
Khurana, JS, Ogino, S, Shen, T, Parekh, H, Scherbel, U, Delong, W, Feldman, MD, Zhang, PJ, Wolfe, HJ, and Alman, BA. "Bone Morphogenetic Proteins Are Expressed by Both Bone-Forming and Non-Bone-Forming Lesions." Arch Pathol Lab Med 128.11 (November 2004): 1267-1269.
PMID
15506826
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
128
Issue
11
Publish Date
2004
Start Page
1267
End Page
1269
DOI
10.1043/1543-2165(2004)128<1267:BMPAEB>2.0.CO;2

Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis.

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) regulate the degradation of extracellular matrix components and play important roles in the progression of select neoplastic processes. The locally invasive soft tissue tumor, aggressive fibromatosis (also called desmoid tumor), is caused by mutations resulting in beta-catenin-mediated T-cell factor (tcf)-dependent transcriptional activity. Because beta-catenin can regulate MMP expression, we investigated the expression of several MMPs and TIMPs in aggressive fibromatosis tumors that develop in Apc+/Apc1638N mice. Mmp-3 and Timp-1 were differentially regulated (5-fold and 0.5-fold, respectively) in tumors compared with normal fibrous tissue. Conditioned media from tumor cells showed an increased ability to degrade collagen, and inhibition of MMPs using GM6001 decreased the ability of the tumor cells to invade through Matrigel. Both the treatment of Apc/Apc1638N mice with GM6001 or crossing with a transgenic mouse that overexpresses Timp-1 resulted in a significant reduction in tumor volume. Surprisingly, overexpression of Timp-1 also resulted in a 50% increase in tumor number. Although TIMP-1 can induce growth stimulatory effects in some cell types, we found no difference in proliferation or apoptosis rate in cells from tumors that developed in the Timp-1-transgenic mice compared with mice that did not express the Timp-1 transgene, suggesting that TIMP-1 promotes aggressive fibromatosis tumor formation through an alternate mechanism. These data suggest that MMPs play a crucial role in regulating the invasiveness of mesenchymal cells and in modulating aggressive fibromatosis tumor progression. Because this is a locally invasive tumor, MMP inhibition could slow tumor growth and may prove to be an effective adjuvant therapy.

Authors
Kong, Y; Poon, R; Nadesan, P; Di Muccio, T; Fodde, R; Khokha, R; Alman, BA
MLA Citation
Kong, Y, Poon, R, Nadesan, P, Di Muccio, T, Fodde, R, Khokha, R, and Alman, BA. "Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis." Cancer Res 64.16 (August 15, 2004): 5795-5803.
PMID
15313922
Source
pubmed
Published In
Cancer Research
Volume
64
Issue
16
Publish Date
2004
Start Page
5795
End Page
5803
DOI
10.1158/0008-5472.CAN-03-3112

Complications of elastic stable intramedullary nail fixation of pediatric femoral fractures, and how to avoid them.

Flexible intramedullary nailing has become a popular method of fixation of pediatric femoral fractures. The authors analyzed their first 5-year experience with titanium elastic stable intra-medullary nailing, specifically to report the complications associated with this technique and to provide recommendations to avoid these complications. Seventy-eight children with 79 femoral fractures were treated by this method. Complications included pain/irritation at the insertion site (41), radiographic malunion (8), refracture (2), transient neurologic deficit (2), and superficial wound infection (2). Ten patients required reoperation prior to union. Malunion and/or loss of reduction requiring reoperation was strongly associated with the use of nails of mismatched diameters (odds ratio = 19.4) and comminution of more than 25% (odd ratio = 5.5). Pain at the insertion site was significantly associated with bent or prominent nail ends. Most complications are minor, and many are preventable. Surgeons should advance nail ends to lie against the supracondylar flare of the femur to avoid symptoms at the insertion site and should avoid implanting nails of two different diameters. Comminuted fractures should be monitored carefully and might benefit from additional immobilization.

Authors
Narayanan, UG; Hyman, JE; Wainwright, AM; Rang, M; Alman, BA
MLA Citation
Narayanan, UG, Hyman, JE, Wainwright, AM, Rang, M, and Alman, BA. "Complications of elastic stable intramedullary nail fixation of pediatric femoral fractures, and how to avoid them." J Pediatr Orthop 24.4 (July 2004): 363-369.
PMID
15205616
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
24
Issue
4
Publish Date
2004
Start Page
363
End Page
369

Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.

Brachmann-de Lange syndrome (BDLS) is a disorder of unknown cause that is recognized on the basis of characteristic facies in association with growth retardation, mental retardation and, in many cases, upper limb anomalies. Because of its association with skeletal anomalies, patients with the syndrome are often referred to the paediatric orthopaedic surgeon. Thirty-four patients with Brachmann-de Lange syndrome were evaluated for the prevalence and pattern of musculoskeletal involvement. The average age of the patients was 10.2 years (range, 1 month to 44 years). Both sexes were affected equally. The common orthopaedic manifestation affected the hand (100%), elbow (47%), and the heel cord (26%). Severe bony anomalies included complete absence of the hand in one case, and ulna hemimelia in two cases. In two patients bilateral Legg-Perthes-like changes were noted. Scoliosis presented in four cases, all before the age of 10 years. Surgery was performed in two patients with severe bilateral equinovarus feet. Despite the constellation of musculoskeletal findings, most of the patients did not have surgical intervention for their deformities.

Authors
Roposch, A; Bhaskar, AR; Lee, F; Adedapo, S; Mousny, M; Alman, BA
MLA Citation
Roposch, A, Bhaskar, AR, Lee, F, Adedapo, S, Mousny, M, and Alman, BA. "Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients." J Pediatr Orthop B 13.2 (March 2004): 118-122.
PMID
15076591
Source
pubmed
Published In
Journal of Pediatric Orthopaedics Part B
Volume
13
Issue
2
Publish Date
2004
Start Page
118
End Page
122

Steroid treatment and the development of scoliosis in males with duchenne muscular dystrophy.

BACKGROUND: Scoliosis due to progressive muscle weakness occurs in almost all males with Duchenne muscular dystrophy, and it progresses relentlessly. Previous studies have shown that corticosteroid treatment slows the decline in muscle strength and stabilizes muscle strength in patients with this disease. We hypothesized that steroids may also attenuate the development of scoliosis. The purpose of this study was to compare the prevalence of scoliosis in male patients with Duchenne muscular dystrophy who received steroids with a control group of such patients who did not. METHODS: A group of seven to ten-year-old boys with Duchenne muscular dystrophy who were able to walk were enrolled in a nonrandomized comparative study to determine the effect of deflazacort (a derivative of prednisone) on muscle strength and pulmonary function. Thirty patients were treated with deflazacort (treatment group), and twenty-four were not (control group). The patients were matched for age and pulmonary function at baseline. To assess the development of scoliosis, the patients in each group were followed for at least five years. Survival curves were plotted to determine the chance of scoliosis of >/==" BORDER="0">20 degrees developing. The difference between the groups with respect to the chance of scoliosis developing was determined with Kaplan-Meier analysis. RESULTS: A curve of >/==" BORDER="0">20 degrees developed during the follow-up period in sixteen (67%) of the twenty-four patients in the control group but in only five (17%) of the thirty patients in the treatment group. Fifteen of the twenty-four patients in the control group underwent spine surgery, at a mean age of thirteen years, whereas only five of the thirty patients in the treatment group underwent spine surgery, at a mean age of fifteen years. Kaplan-Meier analysis demonstrated a significant difference between the two groups with regard to development of scoliosis of >/==" BORDER="0">20 degrees (p < 0.001). Cataracts developed in ten patients in the treatment group, and stress fractures developed in three patients in the treatment group. Patients in the treatment group weighed a mean of 3.7 kg more than did those in the control group. CONCLUSIONS: Steroid treatment slows the progression of scoliosis in males with Duchenne muscular dystrophy; however, longer-term evaluation will be necessary to determine if the treatment prevents the development of scoliosis or just delays its onset. At the very least, steroid treatment delays the need for spinal surgery. LEVEL OF EVIDENCE: Therapeutic study, Level II-1 (prospective cohort study). See Instructions to Authors for a complete description of levels of evidence.

Authors
Alman, BA; Raza, SN; Biggar, WD
MLA Citation
Alman, BA, Raza, SN, and Biggar, WD. "Steroid treatment and the development of scoliosis in males with duchenne muscular dystrophy." J Bone Joint Surg Am 86-A.3 (March 2004): 519-524.
PMID
14996877
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
86-A
Issue
3
Publish Date
2004
Start Page
519
End Page
524

Steroid treatment and the development of scoliosis in males with Duchenne muscular dystrophy

Authors
Alman, BA; Raza, SN; Biggar, WD
MLA Citation
Alman, BA, Raza, SN, and Biggar, WD. "Steroid treatment and the development of scoliosis in males with Duchenne muscular dystrophy." JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME 86A.3 (March 2004): 519-524.
Source
wos-lite
Published In
The Journal of Bone and Joint Surgery
Volume
86A
Issue
3
Publish Date
2004
Start Page
519
End Page
524

Growth factors regulate beta-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing.

Beta-catenin is a critical regulator of cell behavior during embryogenesis and neoplastic processes. It also plays a crucial role in repair by modulating dermal fibroblast activity during the proliferative phase of cutaneous wound healing. We hypothesize that growth factors liberated during the initial phase of wound healing convey signals to induce activation of beta-catenin-mediated TCF-dependent signaling during the proliferative phase. Dermal fibroblasts were isolated and cultured from mice containing a beta-galactosidase reporter responsive to beta-catenin-TCF transactivation (TCF-beta-gal). Cells were stimulated with growth factors present at the initial phase of wound healing. EGF and TGF-beta1 significantly increased beta-catenin protein levels and transcriptional activity, whereas beta-catenin mRNA expression was unaffected. This increase was attributed to inactivation of GSK-3beta, a kinase important for beta-catenin destabilization. Subcutaneous injection of EGF or TGF-beta1 before wounding of TCF-beta-gal mice resulted in larger scars and fibroblasts within these wounds that strongly stained for beta-galactosidase, indicating significant beta-catenin transcriptional activity in vivo. Thus, beta-catenin-mediated signaling is activated downstream of growth factors released during the initial phase of wound repair, and may act during the proliferative phase of wound healing to integrate signals from initial phase factors into the expression of genes important during the later, remodeling phase.

Authors
Cheon, SS; Nadesan, P; Poon, R; Alman, BA
MLA Citation
Cheon, SS, Nadesan, P, Poon, R, and Alman, BA. "Growth factors regulate beta-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing." Exp Cell Res 293.2 (February 15, 2004): 267-274.
PMID
14729464
Source
pubmed
Published In
Experimental Cell Research
Volume
293
Issue
2
Publish Date
2004
Start Page
267
End Page
274

Identification of IGFBP-6 as a significantly downregulated gene by beta-catenin in desmoid tumors.

Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors in which beta-catenin-mediated TCF-3-dependent transcription is activated. To provide more insight into the pathophysiology of these tumors, expression profiles were generated using oligonucleotide arrays (Affymetrix). In total, 69 differentially expressed genes were identified in desmoids compared to normal fibroblasts (fascia) from the same patients. The differential expression of a selection of genes was confirmed using RT-PCR and Northern blotting. We further evaluated the insulin-like growth factor-binding protein 6 (IGFBP-6), a gene that was consistently downregulated in all desmoids tested. Promotor studies and electromobility shift assays revealed two functional beta-catenin/TCF-responsive elements in the human IGFBP-6 promoter. These findings suggest that IGFBP-6 is directly downregulated by the beta-catenin/TCF complex in desmoid tumors, and imply a role for the IGF axis in the proliferation of desmoid tumors.

Authors
Denys, H; Jadidizadeh, A; Amini Nik, S; Van Dam, K; Aerts, S; Alman, BA; Cassiman, J-J; Tejpar, S
MLA Citation
Denys, H, Jadidizadeh, A, Amini Nik, S, Van Dam, K, Aerts, S, Alman, BA, Cassiman, J-J, and Tejpar, S. "Identification of IGFBP-6 as a significantly downregulated gene by beta-catenin in desmoid tumors." Oncogene 23.3 (January 22, 2004): 654-664.
PMID
14737101
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
23
Issue
3
Publish Date
2004
Start Page
654
End Page
664
DOI
10.1038/sj.onc.1207160

Deflazacort in Duchenne muscular dystrophy: A comparison of two different protocols

We compare the long-term benefits and side effects of deflazacort using two treatment protocols from Naples (N) and Toronto (T). Boys with Duchenne muscular dystrophy between the ages of 8 and 15 years and who had four or more years of deflazacort treatment were reviewed. Diagnostic criteria included males with proximal muscle weakness evident before 5 years, increased serum creatine kinase and genetic testing and/or a muscle biopsy consistent with Duchenne muscular dystrophy. Thirty-seven boys were treated with protocol-N using deflazacort at a dose of 0.6 mg/kg per day for the first 20 days of the month and no deflazacort for the remainder of the month. Boys with osteoporosis received daily vitamin D and calcium. Deflazacort treatment started between 4 and 8 years of age. Thirty-two were treated with protocol-T using deflazacort at a dose of 0.9 mg/kg per day, plus daily vitamin D and calcium. Treatment started between 6 and 8 years of age. All boys were monitored every 4-6 months. The results were compared with age-matched controls in the two groups (19 for protocol-N and 30 for protocol-T). For the boys treated with protocol-N, 97% were ambulatory at 9 years (control, 22%), 35% at 12 years (control, 0%), 25% at 15 years (control, 0%). For the 32 boys treated with protocol-T, 100% were ambulatory at 9 years (control, 48%), 83% at 12 years (control, 0%) and 77% at 15 years (control, 0%). No aids or leg braces were used for ambulation. In boys 13 years and older, a scoliosis of >20°developed in 30% of the boys on protocol-N, 16% on protocol-T and 90% of controls. For protocol-N, no cataracts were observed while in protocol-T, 30% of boys had asymptomatic cataracts that required no treatment. Fractures occurred in 19% (control 16%) of boys on protocol-N and 16% (control, 20%) of boys on protocol-T. This report illustrates: (a) the importance of collaborative studies in developing treatment protocols in Duchenne muscular dystrophy and (b) the long-term beneficial effects of deflazacort treatment in both protocols. However, the protocol-T seems to be more effective and frequently is associated with asymptomatic cataracts. © 2004 Elsevier B.V. All rights reserved.

