CONFERENCE
ON
Multiple Hereditary Exostoses
Insights Into Pathogenesis
November 3-5, 2005
Shriners Hospital of Houston
6977 Main Street
Houston, Texas
and the
Houston Marriott Medical Center
6580 Fannin Street
Houston, Texas
Sponsored By:
The Shriners Hospital
The National Institutes of Health
American Association of Enchondroma Diseases
March of Dimes Birth Defects Foundation
The Orthopaedic Research Society
The MHE Coalition
Gene Dx, DNA Diagnostic Services
The Mizutani Foundation for Glycoscience
Organizers: Dan Wells, Ph.D., Jacqueline Hecht, Ph.D., Sarah Ziegler
The document discusses whether osteoarthritis (OA) should be considered one disease or many, as there is evidence that OA is a heterogeneous condition influenced by different risk factors, molecular pathways, and disease mechanisms. Genome-wide association studies have linked over 100 genetic loci to OA risk, indicating different pathways can contribute to OA in different patients. While some genes have been shown to play different roles in different mouse models of OA, together this suggests OA may comprise distinct subtypes that could require targeted treatment approaches.
The document discusses factors that can contribute to hernia recurrence, including patient factors, surgeon factors, and technical factors. It presents strategies surgeons can use to reduce recurrence rates, such as tailoring the surgical approach based on a patient's risk level, improving surgical skills through education and experience, and selecting the appropriate anesthesia and mesh type.
Human Genome Project is a worldwide scientific achievement. It was a thirteen-year project initiated in 1990 and completed in 2003. Human Genome Project helped a lot in the identification of diseased genes as DNA is very significant for understanding the diseased gene and their functions. It helped in the identification of disease loci for many diseases and presented their treatment through preventive measures. It identified the gene loci for many diseases like cancer, asthma, high blood pressure, diabetes type 2, obesity, Alzheimer's disease, Down's syndrome, Turner's syndrome, depression and many types of heart diseases including cardiovascular disease and coronary artery disease. This project does not directly treat the diseases but it helps in the identification of disease gene loci and then allows the treatment of disease through its preventive measures before the appearance of symptoms or at the initial stages of the disease through many techniques like gene therapy, pharmacogenomics, and targeted drug therapy. These are the helpful techniques in the diagnoses of the human disease gene locus.
This paper discusses Tay-Sachs disease (TSD), a rare genetic lysosomal storage disorder. TSD is caused by mutations in the HEXA gene resulting in a deficiency of the enzyme beta-hexosaminidase A. This causes a toxic buildup of gangliosides that damage nerve cells. While the underlying genetic cause is known, the exact pathogenesis remains unclear. Research using cell models and animal models like sheep aim to further understand TSD at the cellular level to develop improved treatments beyond just carrier screening.
The document discusses recent scientific discoveries from the UCSD Department of Pediatrics and Rady Children's Hospital. It includes summaries of research on:
1) Soluble Thy-1 promoting resolution of pulmonary fibrosis by reversing the profibrotic differentiation of fibroblasts in injured lungs.
2) Genomic studies of human populations at high altitude in Ethiopia and the Andes identifying genes that modulate adaptation to low oxygen environments.
3) Epigenetic modifications changing the expression of relevant genes in pulmonary fibrosis through alterations in DNA methylation.
This study developed an efficient monolayer system to differentiate human pluripotent stem cells into skeletal muscle cells in 26 days without cell sorting or genetic manipulation. Skeletal muscle cells derived from FSHD1-affected stem cell lines exhibited FSHD-specific phenotypes, including exclusive expression of the FSHD pathogenic marker DUX4 and thinner myotubes compared to unaffected lines. FSHD1 myotubes also differentially regulated genes involved in cell cycle control, oxidative stress response and cell adhesion. This is the first human stem cell-based cellular model of a muscular dystrophy suitable for high-throughput screening and drug development.
prognostic and predictive biomarkers of canine osteosarcomaJ.L. Gall
The document discusses prognostic and predictive biomarkers for canine osteosarcoma. It begins by providing background on canine osteosarcoma, including that it is an aggressive bone tumor that is difficult to treat and has a poor prognosis. It then discusses the potential use of biomarkers for diagnosing osteosarcoma subtypes, predicting patient outcomes, and assessing response to therapies. Several potential prognostic biomarkers are mentioned, such as tumor grade, size, location, and serum alkaline phosphatase levels, but it notes that no single biomarker has been validated to enhance prognosis. The review explores using molecular profiling to identify new prognostic and predictive biomarkers that could help tailor treatment for canine osteosarcoma.
This document provides summaries of several genetics studies:
1) A study identifies genetic variants in genes related to heat shock and hormone response pathways that influence flowering time in Arabidopsis thaliana under seasonal warming.
2) Research in mice finds that meiotic chromosome dynamics and recombination patterns are influenced by paternal age, though effective elimination of defective cells prevents errors from completing meiosis.
3) A paper revisits the "thrifty gene hypothesis" using data from 65 loci associated with type 2 diabetes susceptibility, finding some evidence of positive selection at a few loci but concluding that the current prevalence cannot be fully explained by this hypothesis.
The document discusses whether osteoarthritis (OA) should be considered one disease or many, as there is evidence that OA is a heterogeneous condition influenced by different risk factors, molecular pathways, and disease mechanisms. Genome-wide association studies have linked over 100 genetic loci to OA risk, indicating different pathways can contribute to OA in different patients. While some genes have been shown to play different roles in different mouse models of OA, together this suggests OA may comprise distinct subtypes that could require targeted treatment approaches.
The document discusses factors that can contribute to hernia recurrence, including patient factors, surgeon factors, and technical factors. It presents strategies surgeons can use to reduce recurrence rates, such as tailoring the surgical approach based on a patient's risk level, improving surgical skills through education and experience, and selecting the appropriate anesthesia and mesh type.
Human Genome Project is a worldwide scientific achievement. It was a thirteen-year project initiated in 1990 and completed in 2003. Human Genome Project helped a lot in the identification of diseased genes as DNA is very significant for understanding the diseased gene and their functions. It helped in the identification of disease loci for many diseases and presented their treatment through preventive measures. It identified the gene loci for many diseases like cancer, asthma, high blood pressure, diabetes type 2, obesity, Alzheimer's disease, Down's syndrome, Turner's syndrome, depression and many types of heart diseases including cardiovascular disease and coronary artery disease. This project does not directly treat the diseases but it helps in the identification of disease gene loci and then allows the treatment of disease through its preventive measures before the appearance of symptoms or at the initial stages of the disease through many techniques like gene therapy, pharmacogenomics, and targeted drug therapy. These are the helpful techniques in the diagnoses of the human disease gene locus.
This paper discusses Tay-Sachs disease (TSD), a rare genetic lysosomal storage disorder. TSD is caused by mutations in the HEXA gene resulting in a deficiency of the enzyme beta-hexosaminidase A. This causes a toxic buildup of gangliosides that damage nerve cells. While the underlying genetic cause is known, the exact pathogenesis remains unclear. Research using cell models and animal models like sheep aim to further understand TSD at the cellular level to develop improved treatments beyond just carrier screening.
The document discusses recent scientific discoveries from the UCSD Department of Pediatrics and Rady Children's Hospital. It includes summaries of research on:
1) Soluble Thy-1 promoting resolution of pulmonary fibrosis by reversing the profibrotic differentiation of fibroblasts in injured lungs.
2) Genomic studies of human populations at high altitude in Ethiopia and the Andes identifying genes that modulate adaptation to low oxygen environments.
3) Epigenetic modifications changing the expression of relevant genes in pulmonary fibrosis through alterations in DNA methylation.
This study developed an efficient monolayer system to differentiate human pluripotent stem cells into skeletal muscle cells in 26 days without cell sorting or genetic manipulation. Skeletal muscle cells derived from FSHD1-affected stem cell lines exhibited FSHD-specific phenotypes, including exclusive expression of the FSHD pathogenic marker DUX4 and thinner myotubes compared to unaffected lines. FSHD1 myotubes also differentially regulated genes involved in cell cycle control, oxidative stress response and cell adhesion. This is the first human stem cell-based cellular model of a muscular dystrophy suitable for high-throughput screening and drug development.
prognostic and predictive biomarkers of canine osteosarcomaJ.L. Gall
The document discusses prognostic and predictive biomarkers for canine osteosarcoma. It begins by providing background on canine osteosarcoma, including that it is an aggressive bone tumor that is difficult to treat and has a poor prognosis. It then discusses the potential use of biomarkers for diagnosing osteosarcoma subtypes, predicting patient outcomes, and assessing response to therapies. Several potential prognostic biomarkers are mentioned, such as tumor grade, size, location, and serum alkaline phosphatase levels, but it notes that no single biomarker has been validated to enhance prognosis. The review explores using molecular profiling to identify new prognostic and predictive biomarkers that could help tailor treatment for canine osteosarcoma.
This document provides summaries of several genetics studies:
1) A study identifies genetic variants in genes related to heat shock and hormone response pathways that influence flowering time in Arabidopsis thaliana under seasonal warming.
2) Research in mice finds that meiotic chromosome dynamics and recombination patterns are influenced by paternal age, though effective elimination of defective cells prevents errors from completing meiosis.
3) A paper revisits the "thrifty gene hypothesis" using data from 65 loci associated with type 2 diabetes susceptibility, finding some evidence of positive selection at a few loci but concluding that the current prevalence cannot be fully explained by this hypothesis.
Ton Beniers_publicatielijst overzicht 2015Ton Beniers
This document lists publications by Beniers and others from 1987-2001 related to experimental cytokine therapy for renal cell carcinoma and Wilms' tumor. It includes 18 journal publications, 5 book chapters, and 1 PhD thesis by Beniers on experimental cytokine therapy for renal cell carcinoma. The publications examine the in vitro and in vivo effects of interferons and tumor necrosis factor on renal tumor cell lines and xenografts, and differential expression of drug resistance and heat shock proteins in histological compartments of nephroblastomas.
This talk was given by Dr. Grant Schulert Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
Ibd twin research wingate institute talkgoldcat2013
This document discusses the role of twin studies in IBD research. It begins with a brief history of twin studies dating back to 1875 and how they have been used to distinguish the roles of nature vs nurture in disease. The document then reviews how twin studies of IBD have shown a genetic basis and environmental components for both Crohn's and ulcerative colitis. It also discusses new molecular techniques being applied to twin studies, such as analyzing the microbiome, epigenetics, metabolomics and miRNA expression in twins concordant and discordant for IBD. The document promotes the ongoing UK IBD Twin registry and biobank for continued twin research in the omics era.
Scientific Publications and Scholarly National and International PresentationsTheresa Swift-Scanlan
Theresa Swift-Scanlan has authored 34 scientific publications and given 32 scholarly presentations both nationally and internationally. Her publications span from 1992 to the present and cover topics including breast cancer research, DNA methylation profiling, dopamine signaling, and bipolar disorder genetics. She has served as senior or corresponding author on many publications and her work has been published in high impact factor journals such as Cancer, Epidemiology, Biomarkers and Prevention, Breast Cancer Research, and Journal of Cognitive Neuroscience.
This document summarizes genetic factors associated with periodontitis. It discusses various genetic studies related to chronic and aggressive periodontitis, including studies on gene polymorphisms like IL1, TNF, FCγR, IL10, and others. It also covers genetic terminology, types of genetic studies like twin studies, family studies, case-control studies and genome-wide association studies. Specific gene mutations linked to syndromes associated with periodontitis are mentioned.
Therapeutic cloning involves harvesting somatic cells from a patient and using them to create patient-specific embryonic stem cells via somatic cell nuclear transfer. These stem cells could potentially be used to treat various diseases by replacing damaged tissues and organs, repairing autoimmune disorders, or delivering gene therapy. However, significant technological and moral barriers remain, including the inability to reliably create human embryonic stem cells through cloning and opposition from groups who believe such embryos should be considered viable human life. Further research is still needed to ensure stem cells can safely differentiate, survive in patients, and function properly without harm. A legal definition of when an embryo becomes an organism could help resolve some moral debates over therapeutic cloning.
Rare Pulmonary Diseases in Systemic JIA. This presentation tracks the increased use of biologics to treat SJIA and observes the trends in rare pulmonary diseases.
This study investigated the role of Yes-associated protein (YAP) in regulating cell proliferation during sea urchin embryogenesis. The researchers inhibited YAP using the drug verteporfin and observed its effects on development at various concentrations. They found that YAP inhibition slowed growth and altered cell distribution, especially of skeletogenic cells and those forming the archenteron. While early cleavage was not strongly affected, later stages of proliferation and morphogenesis from 8-48 hours were disrupted. Therefore, YAP plays an important role in sea urchin embryogenesis by promoting proper cell proliferation and positioning during development.
THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE OF HOMEOPATHY IN FRANCEhome
PB7 445 THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE
OF HOMEOPATHY IN FRANCE
J. BILLOT* (AP-HP Hôpital Corenton-Celton, Issy-les -Moulineaux, France)
Introduction At least 30% of the French population has recourse to homeopathy, with a large
proportion of elderly persons. Some 25000 practitioners prescribe homeopathic treatments.