Authors
Biggar, WD; Politano, L; Harris, VA; Passamano, L; Vajsar, J; Alman, B; Palladino, A; Comi, LI; Nigro, G
MLA Citation
Biggar, WD, Politano, L, Harris, VA, Passamano, L, Vajsar, J, Alman, B, Palladino, A, Comi, LI, and Nigro, G. "Deflazacort in Duchenne muscular dystrophy: A comparison of two different protocols." Neuromuscular Disorders 14.8-9 (2004): 476-482.
PMID
15336688
Source
scival
Published In
Neuromuscular Disorders
Volume
14
Issue
8-9
Publish Date
2004
Start Page
476
End Page
482
DOI
10.1016/j.nmd.2004.05.001

Invasion and MMP expression profile in desmoid tumours

Desmoid tumours are locally invasive soft tissue tumours in which β-catenin mediated TCF-dependent transcription is activated. The role of soluble factors secreted by the myofibroblastic desmoid tumour, which could stimulate tumour invasiveness, was investigated. Using collagen gel invasion assays, the presence of factors stimulating invasion in desmoid conditioned media (CM) could be established. Since matrix metalloproteinases (MMPs) have been implicated in the process of tumoral invasion, the expression levels of the MMP family members were evaluated. Quantitative reverse transcription - PCR was used to determine the expression levels of MMP1, MMP2 MMP3, MMP7, MMP11, MMP12, MMP13, MMP14 and the inhibitors TIMP1, TIMP2 and TIMP3. Besides overexpression of MMP7, a known TCF-dependent target gene, a striking upregulation of the expression levels of MMP1, MMP3, MMP11, MMP12 and MMP13 in desmoid tumours, compared to unaffected fibroblasts from the same patients, was found. Treating the CM of desmoids with a synthetic and a physiologic MMP inhibitor reduced the invasion-stimulating capacity of the desmoid CM by approximately 50%. These results suggest the involvement of soluble factors, released by the desmoid cells, in stimulating invasion and implicate the MMPs as facilitators of invasion. © 2004 Cancer Research UK.

Authors
Denys, H; Wever, OD; Nusgens, B; Kong, Y; Sciot, R; Le, A-T; Dam, KV; Jadidizadeh, A; Tejpar, S; Mareel, M; Alman, B; Cassiman, J-J
MLA Citation
Denys, H, Wever, OD, Nusgens, B, Kong, Y, Sciot, R, Le, A-T, Dam, KV, Jadidizadeh, A, Tejpar, S, Mareel, M, Alman, B, and Cassiman, J-J. "Invasion and MMP expression profile in desmoid tumours." British Journal of Cancer 90.7 (2004): 1443-1449.
PMID
15054469
Source
scival
Published In
British Journal of Cancer
Volume
90
Issue
7
Publish Date
2004
Start Page
1443
End Page
1449
DOI
10.1038/sj.bjc.6601661

Steroid Treatment and the Development of Scoliosis in Males with Duchenne Muscular Dystrophy

Background: Scoliosis due to progressive muscle weakness occurs in almost all males with Duchenne muscular dystrophy, and it progresses relentlessly. Previous studies have shown that corticosteroid treatment slows the decline in muscle strength and stabilizes muscle strength in patients with this disease. We hypothesized that steroids may also attenuate the development of scoliosis. The purpose of this study was to compare the prevalence of scoliosis in male patients with Duchenne muscular dystrophy who received steroids with a control group of such patients who did not. Methods: A group of seven to ten-year-old boys with Duchenne muscular dystrophy who were able to walk were enrolled in a nonrandomized comparative study to determine the effect of deflazacort (a derivative of prednisone) on muscle strength and pulmonary function. Thirty patients were treated with deflazacort (treatment group), and twenty-four were not (control group). The patients were matched for age and pulmonary function at baseline. To assess the development of scoliosis, the patients in each group were followed for at least five years. Survival curves were plotted to determine the chance of scoliosis of ≥20° developing. The difference between the groups with respect to the chance of scoliosis developing was determined with Kaplan-Meier analysis. Results: A curve of ≥20° developed during the follow-up period in sixteen (67%) of the twenty-four patients in the control group but in only five (17%) of the thirty patients in the treatment group. Fifteen of the twenty-four patients in the control group underwent spine surgery, at a mean age of thirteen years, whereas only five of the thirty patients in the treatment group underwent spine surgery, at a mean age of fifteen years. Kaplan-Meier analysis demonstrated a significant difference between the two groups with regard to development of scoliosis of ≥20° (p < 0.001). Cataracts developed in ten patients in the treatment group, and stress fractures developed in three patients in the treatment group. Patients in the treatment group weighed a mean of 3.7 kg more than did those in the control group. Conclusions: Steroid treatment slows the progression of scoliosis in males with Duchenne muscular dystrophy; however, longer-term evaluation will be necessary to determine if the treatment prevents the development of scoliosis or just delays its onset. At the very least, steroid treatment delays the need for spinal surgery. Level of Evidence: Therapeutic study, Level II-1 (prospective cohort study). See Instructions to Authors for a complete description of levels of evidence.

Authors
Alman, BA; Raza, SN; Biggar, WD
MLA Citation
Alman, BA, Raza, SN, and Biggar, WD. "Steroid Treatment and the Development of Scoliosis in Males with Duchenne Muscular Dystrophy." Journal of Bone and Joint Surgery - Series A 86.3 (2004): 519-524.
Source
scival
Published In
Journal of Bone and Joint Surgery - Series A
Volume
86
Issue
3
Publish Date
2004
Start Page
519
End Page
524

Defective Limb Embryology

Authors
Yassir, WK; Alman, BA; Goldberg, MJ
MLA Citation
Yassir, WK, Alman, BA, and Goldberg, MJ. "Defective Limb Embryology." Fetal and Neonatal Physiology: Third Edition. December 1, 2003. 1844-1849.
Source
scopus
Volume
2-2
Publish Date
2003
Start Page
1844
End Page
1849
DOI
10.1016/B978-0-7216-9654-6.50183-1

NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia.

Growth plate chondrocytes undergo a coordinated differentiation process resulting in terminal differentiation and new bone formation. Enchondromas are pre-malignant, benign cartilaginous lesions that arise from growth plate chondrocytes that fail to undergo terminal differentiation. NOV (nephroblastoma overexpressed) is a member of the CCN family of proteins, which share a common multi-modular organization. While the role of NOV in chondrocyte development and cartilage neoplasia is not known, other CCN family members play a role in chondrocyte differentiation, or are differentially regulated in cartilage neoplasia. In embryonic murine growth plates, NOV was expressed in pre-hypertrophic and early hypertrophic chondrocytes. PTHrP treatment (which inhibits terminal differentiation) decreased NOV expression in murine femurs maintained in organ culture, and decreased the activity of a NOV reporter construct in vitro. Expression of the CCN family members NOV, CTGF, CYR61, and WISP-1 was examined in 15 chondrosarcomas of various grades and in three enchondromas. Expression of all of the family members was lower in the higher-grade tumours. As identification of the grade of cartilage neoplasia can sometimes be difficult using histology alone, the level of expression of CCN family members could be a useful adjunct in the determination of tumour grade.

Authors
Yu, C; Le, A-T; Yeger, H; Perbal, B; Alman, BA
MLA Citation
Yu, C, Le, A-T, Yeger, H, Perbal, B, and Alman, BA. "NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia." J Pathol 201.4 (December 2003): 609-615.
PMID
14648665
Source
pubmed
Published In
The Journal of Pathology
Volume
201
Issue
4
Publish Date
2003
Start Page
609
End Page
615
DOI
10.1002/path.1468

Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis (desmoid tumor) is a locally invasive soft tissue neoplasm associated with mutations resulting in beta-catenin-mediated transcriptional activation. This tumor is composed of cells with histological and molecular characteristics common to proliferating mesenchymal cells of dermal wounds. Using immunohistochemistry and RT-PCR, we show that Rhamm, a protein with an important role in wound healing and neoplastic progression, is also expressed at high levels in aggressive fibromatosis. A mouse harboring a targeted deletion in Rhamm was generated, resulting in viable Rhamm-/- animals. Rhamm-/- mice were crossed with Apc/Apc1638N mice, which harbor a targeted mutation in the Apc gene predisposing animals to gastrointestinal and aggressive fibromatosis tumors. Rhamm deficiency significantly decreased the number of aggressive fibromatosis tumors formed, but did not alter the number of gastrointestinal polyps. Cell culture studies show that Rhamm regulates cell proliferation in both fibroblasts and fibromatosis cells under conditions of low density, but not high density. These results suggest that Rhamm regulates proliferation of cells with sparse cell-cell contacts, such as occurs in aggressive fibromatosis; provides the first genetic evidence implicating Rhamm in tumor pathology; and suggest Rhamm blockade as a potential therapeutic target for this otherwise difficult-to-treat neoplasm.

Authors
Tolg, C; Poon, R; Fodde, R; Turley, EA; Alman, BA
MLA Citation
Tolg, C, Poon, R, Fodde, R, Turley, EA, and Alman, BA. "Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor)." Oncogene 22.44 (October 9, 2003): 6873-6882.
PMID
14534534
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
22
Issue
44
Publish Date
2003
Start Page
6873
End Page
6882
DOI
10.1038/sj.onc.1206811

Developmental pathways in musculoskeletal neoplasia: involvement of the Indian Hedgehog-parathyroid hormone-related protein pathway.

There are many crucial genes and signaling pathways in the proper development of an organism. Pathologies may arise from a deregulation of these pathways. The Indian Hedgehog-PTH-related protein (Ihh-PTHrP) pathway is vital in the proper development of endochondral bones, such as the long bones. The Ihh-PTHrP pathway regulates the rate at which chondrocytes within the growth plate proliferate and differentiate. Thus, this pathway allows for the longitudinal growth of bones. However, a disruption in this pathway may lead to enchondromas and osteochondromas, which are both childhood cartilaginous neoplasms. Recently, our lab identified a mutant receptor for PTHrP in enchondroma samples. Mice expressing this mutant receptor and mice with increased Ihh activity develop conditions similar to human enchondromatosis. Linkage analysis shows an association between EXT genes and osteochondromas in hereditary multiple exostoses syndrome. Studies in Drosophila and mice suggest EXT gene products play a role in the diffusion of hedgehog proteins. A mutation in EXT genes may result in an abnormal Ihh diffusion pattern leading to an osteochondroma. There are agents that inhibit Hedgehog signaling. These agents may be useful in the treatment of enchondromas and osteochondromas. This review will discuss the discovery of the Ihh-PTHrP pathway and its involvement in neoplasia, and will suggest possible novel therapeutic agents in the treatment of these cartilaginous neoplasms.

Authors
Tiet, TD; Alman, BA
MLA Citation
Tiet, TD, and Alman, BA. "Developmental pathways in musculoskeletal neoplasia: involvement of the Indian Hedgehog-parathyroid hormone-related protein pathway." Pediatr Res 53.4 (April 2003): 539-543. (Review)
PMID
12612211
Source
pubmed
Published In
Pediatric Research
Volume
53
Issue
4
Publish Date
2003
Start Page
539
End Page
543
DOI
10.1203/01.PDR.0000054688.93486.18

Beta-catenin expression in Dupuytren's disease: Potential role for cell-matrix interactions in modulating beta-catenin levels in vivo and in vitro

Dupuytren's disease (DD) is a superficial fibromatosis of the hand. Although the molecular mechanisms responsible for this disease are unknown, recent studies suggest that beta-catenin may be a key factor involved in fibromatosis. In this study, we analysed the in vivo and in vitro expression levels of beta-catenin in DD, using surgical specimens and primary cell lines. Although no somatic mutations (exon 3) of beta-catenin were detected, Western blot analysis revealed high levels of beta-catenin in diseased palmar fascia, and low to undetectable levels of beta-catenin in patient-matched normal palmar fascia. Immunohistochemistry analysis showed high levels of beta-catenin expression within the disease fascia, as well as cytoplasmic and nuclear accumulations of the protein. Immunoprecipitation of beta-catenin from seven patient lesions showed the protein to be tyrosine phosphorylated. Lastly, Western analysis of three patient-matched (disease and normal fascia) primary cell cultures showed significantly elevated levels of beta-catenin in disease cells cultured in three-dimensional collagen lattices. This is the first extensive in vivo and in vitro characterization of beta-catenin in DD, and the first to suggest that the extracellular matrix may play an important role in modulating beta-catenin stability in DD.

Authors
Varallo, VM; Gan, BS; Seney, S; Ross, DC; Roth, JH; Richards, RS; McFarlane, RM; Alman, B; Howard, JC
MLA Citation
Varallo, VM, Gan, BS, Seney, S, Ross, DC, Roth, JH, Richards, RS, McFarlane, RM, Alman, B, and Howard, JC. "Beta-catenin expression in Dupuytren's disease: Potential role for cell-matrix interactions in modulating beta-catenin levels in vivo and in vitro." Oncogene 22.24 (2003): 3680-3684.
PMID
12802275
Source
scival
Published In
Oncogene
Volume
22
Issue
24
Publish Date
2003
Start Page
3680
End Page
3684
DOI
10.1038/sj.onc.1206415

Elevated levels of β-catenin and fibronectin in three-dimensional collagen cultures of Dupuytren's disease cells are regulated by tension in vitro

Background: Dupuytren's contracture or disease (DD) is a fibro-proliferative disease of the hand that results in the development of scar-like, collagen-rich disease cords within specific palmar fascia bands. Although the molecular pathology of DD is unknown, recent evidence suggests that β-catenin may play a role. In this study, collagen matrix cultures of primary disease fibroblasts show enhanced contraction and isometric tension-dependent changes in β-catenin and fibronectin levels. Methods: Western blots of β-catenin and fibronectin levels were determined for control and disease primary cell cultures grown within stressed- and attached-collagen matrices. Collagen contraction was quantified, and immunocytochemistry analysis of filamentous actin performed. Results: Disease cells exhibited enhanced collagen contraction activity compared to control cells. Alterations in isometric tension of collagen matrices triggered dramatic changes in β-catenin and fibronectin levels, including a transient increase in β-catenin levels within disease cells, while fibronectin levels steadily decreased to levels below those seen in normal cell cultures. In contrast, both fibronectin and β-catenin levels increased in attached collagen-matrix cultures of disease cells, while control cultures showed only increases in fibronectin levels. Immunocytochemistry analysis also revealed extensive filamentous actin networks in disease cells, and enhanced attachment and spreading of disease cell in collagen matrices. Conclusion: Three-dimensional collagen matrix cultures of primary disease cell lines are more contractile and express a more extensive filamentous actin network than patient-matched control cultures. The elevated levels of β-catenin and Fn seen in collagen matrix cultures of disease fibroblasts can be regulated by changes in isometric tension.