Object: Development of a system of reference for the medical practice of homeopathy in
order to meet with the legal obligations of evaluation and training of homeopaths. Method :
1- Creation by the Société Française d’Homéopathie of a working group of expert specialists
representative of the medical practice of homeopathy to determine: - a basic methodology:
self-evaluation according to the method of practice groups; - the subject: « the homeopathic
medical file»; - the aims and requirements of quality; - the standards of evaluation; - the
number and content of items or inquiries 2- Verification of the text’s form by a reader’s
group; 3- Verification of acceptability and feasibility by a group test; 4- New meeting of the
working group to register the modifications shown necessary by the feasibility study; 5-
Presentation of the text to the methodologists approved by the Haute Autorité de la Santé
(Health Department); 6- Finalization of the project and transmission to the Haute Autorité de
la Santé for validation. Results: Elaboration of a system of analysis with reference to the
«homeopathic medical file», according to the method of practice groups. This system of
reference includes a questionnaire concerning the symptoms noted in the patient’s file: in
order to be of homeopathic value, the symptoms must be precisely characterized and
organized according to their relative importance. Conclusion This system of reference was
validated by the Haute Autorité de la Santé in February 2007. Several practice groups have
already used this system of reference to validate the legal obligations of their profesional
practice. The complete text of this system of reference can be downloaded on web-site:
WWW. homeopathie- francaise. fr
This document provides a summary of qualifications and work experience for Jenne M. Westberry, PhD. She has over 10 years of postgraduate laboratory experience in neuroscience, aging, women's health and epigenetics. Her experience includes managing laboratories, writing and overseeing NIH grants, scientific writing and editing, course instruction, and conducting experiments using techniques such as immunohistochemistry and methylation-specific PCR. She has a strong publication record and has presented her research findings at numerous scientific conferences.
This document summarizes a research article that investigated the genomic determinants of Mycobacterium tuberculosis transmission. The study identified regions of the M. tuberculosis genome, through analysis of over 200 strains, that were associated with transmission and the occurrence of secondary tuberculosis cases. These regions encoded proteins or influenced immune responses. Specifically, the study found mutations in five genomic regions, including three genes and two intergenic regions, that were statistically associated with transmission. Mutations in two of these genes were found to decrease immune system cytokine production in a way that could influence transmissibility. This research helps further the understanding of the genetic factors that influence the transmissibility of M. tuberculosis strains.
This study strengthens evidence that a genetic variant in the CST3 gene, which encodes cystatin C, increases risk of age-related macular degeneration (AMD) in a recessive manner similar to its known effect on Alzheimer's disease (AD) risk. The researchers genotyped 350 patients with exudative AMD and found that those homozygous for the variant allele had a significantly increased risk, whereas heterozygous individuals did not. Bringing these results together with a previous AMD association study and AD meta-analysis showed a high correlation between effect sizes for AMD and AD. This supports the hypothesis that this variant confers recessive risk to both neurodegenerative diseases.
Epigenetics and cell fate in JIA and pulmonary fibrosis by Jim HagoodSystemic JIA Foundation
This document discusses the potential role of epigenetic mechanisms in idiopathic pulmonary fibrosis (IPF) and juvenile idiopathic arthritis (JIA). It outlines how epigenetic changes like DNA methylation and histone modifications can alter gene expression and cell phenotypes, contributing to diseases like IPF that involve remodeling of lung tissue. Studies have found differential methylation and expression of genes in IPF lung tissue. Epigenetic therapies targeting mechanisms like DNA methylation and histone acetylation may one day help treat IPF and other diseases. The document also discusses how epigenetics may contribute to autoimmunity and JIA, noting differences in T cell methylation profiles between JIA patients and controls.
This document summarizes a thesis submitted by Seamus McKim to the University of Aberdeen in 2012 investigating gene expression following chronic viral infection suspected to be pancreas disease (PD) in farmed Atlantic salmon. McKim analyzed gene expression of immune function genes, protein degradation genes, and a viral detection gene in healthy and diseased fish from a farm with a history of PD. Results showed upregulation of immune genes in diseased tissues. Condition factor and stomach fullness were lower in diseased fish, indicating reduced feeding and growth. While viral detection was inconclusive, gene expression analysis provided insights into the molecular response to chronic PD infection.
Idiopathic Scoliosis is a genetic disease (complex trait)Nelson Tang
Idiopathic Scoliosis (AIS) is caused by genetic factors in a complex trait model. It predicted the success of GWAS for AIS. On the other hand, genetic markers do not predict the progression of the curve for the majority of AIS patients.
This document lists 32 peer-reviewed journal articles authored or co-authored by Bal Sanghera related to positron emission tomography (PET) imaging. The articles cover a range of topics including evaluating PET tracers and reconstruction algorithms for assessing tumor hypoxia and proliferation, optimizing PET-CT protocols to reduce radiation dose, and assessing the impact of various factors on standardized uptake value (SUV) measurements. Dates of publication range from 1991 to 2016.
This document discusses several studies on monogenic disorders and their potential medical applications. It first introduces monogenic disorders as involving mutations in a single gene, which can be inherited or spontaneous. Two studies are then summarized: one finding that brain stimulation may help restore breathing capacity in Duchenne muscular dystrophy patients by activating the diaphragm muscle, and another observing changes in mucus protein structure in cystic fibrosis patients that could provide insight into treatment. The document concludes that these studies bring researchers closer to potential treatments for currently incurable genetic diseases and improve patients' quality of life.
This document summarizes information about cancer logistics and genetics. It discusses how normal cells can develop mutations during cell division, leading to cancer. Genetic mapping of genes has helped determine cancer risks and treatments. The document also covers DNA and genetic testing, how mutations occur, cancer inheritance patterns, and statistics on cancer survival rates. Prevention methods like avoiding smoking and limiting alcohol are discussed as ways to reduce cancer risks.
- Molecular and cellular biologist with extensive experience in oncology research including target validation, biomarker discovery, drug mechanism, immunology, and translational research.
- Experienced project leader able to effectively manage collaborative projects and communicate across teams.
- Background includes positions at Pharmacyclics, Inc., Stanford University, and MD Anderson Cancer Center investigating various areas of cancer research including B cell lymphomas, acute myeloid leukemias, biomarkers, drug combinations, and tumor microenvironment.
Idiopathic scoliosis is a spinal deformity that affects otherwise healthy children and adolescents during growth. Genetic factors are known to play a role based on twin studies. While over 35 candidate genes have been identified, the genetic variants that affect susceptibility to spinal curvature and progression remain unknown. Estrogen receptors have been extensively examined as candidates due to their role in bone growth, but studies on the association between idiopathic scoliosis and estrogen receptor genes like ESR1 and ESR2 have had inconsistent results. More research is needed to better understand the genetic basis and identify individuals at risk of progression to help improve treatment options.
1st International Conference Models of Human Diseases oral presentations abstracts feature recent findings in development or emplyment of various models of diseases to advance biomedical research.
Hereditary multiple exostoses is characterized by growths of multiple benign bone tumors (exostoses) that arise from long bone growth plates. Exostoses can cause bone deformities, joint issues, and rarely malignant transformation. The condition is inherited in an autosomal dominant pattern with high penetrance. Diagnosis is based on clinical or radiographic findings of multiple exostoses in an individual or family members. Treatment involves surgery to address deformities, pain, or leg length discrepancies. There is a low lifetime risk of malignant transformation of the exostoses.
Ton Beniers_publicatielijst overzicht 2015Ton Beniers
This document lists publications by Beniers and others from 1987-2001 related to experimental cytokine therapy for renal cell carcinoma and Wilms' tumor. It includes 18 journal publications, 5 book chapters, and 1 PhD thesis by Beniers on experimental cytokine therapy for renal cell carcinoma. The publications examine the in vitro and in vivo effects of interferons and tumor necrosis factor on renal tumor cell lines and xenografts, and differential expression of drug resistance and heat shock proteins in histological compartments of nephroblastomas.
This talk was given by Dr. Grant Schulert Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
Ibd twin research wingate institute talkgoldcat2013
This document discusses the role of twin studies in IBD research. It begins with a brief history of twin studies dating back to 1875 and how they have been used to distinguish the roles of nature vs nurture in disease. The document then reviews how twin studies of IBD have shown a genetic basis and environmental components for both Crohn's and ulcerative colitis. It also discusses new molecular techniques being applied to twin studies, such as analyzing the microbiome, epigenetics, metabolomics and miRNA expression in twins concordant and discordant for IBD. The document promotes the ongoing UK IBD Twin registry and biobank for continued twin research in the omics era.
Scientific Publications and Scholarly National and International PresentationsTheresa Swift-Scanlan
Theresa Swift-Scanlan has authored 34 scientific publications and given 32 scholarly presentations both nationally and internationally. Her publications span from 1992 to the present and cover topics including breast cancer research, DNA methylation profiling, dopamine signaling, and bipolar disorder genetics. She has served as senior or corresponding author on many publications and her work has been published in high impact factor journals such as Cancer, Epidemiology, Biomarkers and Prevention, Breast Cancer Research, and Journal of Cognitive Neuroscience.
This document summarizes genetic factors associated with periodontitis. It discusses various genetic studies related to chronic and aggressive periodontitis, including studies on gene polymorphisms like IL1, TNF, FCγR, IL10, and others. It also covers genetic terminology, types of genetic studies like twin studies, family studies, case-control studies and genome-wide association studies. Specific gene mutations linked to syndromes associated with periodontitis are mentioned.
Therapeutic cloning involves harvesting somatic cells from a patient and using them to create patient-specific embryonic stem cells via somatic cell nuclear transfer. These stem cells could potentially be used to treat various diseases by replacing damaged tissues and organs, repairing autoimmune disorders, or delivering gene therapy. However, significant technological and moral barriers remain, including the inability to reliably create human embryonic stem cells through cloning and opposition from groups who believe such embryos should be considered viable human life. Further research is still needed to ensure stem cells can safely differentiate, survive in patients, and function properly without harm. A legal definition of when an embryo becomes an organism could help resolve some moral debates over therapeutic cloning.
Rare Pulmonary Diseases in Systemic JIA. This presentation tracks the increased use of biologics to treat SJIA and observes the trends in rare pulmonary diseases.
This study investigated the role of Yes-associated protein (YAP) in regulating cell proliferation during sea urchin embryogenesis. The researchers inhibited YAP using the drug verteporfin and observed its effects on development at various concentrations. They found that YAP inhibition slowed growth and altered cell distribution, especially of skeletogenic cells and those forming the archenteron. While early cleavage was not strongly affected, later stages of proliferation and morphogenesis from 8-48 hours were disrupted. Therefore, YAP plays an important role in sea urchin embryogenesis by promoting proper cell proliferation and positioning during development.
THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE OF HOMEOPATHY IN FRANCEhome
PB7 445 THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE
OF HOMEOPATHY IN FRANCE
J. BILLOT* (AP-HP Hôpital Corenton-Celton, Issy-les -Moulineaux, France)
Introduction At least 30% of the French population has recourse to homeopathy, with a large
proportion of elderly persons. Some 25000 practitioners prescribe homeopathic treatments.
Object: Development of a system of reference for the medical practice of homeopathy in
order to meet with the legal obligations of evaluation and training of homeopaths. Method :
1- Creation by the Société Française d’Homéopathie of a working group of expert specialists
representative of the medical practice of homeopathy to determine: - a basic methodology:
self-evaluation according to the method of practice groups; - the subject: « the homeopathic
medical file»; - the aims and requirements of quality; - the standards of evaluation; - the
number and content of items or inquiries 2- Verification of the text’s form by a reader’s
group; 3- Verification of acceptability and feasibility by a group test; 4- New meeting of the
working group to register the modifications shown necessary by the feasibility study; 5-
Presentation of the text to the methodologists approved by the Haute Autorité de la Santé
(Health Department); 6- Finalization of the project and transmission to the Haute Autorité de
la Santé for validation. Results: Elaboration of a system of analysis with reference to the
«homeopathic medical file», according to the method of practice groups. This system of
reference includes a questionnaire concerning the symptoms noted in the patient’s file: in
order to be of homeopathic value, the symptoms must be precisely characterized and
organized according to their relative importance. Conclusion This system of reference was
validated by the Haute Autorité de la Santé in February 2007. Several practice groups have
already used this system of reference to validate the legal obligations of their profesional
practice. The complete text of this system of reference can be downloaded on web-site:
WWW. homeopathie- francaise. fr
This document provides a summary of qualifications and work experience for Jenne M. Westberry, PhD. She has over 10 years of postgraduate laboratory experience in neuroscience, aging, women's health and epigenetics. Her experience includes managing laboratories, writing and overseeing NIH grants, scientific writing and editing, course instruction, and conducting experiments using techniques such as immunohistochemistry and methylation-specific PCR. She has a strong publication record and has presented her research findings at numerous scientific conferences.
This document summarizes a research article that investigated the genomic determinants of Mycobacterium tuberculosis transmission. The study identified regions of the M. tuberculosis genome, through analysis of over 200 strains, that were associated with transmission and the occurrence of secondary tuberculosis cases. These regions encoded proteins or influenced immune responses. Specifically, the study found mutations in five genomic regions, including three genes and two intergenic regions, that were statistically associated with transmission. Mutations in two of these genes were found to decrease immune system cytokine production in a way that could influence transmissibility. This research helps further the understanding of the genetic factors that influence the transmissibility of M. tuberculosis strains.
This study strengthens evidence that a genetic variant in the CST3 gene, which encodes cystatin C, increases risk of age-related macular degeneration (AMD) in a recessive manner similar to its known effect on Alzheimer's disease (AD) risk. The researchers genotyped 350 patients with exudative AMD and found that those homozygous for the variant allele had a significantly increased risk, whereas heterozygous individuals did not. Bringing these results together with a previous AMD association study and AD meta-analysis showed a high correlation between effect sizes for AMD and AD. This supports the hypothesis that this variant confers recessive risk to both neurodegenerative diseases.
Epigenetics and cell fate in JIA and pulmonary fibrosis by Jim HagoodSystemic JIA Foundation
This document discusses the potential role of epigenetic mechanisms in idiopathic pulmonary fibrosis (IPF) and juvenile idiopathic arthritis (JIA). It outlines how epigenetic changes like DNA methylation and histone modifications can alter gene expression and cell phenotypes, contributing to diseases like IPF that involve remodeling of lung tissue. Studies have found differential methylation and expression of genes in IPF lung tissue. Epigenetic therapies targeting mechanisms like DNA methylation and histone acetylation may one day help treat IPF and other diseases. The document also discusses how epigenetics may contribute to autoimmunity and JIA, noting differences in T cell methylation profiles between JIA patients and controls.
This document summarizes a thesis submitted by Seamus McKim to the University of Aberdeen in 2012 investigating gene expression following chronic viral infection suspected to be pancreas disease (PD) in farmed Atlantic salmon. McKim analyzed gene expression of immune function genes, protein degradation genes, and a viral detection gene in healthy and diseased fish from a farm with a history of PD. Results showed upregulation of immune genes in diseased tissues. Condition factor and stomach fullness were lower in diseased fish, indicating reduced feeding and growth. While viral detection was inconclusive, gene expression analysis provided insights into the molecular response to chronic PD infection.
Idiopathic Scoliosis is a genetic disease (complex trait)Nelson Tang
Idiopathic Scoliosis (AIS) is caused by genetic factors in a complex trait model. It predicted the success of GWAS for AIS. On the other hand, genetic markers do not predict the progression of the curve for the majority of AIS patients.
This document lists 32 peer-reviewed journal articles authored or co-authored by Bal Sanghera related to positron emission tomography (PET) imaging. The articles cover a range of topics including evaluating PET tracers and reconstruction algorithms for assessing tumor hypoxia and proliferation, optimizing PET-CT protocols to reduce radiation dose, and assessing the impact of various factors on standardized uptake value (SUV) measurements. Dates of publication range from 1991 to 2016.
This document discusses several studies on monogenic disorders and their potential medical applications. It first introduces monogenic disorders as involving mutations in a single gene, which can be inherited or spontaneous. Two studies are then summarized: one finding that brain stimulation may help restore breathing capacity in Duchenne muscular dystrophy patients by activating the diaphragm muscle, and another observing changes in mucus protein structure in cystic fibrosis patients that could provide insight into treatment. The document concludes that these studies bring researchers closer to potential treatments for currently incurable genetic diseases and improve patients' quality of life.
This document summarizes information about cancer logistics and genetics. It discusses how normal cells can develop mutations during cell division, leading to cancer. Genetic mapping of genes has helped determine cancer risks and treatments. The document also covers DNA and genetic testing, how mutations occur, cancer inheritance patterns, and statistics on cancer survival rates. Prevention methods like avoiding smoking and limiting alcohol are discussed as ways to reduce cancer risks.
- Molecular and cellular biologist with extensive experience in oncology research including target validation, biomarker discovery, drug mechanism, immunology, and translational research.
- Experienced project leader able to effectively manage collaborative projects and communicate across teams.
- Background includes positions at Pharmacyclics, Inc., Stanford University, and MD Anderson Cancer Center investigating various areas of cancer research including B cell lymphomas, acute myeloid leukemias, biomarkers, drug combinations, and tumor microenvironment.
Idiopathic scoliosis is a spinal deformity that affects otherwise healthy children and adolescents during growth. Genetic factors are known to play a role based on twin studies. While over 35 candidate genes have been identified, the genetic variants that affect susceptibility to spinal curvature and progression remain unknown. Estrogen receptors have been extensively examined as candidates due to their role in bone growth, but studies on the association between idiopathic scoliosis and estrogen receptor genes like ESR1 and ESR2 have had inconsistent results. More research is needed to better understand the genetic basis and identify individuals at risk of progression to help improve treatment options.
1st International Conference Models of Human Diseases oral presentations abstracts feature recent findings in development or emplyment of various models of diseases to advance biomedical research.
Hereditary multiple exostoses is characterized by growths of multiple benign bone tumors (exostoses) that arise from long bone growth plates. Exostoses can cause bone deformities, joint issues, and rarely malignant transformation. The condition is inherited in an autosomal dominant pattern with high penetrance. Diagnosis is based on clinical or radiographic findings of multiple exostoses in an individual or family members. Treatment involves surgery to address deformities, pain, or leg length discrepancies. There is a low lifetime risk of malignant transformation of the exostoses.
Mutations in eight different genes have been associated with neuronal ceroid lipofuscinoses (NCLs) in various dog breeds, providing canine models for the human NCL diseases. The document describes the pathways used to discover NCL mutations in dogs, including identifying affected dogs, histopathological analysis, whole genome sequencing, and candidate gene analysis. It focuses on the development of a Dachshund model of late-infantile NCL, where a mutation was identified in the TPP1 gene and an affected colony was established. This model is now being used to develop and test potential gene therapy, enzyme replacement therapy, and stem cell therapies for human late-infantile NCL.
Cell-Replacement Therapy with Stem Cells in Neurodegenerative DiseasesSararajputsa
This document summarizes research on using stem cell transplantation as a potential therapy for neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS). It discusses how stem cell transplantation has shown effectiveness in animal models of ALS through mechanisms like cell replacement, neurotrophic factor release, and endogenous stem cell proliferation. Early clinical trials transplanting stem cells into ALS patients showed feasibility and no severe side effects. However, more research is still needed to fully understand stem cell mechanisms and maximize their therapeutic potential for neurodegenerative diseases.
Victor Ozols has over 20 years of experience in laboratory research focusing on diseases such as cancer, Parkinson's, cystic fibrosis, Alzheimer's, and multiple sclerosis. He is looking for a new position where he can utilize his management, education, and research skills and continue enhancing these abilities. He has managed laboratories, identified potential drug compounds, and published numerous papers in peer-reviewed journals.
This paper discusses epigenetic studies using twins to further understand genetic influences on diseases and traits. Identical twins provide a unique opportunity to study epigenetics since they share the same DNA sequence but can differ in phenotypes. The paper reviews studies on Huntington's disease, spinocerebellar ataxia, and Alzheimer's that found epigenetic differences between identical twins affected these diseases. Epigenetic modifications like DNA methylation and histone modifications can influence disease expression. Epigenetic twin studies are also being applied to sociological research areas like criminology.
Discovery of new form of dystrophin protein could lead to therapy for some Duchenne muscular dystrophy patients
&
Genetics, lifestyle have a strong impact on biomarkers for inflammation, cancer
This study found that redheads require more of the anesthetic desflurane than people with dark hair. Specifically:
1) Redheads required a 19% higher concentration of desflurane on average (6.2% vs 5.2%) to prevent movement in response to electrical stimulation, a statistically significant difference.
2) Genetic analysis found that 9 of the 10 redhead participants carried mutations in the melanocortin-1 receptor gene, which is responsible for red hair, while only 5 of 10 dark-haired participants carried mutations.
3) This confirms the anecdotal impression that redheads require higher doses of inhalational anesthetics and provides evidence that anesthetic requirement can be linked to human
Elise Horvath is a 44-year-old medical director at Astellas Pharma US Inc. who has over 20 years of experience in clinical research and oncology. She has held positions at multiple universities and hospitals, and currently leads medical and scientific strategy for acute myeloid leukemia at Astellas. Her CV details her education, employment history, research projects, publications, and leadership activities in oncology clinical trials and committees.
The document announces a paediatric leukaemia symposium to be held on March 18, 2011 in Kuala Lumpur, Malaysia. The keynote speaker will be Dr. Pui Ching-Hon from St. Jude Children's Research Hospital who will give a lecture on clofarabine for paediatric leukaemia. The symposium will include discussions on difficult paediatric leukaemia cases and potential research initiatives in Malaysia. It will be held at the Auditorium Ungku Omar of the Institute for Medical Research and is sponsored by Genzyme Malaysia through the Malaysian Society of Paediatric Haematology and Oncology.
This document summarizes key findings in the new field of epigenetics. It discusses how environmental factors like diet and stress can induce epigenetic changes that alter gene expression without changing DNA. Specifically, it describes an experiment where changing mother mice's diet resulted in offspring with different physical traits and disease risks. The document also discusses how epigenetic changes can be passed down generations, how the human epigenome is as important as DNA, links between epigenetics and diseases like cancer, and how nurturing behaviors in rats can induce epigenetic changes in offspring's brains that affect stress responses.
Role of polycystin 1 in bone remodeling- orthodontic tooth movement study in ...EdwardHAngle
Objective: To test the hypothesis that polycystin-1 (PC1) is involved in orthodontic tooth movement as a mechanical sensor.
Materials and Methods: The response to force application was compared between three mutant and four wild-type 7-week-old mice. The mutant mice were PC1/Wnt1-cre, lacking PC1 in the craniofacial region. An orthodontic closed coil spring was bonded between the incisor and the left first molar, applying 20 g of force for 4 days. Micro–computed tomography, hematoxylin and eosin staining, and tartrate-resistent acid phosphatase (TRAP) staining were used to study the differences in tooth movement among the groups.
Results: In the wild-type mice the bonded molar moved mesially, and the periodontal ligament (PDL) was compressed in the compression side. The compression side showed a hyalinized zone, and osteoclasts were identified there using TRAP staining. In the mutant mice, the molar did not move, the incisor tipped palatally, and there was slight widening of the PDL in the tension area. Osteoclasts were not seen on the bone surface or on the compression side. Osteoclasts were only observed on the other side of the bone—in the bone marrow.
Conclusions: These results suggest a difference in tooth movement and osteoclast activity between PC1 mutant mice and wild-type mice in response to orthodontic force. The impaired tooth movement and the lack of osteoclasts on the bone surface in the mutant working side may be related to lack of signal from the PDL due to PC1 deficiency.
Thousands of genes evolved expression in the mammalian uterus during the evolution of pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. The researchers analyzed gene expression data from uterine/endometrial tissues of 14 species, including mammals, a reptile, bird, and frog. They found that over 2,000 genes gained expression in the uterus of early mammals compared to their ancestors. Many of these genes showed enriched expression in decidualized endometrial stromal cells, which differentiate during pregnancy to support fetal development. Ancient transposable elements likely contributed regulatory sequences that mediated the recruitment of these genes and the evolution of uterine gene networks important for pregnancy.
This document provides a summary of Evmorfia Tzagkaraki's resume. She has over 15 years of experience as a molecular biologist and geneticist. Currently, she is the Head of the Molecular Biology Department at Diagnosis Medical Diagnostic Centre in Rethymnon, Greece, where she helped develop the department. Previously, she was Head of Laboratory at Omnigen Biotechnological Applications SA. She holds a PhD in molecular investigation of genetic diseases from the University of Crete and has published papers in peer-reviewed journals. She is proficient in molecular biology techniques and has experience managing medical laboratories.
Repurposing large datasets for exposomic discovery in diseaseChirag Patel
This document discusses the need for large-scale studies of environmental exposures (the exposome) analogous to genome-wide association studies (GWAS) to better understand environmental contributions to health and disease. It notes that while genetics research has made great strides with GWAS, understanding of environmental influences lacks comparable methods and data. The author argues that characterizing the exposome through high-throughput methods could discover new environmental factors in phenotypes, as GWAS did for genetics. National Health and Nutrition Examination Survey is presented as a model for collecting comprehensive human exposure data on a large scale.
Adrian L. Winters III has over 30 years of experience in pathology laboratories. He has worked as a pathologists' assistant, medical technologist, and research assistant. His experience includes positions at hospitals in Texas, Oklahoma, Oregon, Arizona, and Missouri. He maintains certifications as a pathologists' assistant, medical technologist, and Reiki master practitioner. Winters has authored publications on cancer research and presented on complementary medicine. He received a PhD in Integrative and Complementary Medicine and holds an MS in Microbiology and Immunology.
This study examined the association between estrogen receptor alpha (ERα) gene haplotypes and radiographic osteoarthritis (OA) of the knee in 1,483 elderly men and women. Three haplotypes (px, PX, Px) were identified. Carriage of the PX haplotype was associated with an increased prevalence and severity of radiographic knee OA, with odds ratios of 1.3 for heterozygotes and 2.2 for homozygotes. Separate analyses showed the association was driven by osteophytosis. This study provides evidence that polymorphisms in the ERα gene are risk factors for radiographic knee OA in both men and women.
Mutations in the mitochondrial asparaginyl-tRNA synthetase gene NARS2 were found to cause two distinct genetic disorders: 1) nonsyndromic hearing loss and 2) Leigh syndrome, a neurodegenerative disease. A missense mutation was found to cause nonsyndromic hearing loss, while compound heterozygous mutations, including a nonsense mutation, were found to cause Leigh syndrome. The mutations had different effects on the structure and levels of the NARS2 protein and mitochondrial functioning. Overexpression of wildtype but not mutant NARS2 rescued defects in patient cells, demonstrating the pathogenic effects of the mutations. This establishes NARS2 mutations as a new genetic cause of these disorders.
Emily is a 13-year-old girl who has been diagnosed with MHE (Multiple Hereditary Exostoses) since she was 5 years old. She has undergone two surgeries on her right leg to remove tumors, and recently discovered another tumor in her right shoulder. Despite the pain from her condition and operations, Emily maintains a positive attitude and encourages others not to worry about problems but instead to make the most of their lives and create good memories.