Authors
Howard, JC; Varallo, VM; Ross, DC; Roth, JH; Faber, KJ; Alman, B; Gan, BS
MLA Citation
Howard, JC, Varallo, VM, Ross, DC, Roth, JH, Faber, KJ, Alman, B, and Gan, BS. "Elevated levels of β-catenin and fibronectin in three-dimensional collagen cultures of Dupuytren's disease cells are regulated by tension in vitro." BMC Musculoskeletal Disorders 4 (2003): 1-12.
PMID
12866952
Source
scival
Published In
BMC Musculoskeletal Disorders
Volume
4
Publish Date
2003
Start Page
1
End Page
12
DOI
10.1186/1471-2474-4-1

Eosinophilic granuloma. A different behaviour in children than in adults.

Localised Langerhans-cell histiocytosis of bone (eosinophilic granuloma) is a benign tumour-like condition with a variable clinical course. Different forms of treatment have been reported to give satisfactory results. However, previous series all contain patients with a wide age range. Our aim was to investigate the effect of skeletal maturity on the rate of recurrence of isolated eosinophilic granuloma of bone excluding those arising in the spine. We followed up 32 patients with an isolated eosinophilic granuloma for a mean of five years; 17 were skeletally immature. No recurrences were noted in the skeletally immature group even after biopsy alone. By contrast, four of 13 skeletally mature patients had a recurrence and required further surgery. This suggests that eosinophilic granuloma has a low rate of recurrence in skeletally immature patients.

Authors
Plasschaert, F; Craig, C; Bell, R; Cole, WG; Wunder, JS; Alman, BA
MLA Citation
Plasschaert, F, Craig, C, Bell, R, Cole, WG, Wunder, JS, and Alman, BA. "Eosinophilic granuloma. A different behaviour in children than in adults." J Bone Joint Surg Br 84.6 (August 2002): 870-872.
PMID
12211681
Source
pubmed
Published In
Journal of Bone and Joint Surgery (British Volume)
Volume
84
Issue
6
Publish Date
2002
Start Page
870
End Page
872

Genetic etiology does not supplant the need to understand orthopaedic disorders.

Authors
Alman, BA
MLA Citation
Alman, BA. "Genetic etiology does not supplant the need to understand orthopaedic disorders." Clin Orthop Relat Res 401 (August 2002): 2-3.
PMID
12151875
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Issue
401
Publish Date
2002
Start Page
2
End Page
3

A classification for genetic disorders of interest to orthopaedists.

The genetic etiology of many disorders of interest to the orthopaedist now is known. Based on this information, these disorders can be grouped broadly based on the function of the causative gene into five categories: structural, tumor and cell regulatory, developmental, important in nerve or muscle function, and protein processing (enzymes). In addition, some disorders are caused by large chromosomal abnormalities, which comprise a sixth class. Disorders in each of these categories share similarities in their clinical manifestations, treatment, prognosis, and inheritance pattern. This classification is a useful way to remember the major clinical manifestations and treatment principles for genetic disorders of interest to the orthopaedist.

Authors
Alman, BA
MLA Citation
Alman, BA. "A classification for genetic disorders of interest to orthopaedists." Clin Orthop Relat Res 401 (August 2002): 17-26.
PMID
12151878
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Issue
401
Publish Date
2002
Start Page
17
End Page
26

Eosinophilic granuloma - A different behaviour in children than in adults

Authors
Plasschaert, F; Craig, C; Bell, R; Cole, WG; Wunder, JS; Alman, BA
MLA Citation
Plasschaert, F, Craig, C, Bell, R, Cole, WG, Wunder, JS, and Alman, BA. "Eosinophilic granuloma - A different behaviour in children than in adults." JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME 84B.6 (August 2002): 870-872.
Source
wos-lite
Published In
Journal of Bone and Joint Surgery (British Volume)
Volume
84B
Issue
6
Publish Date
2002
Start Page
870
End Page
872
DOI
10.1302/0301-620X.84B6.12585

beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds.

Fibroproliferative processes are a group of disorders in which there is excessive proliferation of spindle (mesenchymal fibroblast-like) cells. They range from hypertrophic scars to neoplasms such as aggressive fibromatosis. Cells from these disorders share cytologic similarity with fibroblasts present during the proliferative phase of wound healing, suggesting that they represent a prolonged wounding response. A critical role for beta-catenin in mesenchymal cells in fibroproliferative processes is suggested by its high rate of somatic mutation in aggressive fibromatosis. Using a Tcf-reporter mouse we found that beta-catenin protein level and Tcf-transcriptional activity are elevated in fibroblasts during the proliferative phase of healing. We generated a transgenic mouse in which stabilized beta-catenin is expressed in mesenchymal cells under control of a tetracycline-regulated promoter. Fibroblasts from the transgenic mice exhibited increased proliferation, motility, and invasiveness when expressing stabilized beta-catenin and induced tumors after induction of the transgene when grafted into nude mice. Mice developed aggressive fibromatoses and hyperplastic gastrointestinal polyps after 3 months of transgene induction and healed with hyperplastic cutaneous wounds compared with control mice, which demonstrates an important function for beta-catenin in mesenchymal cells and shows a central role for beta-catenin in wound healing and fibroproliferative disorders.

Authors
Cheon, SS; Cheah, AYL; Turley, S; Nadesan, P; Poon, R; Clevers, H; Alman, BA
MLA Citation
Cheon, SS, Cheah, AYL, Turley, S, Nadesan, P, Poon, R, Clevers, H, and Alman, BA. "beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds." Proc Natl Acad Sci U S A 99.10 (May 14, 2002): 6973-6978.
PMID
11983872
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
99
Issue
10
Publish Date
2002
Start Page
6973
End Page
6978
DOI
10.1073/pnas.102657399

A mutant PTH/PTHrP type I receptor in enchondromatosis.

Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH). PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.

Authors
Hopyan, S; Gokgoz, N; Poon, R; Gensure, RC; Yu, C; Cole, WG; Bell, RS; Jüppner, H; Andrulis, IL; Wunder, JS; Alman, BA
MLA Citation
Hopyan, S, Gokgoz, N, Poon, R, Gensure, RC, Yu, C, Cole, WG, Bell, RS, Jüppner, H, Andrulis, IL, Wunder, JS, and Alman, BA. "A mutant PTH/PTHrP type I receptor in enchondromatosis." Nat Genet 30.3 (March 2002): 306-310.
PMID
11850620
Source
pubmed
Published In
Nature Genetics
Volume
30
Issue
3
Publish Date
2002
Start Page
306
End Page
310
DOI
10.1038/ng844

Eosinophilic granuloma

Localised Langerhans-cell histiocytosis of bone (eosinophilic granuloma) is a benign tumour-like condition with a variable clinical course. Different forms of treatment have been reported to give satisfactory results. However, previous series all contain patients with a wide age range. Our aim was to investigate the effect of skeletal maturity on the rate of recurrence of isolated eosinophilic granuloma of bone excluding those arising in the spine. We followed up 32 patients with an isolated eosinophilic granuloma for a mean of five years; 17 were skeletally immature. No recurrences were noted in the skeletally immature group even after biopsy alone. By contrast, four of 13 skeletally mature patients had a recurrence and required further surgery. This suggests that eosinophilic granuloma has a low rate of recurrence in skeletally immature patients.

Authors
Plasschaert, F; Craig, C; Bell, R; Cole, WG; Wunder, JS; Alman, BA
MLA Citation
Plasschaert, F, Craig, C, Bell, R, Cole, WG, Wunder, JS, and Alman, BA. "Eosinophilic granuloma." Journal of Bone and Joint Surgery - Series B 84.6 (2002): 870-872.
Source
scival
Published In
Journal of Bone and Joint Surgery - Series B
Volume
84
Issue
6
Publish Date
2002
Start Page
870
End Page
872

Idiopathic scoliosis in families of children with congenital scoliosis

Although most cases of congenital scoliosis are thought to be of sporadic etiology, it is not known whether other types of spinal deformity occur in families of individuals with this type of scoliosis. Children with congenital scoliosis were identified through a review of health records and radiographic report databases. Of 237 children with congenital scoliosis investigated, 49 (20.7%) reported a family history of spinal deformity. Detailed pedigrees were done, which showed a history of idiopathic scoliosis in 17.3% of the 237 families. This is a higher than expected rate of spinal deformity in families of children with congenital scoliosis, and the strong association of idiopathic scoliosis in families of children with congenital scoliosis has not been reported previously. Although this finding could be related to the chance occurrence of multiple genetic abnormalities or sporadic events in these families, it does raise the possibility that one genetic defect at least predisposes these families to having different types of spinal deformity develop.

Authors
Purkiss, SB; Driscoll, B; Cole, WG; Alman, B
MLA Citation
Purkiss, SB, Driscoll, B, Cole, WG, and Alman, B. "Idiopathic scoliosis in families of children with congenital scoliosis." Clinical Orthopaedics and Related Research 401 (2002): 27-31.
PMID
12151879
Source
scival
Published In
Clinical Orthopaedics and Related Research
Issue
401
Publish Date
2002
Start Page
27
End Page
31

Editorial comment

Authors
Alman, BA
MLA Citation
Alman, BA. "Editorial comment." Clinical Orthopaedics and Related Research 401 (2002): 2-3.
Source
scival
Published In
Clinical Orthopaedics and Related Research
Issue
401
Publish Date
2002
Start Page
2
End Page
3

Fibromatoses in childhood: the desmoid/fibromatosis complex.

Authors
Dormans, JP; Spiegel, D; Meyer, J; Asada, N; Alman, BA; Pill, SG; Himelstein, B; Womer, R
MLA Citation
Dormans, JP, Spiegel, D, Meyer, J, Asada, N, Alman, BA, Pill, SG, Himelstein, B, and Womer, R. "Fibromatoses in childhood: the desmoid/fibromatosis complex." Med Pediatr Oncol 37.2 (August 2001): 126-131. (Review)
PMID
11496351
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
37
Issue
2
Publish Date
2001
Start Page
126
End Page
131
DOI
10.1002/mpo.1181

Tcf-3 expression and beta-catenin mediated transcriptional activation in aggressive fibromatosis (desmoid tumour).

Aggressive fibromatosis harbours mutations resulting in beta-catenin protein stabilization. Primary cell cultures demonstrate constitutive tcf activation in aggressive fibromatosis. Expression and co-immunoprecipitation studies suggest that beta-catenin binds and activates tcf-3 in this tumour. This is the first demonstration of tcf-3 activation by beta-catenin stabilization in a human neoplastic process.

Authors
Tejpar, S; Li, C; Yu, C; Poon, R; Denys, H; Sciot, R; Van Cutsem, E; Cassiman, JJ; Alman, BA
MLA Citation
Tejpar, S, Li, C, Yu, C, Poon, R, Denys, H, Sciot, R, Van Cutsem, E, Cassiman, JJ, and Alman, BA. "Tcf-3 expression and beta-catenin mediated transcriptional activation in aggressive fibromatosis (desmoid tumour)." Br J Cancer 85.1 (July 6, 2001): 98-101.
PMID
11437409
Source
pubmed
Published In
British Journal of Cancer
Volume
85
Issue
1
Publish Date
2001
Start Page
98
End Page
101
DOI
10.1054/bjoc.2001.1857

Potential treatment for clubfeet based on growth factor blockade.

Select soft tissues in clubfeet are contracted, resulting in stiffness. These contracted tissues share ultrastructural characteristics with palmar fibromatosis (Dupuytren contracture), in which the growth factors transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) are expressed and play a role in regulating cell behavior. More contracted tissue (medial side of the foot) and less contracted tissue (lateral side of the foot) from 20 clubfeet were studied using reverse transcription-polymerase chain reaction and western analysis for expression of TGF-beta and PDGF (along with collagen type I and type III). Cell cultures were established from the more contracted tissues to determine the effect of blockade of these factors with neutralizing antibodies on proliferation, chemotaxis, and collagen expression. Both growth factors were expressed at higher levels by the contracted tissues, and blockade led to decreased collagen expression, proliferation, and chemotaxis. Growth factor blockade has the potential to change the behavior of these cells in a way that would lessen the severity of the contractures, perhaps improving the outcome of clubfoot treatment.

Authors
Li, C; Nguyen, Q; Cole, WG; Alman, BA
MLA Citation
Li, C, Nguyen, Q, Cole, WG, and Alman, BA. "Potential treatment for clubfeet based on growth factor blockade." J Pediatr Orthop 21.3 (May 2001): 372-377.
PMID
11371823
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
21
Issue
3
Publish Date
2001
Start Page
372
End Page
377

Bone morphogenetic proteins (BMPs) and its receptors (BMPR) are expressed by both bone forming and non bone forming lesions

Authors
Khurana, JS; Ogino, S; McHale, T; Feldman, M; Scherbel, U; Wirganowicz, P; Schultz, P; Alman, BA
MLA Citation
Khurana, JS, Ogino, S, McHale, T, Feldman, M, Scherbel, U, Wirganowicz, P, Schultz, P, and Alman, BA. "Bone morphogenetic proteins (BMPs) and its receptors (BMPR) are expressed by both bone forming and non bone forming lesions." BONE 28.5 (May 2001): S112-S112.
Source
wos-lite
Published In
BONE
Volume
28
Issue
5
Publish Date
2001
Start Page
S112
End Page
S112

Local complications after limb-salvage surgery for pediatric bone tumours: a pictorial essay.