O documento relata o caso de um paciente de 57 anos que apresentava um osteocondroma na região cervical da coluna vertebral, causando dor e outros sintomas. Foi realizada uma cirurgia para remover o tumor com sucesso e o paciente teve melhora dos sintomas após o procedimento.
Hereditary multiple exostoses (HME), also known as diaphyseal aclasis, is a rare genetic disorder characterized by multiple bony growths (exostoses) on the long bones. These exostoses are covered in cartilage and usually grow until after puberty, sometimes causing deformities or limiting movement. While the exostoses are generally benign, rare malignant transformation can occur in 1% of cases. Treatment may include surgical removal of symptomatic exostoses to relieve pain or correct deformities.
Apresentação sobre deformidades no pulso devido a Exostoses multiplas hereditárias.
Apresentação feita pelo Dr. Jeff Auyeung, cirurgião consultor do Hospital Universitário de North Dunham.
MADELUNG
AND MULTIPLE EXOSTOSES
Jeff Auyeung
Consultant Hand Surgeon
University Hospital of North Durham
Abstract: This study was undertaken to characterize pain in
individuals with hereditary multiple exostosis (HME). Two hundred
ninety-three patients with HME completed a questionnaire designed
to assess pain as well as its impact on their life. Eighty-four percent of
participants reported having pain, indicating that pain is a real
problem in HME. Of those with pain, 55.1% had generalized pain.
Two factors were found to be associated with pain outcome: HMErelated
complications and surgery. Individuals who had HME-related
complications were five times more likely to have pain, while those
who had surgery were 3.8 more likely to have pain. No differences
were found between males and females with respect to pain, surgery,
or HME-related complications. The results of this study indicate that
the number of individuals with HME who have pain has been
underestimated and that pain is a problem that must be addressed
when caring for individuals with HME.
Key Words: hereditary multiple exostosis, pain, exostoses, osteochondromas,
support group
(J Pediatr Orthop 2005;25:369–376)
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Does Over-Masturbation Contribute to Chronic Prostatitis.pptxwalterHu5
In some case, your chronic prostatitis may be related to over-masturbation. Generally, natural medicine Diuretic and Anti-inflammatory Pill can help mee get a cure.
Does Over-Masturbation Contribute to Chronic Prostatitis.pptx
Mhe 2005 abstractbook_mherf.org
1. CONFERENCE
ON
Multiple Hereditary Exostoses
Insights Into Pathogenesis
November 3-5, 2005
Shriners Hospital of Houston
6977 Main Street
Houston, Texas
and the
Houston Marriott Medical Center
6580 Fannin Street
Houston, Texas
Organizers: Dan Wells, Ph.D., Jacqueline Hecht, Ph.D., Sarah Ziegler
Sponsored By:
The Shriners Hospital
The National Institutes of Health
American Association of Enchondroma Diseases
March of Dimes Birth Defects Foundation
The Orthopaedic Research Society
The MHE Coalition
Gene Dx, DNA Diagnostic Services
The Mizutani Foundation for Glycoscience
2. HME: Insights into Pathogenesis.
Schedule of Events
Thursday November 3, 2005
8:30-9:00 Arrive at Shriners (Coffee and Pastries)
9:00-9:10 Dan Wells, Ph.D. Welcome to conference
9:10-9:30 Jacqueline Hecht, Ph.D. Introduction to genetics and natural history MHE
ORTHOPAEDICS AND CLINICAL GENETICS (Christine Alvarez)
9:30-10:10 Christine Alvarez, M.D. Introduction of orthopaedics and defining severity of
Hereditary Multiple Exostosis
10:10-10:40 Luca Sangiorgi, M.D., Ph.D.
Mutational analysis and clinical expression of disease in patients with HME.
10:40-11:00 BREAK
11:00-11:30 Wim Wuyts, Ph.D.
Mutation detection strategies for molecular screening in patients with HME.
11:30-12:00 George Thompson, M.D.
Clinical treatments and surgical procedures.
12:00-1:15 LUNCH
BONE DEVELOPMENT (Dan Wells)
1:15-1:45 John R. Hassell, Ph.D.
FGF binding to percelan isolated from the growth plate.
1:45-2:15 David Ornitz, M.D., Ph.D.
FGF that regulate growth plate development.
2:15-2:45 Maurizio Pacifici, M.D., Ph.D.
Syndecans: Cell surface modulators of growth plate chondrocytes
2:45-3:15 T. Michael Underhill, Ph.D.
Delineation of regulatory networks underlying BMP action in chondrogensis
3:15-3:30 BREAK
3:30-4:00 Henry Kronenberg, M.D., Ph.D.
How PTHrP regulates chondrocytes in the growth plate.
4:00-4:30 Andrea Vortkamp, Ph.D.
Ihh signaling in the growth plate.
4:30-5:00 Matthew Hilton, Ph.D.
Multiple Aspects of Ihh Signaling in the Endochondral Skeleton.
5:00 Transport back to hotel
6:30- Leave for Dinner at Las Alamedas
3. Friday November 4, 2005
8:30-9:00 Arrive at Shriners (Coffee and Pastries)
EXOSTOSIS/DEVELOPMENT (Jacqui Hecht)
9:00-9:30 Jacqueline Hecht, Ph.D.
Analysis of human exostoses and derived cells.
9:30-10:00 Jeffrey Esko, Ph.D.
Signaling defects in chondrocytes give rise to exostoses
10:00-10:30 Dominique Stickens, Ph.D.
Mice deficient in EXT2 lack heparan sulfate and develop exostoses.
10:30-10:45 BREAK
10:45-11:15 Pancras Hogendoorn, M.D., Ph.D.
Profiling of osteochondromas and peripheral chondrosarcomas.
EXT FUNCTION AND NON-MAMMALIAN MODELS (Scott Selleck)
11:15-11:45 Marion Kusche-Gullberg, Ph.D.
EXT1 and EXT2 proteins and heparan sulfate biosynthesis
11:45-12:15 Scott Selleck, M.D., Ph.D.
Heparan sulfate biosynthesis and sulfation.
12:15-1:30 LUNCH
2:00-2:30 Catherine Merry, Ph.D.
ES Cells and the role of Heparan Sulphate in Development and Disease.
2:30-3:00 Rahul Warrior, Ph.D.
Developmental regulation of HSPG synthesis during Drosophila development
3:00-3:30 Malorzata Wiweger, Ph.D.
Zebrafish as a model for studies on Hereditary Multiple Exostosis
3:30-3:30 BREAK
NON-BONE PHENOTYPES (Yu Yamaguchi)
3:30-4:00 Yu Yamaguchi, M.D.,Ph.D.
Phenotypes of conditional EXT1 knockout mice: Non-skeletal symptoms.
4:00-4:30 Jeremy Turnbull, Ph.D.
Structure and biosynthesis of mouse brain heparan sulfate.
4:30-5:00 Harish Hosalkar, M.D.
Keloid Formation Following Surgical Treatment of MHE.
5:00 Transport back to hotel
7:00- Banquet at Hotel
4. Saturday November 5, 2005
8:30-9:00 Continental Breakfast at Hotel
HME-RELATED DISEASES (Benjamin Alman)
9:00-9:30 Benjamin Alman, M.D.
p53 and Rb in Cartilage Tumors in Mice.
9:30-10:00 Roland M. Leach, Ph.D.
Tibia Dyschondroplasia; Ihh signaling.
10:00-10:30 Pancras Hogendoorn, M.D. Ph.D.
Olliers and Mafucci.
10:30-11:00 James Martin, Ph.D.
Malignant transformation in human chondrosarcoma cells.
11:00-11:30 Meeting Summary and Review (Wells and Hecht)
11:30-1:00 LUNCH
ABC’s of MHE WORKSHOP (Sarah Ziegler)
1:00-1:30 Jeffrey Esko, Ph.D. and Scott Selleck, M.D., Ph.D.
Overview of the scientific sessions of the conference.
1:30-2:00 Wim Wuyts, Ph.D.
Genetics of HME.
2:00-2:30 Jacqueline Hecht, Ph.D., and Sandra Darilek, M.S.
Presenting study results, Hereditary Multiple Exostoses and Pain.
2:30-2:45 BREAK
2:45-3:15 Ashish Sinha, M.D., Ph.D.
Chronic pain and the need for treatment
3:15-3:45 Harish Hosalkar, M.D., John P. Dormans, M.D.
ABC's of MHE.
3:45-4:15 John E. Herzenberg, M.D., FRCSC
Use of Fixators.
4:15-5:00 Questions and Discussion
5:00- Buffet Reception
5. Session 1
Thursday November 3, 2005
9:30am - 12:00pm
ORTHOPAEDICS AND
CLINICAL GENETICS
Christine Alvarez, Chair
6. Defining the Severity of Hereditary Multiple Exostosis
Christine Alvarez
Department of Orthopaedics, University of British Columbia,
British Columbia’s Children’s Hospital, Canada.
Introduction: Hereditary Multiple Exostoses (HME) is a genetic disorder with a wide
phenotypic expression involving limb alignment, limb lengths and height, lesion factors, and
potential for sarcomatous transformation. The clinical impact of HME is likely related to
number of lesions a patient has. It remains unclear what factors are predictive of the number of
lesions an individual becomes riddled with. However, these factors are likely related to the
patient’s genotype. HME results from mutations in the exostoses genes: EXT1 and EXT2. The
function of these genes involves controlling physeal chondrocyte proliferation and
differentiation. Mutation of either gene results in loss of control of the physeal maturation
gradient which eventually leads to excess chondrocyte proliferation and presumptive
osteochondroma formation. EXT 1 has a more dominant role in this mechanism and therefore an
EXT 1 mutation would likely have greater impact and result in a greater loss of chondrocyte
regulation in the zone of proliferation and thus, more potential for exotosis formation.
Previous work examining the potential for a genotype phenotype relationship showed that EXT1
patients showed a worse phenotype. This study however had a small sample size and though
trends in many of the 58 phenotypic parameters tested were identified statistical significance was
not uniformly met. Other studies also have found a similar relationship of EXT 1 being worse
phenotypically but phenotypic parameters were incomplete, in some studies the sample was still
small, and in some cases genotypic was based on linkage analysis only and not definite
mutations. Thus, a more descriptive and extensive clinically significant evaluation of these
patients is required as well as a study involving a greater number of patients to provide sufficient
power to address issues of statistical and clinical significance.
Purpose:
The purpose of this study was to build on the original studies on genotype phenotype correlation
in HME. This project was designed to establish an extensive phenotype profile, define genotype
and have large sample size. This study will then therefore define the genotype phenotype
relationship in HME.
Materials and Methods:
Genotyping was performed at the Molecular Diagnostic Laboratory at BC Children’s Hospital.
EXT1 and EXT2 mutations were analyzed by direct sequencing of entire gene coding regions,
including flanking intronic sequences. Phenotyping was performed at the HME Clinic and
involved collection of radiographic and clinical parameters divided across three categories of
lesion quality, limb segment lengths, and limb alignment.
Results:
Sixty-eight affected individuals with HME participated in the study. Genotype data was collected
for all participants. Phenotype data including lesion number and quality (17 parameters), limb
segment lengths (6 parameters x 2 side), longitudinal height, and limb alignment (28 parameters)
were collected. Baseline demographics were established considering number of patients affected
with EXT 1 vs. EXT 2 mutations, gender, and age (classified into four age categories: 0-5, 6-10
11-15 and +16 years). The primary premise, that more lesion cause worse severity, was
established, and then applied to the principal hypothesis that EXT 1 mutations produce a worse
phenotype.
7. Mutational analysis of EXT1 and EXT2 genes and a new system for “grading” clinical
expression of disease in patients with Hereditary Multiple Exostoses.
1
Luca Sangiorgi, 2Nicola Fabbri, 2Laura Campanacci, 1Elena Pedrini, 1Veronica Maini, 1Silvia
Capponcelli, 1Marina Mordenti and 2Mario Mercuri.
1
Genetics Unit, 2V Surgery Division, Rizzoli Orthopedic Institute, Bologna, Italy.
Introduction: Several mutations dispersed throughout the EXT1 and EXT2 genes have been
identified in HME patients. Most of these are responsible of the truncation of EXT1 or EXT2
proteins which are likely to become inactive and degrade rapidly, resulting in a nearly complete
loss-of-function. A prospective longitudinal study was undertaken to correlate genotype and
phenotype of the disease in families and sporadic cases, with the purpose of defining the disease
spectrum of expression.
Method: A multidisciplinary clinic, involving geneticists and orthopaedic surgeons, is weekly
carried out at the Rizzoli Institute. In order to evaluate the spectrum and distribution of mutations
leading to HME in the Rizzoli cohort of patients, a new multi-step DHPLC-based mutation
screening method was optimised. For informative families, we adopted a pre-screening linkage
analysis to selectively focus the DHPLC testing on either EXT1 or EXT2. Patient clinical
assessment is carried out using a new classification system substantially based on deformity and
functional limitation and the genotype-phenotype study is performed using this system.
Results: In a small pilot we enrolled 36 unrelated probands, representing 20 families and 14
sporadic cases for the presence of mutations in either EXT1 or EXT2 genes. Thirty-one out of
36 probands (86%) had mutations either in EXT1 (24/31; 77%) or EXT2 (7/31; 23%), mainly
distributed in the amino-terminal region of the proteins and the vast majority of them are
responsible of a premature protein truncation. Most mutations were distributed towards the 5’
end of EXT1 and EXT2 genes. In accordance with the most recent data, 23 of 31 mutations
(74%) were novel. No novel missense or splice site mutations were detected in 200 control
chromosomes. All splice site mutations were present in the highly conserved AG and GT
positions of the splice acceptor and donor junctions, and only one of these (c.IVS6+1G>T in the
EXT1 gene) had been previously reported in the HGMD database. The 3 missense mutations
clustered within exon 2 of the EXT1 gene and caused amino acid substitutions in residues 339
and 340. Two of these (c.1018C>T (p.R340C), c.1019G>A (p.R340H)) had been already
described whereas the third one (c.1016G>T (p.G339V)) was a novel mutation responsible for
substitution of a glycine codon with a valine within an important key element for EXT1 function.
The overall mutation frequency in 36 probands was 86% (67% in EXT1 and 19% in EXT2).
Mutations were found in 10 of 14 sporadic cases (71%) and in 20 of 21 familial cases (95%). No
disease-causing mutation has been detected in 5 of 36 patients. A new clinical classification
based on clinical evaluation and orthopaedic problems has been defined. A preliminary study
performed on 153 pts have shown that most (80%) are not substantially limited by the disease.
Using the DHPLC based screening technique and the clinical classification system, we are
currently running a genotype/phenotype study on 170 patients. Preliminary results indicate that
mutations on specific exons of the EXT1 gene correlate with more relevant clinical limitations.
Conclusions: Our results identified several novel and many private mutations in a large cohort
of patients, confirming the strong allelic heterogeneity of EXT1 and EXT2 genes. Our optimised
DHPLC-based approach represents a reliable, efficient and highly sensitive diagnostic strategy
for rapid detection of germline mutations in HME patients. The genotype-phenotype study is
giving indication regarding association of alterations and clinical presentation of the disease.
8. Mutation detection strategies for molecular screening in patients with MHE.
Wim Wuyts
Department of Medical Genetics University of Antwerp, Belgium.
Hereditary multiple exostoses (HME) is an autosomal dominant bone disorder characterized by
the presence of bony outgrowths (exostoses) on the long bones. HME is a genetically
heterogeneous condition and at present two causal genes have been identified: EXT1 on
chromosome 8q23-q24 and EXT2 on chromosome 11p11.2. A third locus, EXT3 on
chromosome 19p has been suggested but is controversial.
Since the identification of the HME causing genes, molecular analysis of HME patients has been
optimized to increase sensitivity of the testing and reduce the cost. Recently, we further
optimized the mutation screening protocol for both EXT1 and EXT2. For all coding exons
DHPLC conditions were optimized and validated in a large set of HME patients with a known
EXT1 or EXT2 mutation. All mutations could be detected under at least 1 DHPLC condition,
providing a robust and sensitive alternative for labor extensive and more expensive sequencing
analysis.
However, approximately 15 to 20% of HME patients does not show a mutation after extended
sequence analysis of EXT1 and EXT2. We therefore expanded the screening protocol with FISH,
MLPA and RNA analysis. This enabled us to detect (partial) EXT1 or EXT2 deletions in
approximately 30% of EXT1/EXT2 mutation negative patients. At least one patient with two
copies of both EXT genes showed loss of one EXT1 allele on the RNA level, but the underlying
cause is still under investigation.
The various mutation detection strategies will be discussed as well as the mutation spectrum
observed in HME patients.
9. Management of Multiple Hereditary Exostosis
of The Axial (Hip And Spine) Skeleton
George H. Thompson, M.D.,
Professor, Orthopaedic Surgery and Pediatrics, Director, Pediatric Orthopaedics,
Rainbow Babies and Children’s Hospital, Case Western Reserve University,
Cleveland, OH 44106
Exostoses of the axial skeleton are uncommon lesions. Those involving the spine represent 4 to
7 percent of all primary benign spinal tumors. They can occur as solitary exostoses or in
association with multiple hereditary exostoses (MHE). Pelvic exostoses, including those
involving the proximal femur are also uncommon.
Spinal Lesions: We have recently evaluated our experience with spinal exostoses seen between
1972 and 2002. There were 12 patients, including 7 females and 5 males with a mean age at
presentation of 24.2 years (range, 7-52 years). Five patients had MHE, while 7 had solitary
exostoses. The mean age at presentation of the patients with MHE was younger at 16.8 years
(range, 7-34 years) compared to 29.5 years (range, 22-52 years) for those with solitary lesions.
Eight of the 12 patients had intraspinal lesions. These occurred most commonly in the cervical
spine. All five patients with MHE had intraspinal exostoses. Three at C2 and one each in the
thoracic spine and sacrum. The solitary intraspinal lesions occurred in the cervical (C2 and C6)
or thoracic (T11). The most common chief complaint was pain (8 patients). Seven of these
lesions resulted in symptoms consistent with spinal cord nerve root compression. Three patients
with MHE and 4 with solitary exostoses had symptoms or findings consistent with neurological
compression. Eight exostoses were treated surgically with eventual resolution of symptoms.
The mean follow-up for patients treated surgically was 5.6 years (range, 0.5-13 years). Two
patients had recurrence following resection of intraspinal lesions. Both had solitary lesions and
underwent successful revision surgery. There was only one complication in the 8 patients treated
operatively. This consisted of an anterior compartment syndrome following prolonged surgery
for wide excision and stabilization of a thoracolumbar exostosis.
Pelvic Lesions: Pelvic lesions in MHE are relatively uncommon. When present, they usually
involve the ilium and proximal femur but occasionally occur in the acetabulum, resulting in
progressive subluxation of the femoral head. Lesions involving the proximal femur are usually a
dysplasia rather than a true exostosis, but these too can become enlarged resulting in progressive
hip subluxation. Excision of lesions about the pelvis include excision and possibly a proximally
femoral osteotomy, if there is subluxation of the hip. An enlarging pelvic lesion in a skeletally
mature individual is suggestive of malignant degeneration.
Conclusions: Exostoses involving the axial skeleton are relatively uncommon. Those involving
the spine have a higher incidence of neurological symptoms due to spinal cord or nerve root
compression. Any child with MHE presenting with neurological signs or symptoms should be
evaluated by both computed tomography and magnetic resonance imaging. Without appropriate
treatment, progressive neurological symptoms can occur. Lesions of the pelvis are also rare and
a common site of malignant degeneration as an adult. The indications for treatment are pain,
disfiguring mass, and progressive hip subluxation.
11. Fibroblast growth factor binding to perlecan isolated from the growth plate
Leigh Westa, Prasanthi Govindraja, Xiuqin Zhangb, David M. Ornitzb
and John R. Hassela,c
a
Center for Research in Skeletal Development and Pediatric Orthopaedics,
Shriners Hospitals for Children – Tampa, FL 33612
and bDepartment of Molecular Biology and Pharmacology,
Washington University Medical School, 660 S. Euclid Avenue, St. Louis, MO 63310
and the cDepartment of Biochemistry and Molecular Biology,
College of Medicine, University of South Florida, Tampa, FL 33612
Fibroblast growth factor (FGF)-2, FGF-9 and FGF-18 are three FGF's that have been shown to
regulate chondrocyte proliferation in the growth plate. Heparin and heparan sulfate
proteoglycans from endothelial cells have been shown to bind FGF-2. Perlecan is present in the
growth plate as a proteoglycan containing both heparan and chondroitin sulfate chains and the
phenotype of the perlecan knockout mouse shows it is necessary for the proliferation of
chondrocytes in the growth plate. We evaluated the binding of FGF's to perlecan from the
growth plate using a cationic filtration assay. We found FGF-2 bound primary to the heparan
sulfate chains on perlecan but that the core protein was also involved in FGF-2 binding when the
heparan sulfate chains were present. Removal of Chondroitin sulfate chains on perlecan
enhanced FGF-2 binding slightly. FGF-1, FGF-9 and FGF-18 showed no binding to perlecan but
FGF-7 showed a low level of binding. We also found, using recombinant FGF receptors in a
separate capture assay that while the receptors would bind to a heparin-FGF-2 complex, the
receptors would not bind to the perlecan-FGF-2 complex. Similarly, perlecan did not augment
FGF-2 stimulation of [3H]-thymine incorporation in BaF3 cells. These data show perlecan can
bind to FGF-2 by its heparan sulfate chains but that chondroitin sulfate chains on the perlecan
acts to block transfer of the bound FGF-2 to the receptor.
12. FGFs that regulate growth plate development.
David M. Ornitz, Irene Hung, Zhonghao Liu,
Kory Lavine, Kai Yu, Hidemi Kanazawa, Ann Jacob.
Department of Molecular Biology and Pharmacology,
Washington University School of Medicine.
Fibroblast growth factors (FGFs) are essential molecules for mammalian development. A
growing number of human genetic diseases that affect skeletal development are caused by point
mutations in the genes encoding FGF receptors 1, 2 and 3. These disorders result in
craniosynostosis and chondrodysplasia syndromes and thus demonstrate that FGF signaling
pathways are essential regulators of chondrogenesis and osteogenesis. Loss of function and
skeletal-specific conditional loss of function mutations in mouse FGF receptors 1-3 also show
specific defects in skeletal development and in the structure and integrity of adult bone.
In contrast to the increasing amount of data demonstrating a role for FGFRs in skeletogenesis,
there is very little information on the FGF ligands that signal to these receptors to regulate
skeletal development, growth, remodeling and repair. Mice lacking FGF2 (bFGF) have a mild
decrease in bone mass and trabecular bone formation, but no morphological defects in their
skeleton.
Examination of skeletal development in mice lacking FGF18 revealed moderate skeletal
dysmorphology and a significant delay in ossification of distal bones that is not seen in mice
lacking FGF receptors 1, 2 or 3 in osteoblast or chondrocyte lineages. In contrast, analysis of
mice lacking Fgf9 revealed a delay in ossification primarily affecting proximal bones. The
dysmorphology and delayed ossification phenotype of these knockout mice suggest that FGF9
and FGF18 signal to skeletal cells (chondrocytes and osteoblasts) to regulate early skeletal
development and to non-skeletal mesenchymal cells to regulate peri-skeletal vasculogenesis and
vascular invasion of the primitive growth plate.
We have also observed that mice lacking both FGF9 and FGF18 have very severe skeletal
dysmorphology with delayed ossification and agenesis of the intramembranous bones of the
cranium. These data further suggest that FGF9 and FGF18 form overlapping and inverted
gradients in the appendicular skeleton that regulate both development and vascularization.
13. Syndecans: Cell Surface Modulators of Growth Plate Chondrocyte
Behavior and Function
Maurizio Pacifici
Department of Orthopaedic Surgery,
Thomas Jefferson University College of Medicine,
Philadelphia, PA 19107
Syndecans are single-pass integral membrane components that serve as co-receptors for growth
factors and cytokines and can elicit signal transduction via their cytoplasmic tails. We will
present studies from our group on syndecan biology and function in the growth plates of
developing long bones in chick and mouse embryos. Gain- and loss-of-function data indicate that
syndecan-3 has important roles in restricting mitotic activity to the proliferative zone of growth
plate and may do so in close cooperation and interaction with the signaling molecule Indian
hedgehog (Ihh), and that syndecan-2 may participate in growth plate-associated ossification.
Biochemical and protein-modeling data suggest a dimeric/oligomeric configuration for
syndecan-3 on the chondrocyte’s cell surface. Analyses of embryos mis-expressing syndecan-3
or lacking Ihh provide further clues on syndecan-3/Ihh interdependence and interrelationships.
The data and the conclusions reached provide insights into mechanisms fine-tuning chondrocyte
proliferation and function and ossification events in the developing and growing skeleton and
into how abnormalities in these fundamental mechanisms may subtend human congenital
pathologies, including osteochondromas in hereditary multiple exostoses syndrome.
14. Delineation of Regulatory Networks Underlying BMP Action in Chondrogenesis
T. Michael Underhill1, Linsay M. Drysdale2, Konstantina Karamboulas1,
Matthew F. Cowan1, Jian Wang3, William A. Horton4 and Lisa M. Hoffman2
1
Department of Cellular and Physiological Sciences, University of British Columbia,
Vancouver, BC, Canada, V6T 1Z3; 2Department of Physiology, Faculty of Medicine &
Dentistry, University of Western Ontario, London, ON, Canada, N6A 5C1; 3Robarts Research
Institute, 100 Perth Dr., London, ON, Canada, N6A 5K8; 4Shriner’s Children’s Hospital, 3101
SW Sam Jackson Park Road, Portland, OR, USA, 97239
The BMP and GDF signaling pathways have well-established and essential roles within the
developing skeleton in coordinating formation of cartilaginous anlagen. However, identification
of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has
remained elusive. Using microarray-based methods coupled with functional profiling, we have
identified the retinoic acid (RA) synthesis enzyme, Aldh1a2, as a principal target of BMP
signaling—prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and
consequently, reduced activation of the retinoid signaling pathway. Consistent with this,
antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the
chondrogenic stimulatory activity of BMP4. Further, moderate fold changes in endogenous
retinoid signaling (< 4.5 fold) are sufficient to regulate expression of the chondroblast
phenotype. In aggregate, these results establish a hierarchical relationship between the BMP and
retinoid signaling pathways in chondrogenesis. These results will be presented along with
additional findings that provide a molecular framework for understanding BMP action in the
chondrogenic program. This research was supported by grants to T.M.U. from the Canadian
Institutes of Health Research and the Canadian Arthritis Network.