The prognosis for patients with bone sarcoma treated with LSS has improved considerably over the past 2 decades, but this has also lead to an increase in the number of complications requiring treatment. Imaging plays an important role, not only in assessing the primary tumour, but also in identifying postsurgical complications. Plain radiography demonstrates the majority of the complications associated with LSS and remains the mainstay of follow-up imaging. Complications such as fractures are common and warrant frequent plain film follow-up. Imaging with scintigraphy, MRI and CT should be tailored to the patient's clinical history, type of surgery and suspected complications. A baseline postoperative bone scan examination can be helpful for comparisons with subsequent scans for the detection of complications. Sonography should be considered if infection is suspected. Finally, tumour recurrence may be frequent enough to consider more extensive use of MRI.

Authors
Babyn, PS; Wihlborg, CE; Tjong, JK; Alman, BA; Silberberg, PJ
MLA Citation
Babyn, PS, Wihlborg, CE, Tjong, JK, Alman, BA, and Silberberg, PJ. "Local complications after limb-salvage surgery for pediatric bone tumours: a pictorial essay." Can Assoc Radiol J 52.1 (February 2001): 35-42.
PMID
11247264
Source
pubmed
Published In
Canadian Association of Radiologists Journal
Volume
52
Issue
1
Publish Date
2001
Start Page
35
End Page
42

Cyclooxygenase-two (COX-2) modulates proliferation in aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis is a locally invasive soft tissue lesion. Seventy-five per cent of cases harbor a somatic mutation in either the APC or beta-catenin genes, resulting in beta-catenin protein stabilization. Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin synthesis that modulates the formation of colonic neoplasia, especially in cases due to mutations resulting in beta-catenin stabilization. Human aggressive fibromatoses and lesions from the Apc+/Apc1638N mouse (a murine model for Apc-driven fibromatosis) demonstrated elevated COX-2 levels. COX-2 blockade either by the selective agent DFU or by non-selective COX blocking agents results in reduced proliferation in human tumor cell cultures. Breeding mice with Cox-2-/- mice resulted in no difference in number of aggressive fibromatoses formed, but in a smaller tumor size, while there was a decrease in number of GI lesions by 50%. Mice fed various COX blocking agents also showed a decline in tumor size. COX-2 expression was regulated by tcf-dependent transcription in this lesion. COX-2 partially regulates proliferation due to beta-catenin stabilization in aggressive fibromatosis. Although COX blockade alone does not cause tumor regression, this data suggests that it may have a role as an adjuvant therapy to slow tumor growth in this lesion.

Authors
Poon, R; Smits, R; Li, C; Jagmohan-Changur, S; Kong, M; Cheon, S; Yu, C; Fodde, R; Alman, BA
MLA Citation
Poon, R, Smits, R, Li, C, Jagmohan-Changur, S, Kong, M, Cheon, S, Yu, C, Fodde, R, and Alman, BA. "Cyclooxygenase-two (COX-2) modulates proliferation in aggressive fibromatosis (desmoid tumor)." Oncogene 20.4 (January 25, 2001): 451-460.
PMID
11313976
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
20
Issue
4
Publish Date
2001
Start Page
451
End Page
460
DOI
10.1038/sj.onc.1204107

Sensitivity of a clinical examination to predict need for radiography in children with ankle injuries: A prospective study

Background: Radiographs are ordered routinely for children with ankle trauma. We assessed the predictive value of a clinical examination to identify a predefined group of low-risk injuries, management of which would not be affected by absence of a radiograph. We aimed to show that no more than 1% of children with low-risk examinations (signs restricted to the distal fibula) would have high-risk fractures (all fractures except avulsion, buckle, and non-displaced Salter-Harris I and II fractures of the distal fibula), and to compare the potential reduction in radiography in children with low-risk examinations with that obtained by application of the Ottawa ankle rules (OAR). Methods: Standard clinical examinations and subsequent radiographs were prospectively and independently evaluated in two tertiary-care paediatric emergency departments in North America. Eligible participants were healthy children aged 3-16 years with acute ankle injuries. Sample size, negative and positive predictive values, sensitivity, and specificity were calculated. McNemar's test was used to compare differences in the potential reduction in radiographs between the low-risk examination and the OAR. Findings: 607 children were enrolled; 581 (95.7%) received follow-up. None of the 381 children with low-risk examinations had a high-risk fracture (negative predictive value 100% [95% CI 99.2-100]; sensitivity 100% [93.3-100]). Radiographs could be omitted in 62.8% of children with low-risk examinations, compared with only 12.0% reduction obtained by application of the OAR (p<0.0001). Interpretation: A low-risk clinical examination in children with ankle injuries identifies 100% of high-risk diagnoses and may result in greater reduction of radiographic referrals than the OAR.

Authors
Boutis, K; Komar, L; Jaramillo, D; Babyn, P; Alman, B; Snyder, B; Mandl, KD; Schuh, S
MLA Citation
Boutis, K, Komar, L, Jaramillo, D, Babyn, P, Alman, B, Snyder, B, Mandl, KD, and Schuh, S. "Sensitivity of a clinical examination to predict need for radiography in children with ankle injuries: A prospective study." Lancet 358.9299 (2001): 2118-2121.
PMID
11784626
Source
scival
Published In
The Lancet
Volume
358
Issue
9299
Publish Date
2001
Start Page
2118
End Page
2121
DOI
10.1016/S0140-6736(01)07218-X

Suppressor of Fused Negatively Regulates β-Catenin Signaling

Suppressor of fused (Su(fu)) is a negative regulator of the Hedgehog signaling pathway that controls the nuclear-cytoplasmic distribution of Gli/Ci transcription factors through direct protein-protein interactions. We show here that Su(fu) is present in a complex with the oncogenic transcriptional activator β-catenin and functions as a negative regulator of T-cell factor (Tcf)-dependent transcription. Overexpression of Su(fu) in SW480 (APC mut) colon cancer cells in which β-catenin protein is stabilized leads to a reduction in nuclear β-catenin levels and in Tcf-dependent transcription. This effect of Su(fu) overexpression can be blocked by treatment of these cells with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export. Overexpression of Su(fu) suppresses growth of SW480 (APCmut) tumor cells in nude mice. These observations indicate that Su(fu) negatively regulates β-catenin signaling and that CRM-1-mediated nuclear export plays a role in this regulation. Our results also suggest that Su(fu) acts as a tumor suppressor.

Authors
Meng, X; Poon, R; Zhang, X; Cheah, A; Ding, Q; Hui, C-C; Alman, B
MLA Citation
Meng, X, Poon, R, Zhang, X, Cheah, A, Ding, Q, Hui, C-C, and Alman, B. "Suppressor of Fused Negatively Regulates β-Catenin Signaling." Journal of Biological Chemistry 276.43 (2001): 40113-40119.
PMID
11477086
Source
scival
Published In
Journal of Biological Chemistry
Volume
276
Issue
43
Publish Date
2001
Start Page
40113
End Page
40119
DOI
10.1074/jbc.M105317200

Short stature as a screening test for endocrinopathy in slipped capital femoral epiphysis

Slipped capital femoral epiphysis may be associated with hypothyroidism and other endocrinopathies. Routine screening for such abnormalities is unlikely to be cost-effective since the overall incidence of these disorders, in association with slipped capital femoral epiphysis, is low. The identification of a presenting characteristic which would predict the chance of an associated endocrinopathy would allow only selected children to be screened. Our aim was to determine if certain characteristics were useful as a screen for patients with an underlying endocrinopathy who presented with slipped capital femoral epiphysis. Between January 1988 and December 1996 we recorded gender, age, height, unilateral or bilateral involvement and an associated diagnosis of endocrinopathy for all patients who were treated for slipped capital femoral epiphysis. Of 166 such patients 13 (7.8%) had an endocrinopathy. Height was the only useful screening characteristic, although bilateral involvement was more likely in those with an endocrinopathy. Most (90.9%) of this latter group were below the tenth percentile for height compared with only 5.4% in those who did not have an endocrinopathy (p < 0.005). The sensitivity and negative predictive value of detecting an underlying endocrinopathy in a patient presenting with a slipped capital femoral epiphysis and short stature (tenth percentile or less) were 90.2% and 98.6%, respectively. Patients who are on or below the tenth percentile for height at the time of presentation should be screened for a possible endocrine abnormality using measurement of thyroid-stimulating hormone and free thyroxine as a preliminary screening test. These hormones are most likely to be abnormal in the presence of endocrine dysfunction.

Authors
Burrow, SR; Alman, B; Wright, JG
MLA Citation
Burrow, SR, Alman, B, and Wright, JG. "Short stature as a screening test for endocrinopathy in slipped capital femoral epiphysis." Journal of Bone and Joint Surgery - Series B 83.2 (2001): 263-268.
PMID
11284578
Source
scival
Published In
Journal of Bone and Joint Surgery - Series B
Volume
83
Issue
2
Publish Date
2001
Start Page
263
End Page
268

Congenital clubfoot

Congenital clubfoot, one of the most common musculoskeletal anomalies, varies considerably in severity and its response to treatment. The aetiology, pathogenesis and treatment have been subjects of wide debate since antiquity. Even today, there is little consensus on how the deformity is best treated and the literature devoted to clubfoot is voluminous and confusing. A comprehensive review article could take up an entire issue of this journal yet provide little insight into practical aspects of management. We have therefore decided to provide a brief overview of the subject and to emphasize two areas of current major interest; the aetiology and late management of the deformity in the adolescent and young adult. The aetiology is important because a true understanding of the precise nature of the deformity will ultimately be essential in determining the preferred method and timing of early correction. Historically, less emphasis has been placed on how best to manage impairment of function at skeletal maturity secondary to residual deformity and the sequelae of treatment in early childhood. A review article by Ponseti describes the early management in detail from a traditional and conservative point of view. © 2001 Harcourt Publishers Ltd.

Authors
Wedge, JH; Daniels, TR; Alman, BA
MLA Citation
Wedge, JH, Daniels, TR, and Alman, BA. "Congenital clubfoot." Current Paediatrics 11.5 (2001): 332-340.
Source
scival
Published In
Current Paediatrics
Volume
11
Issue
5
Publish Date
2001
Start Page
332
End Page
340
DOI
10.1054/cupe.2001.0214

Prominent expression of mRNA for proinflammatory cytokines in synovium in patients with juvenile rheumatoid arthritis or chronic Lyme arthritis.

OBJECTIVE: To examine the cytokine profiles in synovium of patients with juvenile rheumatoid arthritis (JRA) or Lyme arthritis, 2 chronic inflammatory arthritides that affect children. METHODS: We used in situ hybridization with specific riboprobes to determine the expression of mRNA for proinflammatory or antiinflammatory cytokines in synovial samples from 5 patients with early, untreated JRA, 15 patients with late, treated JRA, and 9 patients with chronic Lyme arthritis. For comparison, synovia were examined from 6 patients with rheumatoid or psoriatic arthritis, and from 9 patients with various orthopedic conditions. RESULTS: Among the children with early, untreated JRA, a median of 3 to 8% of inflammatory cells in synovial samples expressed mRNA for the proinflammatory cytokines interleukin 1beta (IL-1beta), tumor necrosis factor-alpha(TNF-alpha), or interferon-gamma (IFN-gamma). Although a median of 3.9% of the cells expressed mRNA for the antiinflammatory cytokine IL-10, none had IL-4 mRNA. Most of the patients with late, treated JRA, chronic Lyme arthritis, rheumatoid, or psoriatic arthritis had mRNA for each of these proinflammatory cytokines in about 1% of the cells, whereas mRNA for the antiinflammatory cytokines was less frequent. The inflammatory cell density was much less in the synovium of patients with various orthopedic conditions, but about 1% of the infiltrating cells expressed mRNA for at least one of the proinflammatory cytokines. CONCLUSION: Patients with early or late JRA or chronic Lyme arthritis have expression of mRNA in synovial tissue primarily for proinflammatory cytokines, with less expression of antiinflammatory cytokines.

Authors
Harjacek, M; Diaz-Cano, S; Alman, BA; Coburn, J; Ruthazer, R; Wolfe, H; Steere, AC
MLA Citation
Harjacek, M, Diaz-Cano, S, Alman, BA, Coburn, J, Ruthazer, R, Wolfe, H, and Steere, AC. "Prominent expression of mRNA for proinflammatory cytokines in synovium in patients with juvenile rheumatoid arthritis or chronic Lyme arthritis." J Rheumatol 27.2 (February 2000): 497-503.
PMID
10685820
Source
pubmed
Published In
The Journal of rheumatology
Volume
27
Issue
2
Publish Date
2000
Start Page
497
End Page
503

A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor

Desmoid tumors arise sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis (FAP). In FAP, two distinct clinical presentations of the desmoid phenotype are seen: 1) one or a few desmoid tumors present predominantly in the abdominal wall or the abdomen; 2) a florid proliferation of tumors early in life, mostly near the axial skeleton or extremities. These different phenotypes have been associated with different sites of germline mutations in the adenomatous polyposis coli gene (APC gene). We present a large, French-Canadian kindred with a florid desmoid tumor phenotype caused by a germline mutation at codon 2643-2644 of the APC gene. The phenotype was characterized by the early onset of multiple tumors, arising near the axial skeleton and in proximal extremities. The penetrance of desmoid tumors was near 100% in this kindred. However, the expression of the disease was variable amongst the different affected relatives. Many gene carriers had cutaneous cysts. Polyposis of the colon was rarely observed in the affected individuals and we did not document upper gastro-intestinal polyps. The mutant APC allele did not express a stable truncated protein in vivo. Molecular analysis of the proband's tumor DNA revealed a somatic inactivating mutation of the wild-type allele. Immunohistochemistry on the tumor also demonstrated elevated levels of beta-catenin. The present study demonstrates that this extreme 3' APC mutation is associated with a severely penetrant desmoid phenotype and attenuated polyposis coli. It also suggests the involvement of the beta-catenin pathway in the development of desmoid tumors in FAP. The natural history of the disease is variable between individuals, and surgical interventions have to be timed appropriately due to the frequent recurrences.