15. How PTHrP regulates chondrocytes in the growth plate
Henry M. Kronenberg
Endocrine Unit, Massachusetts General Hospital and
Harvard Medical School, Boston, MA 02114
Chondrocytes in the growth plate are the engine that causes bone lengthening. Chondrocytes
proliferate and secrete matrix. They then stop proliferating, enlarge several fold (hypertrophy),
mineralize the matrix surrounding them, and then die. The matrix remaining provides a scaffold
for subsequent formation of bone by osteoblasts. To assure a proper balance between
chondrocyte proliferation and hypertrophy, elaborate regulatory mechanisms have evolved.
Parathyroid hormone-related protein (PTHrP), a relative of the calcium-regulating hormone,
parathyroid hormone, is secreted by perichondrial cells and chondrocytes at the ends of long
bones of the limb. PTHrP acts to keep chondrocytes proliferating, thereby allowing the
generation of more chondrocytes and delaying the onset of chondrocyte hypertrophy. Only when
chondrocytes bearing receptors for PTHrP are sufficiently far from a source of PTHrP do the
chondrocytes then stop proliferating.
PTHrP works by activating a receptor of the G protein-coupled receptor family. Activation
stimulates the heterotrimeric G protein, Gs; this activation leads to generation of cyclic AMP and
activation of protein kinase A. These processes lead to suppression of the cell cycle inhibitor,
p57, and also suppression of the expression of the transcription factor, Runx2. Suppression of
p57 is a major mechanism that results in the continued proliferation of chondrocytes. Since
Runx2 is a major inducer of chondrocyte hypertrophy, the suppression of Runx2 expression by
PTHrP also contributes to the continued proliferation and delay of hypertrophy of chondrocytes.
As chondrocytes stop proliferating, they begin secreting Indian hedgehog. Indian hedgehog
(Ihh) has multiple roles in regulating the growth plate. Ihh stimulates the synthesis of PTHrP, a
role that then leads to further expansion of the layers of proliferating chondrocytes. Since these
proliferating chondrocytes do not synthesize Ihh, the stimulation of PTHrP synthesis by Ihh
serves to negatively regulate the expression of Ihh. Ihh also accelerates the conversion of round
chondrocytes, found at the top of the growth plate, into flat columnar chondrocytes. Since the
flat columns formed by these cells align in the primary axis of growth of the growth plate, this
action of Ihh serves to help determine the final length and shape of the bones. Ihh also
stimulates the proliferation of chondrocytes and acts on adjacent perichondrial cells to convert
them to osteoblasts. Thus, Ihh is a master regulator of the growth plate which controls
chondrocyte proliferation and differentiation, as well as the differentiation of adjacent
osteoblasts.
16. Ihh signaling in the growth plate.
Andrea Vortkamp
Centre for Medical Biotechnology, Department of Developmental Biology,
University Duisburg-Essen, 45117 Essen, Germany
Endochondral ossification is a multistep process during which a cartilage template is
successively replaced by bone tissue. Chondrocytes in the cartilage anlagen undergo several
steps of differentiation until they become terminal hypertrophic and are subsequently replaced by
bone. The secreted growth factor Indian hedgehog (Ihh) is expressed in a distinct population of
chondrocytes that undergo hypertrophic differentiation. Ihh interacts with a second secreted
molecule, Parathyroid Hormone related Protein (PTHrP), expressed in the distal ends of the
cartilage elements in a negative feedback mechanism to regulate the onset of hypertrophic
differentiation.
Analyzing a mouse line carrying a hypomorphic allele of Ext1, a glycosytransferase necessary
for the synthesis of heparan sulfates (HS), we have recently shown that HS negatively regulates
the propagation of the Ihh signal in a concentration dependent manner. Our data strongly indicate
that Ihh acts as a long range morphogen directly inducing the expression of PTHrP.
To further investigate the interaction between Ihh and PTHrP, we have started to analyze the role
of the zinc finger transcription factor Gli3, which acts downstream of hedgehog signals in other
organs. Ihh;Gli3 double mutants indicate that Gli3 acts as a repressor downstream of Ihh in
regulating chondrocyte proliferation and the expression of PTHrP, and, thus, the onset of
hypertrophic differentiation. Furthermore, our studies identified a new function of the Ihh/Gli3
system in negatively regulating the differentiation of distal, low proliferating (zoneI) into central,
high proliferating (zone II) chondrocytes. Whereas the domain of zone II chondrocytes is
determined by the level of PTHrP, the transition of zone I into zone II chondrocytes is regulated
by Gli3R independent of PTHrP.
17. Multiple Aspects of Ihh Signaling in the Endochondral Skeleton
Matthew Hilton
Department of Internal Medicine, Division of Bone and Mineral Diseases
Washington University School of Medicine
St. Louis, MO 63110
Indian hedgehog (Ihh) is indispensable for proper endochondral bone development. In the
developing cartilage, Ihh expressed in the prehypertrophic and early hypertrophic chondrocytes
signals through chondrocytes and the perichondrium to regulate chondrocyte proliferation and
hypertrophy. Previous studies have shown that Ihh on one hand directly regulates chondrocyte
proliferation, and on the other hand indirectly controls chondrocyte maturation through
regulation of Parathyroid hormone like hormone (Pthlh). However, it has not been understood 1)
how Ihh transports through the cartilage, and 2) whether Ihh directly controls pthlh expression.
Our recent studies with Exostosin1 (Ext1) heterozygous mice, supports that heparan sulfate
synthesis normally restricts the transportation of Ihh within the growth plate cartilage. More
recently, through localized removal of Smoothened (Smo), the key mediator of hedgehog
signaling, using a tamoxifen inducible Col2Cre transgenic mouse, we demonstrated that Ihh
directly regulates pthlh expression in the immature articular chondrocytes. Additionally, we
uncovered that Ihh may directly regulate the organization of columnar chondrocytes in a Pthlh-
independent manner.
19. Differentiation-induced loss of heparan sulfate
in human exostosis derived chondrocytes
Jacqueline T. Hecht1,2 Richard Haynes2, William G. Cole3,
Robert J. Long4, Mary C. Farach-Carson4, Daniel D. Carson4
1
University of Texas Medical School at Houston, 2Shriners Hospital-Houston, Houston,
3
Department of Surgery, Hospital for Sick Children, Toronto, Canada, 4Department of Biological
Sciences, University of Delaware
An exostosis or osteochondroma is an aberrant bony growth occurring next to the growth plate
either as an isolated growth abnormality or as part of the Hereditary Multiple Exostosis (HME)
syndrome. Mutations in either exostosin 1 (EXT1) or exostosin 2 (EXT2) gene cause the HME
syndrome and also some isolated osteochondromas. The EXT1 and EXT2 genes are
glycosyltransferases that function as hetero-oligomers in the Golgi to add repeating
glycosaminoglycans (GAGs) to heparan sulfate (HS) chains. Previously, we demonstrated that
HS is markedly diminished in the exostosis cartilage cap and that the HS proteoglycan, perlecan,
has an abnormal distribution in these caps. The present studies were undertaken to evaluate
which chondrocyte-specific functions are associated with diminished HS synthesis in human
chondrocytes harboring either EXT1 or EXT2 mutations. Systematic evaluation of exostosis
cartilage caps and chondrocytes, both in vitro and in vivo, suggests that chondrocyte-specific cell
functions account for diminished HS levels. In addition, we provide evidence that perichondrial
cells give rise to chondrocytes that clonally expand and develop into an exostosis.
Undifferentiated EXT chondrocytes synthesized amounts of HS similar to control chondrocytes;
however, EXT chondrocytes displayed very poor survival in vitro under conditions that promote
normal chondrocyte differentiation with high efficiency. Collectively, these observations suggest
that loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial
chondrocytes’ ability to differentiate normally and to survive in a differentiated state in vitro. In
vivo, these compromised responses may lead to abnormal chondrocyte growth, perhaps from a
perichondrial stem cell reserve.
20. Analysis of exostoses in mice indicate signaling defects in chondrocytes
give rise to ectopic growth.
Beverly M. Zak†, Manuela Schuksz†, Dominique Stickens‡, Dan Wells*, and Jeffrey D. Esko†
†
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500
Gilman Drive, La Jolla, CA, 92093-0687; ‡ Department of Anatomy, University of California,
San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0452; * Department of Biology
and Biochemistry, University of Houston, Houston, TX 77204
Hereditary Multiple Exostoses (HME) is an autosomal dominant disease characterized by
osteochondromas on the ends of bones that form by endochondral ossification. The disease has
been linked to mutations in EXT1 and EXT2, which encode subunits of the heparan sulfate
copolymerase. To understand how a change in heparan sulfate biosynthesis might result in
exostoses, null alleles of each gene have been created in mice. Homozygous null embryos arrest
development at gastrulation, but heterozygous embryos appear normal, develop to maturity, and
reproduce. They also exhibit occasional exostoses on the ribs and more rarely on other
endochondral bones. EXT1 and EXT2 heterozygotes form exostoses at approximately the same
frequency (14/101 and 20/120, respectively), whereas compound heterozygotes (EXT1+/-EXT2+/-
) develop exostoses more frequently (60/165) consistent with the two genes acting through a
common pathway. The exostoses arising in single and compound heterozygotes are
indistinguishable by a number of criteria. Immunohistochemical and biochemical analyses
revealed reduction of heparan sulfate in affected growth plates and in cultured chondrocytes,
leading to shorter heparan sulfate chains. This in turn results in growth factor signaling defects
in isolated chondrocytes. Exostoses appear to arise in perichondrial chondrocytes based on the
histology of affected ribs and the appearance of exostoses in mice harboring a chondrocyte-
specific inactivation of EXT1. Thus, we propose that signaling defects specifically in
chondrocytes give rise to ectopic growth. The actual signaling pathway altered in heterozygous
EXT animals will be discussed along with other phenotypes of mice altered in heparan sulfate
biosynthesis.
21. Mice deficient in Ext2 lack heparan sulfate and develop exostoses
Dominique Stickens1, Beverly M. Zak2¶, Nathalie Rougier1¶+,
Jeffrey D. Esko2 and Zena Werb1*
1
Department of Anatomy, University of California, San Francisco, CA 94143-0452
2
Department of Cellular and Molecular Medicine, University of California, San Diego,
9500 Gilman Drive, La Jolla, CA, 92093-0687
Hereditary Multiple Exostoses (HME) is a genetically heterogeneous human disease
characterized by the development of bony outgrowths near the ends of long bones. HME results
from mutations in EXT1 and EXT2, genes that encode glycosyltransferases that synthesize
heparan sulfate chains. To study the relationship of the disease to mutations in these genes, we
generated Ext2-null mice by gene targeting. Homozygous mutant embryos developed normally
until embryonic day 6.0, when they became growth-arrested and failed to gastrulate, pointing to
the early essential role for heparan sulfate in developing embryos. Heterozygotes had a normal
lifespan and were fertile, however, analysis of their skeletons showed that about 1/3 of the
animals formed one or more ectopic bone growths (exostoses). Significantly, all of the mice
showed multiple abnormalities in cartilage differentiation, including disorganization of
chondrocytes in long bones and premature hypertrophy in costochondral cartilage. The finding
that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the complex
molecular mechanisms underlying the development of exostoses.
22. Profiling of hereditary and solitary osteochondromas and peripheral chondrosarcomas on
genomic, gene expression and protein level.
L. Hameetman, A.M. Cleton-Jansen, G. David, J.V.M.G. Bovee, P.C.W. Hogendoorn.
Department of Pathology Leiden University Medical Center, Leiden The Netherlands and
University of Leuven, Belgium
Osteochondroma is a cartilage capped benign bony neoplasm on the outer surface of bones
preformed by endochondral ossification. The cartilage cap of osteochondroma histologically
resembles the morphological organization of an epiphyseal growth plate. A small percentage
osteochondromas transform towards their malignant counter part, secondary peripheral
chondrosarcoma. For Multiple Osteochondromas EXT1 located at 8q24 was shown to act as
tumor suppressor gene in tumours of EXT1 mutant patients. We demonstrate that in hereditary
tumors EXT expression is correlated with mutation status of the patient. Furthermore, EXT1, but
not EXT2, is down-regulated in sporadic tumors, where 8q24 loss is a frequent phenomenon, but
mutations or promoter hypermethylation are not found till now.
EXT genes are involved in biosynthesis of heparan sulphate proteoglycans (HSPGs).
Immunohistochemical evaluation of a series (n=70) of both hereditary and solitary tumors
revealed intracellular accumulation of HSPG core proteins and of shorter or less complex HS
chains, in contrast to the extracellular expression of these molecules found in growth plates.
HSPGs are involved in several growth signaling pathways, including in the negative feedback
loop of the Indian Hedgehog (IHH) and parathyroid hormone–like hormone (PTHLH). PTHLH
signaling is absent in osteochondromas, but reactivated upon malignant transformation towards
chondrosarcoma. Disturbed expression of IHH signaling molecules has also been implicated in
osteochondroma. With quantitative RT-PCR we were able to demonstrate similar expression
levels of IHH signaling in osteochondromas as compared to the growth plate. A gradual decrease
in expression of IHH signaling molecules was observed with increasing malignancy, suggesting
that IHH signaling is inactived and PTHLH signaling is IHH-independent in chondrosarcomas.
cDNA expression profiling and immunohistochemical studies suggest that TGF-β-mediated
proliferative signaling is upregulated in high-grade chondrosarcomas. TGF-β is a good candidate
to regulate PTHLH signaling in high-grade tumors. Chondrosarcoma progression is further
accompanied by down-regulation of energy metabolism-related genes and upregulation of the
proto-oncogene jun B.
Dysplasia Epiphysealis Hemimelica (DEH, Trevor's disease) and metachondromatosis (MC)
are considered in the differential diagnosis of solitary and hereditary osteochondromas. In a
comparative study between DEH, MC and osteochondroma we were able to demonstrate that
histologically DEH differs from conventional osteochondroma, while MC-related lesions do not.
With qPCR we show that in contrast to osteochondroma, MC and DEH still express the EXT
genes and immunohistochemical analysis showed that EXT downstream pathways are active.
These results indicate that DEH and MC are indeed different entities and that so far unknown
molecular defects in these lesions do not affect EXT signaling.
23. Session 4
Friday November 4, 2005
11:15am - 3:30pm
EXT FUNCTION AND
NON-MAMMALIAN MODEL
Scott Selleck, Chair
24. EXT1 and EXT2 proteins and heparan sulfate biosynthesis
Maria Wilén1, Marta Busse1 and Marion Kusche-Gullberg1,2
1
Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala,
Sweden and 2Department of Biomedicine, Division of Physiology,
University of Bergen, Bergen, Norway
Heparan sulfate is a complex polysaccharide that plays an important role in several cellular
processes, including normal fetal development, wound healing and inflammation. Defects in
enzymes involved in heparan sulfate synthesis result in different abnormalities including
abnormal skeletal and kidney development. Heparan sulfate is elongated by the alternating
transfer of glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc) units. Concomitant with
elongation, the polymer is modified through a series of reactions that requires the action of
several different enzymes. The extent of these reactions varies, giving rise to heparan sulfate
chains with different structural properties. The chain elongation reaction has been ascribed to a
hetero-oligomeric complex of EXT1 and EXT2. Mutations in either EXT1 or EXT2 have been
linked to the human disorder, hereditary multiple exostoses (HME), characterized by the
formation of cartilage-capped bony outgrowths at the end of the long bones.
The individual functions of EXT1 and EXT2 in heparan sulfate chain elongation are currently
unknown. EXT1 alone has the capacity to elongate heparan sulfate chains in vitro. Furthermore,
reduced EXT1 expression levels results in the formation of heparan sulfate chains that are shorter
than those normally synthesized. The level of EXT2 protein modifies the catalytic properties of
EXT1 but the role of EXT2 in heparan sulfate chain elongation is not clear.
To evaluate the effect of EXT2-mutations on heparan sulfate structure, we have generated
transgenic mice with a general and constitutive tissue expression of wild-type or mutated EXT2.
To understand the individual roles of EXT1 and EXT2, we have overexpressed the proteins or
reduced their levels in mammalian cell systems and studied the effects of these manipulations on
heparan sulfate structure.
25. Heparan sulfate biosynthesis and sulfation:
Exploring function in synapse assembly and vascular development
Scott B. Selleck, Melissa Rusch, Steve Ekker, Catherine Kirkpatrick, and Yi Ren
The Developmental Biology Center, and Depts. of Pediatrics and Genetics,
Cell Biology and Development, The University of Minnesota, Minneapolis, MN 55455
Heparan sulfate is a structurally diverse molecule that is important for both the control of cellular
responses to secreted growth factors, and controlling their distributions in the matrix. Our group
employs a number of model organisms and systems to understand the functions of heparan
sulfate-modified proteoglycans during development. HSPGs have long been known to be
present at the neuromuscular junction in vertebrates, but the function of this class of molecules
has not been explored at this well studied synapse. We have used mutations affecting the
proteins responsible for HS chain initiation (brother of tout-velu, botv, an ortholog of and Extl),
chain polymerization (tout-velu, ttv; sister-of-tout-velu, sotv, orthologs of vertebrate Ext genes)
and sulfation (sulfateless, sfl; ortholog of N-deacetylase N-sulfotransferase) in the fruitfly
Drosophila to assess the role of HS in neuromuscular development and function. We find that
animals defective for the HS biosynthetic and modifying enzymes show defects in synaptic
transmission. Compensation to presynaptic defects remains however, with increases in muscle
responses and elevated levels of glutamate receptors in the postsynaptic cell.
Our studies of the requirement for HS in vascular development employ the zebrafish Danio
rerio. Using both mutants affecting Ext2 and Extl3 (boxer and dackel, respectively), as well as
morpholinos directed against the mRNAs from these genes, we have found that HS synthesis is
required for normal angiogenesis in zebrafish embryos. We have also established methods for
identifying small molecule inhibitors of HS synthesis and modification using human tissue
culture cells. A small molecules derived from this screen affects HS biosynthesis in zebrafish
embryos and likewise disrupts normal vascular development.
26. Embryonic Stem Cells can be used to investigate the role of Heparan Sulphate in
Development and Disease
Claire E. Johnson, Rebecca Baldwin, Annie Wat, Graham Rushton,
John T. Gallagher and Catherine L.R. Merry
Cancer Research UK and University of Manchester Department of Medical Oncology,
Christie Hospital Research Centre, Manchester, UK.
For several years now, work using model organisms has demonstrated that heparan sulphate
(HS) in association with specific core proteins is a downstream effecter of several regulatory
molecules that modulate changes in the morphology, mobility and proliferation of developing
cells. The genetic analysis of inherited diseases such as HME has revealed the importance of HS
in cell growth regulation and tissue-specific patterning during human development. In addition
to our on-going study of the role of HS at the molecular level, we have established the novel
approach of using murine and human embryonic stem (ES) cells to provide in vitro model
systems for the study of the developmental biology of HS. ES cells undergo symmetrical self-
renewal in culture whilst retaining the ability to differentiate into all foetal and adult lineages.
There are three alternative fates for ES cells; they can remain pluripotent, they can differentiate
or they can undergo apoptosis. The signalling molecules that control this decision process are
complex, and consist of a subtle interplay of secreted factors, cell-autonomous factors and cell-
adhesion molecules. Many of these signalling proteins are familiar to the proteoglycan (PG)
field, being HS-dependent growth factors, morphogens or matrix-resident PGs secreted by the
ES cells, or by the fibroblasts used as a feeder layer. ES cells therefore present an
experimentally tractable in vitro system in which the role of HS in multiple interacting signalling
processes can be assessed. The major benefit of the system is that we can monitor cells as they
transform from a pluripotent phenotype to differentiated lineages. This enables us to study the
relationship between developmentally-regulated expression of HS-biosynthetic enzymes (such as
EXT-1) and the structural and functional attributes of HS. This has become a hotly debated issue
in the field as evidence has emerged concerning the deleterious effects of mutations in these
enzymes on embryogenesis and the functions of HS in the adult. We are currently using an ext1
knock-out mouse ES cell line (from Prof. Esko, UCSD) to detail the role of cell-surface HS in
the earliest stages of differentiation and lineage commitment. This work will enable us to better
understand the function of HS in co-ordinating the multiple interacting pathways influencing cell
development and differentiation in the normal and disease state.
27. Developmental regulation of heparan sulfate proteoglycan synthesis
during Drosophila embryogenesis.
Douglas Bornemann, Sangbin Park and Rahul Warrior. Department of
Developmental and Cell Biology and the Developmental Biology Center,
University of California, Irvine, Irvine CA 92617.
Signaling by the BMP4 homolog Decapentaplegic (Dpp) is critical for cell fate specification in a
wide variety of tissues and at several stages during Drosophila development. The most
extensively studied roles for Dpp are in patterning the dorsal region of the early embryo and in
regulating cell proliferation and patterning in the wing imaginal discs. Dpp activity in the wing
disc requires heparan sulfate proteoglycans (HSPGs), and mutations in tout velou (ttv) and sister
of tout velou (sotv) that encode the GAG chain polymerases, impair Dpp signaling. Ttv and Sotv
activities are also essential for Hedgehog (Hh) and Wingless (Wg) signaling, both in the
imaginal discs as well as in the embryo. Surprisingly however, embryos lacking ttv, sotv and
other HSPG biosynthetic enzymes do not show any alterations in dorsal patterning, a phenotype
characteristic of disruptions in the Dpp pathway. Thus our data suggested that the Dpp pathway,
in contrast to the Hh and Wg pathways, appears to be differentially sensitive to loss of HSPGs at
different developmental stages.
In order to understand the basis for these observations we examined the temporal regulation of
GAG chain addition to HSPG core proteins. We found that GAG chain synthesis is under tight
developmental control. Essentially no synthetic activity is detectable in the first three hours of
embryogenesis with a rapid onset between three and four hours following fertilization. The
early time period when the biosynthetic process is inactive correlates precisely with the interval
during which a Dpp/BMP activity gradient is established, while the onset of GAG chain addition
coincides with the time when Hh and Wg signaling first become active in patterning the
embryonic epidermis. We find that the timing of GAG chain addition is not controlled by the
regulated expression or activity of a pathway component. Instead our data argue that GAG chain
synthesis is controlled at a post-transcriptional level through regulated translation of at least one
of the GAG chain polymerases. Interestingly, this regulatory mechanism appears to be
phylogenetically conserved, suggesting that stage or tissue-specific regulation of GAG chain
addition could represent an important strategy in altering the sensitivity of specific signaling
pathways at unique stages during development.
28. Zebrafish as a model for studies on the hereditary multiple exostosis.
Malgorzata Wiweger, Aurélie Clément and Henry Roehl
Centre for Developmental Genetics, Department of Biomedical Science,
University of Sheffield, Firth Court, Sheffield S10 2TN, UK.
Zebrafish is an easy to maintain, small tropical fish with transparent embryos that develop
outside the mother’s body. Their short generation time (3-4 months), high fertility rate (hundreds
of eggs per week), rapid development (most organs develop within first 48 hours post
fertilization) and advanced genetic techniques (transgenics, forward and reverse genetics) make
them an outstanding model for biomedical research. Furthermore, development of their
cartilaginous skeleton occurs by similar mechanisms to that of humans, which means zebrafish
are suitable as a model for studies on human skeletal diseases. Using forward genetic screens,
hundreds of zebrafish mutations that affect cartilage morphogenesis and/or differentiation have
been identified. We positionally cloned two mutations in exostosin genes: dackel (dak/ext2) and
boxer (box/exlt3) (Lee et al., 2004, Neuron. 44: 947-960) and are currently using these to study
the development of exostoses. Homozygous dak/ext2 mutants show a similar disorganization of
cartilaginous skeleton to that seen in HME tumors i.e. chondrocytes, instead of forming long
stacks of flattened cells, form non-polarized clusters of rounded cells. Cartilage formation and
differentiation remains unaffected in dak/ext2 mutants, which suggest that the dak/ext2
phenotype probably results from changes in cell division planes or/and cell movements. In
support, electron microscope observations verified the presence of abnormalities in the
cytoskeleton of dak/ext2 mutant chondrocytes. Furthermore, malformations of cartilage similar
to those seen in dak/ext2 are also present in another zebrafish mutant called pipetail (ppt/wnt5a)
that is involved in the non-canonical Wnt/Ca2+ planar polarity pathway. Interestingly, both dak
and ppt mutants show a significant delay in endochondrial ossification whereas membranous
bones are formed normally. The similarities between these two mutants suggest Ext2 may act
through non-canonical Wnt signaling.
In addition to the exostoses-like phenotype, dak/ext2 and box/exlt3 also share other
developmental defects (missorted retinotectal projections and malformed pectoral fins) and both
of these mutants have significantly reduced level of heparan sulfate proteoglycans (HSPGs). A
third mutant, called pinscher (pic), also has the mentioned above defects, suggesting that pic is in
the same genetic pathway. We have recently positionally cloned pic and shown it does not
belong the to exostosin gene family. This strengthens the possibility that non-Ext1/Ext2-related
cases of HME might be due to mutations in other genes involved in the synthesis of HSPGs.
This work is supported by Wellcome Trust and Cancer Research UK.
30. Phenotypes of conditional Ext1 knockout mice:
Insights into non-skeletal symptoms of MHE
Yu Yamaguchi, M.D., Ph.D.
Developmental Neurobiology Program,
The Burnham Institute, La Jolla, CA 92037
Heparan sulfate proteoglycans have been implicated in various cell biological and developmental
processes, such as growth factor and morphogen signaling, cell adhesion and migration, and
extracellular matrix assembly. To study the physiological roles of heparan sulfate proteoglycans
in the mammalian development, we created conditional allele of Ext1, the gene encoding a
glycosyltransferase required for heparan sulfate biosynthesis. Mice carrying this allele have
been crossed with several Cre transgenic mice to determine the function of heparan sulfate in
different embryonic and adult tissues. I will present our recent findings on the phenotypes of
these conditional knockout mice, and discuss molecular mechanisms underlying such phenotypes
and potential implications into non-skeletal symptoms of MHE.
31. Structure and Biosynthesis of Mouse Brain Heparan Sulphate.
Jeremy Turnbull, Katherine Drummond, Alex Holme & Scott Guimond
School of Biological Sciences, University of Liverpool,
Crown Street, Liverpool, L69 7ZB. England, UK.
Heparan sulfate (HS) biosynthesis involves the action of a complex set of enzymes with
polymerase (EXT), epimerase and sulfotransferase (ST) activities. Multiple isoforms of N- and
O-STs decorate the nascent HS chains with specific sulfation patterns which confer selective
biological functions. We have been studying HS structure and biosynthesis in model organisms
such as mice and nematode worms since they provide opportunities to study the expression of
these enzymes in relation to the structure and activities of the HS produced. In previous studies
in mice we found that there are stage-specific combinations and distinct spatiotemporal
expression patterns of HSST isozymes that underlie the synthesis of different HS species in
developing brain. This data indicated that differential HS biosynthesis results in the synthesis of
structurally variant HS species which form functional signaling complexes with growth factors
essential for normal brain development. Regulated synthesis and the levels of specific HS
species could be a mechanism for regulation of proliferation and differentiation in the developing
brain. In recent studies we have become interested in the possibility that the levels or structures
of HS may be altered in the brain tissues of mice heterozygous for the EXT1 gene, and that
biochemical defects of this type could underly nervous system abnormalities observed in humans
with this genotype. We have purified HS from normal and EXT1 +/- mice and are currently
performing detailed structural analyses on these samples. Data will be presented to address the
question as to whether there are alterations in the amounts and/or structures of HS produced in
the brains of EXT1 +/- mice.