Authors
Couture, J; Mitri, A; Lagace, R; Smits, R; Berk, T; Bouchard, H-L; Fodde, R; Alman, B; Bapat, B
MLA Citation
Couture, J, Mitri, A, Lagace, R, Smits, R, Berk, T, Bouchard, H-L, Fodde, R, Alman, B, and Bapat, B. "A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor." Clinical Genetics 57.3 (2000): 205-212.
PMID
10782927
Source
scival
Published In
Clinical Genetics
Volume
57
Issue
3
Publish Date
2000
Start Page
205
End Page
212
DOI
10.1034/j.1399-0004.2000.570306.x

A shortened course of parenteral antibiotic therapy in the management of acute septic arthritis of the hip

We reviewed 20 consecutive patients with a culture-proven acute septic arthritis of the hip who were treated with a shortened course of parenteral antibiotic therapy after a surgical drainage. Patients were switched over to an oral antibiotic when they showed clinical improvement. Sixteen of the 20 patients had parenteral antibiotic therapy of <10 days, whereas nine of these patients received <7 days of parenteral therapy (mean, 8.2 days). No recurrence of infection, readmission, or osteomyelitis was observed after the discharge. At the follow-up interview (mean, 32 months), 18 patients were completely asymptomatic, and two patients had occasional hip pain with activity but no physical limitations. All 20 patients had normal hip range of motion and gait. Their latest radiographs (mean, 26 months) revealed 11 patients with normal findings, six patients with mild coxa magna, and three patients with a smaller ossific nucleus compared with the unaffected side. We conclude that a community-acquired, acute gram-positive septic arthritis of the hip can be managed safely with a surgical drainage and a shortened course of parenteral antibiotic therapy, which can be switched over to an oral therapy based on the patient's response to the therapy.

Authors
Kim, HKW; Alman, B; Cole, WG
MLA Citation
Kim, HKW, Alman, B, and Cole, WG. "A shortened course of parenteral antibiotic therapy in the management of acute septic arthritis of the hip." Journal of Pediatric Orthopaedics 20.1 (2000): 44-47.
PMID
10641687
Source
scival
Published In
Journal of Pediatric Orthopaedics
Volume
20
Issue
1
Publish Date
2000
Start Page
44
End Page
47
DOI
10.1097/00004694-200001000-00010

Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis (also called desmoid tumor) occurs as a sporadic lesion or as part of Familial Adenomatous Polyposis, which is caused by germ line mutations in the Adenomatous polyposis Coli (APC) gene. APC is involved in the regulation of the cellular level of beta-catenin, which is a mediator in Wnt signaling. Mutational analysis of the beta-catenin and APC genes was performed in 42 sporadic aggressive fibromatoses. Nine tumors had mutations in APC, and 22 had a point mutation in beta-catenin at either codon 45 or codon 41 (producing a stabilized beta-catenin protein product). Immunohistochemistry showed an elevated beta-catenin protein level in all tumors, regardless of mutational status. Beta-catenin localized to the nucleus, and was not tyrosine phosphorylated in the six tumors in which this was tested. The demonstration of mutations in two mediators in the Wnt-APC-beta-catenin pathway implicates beta-catenin stabilization as the key factor in the pathogenesis of aggressive fibromatosis. This is the first demonstration of somatic beta-catenin mutations in a locally invasive, but non metastatic lesion composed of spindle cells, illustrating the importance of beta-catenin stabilization in a variety of cell types and neoplastic processes. Moreover, this tumor has one of the highest reported frequencies of beta-catenin mutations of any tumor type.

Authors
Tejpar, S; Nollet, F; Li, C; Wunder, JS; Michils, G; dal Cin, P; Van Cutsem, E; Bapat, B; van Roy, F; Cassiman, JJ; Alman, BA
MLA Citation
Tejpar, S, Nollet, F, Li, C, Wunder, JS, Michils, G, dal Cin, P, Van Cutsem, E, Bapat, B, van Roy, F, Cassiman, JJ, and Alman, BA. "Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor)." Oncogene 18.47 (November 11, 1999): 6615-6620.
PMID
10597266
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
18
Issue
47
Publish Date
1999
Start Page
6615
End Page
6620
DOI
10.1038/sj.onc.1203041

Expression of osteocalcin and its transcriptional regulators core-binding factor alpha 1 and MSX2 in osteoid-forming tumours.

Osteosarcoma, fibrous dysplasia, and myositis ossificans contain osteoid-producing cells that are not necessarily morphologically typical osteoblasts. Nevertheless, these pathologic cells may share differentiation steps with osteoblasts at the molecular level. Osteocalcin, a bone-specific extracellular matrix protein, is a marker of mature osteoblasts. Osteocalcin is upregulated by the transcription factor core-binding factor alpha 1, which is responsible for commitment to the osteoblastic lineage, and is downregulated by MSX2, a homeobox-containing transcription factor expressed during the early proliferative phase of osteoblast differentiation. Semiquantitative reverse transcription-polymerase chain reaction was used to compare expression levels of osteocalcin, core-binding factor alpha 1, and MSX2 in 34 osteosarcoma, five fibrous dysplasia, and five myositis ossificans specimens, as well as in seven normal cortical bone samples. Despite normal or elevated levels of core-binding factor alpha-1 expression in most specimens, osteocalcin expression was low or undetectable in most cases of osteosarcoma (25 of 34) and myositis ossificans (4 of 5). Single-strand conformation polymorphism and sequencing did not identify any mutations in the DNA-binding domain of core-binding factor alpha 1. However, a high level of MSX2 expression was demonstrated in these lesions, which may inhibit osteocalcin transcription. The presence of moderate levels of osteocalcin in fibrous dysplasia may contribute to the characteristic disconnected appearance of trabeculae in that entity because osteocalcin is a negative regulator of bone formation.

Authors
Hopyan, S; Gokgoz, N; Bell, RS; Andrulis, IL; Alman, BA; Wunder, JS
MLA Citation
Hopyan, S, Gokgoz, N, Bell, RS, Andrulis, IL, Alman, BA, and Wunder, JS. "Expression of osteocalcin and its transcriptional regulators core-binding factor alpha 1 and MSX2 in osteoid-forming tumours." J Orthop Res 17.5 (September 1999): 633-638.
PMID
10569470
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
17
Issue
5
Publish Date
1999
Start Page
633
End Page
638
DOI
10.1002/jor.1100170503

Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy.

Spinal fusion, ending caudally at L5 rather than at the sacrum, is recommended for selected patients with scoliosis due to Duchenne muscular dystrophy. We present a retrospective review of 48 patients operated on for this condition. Patients having spinal curvature with a Cobb angle of less than 40 degrees and with less than 10 degrees between a line tangential to the superior margins of both iliac crests and a line perpendicular to the spinous processes of L4 and L5, were fused to L5 (38 patients); patients not meeting these criteria were fused to the sacrum (10 patients). Spinal and sitting obliquity increased in patients fused to L5, rather than to the sacrum, but the severity of the worsening obliquity was significantly greater in patients in whom the apex of the curve was below L1. Two of the ten latter patients required revision procedures for worsening obliquity when their pulmonary function deteriorated to less than 25% of predicted values. We recommend fusion to the sacrum for scoliosis in Duchenne muscular dystrophy, especially for patients with an apex to their curve below L1.

Authors
Alman, BA; Kim, HK
MLA Citation
Alman, BA, and Kim, HK. "Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy." J Bone Joint Surg Br 81.5 (September 1999): 821-824.
PMID
10530843
Source
pubmed
Published In
Journal of Bone and Joint Surgery (British Volume)
Volume
81
Issue
5
Publish Date
1999
Start Page
821
End Page
824

Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy

Authors
Alman, BA; Kim, HKW
MLA Citation
Alman, BA, and Kim, HKW. "Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy." JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME 81B.5 (September 1999): 821-824.
Source
wos-lite
Published In
Journal of Bone and Joint Surgery (British Volume)
Volume
81B
Issue
5
Publish Date
1999
Start Page
821
End Page
824
DOI
10.1302/0301-620X.81B5.9383

Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy

Authors
ALMAN, BA
MLA Citation
ALMAN, BA. "Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy." J Bone Joint Surg Br 81 (1999): 821-824.
Source
cinii-english
Published In
J Bone Joint Surg Br
Volume
81
Publish Date
1999
Start Page
821
End Page
824
DOI
10.1302/0301-620X.81B5.9383

Congenital clubfoot

Authors
Daniels, TR; Alman, B; Wedge, JH
MLA Citation
Daniels, TR, Alman, B, and Wedge, JH. "Congenital clubfoot." Current Orthopaedics 13.3 (1999): 229-236.
Source
scival
Published In
Current Orthopaedics
Volume
13
Issue
3
Publish Date
1999
Start Page
229
End Page
236
DOI
10.1016/S0268-0890(99)90008-7

Diagnostic imaging of post limb-salvage complications in pediatric patients with osteogenic sarcoma or Ewing's sarcoma

Authors
Tjong, JK; Babyn, PS; Alman, BA; Silberberg, PJ
MLA Citation
Tjong, JK, Babyn, PS, Alman, BA, and Silberberg, PJ. "Diagnostic imaging of post limb-salvage complications in pediatric patients with osteogenic sarcoma or Ewing's sarcoma." RADIOLOGY 209P (November 1998): 365-365.
Source
wos-lite
Published In
Radiology
Volume
209P
Publish Date
1998
Start Page
365
End Page
365

Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor).

Aggressive fibromatosis is a monoclonal proliferation of spindle (fibroblast-like) cells. A subset of lesions contain somatic truncating adenomatous polyposis coli (APC) gene mutations, and all of the lesions contain an elevated beta-catenin protein level. A major function of APC is to regulate beta-catenin protein level. Beta-catenin has a dual function in the cell: it is a member of the adherens junction, and it binds transcription factors in the tcf-lef family, transactivating transcription. Cell cultures from aggressive fibromatoses containing an APC mutation were studied. Transient transfection of the full-length APC gene caused decreased proliferation and beta-catenin protein level in these cultures. To determine whether beta-catenin protein level was responsible for the change in proliferation rate, stable transfections of deltaN89beta-catenin (a stabilized form that is not degraded by APC, but retains all other functions) were achieved in half of the cultures derived from each tumor, whereas the other half were transfected with an empty vector. Transfection of the full-length APC gene in cultures that were stably transfected with deltaN89beta-catenin did not result in a change in proliferation. The type I promotor of p56lck contains an HMG consensus region, to which members of the tcf-lef family can bind. p56lck was expressed in cultures not transfected with the full-length APC gene and in cultures transfected with the full-length APC gene and deltaN89beta-catenin, but not in cultures transfected with only the full-length APC gene. These data show that APC truncating mutations give aggressive fibromatosis cells a proliferative advantage through beta-catenin and suggest that beta-catenin acts to transactivate transcription.

Authors
Li, C; Bapat, B; Alman, BA
MLA Citation
Li, C, Bapat, B, and Alman, BA. "Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor)." Am J Pathol 153.3 (September 1998): 709-714.
PMID
9736021
Source
pubmed
Published In
The American journal of pathology
Volume
153
Issue
3
Publish Date
1998
Start Page
709
End Page
714

Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).

Sporadic aggressive fibromatosis (also called desmoid tumor) is a monoclonal proliferation of spindle (fibrocyte-like) cells that is locally invasive but does not metastasize. A similarity to abdominal fibromatoses (desmoids) in familial adenomatous polyposis and a cytogenetic study showing partial deletion of 5q in a subset of aggressive fibromatoses suggests that the adenomatous polyposis coli (APC) gene plays a role in its pathogenesis. APC helps regulate the cellular level of beta-catenin, which is a downstream mediator in Wnt (Wingless) signaling. beta-Catenin has a nuclear function (binds transcription factors) and a cell membrane function (is a component of epithelial cell adherens junctions). Six cases of aggressive fibromatosis of the extremities from patients without familial adenomatous polyposis, or a family history of colon cancer, were studied. Immunohistochemistry, using carboxy and amino terminus antibodies to APC, and DNA sequencing showed that three of the six contained an APC-truncating mutation, whereas normal tissues did not contain a mutation. Western blot and Northern dot blot showed that all six tumors had a higher level of beta-catenin protein than surrounding normal tissues, despite containing similar levels of beta-catenin mRNA. Immunohistochemistry localized beta-catenin throughout the cell in tumor tissues, although it localized more to the periphery in cells from normal tissues. Reverse transcription polymerase chain reaction showed that the tumors expressed N-cadherin but not E-cadherin (a pattern of expression of proteins making up adherens junctions similar to fibrocytes), suggesting that the specific adherens junctions present in epithelial cells are not necessary for beta-catenin function. Increased beta-catenin may cause the growth advantage of cells in this tumor through a nuclear mechanism. The increased protein level, relative to the RNA level, suggests that beta-catenin is degraded at a lower rate compared with normal tissues. In some cases, this is caused by a somatic mutation resulting in a truncated APC protein.

Authors
Alman, BA; Li, C; Pajerski, ME; Diaz-Cano, S; Wolfe, HJ
MLA Citation
Alman, BA, Li, C, Pajerski, ME, Diaz-Cano, S, and Wolfe, HJ. "Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors)." Am J Pathol 151.2 (August 1997): 329-334.
PMID
9250146
Source
pubmed
Published In
The American journal of pathology
Volume
151
Issue
2
Publish Date
1997
Start Page
329
End Page
334

Differential collagen I gene expression in fetal fibroblasts.

PURPOSE: Fetal wound healing is characterized by the regeneration of normal dermis and the absence of scar. Transforming growth factor beta-1 (TGF-beta1) is a ubiquitous cytokine with potent fibrogenic effects in both postnatal and fetal wounds. Supplementing fetal wounds with TGF-beta1 results in increased fibrosis consisting primarily of collagen I. We hypothesized that the lack of scar formation in fetal wounds may be caused by differential collagen I gene (COL1A1) expression. The authors examined basal collagen Ia gene expression in human fetal, newborn, and adult dermal fibroblasts after stimulation with exogenous TGF-beta1. METHODS: Subconfluent human dermal fibroblasts from fetal, newborn, and adult cell lines were incubated for 24 hours, then stimulated by incubation for 4 hours with 1 ng/mL of human recombinant TGF-beta1, or with media alone for basal collagen gene expression, and then placed in guanidium isothyocyanate buffer. To quantitate COL1A1 gene expression, total cellular RNA was extracted and subjected to northern and slot blot hybridization analysis with Dig-labeled COL1A1 probes. The membrane was exposed to x-ray film for 15 minutes and developed. RESULTS: Scant COL1A1 gene transcript was detected in control fetal fibroblasts. Brief stimulation with of TGF-beta1 upregulated the COL1A1 gene transcription in fetal fibroblasts. Gene expression for COL1A1 in both postnatal cell lines appeared similar in treated and untreated cells. Housekeeping control (GAPDH) confirmed no difference in total amount of RNA at the start or end of the experiment. CONCLUSION: COL1A1 gene expression is notably absent in unstimulated fetal fibroblasts, but is upregulated by TGF-beta1. In contrast, postnatal fibroblasts demonstrate significant constitutive COL1A1 gene expression at baseline and unchanged after TGF-beta1 stimulation. This differential regulation may contribute to the ability of fetal wounds to regenerate without scar and explain the effect of exogenous TGF-beta1 to increase fibroplasia in fetal dermal incisional wounds.

Authors
Gallivan, K; Alman, BA; Moriarty, KP; Pajerski, ME; O'Donnell, C; Crombleholme, TM
MLA Citation
Gallivan, K, Alman, BA, Moriarty, KP, Pajerski, ME, O'Donnell, C, and Crombleholme, TM. "Differential collagen I gene expression in fetal fibroblasts." J Pediatr Surg 32.7 (July 1997): 1033-1036.
PMID
9247228
Source
pubmed
Published In
Journal of Pediatric Surgery
Volume
32
Issue
7
Publish Date
1997
Start Page
1033
End Page
1036

Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder.

Aggressive fibromatosis (also called deep fibromatosis or desmoid tumor) is a proliferation of cytologically benign-appearing fibrocytes, often resulting in significant functional loss. The nature of the lesion is controversial: some evidence suggests that it is a reactive process, whereas other evidence supports a neoplastic etiology. The pattern of X chromosome inactivation, using a technique based on polymerase chain reaction (PCR) amplification of a hypervariable CAG repeat region flanking Hhal restriction sites of the human androgen receptor gene, was determined in four cases in which cryopreserved tumor and adjacent normal tissue were available. All four tumors demonstrated a monoclonal pattern, while the adjacent normal tissues demonstrated a polyclonal pattern. This demonstrates that aggressive fibromatosis is proliferation of cells derived from a single clone with a growth advantage, and thus is likely a neoplastic process.

Authors
Alman, BA; Pajerski, ME; Diaz-Cano, S; Corboy, K; Wolfe, HJ
MLA Citation
Alman, BA, Pajerski, ME, Diaz-Cano, S, Corboy, K, and Wolfe, HJ. "Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder." Diagn Mol Pathol 6.2 (April 1997): 98-101.
PMID
9098648
Source
pubmed
Published In
Diagnostic Molecular Pathology
Volume
6
Issue
2
Publish Date
1997
Start Page
98
End Page
101

APC mutations are present in some sporadic aggressive fibromatosis.

Authors
Alman, BA; Pajerski, ME; Li, C; DiazCano, SJ; Wolfe, HJ
MLA Citation
Alman, BA, Pajerski, ME, Li, C, DiazCano, SJ, and Wolfe, HJ. "APC mutations are present in some sporadic aggressive fibromatosis." LABORATORY INVESTIGATION 76.1 (January 1997): 21-21.
Source
wos-lite
Published In
Laboratory Investigation
Volume
76
Issue
1
Publish Date
1997
Start Page
21
End Page
21

Etiology and treatment of fibrous dysplasia

Fibrous dysplasia is a benign bone lesion composed of a proliferation of spindle cells producing dysplastic bone. It occurs in a monostotic form, a polyostic form, or as part of McCune-Albright syndrome (polyostotic form with endocrinopathies). In all three cases, it is caused by a somatic activating mutation in the trimeric stimulatory guanine nucleotide binding protein, Gs. Treatment depends on the severity of involvement and location of the lesion and consists of observation, internal fixation to stabilize the bone, or osteotomies to correct mechanical deformity. Bisphosphonate therapy increases radiographic bone density and may be helpful in cases that are otherwise difficult to manage. Future treatment may be developed based on the molecular pathology of the Gs mutation.

Authors
Alman, BA
MLA Citation
Alman, BA. "Etiology and treatment of fibrous dysplasia." Current Opinion in Orthopaedics 8.5 (1997): 25-29.
Source
scival
Published In
Current Opinion in Orthopaedics
Volume
8
Issue
5
Publish Date
1997
Start Page
25
End Page
29

Regulation of proliferation and platelet-derived growth factor expression in palmar fibromatosis (Dupuytren contracture) by mechanical strain.

Palmar fibromatosis (Dupuytren contracture) causes fibrosis of specific palmar fascial bands. These bands are subjected to repetitive mechanical strain in situ. Primary cell cultures were derived from (a) palmar fibromatosis from eight patients, (b) uninvolved palmar fascia (Skoog's fibers) from four of these patients, and (c) normal palmar fascia from four additional patients. The cells were plated onto collagen-coated membranes either subjected to cyclic strain (25% maximal strain at 1 Hz) or without strain. Bromodeoxyuridine incorporation showed an increase in proliferation in all cultures subjected to strain. This increase was highest for palmar fibromatosis (10 to 40% nuclear incorporation, p = 0.02). Skoog's fibers and fascia from the normal individuals showed a trend (not significant) toward increase with strain (8 to 25%, p = 0.15 for Skoog's fibers, and 8 to 15%, p = 0.45 for normal fascia). Cyclic strain increased the expression of platelet-derived growth factor-A relative to glyceraldehyde-3-phosphate dehydrogenase in palmar fibromatosis (2.2 to 3.5, p = 0.05) and Skoog's fibers (0.8 to 2.0, p = 0.04). The expression of platelet-derived growth factor-B relative to glyceraldehyde-3-phosphate dehydrogenase was enhanced by cyclic strain only in the fibromatosis tissue (0.7 to 2.1, p = 0.04). The normal fascia did not express platelet-derived growth factor. Platelet-derived growth factor neutralizing antibody decreased bromodeoxyuridine incorporation in fibromatosis cultures subjected to cyclic strain to near levels for those grown in the absence of strain (38 to 16%, p = 0.05). Conditioned medium from fibromatosis cells grown under stain showed a trend toward increased proliferation in additional fibromatosis cultures compared with conditioned medium from fibromatosis cells grown without strain (9 to 15% nuclear incorporation, p = 0.20). The observed palmar fibromatosis contracture can be partially explained on the basis of the cell's response to cyclic strain, which may be mediated by platelet-derived growth factor.

Authors
Alman, BA; Greel, DA; Ruby, LK; Goldberg, MJ; Wolfe, HJ
MLA Citation
Alman, BA, Greel, DA, Ruby, LK, Goldberg, MJ, and Wolfe, HJ. "Regulation of proliferation and platelet-derived growth factor expression in palmar fibromatosis (Dupuytren contracture) by mechanical strain." J Orthop Res 14.5 (September 1996): 722-728.
PMID
8893764
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
14
Issue
5
Publish Date
1996
Start Page
722
End Page
728
DOI
10.1002/jor.1100140507

Molecular genetic and immunohistochemical analysis of the tumor suppressor genes Rb and p53 in palmar and aggressive fibromatosis.

This pilot project analyzed the tumor suppressor genes p53 and Rb in 13 cases of aggressive fibromatoses and six cases of palmar fibromatoses (Dupuytren contracture). Immunohistochemistry, reverse transcription polymerase chain reaction, polymerase chain reaction followed by single-strand confirmation polymorphism analysis, and Southern blot to detect gene rearrangements were used. No abnormalities were detected in p53. The aggressive fibromatoses demonstrated a lack of Rb immunohistochemical staining and decreased mRNA for Rb. No structural mutation in the coding sequence of the Rb gene was detected. The decreased level of Rb gene expression, despite a normal coding sequence, may indicate increased proliferation and may suggest potential treatment schemes.

Authors
Muller, E; Castagnaro, M; Yandel, DW; Wolfe, HJ; Alman, BA
MLA Citation
Muller, E, Castagnaro, M, Yandel, DW, Wolfe, HJ, and Alman, BA. "Molecular genetic and immunohistochemical analysis of the tumor suppressor genes Rb and p53 in palmar and aggressive fibromatosis." Diagn Mol Pathol 5.3 (September 1996): 194-200.
PMID
8866233
Source
pubmed
Published In
Diagnostic Molecular Pathology
Volume
5
Issue
3
Publish Date
1996
Start Page
194
End Page
200

Function of dislocated hips in children with lower level spina bifida.

We reviewed 52 children, born between 1974 and 1985 with spina bifida affecting L3 and L4, who had dislocated hips. Their motor function was stable and they were able to walk at the time of dislocation. They were interviewed and examined physically and radiologically. Physical function was measured by the Rand Health Insurance Study questionnaire (HIS), the Childhood Health Assessment questionnaire (CHAQ), and by determining the functional level of ambulation according to Hoffer et al (1973). In a subgroup of 12 patients with L4 level of involvement from both treatment groups we measured the metabolic energy consumption while walking. Thirty patient (49 hips) had been treated by operative relocation and 22 conservatively. Ten of the hips treated by operation subluxated or redislocated. The function in the two groups (conservative nu operated) was similar (HIS score 7.8 v 8.0, p = 0.45; CHAQ 14 v 13, p = 0.2; level of mobility 0.61 v 0.63, p = 0.5). Patients in whom operation had failed had worse function than did those with successful surgery (HIS score 8.8 v 6.1, p = 0.025) and those with successful surgery had better function than patients treated conservatively (HIS score 8.8 v 8.0, p = 0.15). Function in patients with failed operations, however, was worse than in those who did not have surgical treatment (HIS score 6.6 v 7.8, p = 0.07). In the 12 so examined the operated group had a 30% more energy-efficient gait (0.271 v 0.361 ml O2 kg/m, p = 0.05). Patients with failed operations had worse function than those who were not operated on. The benefit of surgical relocation of the dislocated hips was marginal.

Authors
Alman, BA; Bhandari, M; Wright, JG
MLA Citation
Alman, BA, Bhandari, M, and Wright, JG. "Function of dislocated hips in children with lower level spina bifida." J Bone Joint Surg Br 78.2 (March 1996): 294-298.
PMID
8666645
Source
pubmed
Published In
Journal of Bone and Joint Surgery (British Volume)
Volume
78
Issue
2
Publish Date
1996
Start Page
294
End Page
298

Activating mutations of Gs protein in monostotic fibrous lesions of bone.

Activating mutations of the alpha chain of the heterotrimeric signal transducer Gs disrupt the inherent guanosine triphosphatase activity of the alpha chain, stimulate adenylyl cyclase, and can result in independent cell proliferation. Such mutations are identified in a number of endocrine disorders, including McCune-Albright syndrome, which is a triad of endocrinopathy, café au lait spots, and polyostotic fibrous dysplasia. The mutation in this syndrome is a missense point mutation in exon 8 that results in the substitution of either histidine or cysteine for arginine at position 201. Monostotic fibrous dysplasia is a nonhereditary isolated bone lesion. Other isolated bone lesions that share some cytologic and clinical similarities to fibrous dysplasia are osteofibrous dysplasia and aggressive fibromatosis involving bone. Four cases of monostotic fibrous dysplasia, four cases of aggressive fibromatosis involving bone, and one case of osteofibrous dysplasia were studied to determine if a mutation was present in exon 8 of the alpha chain of Gs. A missense mutation was present in all of the fibrous dysplasias. The other fibrous lesions and uninvolved tissue did not contain a mutation. Somatic activating mutations of Gs differentiate fibrous dysplasia from the other lesions and may be responsible for the loss of control of local proliferation and growth factor expression.

Authors
Alman, BA; Greel, DA; Wolfe, HJ
MLA Citation
Alman, BA, Greel, DA, and Wolfe, HJ. "Activating mutations of Gs protein in monostotic fibrous lesions of bone." J Orthop Res 14.2 (March 1996): 311-315.
PMID
8648511
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
14
Issue
2
Publish Date
1996
Start Page
311
End Page
315
DOI
10.1002/jor.1100140221

Function of dislocated hips in children with lower level spina bifida

Authors
Alman, BA; Bhandari, M; Wright, JG
MLA Citation
Alman, BA, Bhandari, M, and Wright, JG. "Function of dislocated hips in children with lower level spina bifida." JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME 78B.2 (March 1996): 294-298.
Source
wos-lite
Published In
Journal of Bone and Joint Surgery (British Volume)
Volume
78B
Issue
2
Publish Date
1996
Start Page
294
End Page
298

Activating Gs mutations in monostotic fibrous lesions of bone

Authors
Alman, BA; DiazCano, SJ; Greel, DA; Wolfe, HJ
MLA Citation
Alman, BA, DiazCano, SJ, Greel, DA, and Wolfe, HJ. "Activating Gs mutations in monostotic fibrous lesions of bone." LABORATORY INVESTIGATION 74.1 (January 1996): 2-2.
Source
wos-lite
Published In
Laboratory Investigation
Volume
74
Issue
1
Publish Date
1996
Start Page
2
End Page
2

Growth factor and cytokine expression in osteolytic bone metastases

Authors
Alman, BA; Merdek, K; Wolfe, HJ
MLA Citation
Alman, BA, Merdek, K, and Wolfe, HJ. "Growth factor and cytokine expression in osteolytic bone metastases." LABORATORY INVESTIGATION 74.1 (January 1996): 3-3.
Source
wos-lite
Published In
Laboratory Investigation
Volume
74
Issue
1
Publish Date
1996
Start Page
3
End Page
3

Prenatal diagnosis and the pediatric surgeon: The impact of prenatal consultation on perinatal management

Purpose: Pediatric surgeons are increasingly called on by obstetrical colleagues to counsel parents about the implications of a prenatal ultrasound finding. Our understanding of the natural history of many prenatally diagnosed surgical conditions has grown significantly in recent years. Whether prenatal surgical consultation can influence perinatal course had not been investigated. Methods: During an 21-month period, 12,865 prenatal ultrasound studies were performed on a total of 4,551 patients, and 221 prenatal surgical consultations were obtained through a newly established fetal treatment program at a tertiary care prenatal diagnostic center. To evaluate the impact of prenatal pediatric surgical consultation on perinatal course, the authors reviewed changes in management including termination of pregnancy, in utero intervention, and altered site, mode, or timing of delivery. Results: Two hundred twenty-one fetuses were referred for consultation; their 234 congenital anomalies included genitourinary (36%), thoracic (16%), intraabdominal (14.5%), abdominal wall (10.6%), neurological (9%), skeletal (6%), and head and neck (2.5%) defects; 2.5% had tumors and 2.5% were twin pregnancies. Pregnancy was terminated in 9.5% of cases, because of patient request, chromosomal abnormality, or dismal prognosis. In 3.6%, the decision to terminate was changed as a result of consultation. Site of delivery was changed as a result of consultation in 37% to facilitate postnatal evaluation and initiate immediate treatment. Mode of delivery was changed in 6.8% to prevent dystocia, hemorrhage into a tumor, as in sacrococcygeal teratoma, or to provide an emergency airway, as in cervical teratoma. The timing of delivery was changed in 4.5% to avoid further damage to fetal organs in cases of obstructive uropathy, gastroschisis, sacrococcygeal teratoma with high-output failure, and hydrocephalus. Five percent (11) underwent treatment in utero for fetal hydrothorax, obstructive uropathy, twin-twin transfusion syndrome, or lymphangioma. The overall perinatal mortality rate was 2.5%. Conclusion: Prenatal pediatric surgical consultation may have a significant impact on the perinatal management of the fetus with a surgically correctable congenital anomaly. Providing obstetric colleagues and families with valuable insight into the surgical management of anomalies allows fetal intervention when appropriate, and delivery in an appropriate setting, by the safest mode of delivery, and at the gestational age appropriate to minimize effects of the anomaly.

Authors
Crombleholme, TM; D'Alton, M; Cendron, M; Alman, B; Goldberg, MD; Klauber, GT; Cohen, A; Heilman, C; Lewis, M; Harris, BH
MLA Citation
Crombleholme, TM, D'Alton, M, Cendron, M, Alman, B, Goldberg, MD, Klauber, GT, Cohen, A, Heilman, C, Lewis, M, and Harris, BH. "Prenatal diagnosis and the pediatric surgeon: The impact of prenatal consultation on perinatal management." Journal of Pediatric Surgery 31.1 (1996): 156-163.
PMID
8632271
Source
scival
Published In
Journal of Pediatric Surgery
Volume
31
Issue
1
Publish Date
1996
Start Page
156
End Page
163
DOI
10.1016/S0022-3468(96)90340-1

Proximal femoral focal deficiency: results of rotationplasty and Syme amputation.

We reviewed the results of treatment of sixteen patients who had had an isolated unilateral proximal femoral focal deficiency; nine were managed with a rotationplasty and seven, with a Syme amputation combined with an arthrodesis of the knee. We evaluated the perceived physical appearance, gross motor function, and metabolic energy expended in walking. The mean duration of follow-up was 9.9 years (range, four to fourteen years). The mean age of the patients at the time of the study was 13.9 years (range, eight to 18.4 years) in the rotationplasty group and 14.8 years (range, 9.5 to 19.9 years) in the Syme-amputation group. There were three female patients in each group. Roentgenograms showed that the femoral head was in the acetabulum (Aitken class A or B) in four of the seven patients in the Syme-amputation group and in five of the nine patients in the rotationplasty group; the remaining patients did not have this finding (Aitken class C or D). There was no difference in gross motor function or perceived physical appearance between the groups. Rotationplasty was associated with a more energy-efficient gait (mean, 0.153 milliliter of oxygen per kilogram-meter [range, 0.128 to 0.173 milliliter of oxygen per kilogram-meter] than was Syme amputation (mean, 0.169 milliliter of oxygen per kilogram-meter [range, 0.151 to 0.182 milliliter of oxygen per kilogram-meter]). Both types of treatment resulted in a net oxygen utilization per distance (efficiency) that was less than the values reported after amputations performed for non-congenital disorders.

Authors
Alman, BA; Krajbich, JI; Hubbard, S
MLA Citation
Alman, BA, Krajbich, JI, and Hubbard, S. "Proximal femoral focal deficiency: results of rotationplasty and Syme amputation." J Bone Joint Surg Am 77.12 (December 1995): 1876-1882.
PMID
8550656
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
77
Issue
12
Publish Date
1995
Start Page
1876
End Page
1882

Proximal femoral focal deficiency: Results of rotationplasty and Syme amputation

Authors
Alman, BA; Krajbich, JI; Hubbard, S
MLA Citation
Alman, BA, Krajbich, JI, and Hubbard, S. "Proximal femoral focal deficiency: Results of rotationplasty and Syme amputation." JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME 77A.12 (December 1995): 1876-1882.
Source
wos-lite
Published In
The Journal of Bone and Joint Surgery
Volume
77A
Issue
12
Publish Date
1995
Start Page
1876
End Page
1882

Massive allografts in the treatment of osteosarcoma and Ewing sarcoma in children and adolescents.

A retrospective review was performed of the results of all allograft reconstructions that had been done after the resection of an osteosarcoma or an Ewing sarcoma in a skeletally immature patient between 1982 and 1989 at The Hospital for Sick Children in Toronto. There were twenty-six patients. Six reconstructions were intercalary, sixteen were resection arthrodeses, three followed resection of a bone segment including the epiphysis (osteoarticular reconstruction), and one was a replacement of the entire humerus. Resection arthrodesis about the knee was performed with a smooth intramedullary rod and with one growth plate left intact. Six procedures were performed in the upper extremity. Excluding the patients who died, the average duration of follow-up was five years and three months. Twenty-one of the twenty-six patients had reached skeletal maturity at the time of follow-up. Eighteen (69 per cent) of the patients had a good or excellent result, four (15 per cent) had a fair result, and four had a failure. Twenty patients (77 per cent) had at least one complication (other than a limb-length discrepancy), and fourteen (54 per cent) sustained at least one fracture of the allograft. Fifteen patients who had had a reconstruction in the lower extremity had survived with survival of the allograft at the time of the latest follow-up. A limb-length discrepancy of at least two centimeters developed in nine of the fifteen patients. Five were managed with a contralateral epiphyseodesis, and one of them had an unsuccessful attempt at limb-lengthening as well. The patients who had a limb-length discrepancy of more than three centimeters at the time of follow-up had been significantly younger (p < 0.05) at the time of the reconstruction than those who had a smaller discrepancy. Three allografts (12 per cent), two of which were implanted early in the series, became infected. Soft-tissue coverage is of paramount importance for the prevention of infection, and we now routinely perform primary muscle (gastrocnemius or latissimus dorsi) transfers when dealing with an inadequate muscle envelope. Twelve patients were followed for more than four years (average, six years and seven months); they had no complications other than increased limb-length discrepancy and one subluxation of the shoulder after the first four years following the reconstruction. Although the rate of complications is higher than in adults, allograft reconstruction remains a useful option for the management of skeletally immature individuals.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Alman, BA; De Bari, A; Krajbich, JI
MLA Citation
Alman, BA, De Bari, A, and Krajbich, JI. "Massive allografts in the treatment of osteosarcoma and Ewing sarcoma in children and adolescents." J Bone Joint Surg Am 77.1 (January 1995): 54-64.
PMID
7822356
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
77
Issue
1
Publish Date
1995
Start Page
54
End Page
64

Platelet-derived growth factor in fibrous musculoskeletal disorders: a study of pathologic tissue sections and in vitro primary cell cultures.

Despite the great variability in the clinical behavior of fibrous lesions of the musculoskeletal system, they are composed of cytologically similar fibrocytes. Receptors for estrogen or progesterone, or both, are present in some of these lesions and some increase their rate of growth during periods of high levels of sex steroid hormones. The platelet-derived growth factor-B (PDGF-B) proto-oncogene encodes the B chain of PDGF, a mitogen for fibrocytes. Tissue from aggressive fibromatosis, fibrous dysplasia, plantar fibromatosis, and recurrent plantar fibromatosis was analyzed with use of the polymerase chain reaction and in situ hybridization for the expression of PDGF-B and PDGF beta receptor. Cell culture was used to determine if estrogen and progesterone stimulation modulated the expression of PDGF-B. Aggressive fibromatosis, fibrous dysplasia, and recurrent plantar fibromatosis expressed PDGF-B; plantar fibromatosis, normal plantar fascia, normal fascia lata, and mature scar did not. All of the tissues expressed PDGF beta receptor. The level of expression in aggressive fibromatosis and fibrous dysplasia was four times that in the recurrent plantar fibromatosis. Estrogen and progesterone stimulation in aggressive fibromatosis resulted in an increase in the level of expression. Therefore, the detection of PDGF-B may be an adjunct in the pathologic identification of locally invasive lesions. Its production may be a common mechanism leading to a fibroproliferative response through deregulation of the control of growth by both paracrine and autocrine mechanisms.

Authors
Alman, BA; Naber, SP; Terek, RM; Jiranek, WA; Goldberg, MJ; Wolfe, HJ
MLA Citation
Alman, BA, Naber, SP, Terek, RM, Jiranek, WA, Goldberg, MJ, and Wolfe, HJ. "Platelet-derived growth factor in fibrous musculoskeletal disorders: a study of pathologic tissue sections and in vitro primary cell cultures." J Orthop Res 13.1 (January 1995): 67-77.
PMID
7853106
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
13
Issue
1
Publish Date
1995
Start Page
67
End Page
77
DOI
10.1002/jor.1100130111

The expression of platelet-derived growth-factor gene in Dupuytren contracture.

Dupuytren contracture is a disease of the palmar fascia characterized by nodular fibroblastic proliferation; its etiology and pathogenesis are poorly understood. Growth factors are polypeptides that regulate cell growth and differentiation and extracellular matrix production. Platelet-derived growth factor is known to cause fibroblastic proliferation, and it may be involved in the pathogenesis of Dupuytren contracture. The purpose of this study was to determine if the gene for the B chain of platelet-derived growth factor is expressed in Dupuytren contracture. Tissue from patients who had Dupuytren disease was examined immunohistochemically with the 5B5 antibody, which is a marker for fibroblasts. Polymerase chain reaction, gel electrophoresis, Southern blotting, and in situ hybridization were also used to study gene expression in the tissue as well as in normal fascia, A172 cells, and MRC5 cells. Total cellular RNA was extracted from tissue and cells. Polymerase chain reaction was done with oligonucleotide primers complementary to a portion of the platelet-derived growth-factor-B and platelet-derived growth-factor-receptor genes. The platelet-derived growth-factor-B gene was expressed in all six specimens from the patients who had Dupuytren contracture as well as in the A172 cells, but not in the normal fascia lata or the MRC5 cells. These results were confirmed with Southern blotting of the products of the reaction with a platelet-derived growth-factor-B probe. The gene for the platelet-derived growth-factor receptor was expressed by all tissues and cells studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Terek, RM; Jiranek, WA; Goldberg, MJ; Wolfe, HJ; Alman, BA
MLA Citation
Terek, RM, Jiranek, WA, Goldberg, MJ, Wolfe, HJ, and Alman, BA. "The expression of platelet-derived growth-factor gene in Dupuytren contracture." J Bone Joint Surg Am 77.1 (January 1995): 1-9.
PMID
7822340
Source
pubmed
Published In
The Journal of Bone and Joint Surgery
Volume
77
Issue
1
Publish Date
1995
Start Page
1
End Page
9

REGULATION OF PROLIFERATION AND PLATELET-DERIVED GROWTH-FACTOR (PDGF) EXPRESSION IN PALMAR FIBROMATOSIS (DUPUYTRENS DISEASE) BY MECHANICAL STRAIN

Authors
ALMAN, BA; GREEL, DA; WOLFE, HJ
MLA Citation
ALMAN, BA, GREEL, DA, and WOLFE, HJ. "REGULATION OF PROLIFERATION AND PLATELET-DERIVED GROWTH-FACTOR (PDGF) EXPRESSION IN PALMAR FIBROMATOSIS (DUPUYTRENS DISEASE) BY MECHANICAL STRAIN." LABORATORY INVESTIGATION 72.1 (January 1995): A4-A4.
Source
wos-lite
Published In
Laboratory Investigation
Volume
72
Issue
1
Publish Date
1995
Start Page
A4
End Page
A4

THE EXPRESSION OF PLATELET-DERIVED GROWTH-FACTOR GENE IN DUPUYTREN CONTRACTURE

Authors
TEREK, RM; JIRANEK, WA; GOLDBERG, MJ; WOLFE, HJ; ALMAN, BA
MLA Citation
TEREK, RM, JIRANEK, WA, GOLDBERG, MJ, WOLFE, HJ, and ALMAN, BA. "THE EXPRESSION OF PLATELET-DERIVED GROWTH-FACTOR GENE IN DUPUYTREN CONTRACTURE." JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME 77A.1 (January 1995): 1-9.
Source
wos-lite
Published In
The Journal of Bone and Joint Surgery
Volume
77A
Issue
1
Publish Date
1995
Start Page
1
End Page
9

MASSIVE ALLOGRAFTS IN THE TREATMENT OF OSTEOSARCOMA AND EWING SARCOMA IN CHILDREN AND ADOLESCENTS

Authors
ALMAN, BA; DEBARI, A; KRAJBICH, JI
MLA Citation
ALMAN, BA, DEBARI, A, and KRAJBICH, JI. "MASSIVE ALLOGRAFTS IN THE TREATMENT OF OSTEOSARCOMA AND EWING SARCOMA IN CHILDREN AND ADOLESCENTS." JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME 77A.1 (January 1995): 54-64.
Source
wos-lite
Published In
The Journal of Bone and Joint Surgery
Volume
77A
Issue
1
Publish Date
1995
Start Page
54
End Page
64

Amniotic band syndrome in fetal lambs I: Fetoscopic release and morphometric outcome

A fetal lamb model of amniotic band syndrome (ABS) was developed to study the pathophysiology of banded extremities and evaluate the possibility of in utero treatment with the potential for functional recovery. Eight fetal lambs underwent banding of their extremities with umbilical tape at 100 days' gestation. Two lambs aborted after the open fetal surgery. The limbs of two unoperated newborn lambs served as controls in addition to five sham-operated control limbs that had no bands applied. Nine limbs were banded without reducing blood flow assessed by laser doppler (group 1), and 6 limbs were similarly banded and released fetoscopically at 125 days' gestation. Four limbs were banded, with a mean reduction in blood flow to the limb of 18.7% (group 2) by laser doppler flowmeter. Shortly after birth the lambs were killed, and segmental limb length, circumference, joint range of motion, and histology were evaluated. At birth, banded limbs showed marked brawny edema and absence of wool distal to the band. Segmental limb measurements showed shorter distal forelimbs in banded limbs compared with controls (10.97 ± 0.95 versus 12.98 ± 0.69, P < .05). Banded limbs were associated with progressive increase in hoof circumference (P < .03) and a decrease in joint range of motion (P < .003). In sharp contrast, there were no differences between fetoscopically released limbs and control limbs in any of the parameters measured. Histology of banded extremities showed edema, venous and lymphatic congestion, and fibrosis compared with controls. This model of ABS in fetal lambs is simple, reproducible, and replicates all the clinical features of extremity ABS. The data suggest that fetoscopic release of bands allows the extremity to recover and may prevent severe limb deformity caused by amniotic bands. © 1995.

Authors
Crombleholme, TM; Dirkes, K; Whitney, TM; Alman, B; Garmel, S; Connelly, RJ
MLA Citation
Crombleholme, TM, Dirkes, K, Whitney, TM, Alman, B, Garmel, S, and Connelly, RJ. "Amniotic band syndrome in fetal lambs I: Fetoscopic release and morphometric outcome." Journal of Pediatric Surgery 30.7 (1995): 974-978.
PMID
7472956
Source
scival
Published In
Journal of Pediatric Surgery
Volume
30
Issue
7
Publish Date
1995
Start Page
974
End Page
978

Giant marginal ulcer.

Marginal ulcer is a well-known complication of gastroenterostomy. It occurs in 3% of patients post-Billroth II subtotal gastrectomy; it occurs in less than 1% if truncal vagotomy is included but in up to 30% of patients with gastroenterostomy without vagotomy. These ulcers occur at the anastomosis, but always on the jejunal side, and are known to develop complications of their own--e.g., intractable pain; hemorrhage, obstruction, perforation, and fistula formation. Prior to the advent of upper-GI endoscopy the main method of diagnosis was by history and upper GI series but the accuracy of the upper-Gi series was about 50% or less. Now that upper-GI endoscopy is available, the accuracy of diagnosis is 95% or better. Since truncal vagotomy has been widely adopted as an integral part of gastric surgery--e.g., antrectomy, hemigastrectomy, subtotal gastrectomy, and gastroenterostomy--the incidence of marginal ulcer has declined. The use of cimetidine, ranitidine, famotidine, omeprazole, sucralfate, and antacids has improved the medical management of duodenal ulcer to such a degree that in recent years there is much less need for surgical intervention and thus the incidence of marginal ulcer has declined even more. In addition, the H-2 blockers and omeprazole can be used in patients with marginal ulcer and achieve healing; therefore complications that so frequently required surgical intervention are much less frequent.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Gowen, GF; Campbell, RE; McFarland, MM; Alman, BA
MLA Citation
Gowen, GF, Campbell, RE, McFarland, MM, and Alman, BA. "Giant marginal ulcer." Surg Endosc 8.2 (February 1994): 107-110.
PMID
8165479
Source
pubmed
Published In
Surgical Endoscopy
Volume
8
Issue
2
Publish Date
1994
Start Page
107
End Page
110

Subtalar arthrodesis for stabilization of valgus hindfoot in patients with cerebral palsy.

All patients with spastic cerebral palsy who underwent correction of valgus hindfoot by Grice extraarticular subtalar arthrodesis between 1971 and 1986 performed by two surgeons using an identical technique were reviewed. Twenty-nine patients (53 feet) were followed at an average of 8.9 years after operation. Traditional radiographic criteria for measurement of hindfoot alignment in skeletally mature individuals have poor reliability. Talar head uncovering is a useful and reproducible method for evaluation of hindfoot valgus in these patients. Five patients had progressive hindfoot or ankle deformity at latest follow-up. All five of these patients were spastic quadriplegics. There was no recurrence in the 17 patients who were less severely involved than the quadriplegic patients.

Authors
Alman, BA; Craig, CL; Zimbler, S
MLA Citation
Alman, BA, Craig, CL, and Zimbler, S. "Subtalar arthrodesis for stabilization of valgus hindfoot in patients with cerebral palsy." J Pediatr Orthop 13.5 (September 1993): 634-641.
PMID
8376566
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
13
Issue
5
Publish Date
1993
Start Page
634
End Page
641

Digital nerves of the foot: anatomic variations and implications regarding the pathogenesis of interdigital neuroma.

Seventy-one cadaveric feet were dissected, with attention to communicating branches of the digital nerves, the diameters of the digital nerves, the distance between the metatarsal heads, and the presence or absence of interdigital neuromas. A communicating branch was absent in 52 feet (73.2%) and present in 19 specimens (26.8%). The communication was from the fourth to the third web space common digital nerve (i.e., from the lateral to the medial plantar nerve) in 11 specimens. A reverse communication, from the third to the fourth web space common digital nerve (i.e., from the medial to the lateral plantar nerve), was present in eight specimens. Neuromas were identified in the second web space in 26 specimens and in the third web space in 32 feet. The common digital nerve to the third web space was not thicker in feet with a contribution from the fourth to the third web space nerve. Additionally, the incidence of third web space neuroma in feet with this type of communication was not significantly greater than in those feet without an internervous communication. However, the intermetatarsal head distances and the ratios of the intermetatarsal head distance to the digital nerve diameter in web spaces 2 and 3 were significantly smaller in comparison to spaces 1 and 4 (P < .05). The morphometric data lend support to theories that explain the propensity for neuroma formation in both the second and third web spaces on a mechanical basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Levitsky, KA; Alman, BA; Jevsevar, DS; Morehead, J
MLA Citation
Levitsky, KA, Alman, BA, Jevsevar, DS, and Morehead, J. "Digital nerves of the foot: anatomic variations and implications regarding the pathogenesis of interdigital neuroma." Foot Ankle 14.4 (May 1993): 208-214.
PMID
8359767
Source
pubmed
Published In
Foot and Ankle
Volume
14
Issue
4
Publish Date
1993
Start Page
208
End Page
214

Femur fractures in institutionalized patients after hip spica immobilization.

The charts of 77 severely handicapped institutionalized children and young adults were retrospectively reviewed to assess the incidence of femur fractures. No fractures occurred in ambulatory patients. Four of 37 nonambulatory patients who did not have hip surgery (10.9%) had sustained a fracture at some time during their life. Six of 21 (29%) nonambulatory patients who were operated on for subluxed or dislocated hips sustained a femur fracture within 3 months after discontinuation of their spica casts. This risk factor should be taken into account when one considers operation in severely affected nonambulant spastic quadriplegic patients.

Authors
Sturm, PF; Alman, BA; Christie, BL
MLA Citation
Sturm, PF, Alman, BA, and Christie, BL. "Femur fractures in institutionalized patients after hip spica immobilization." J Pediatr Orthop 13.2 (March 1993): 246-248.
PMID
8459020
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
13
Issue
2
Publish Date
1993
Start Page
246
End Page
248

Aggressive fibromatosis.

Ten patients with aggressive fibromatosis of the extremities were prospectively followed for 2-6 years. Results of treatment methods were compared. Five patients underwent three-dimensional imaging with and without intravenous contrast, and the images were compared with the anatomic extent of the resected lesion. Pathologic specimens and control tissue were tested for the presence of estrogen and progesterone receptors and for expression of the c-sis oncogene and platelet-derived growth factor (PDGF), potent mitogens for fibrocytes. Wider surgical resection resulted in a lower recurrence rate, but current chemotherapeutic agents were not effective in eradicating the tumors. Intravenous contrast enhanced the lesions. Two thirds of the tumors tested had estrogen or progesterone receptors. All tumors tested had inappropriate expression of c-sis and PDGF. This inappropriate expression may be responsible for the underlying pathobiology and deregulation of control of growth in aggressive fibromatosis.

Authors
Alman, BA; Goldberg, MJ; Naber, SP; Galanopoulous, T; Antoniades, HN; Wolfe, HJ
MLA Citation
Alman, BA, Goldberg, MJ, Naber, SP, Galanopoulous, T, Antoniades, HN, and Wolfe, HJ. "Aggressive fibromatosis." J Pediatr Orthop 12.1 (January 1992): 1-10.
PMID
1732285
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
12
Issue
1
Publish Date
1992
Start Page
1
End Page
10

INSITU HYBRIDIZATION TO LOCALIZE C-SIS PROTOONCOGENE EXPRESSION IN DUPUYTRENS FIBROMATOSIS

Authors
JIRANEK, WA; ALMAN, BA; TEREK, RM; NABER, SP; RUBY, LK; GOLDBERG, MJ; WOLFE, HJ
MLA Citation
JIRANEK, WA, ALMAN, BA, TEREK, RM, NABER, SP, RUBY, LK, GOLDBERG, MJ, and WOLFE, HJ. "INSITU HYBRIDIZATION TO LOCALIZE C-SIS PROTOONCOGENE EXPRESSION IN DUPUYTRENS FIBROMATOSIS." LABORATORY INVESTIGATION 66.1 (January 1992): A7-A7.
Source
wos-lite
Published In
Laboratory Investigation
Volume
66
Issue
1
Publish Date
1992
Start Page
A7
End Page
A7

INAPPROPRIATE C-SIS PROTOONCOGENE EXPRESSION IN FIBROUS DYSPLASIA - AN INSITU HYBRIDIZATION AND PCR STUDY

Authors
ALMAN, BA; JIRANEK, WA; NABER, SP; TEREK, RM; GOLDBERG, MJ; WOLFE, HJ
MLA Citation
ALMAN, BA, JIRANEK, WA, NABER, SP, TEREK, RM, GOLDBERG, MJ, and WOLFE, HJ. "INAPPROPRIATE C-SIS PROTOONCOGENE EXPRESSION IN FIBROUS DYSPLASIA - AN INSITU HYBRIDIZATION AND PCR STUDY." LABORATORY INVESTIGATION 66.1 (January 1992): A2-A2.
Source
wos-lite
Published In
Laboratory Investigation
Volume
66
Issue
1
Publish Date
1992
Start Page
A2
End Page
A2

Solitary osteochondroma of the clavicle.

There are no clinicopathologic reports of solitary osteochondroma of the clavicle other than listings in tumor registries. Two boys had solitary asymptomatic osteochondroma, in one at the medial and in the other at the lateral aspect of the clavicle. One underwent excision to correct cosmetic deformity. Several histologic and experimental studies have shown that osteochondromas originate from cells of the growth plate. During development of the clavicle, cartilage appears on both the medial and lateral aspects. Histologic studies have suggested that this cartilage is similar to a physeal growth plate. Experimental studies, however, have shown it to be a randomly organized secondary cartilage that develops in membranous bones once ossification has begun. The occurrence of an osteochondroma at the ends of the clavicle lends support to the theory that the cartilage at the ends of the developing clavicle functions as a growth plate.

Authors
Alman, BA; Goldberg, MJ
MLA Citation
Alman, BA, and Goldberg, MJ. "Solitary osteochondroma of the clavicle." J Pediatr Orthop 11.2 (March 1991): 181-183.
PMID
2010516
Source
pubmed
Published In
Journal of Pediatric Orthopaedics
Volume
11
Issue
2
Publish Date
1991
Start Page
181
End Page
183

DIFFERENTIAL EXPRESSION OF THE C-SIS PROTOONCOGENE IN FIBROPROLIFERATIVE LESIONS OF THE EXTREMITIES

Authors
ALMAN, BA; NABER, SP; GOLDBERG, MJ; WOLFE, HJ
MLA Citation
ALMAN, BA, NABER, SP, GOLDBERG, MJ, and WOLFE, HJ. "DIFFERENTIAL EXPRESSION OF THE C-SIS PROTOONCOGENE IN FIBROPROLIFERATIVE LESIONS OF THE EXTREMITIES." LABORATORY INVESTIGATION 64.1 (January 1991): A2-A2.
Source
wos-lite
Published In
Laboratory Investigation
Volume
64
Issue
1
Publish Date
1991
Start Page
A2
End Page
A2

Fracture failure mechanisms in patients with osteogenesis imperfecta

This investigation examines the failure mechanism of bone from patients with osteogenesis imperfecta (OI). Mechanical testing and ultrastructural analysis of surgically obtained bone specimens, from patients with OI and from approximately age matched normal controls, were performed. This study shows that a relatively simple mechanical test utilizing a small amount of bone can differentiate between a diseased state (OI) and a normal state of bone. With this knowledge it will be possible to focus research on the defect that leads to bone fractures and to suggest improvements in patient management.

Authors
Alman, B; Frasca, P
MLA Citation
Alman, B, and Frasca, P. "Fracture failure mechanisms in patients with osteogenesis imperfecta." Journal of Orthopaedic Research 5.1 (1987): 139-143.
PMID
3819906
Source
scival
Published In
Journal of Orthopaedic Research
Volume
5
Issue
1
Publish Date
1987
Start Page
139
End Page
143
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