32. Keloid Formation Following Surgical Treatment of Multiple Hereditary Exostoses
Harish Hosalkar, MD#; John P. Dormans, MD+
#
Orthopaedic Resident, The Children’s Hospital of Philadelphia
+
Chief of Orthopaedic Surgery, The Children’s Hospital of Philadelphia
Professor of Orthopaedic Surgery, University of Pennsylvania School of Medicine
Introduction: Multiple hereditary exostoses (MHE) is an autosomal dominant trait characterized
by numerous cartilage capped tumors in areas of actively growing bone. The formation of
keloids following surgery for MHE has not previously been described.
Methods: A retrospective case-controlled study was undertaken to test the hypothesis that
patients with MHE are at higher risk for keloid formation following excision of an exostosis.
The study population consisted of a study group of 25 children and adolescent cases of MHE
randomly selected from a tumor database at our institution and a control group of 25 age-
matched cases of solitary exostosis (osteochondroma). All patients participated in a phone
interview that consisted of questions regarding the number of surgeries, recurrence of lesions,
wound healing problems, keloid formation, keloid site and dimensions, and any revision surgery.
All patients with wound healing problems or suspected keloids were asked to take clinical
pictures and mail them in. Based on clinical criteria these cases were identified as keloids or non-
keloids.
Results: 83 surgeries were performed in 25 patients with MHE for primary excision of their
exostoses. 25 surgeries were performed in 25 cases of solitary exostoses. 12 keloids formed in 7
patients in the MHE study group. No patients who underwent excision of solitary exostoses
formed keloids. Diagnosis of MHE was a statistically significant risk factor for formation of
keloids following surgery (p<.05). Maximal keloid width ranged from 5-10cm. Scar revision
was performed in four of the seven children with keloid formation with MHE, of whom two
required additional scar revision procedures.
Discussion: Wound healing problems in MHE, in particular a tendency for keloid formation,
have not previously been reported. Our retrospective, case-controlled study demonstrated a
significant correlation between keloid formation and surgery for MHE. The risk for keloid
formation should be discussed with patients as part of informed consent prior to surgery for
removal of exostoses in MHE.
34. P53 and Rb in Cartilage Tumours in Mice
Aneta Stojanovski, Louisa Ho, and Benjamin Alman
The Program in Developmental Biology and Division of Orthopaedic Surgery
The Hospital for Sick Children
Toronto, Ontario Canada
Chondrosarcomas can arise from being cartilage lesions, such as enchondromas and
osteochondromas. In enchondromatosis, there is a high rate of malignant change, reported to be
as high as 50% in cases of Mafucci syndrome. Cytogenetic and mutational analysis studies
identified mutations or deletions in p53 or Rb in roughly one third of chondrosarcomas. As such,
we examined the role of these tumor suppressor genes using a mouse model of
enchondromatosis. We crossed p53 and Rb knockout mice with mice overexpressing Gli2 driven
by the type II collagen regulatory elements. The Gli2 transgenic mice develop cartilaginous rests
in their metaphysis, similar in appearance to enchondromatosis. Embryonic limbs from
Gli2;p53-/- and Gli2;Rb-/- were compared to wild type littermates, and postnatal Gli2;p53+/-
and Gli2;Rb+/- mice were examined at two month intervals until 8 months of age, and their
phenotype compared with wild-type littermates. Mice were sacrificed and limbs analyzed using
histology, Safranin-O staining, type X collagen immunohistochemistry, proliferation rate and
apoptosis rate. Larger, hypercellular, cartilaginous lesions containing pleomorphic cells arose in
the Gli2;p53+/-, at an increasing incidence starting at 2 months of age. By 8 months, 75% of
these mice developed these larger lesions. This was associated with an increase in cell
proliferation. Gli2;Rb+/- mice also developed these larger lesions, but only at 8 months of age.
Examination of the fetal limbs showed an expanded growth plate, involving all zones in the
Gli2;p53-/- mice, compared to the other genotypes. P53 deficiency modulates the effect of
overexpression of Gli2 in chondrocytes, resulting in a change in the growth plate and the
development of larger, hypercellular cartilage lesions, perhaps by increasing the number of
chondrocyte cells in the growth plate. This data also suggests that tumor suppressor genes play a
role in cartilaginous neoplasia.
35. Tibia Dyschondroplasia: An Example of Defective Hedgehog Signaling?
R. M. Leach, Jr., F. M. R. McAvoy, M. Shahnazari, and S. N. Krzysik
Department of Poultry Science, The Pennsylvania State University, University Park, Pa.
Tibial Dyschondroplasia (TD) is a skeletal disease common to rapidly-growing young avians. This
condition is characterized as a mass of avascular cartilage in the epiphyseal growth plate of tibiotarsus
and tarsalmetatarsus. The lesion occurs spontaneously with an incidence ranging from 10-90%.
Exposure to dithiocarbamates induces a high incidence of the lesion without impairing growth rate. The
lesion appears to initiate in the prehypertrophic zone adjacent to the perichondrium, resulting in a
triangular lesion of variable size. The chondrocytes in the lesion fail to achieve complete hypertrophy
and undergo apoptosis. This latter characteristic has severely impaired attempts to identify the
metabolic defect responsible for this skeletal disease. For a number of years, we have been pursuing the
hypothesis that TD occurs as a result of perturbation in Indian Hedgehog (Ihh) signaling. This is based
on the observation that Ihh, which plays a key role in skeletal physiology, is localized in the zone where
the lesion appears to be initiated. Our first approach was to confirm this hypothesis by studying Ihh
expression in cultured chondrocytes. This approach was abandoned due to the extreme cytotoxicity of
the dithiocarbamates. Since sterolization is an important post-translational modification of hedgehog
proteins, an inhibitor of cholesterol biosynthesis (a statin) was fed to young chicks as a means of
perturbing hedgehog activity. These chicks exhibited depressed growth rate and a TD-like lesion in the
prehypertrophic zone of the epiphyseal growth plate. Supplementary dietary cholesterol resulted in
normal growth plate morphology, although the growth rate depression was not reversed. These results
were exciting, but we were faced with a dilemma: which hedgehog is being inhibited? Wu et al. (2002)
have reported that both Ihh and Sonic Hedgehog (Shh) are expressed in the post-natal avian growth
plate, with Shh being expressed distal to Ihh. We have confirmed the presence of Shh in lysates of
hypertrophic chondrocytes with western blotting. The expression of two hedgehogs at different
locations in the growth plate supports previous suggestions that hedgehog proteins have dual actions in
growth plate physiology. Currently we are using immunohistochemistry, western blotting and
microarray technology to identify the downstream targets of hedgehog genes responsible for the
impaired angiogenesis associated with the development of tibial dyschondroplasia.
36. Microarray Analysis Reveals Malignancy-Related Markers in Human Chondrosarcoma
Gourronc, FA, Martin JA, Buckwalter, JA,
Ignacio V. Ponseti Orthopaedic Biology Laboratory,
Department of Orthopaedic Surgery, University of Iowa, Iowa City, Iowa 52242
Introduction: Aggressive chondrosarcomas can be difficult to distinguish histologically from
less aggressive malignant tumors or from benign enchondromas, due in part to the retention of
cartilage-like phenotype. To identify markers of malignancy in chondrosarcomas, we have
performed a comparative transcriptome study of chondrocytes isolated from normal cartilages,
enchondromas and chondrosarcomas of different grades (grade 1 and grade 3) using Affymetrix
Human 133A microarrays. These studies revealed a number of genes that were differentially
expressed in high-grade chondrosarcomas. These results suggest a number of potentially useful
markers of tumor progression in chondrosarcoma.
Essential Results: Microarrays established a list of genes that were differentially expressed in
high grade tumors including thrombospondin-1 (THBS1), decorin, TIMP-3, MGMT (down-
regulated), TRAG-3 and FGF-5 (up- regulated). Among these differentially expressed mRNAs,
Maspin (Serpin B5) was strongly up-regulated in high grade chondrosarcomas (Table 1). The
microarray results were validated at the RNA level by semi-quantitative RT-PCR, on RNA from
a collection of 10 different chondrosarcomas of various grades. This analysis showed increased
Maspin mRNA in each case compared to normal chondrocytes. However, high grade cells
consistently showed the highest expression levels (data not shown). Western blots for Maspin
confirmed that this protein was easily detectable in high grade chondrosarcoma cell extracts but
was virtually absent from normal cells, benign cells, and low-grade chondrosarcoma cells
(Figure). Additional western blots confirmed microarray results that indicated down regulation
of MGMT in high grade chondrosarcomas (data not shown).
Discussion: Our findings show a number of changes in gene expression that distinguish high-
grade chondrosarcoma from low-grade chondrosarcoma, benign enchondroma, and normal
chondrocytes. These results were verified by rtPCR or western blots, indicating that the
microarray results were a valid measure of mRNA levels for these genes. We found that Maspin
was among the most strongly up-regulated genes and western blotting confirmed that this protein
is markedly over-expressed in high-grade cells. Taken together these results show that Maspin
can be a reliable marker of tumor progression in chondrosarcoma. In addition, many of the genes
that were found to be differentially regulated in high-grade cells are known to be regulated by
promoter methylation. The involvment of such an epigenic mechanism in the transcriptional
regulation of those genes is currently under investigation.
References
1. Martin J.A., Mitchell C.J., Klingelhutz A.J., Buckwalter J.A. (2002) Effects of telomerase
and viral oncogene expression on the in vitro growth of human chondrocytes. J Gerontol
A Biol Sci Med Sci 57: B48-53
37. Enchondromatosis
Leida R. Rozeman, J.V.M.G. Bovée, A.M. Cleton-Jansen, P.C.W. Hogendoorn
Dept. of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Enchondromatosis is the term for a collection of syndromes with overlapping clinical features
and is characterized by the presence of multiple enchondromas (1). Enchondromas are benign
cartilage producing tumors located in the medulla of bone. Most often they can be found in the
long bones, especially of hands and feet. In about 25% of enchondromatosis patients malignant
transformation of an enchondroma into a conventional central chondrosarcoma occurs compared
to <1% in patients with a solitary enchondroma (1;2). Signs for malignant transformation are
sudden growth, fatigue and pain in the affected area (3). Pathologic fractures at the side of an
enchondroma can occur, not necessarily pointing to malignant transformation.
The malignant transformation of enchondromas into central chondrosarcomas can result in an
adverse prognosis for the patient, in parallel to malignant transformation of osteochondromas
into peripheral chondrosarcomas. Both central and peripheral chondrosarcomas share
histological similarities and therefore they are graded in the same way. Following the grading
system of Evans et al (4) – the most widely used grading system for chondrosarcomas-, three
grades of malignancy are discerned, grade I, grade II and grade III. Grading is currently the best
prognostic indicator. Where as in grade I chondrosarcomas seldom metastasize, 10-33% of grade
II and ~70% of grade III chondrosarcomas metastasize (4;5).
The two most frequent enchondromatosis syndromes are Ollier disease (6;7) and Maffucci
syndrome (8;9). Both have multiple enchondromas but in Maffucci syndrome this is combined
with multiple haemangiomas and/or lymphangiomas (8). These are rare non-hereditary
syndromes, and in a group of patients unilateral predominance has been described. Skeletal
deformations become apparent after birth. Almost all patients with enchondromatosis have
orthopedic complications, of which short stature is the most prominent (10;11). Additionally,
deformities of the tubular bones resulting in leg-length discrepancy are described (10;11).
Besides Ollier disease and Maffucci other, even more rare, syndromes have described, which
have been subdivided based on the involvement of hands and feet, spine and hereditary (12;13).
For instance, spondyloenchondromatosis is characterized by involvement of spinal cord, mild
involvement of hands and feet and a distribution in a autosomal dominant fashion (12;14).
Generalized enchondromatosis is described to have severe involvement of the hands and feet,
mild involvement of the spinal cord and a distribution in a autosomal recessive fashion (15). One
other interesting subclass is metachondromatosis. This is characterized by the combined presence
of multiple enchondromas and exostoses, which are in contrast to those in Multiple
Osteochondromas (16) pointed toward the nearby joint. In these patients there is no evidence of
spinal involvement and the distribution follows an autosomal dominant pattern (17;18)
38. ABC’s of MHE WORKSHOP
Saturday November 5, 2005
1:00pm – 5:00pm
Sarah Ziegler, Chair
39. The ABC’s of MHE: Everything you need to know about Multiple Hereditary
Exostoses workshop.
Saturday Nov 5, 2005
Speakers
Jeffrey Esko, Ph.D.,# Scott Selleck, M.D., Ph.D., +Presenting an overview of the
scientific sessions of the conference.
# University of California-San Diego, Department of Cellular Molecular Medicine,
Director, Glycobiology Research and Training Center, San Diego, CA.,
+
University of Minnesota Department of Pediatrics, Genetics, Cell Biology and
Development, Minneapolis, MN.
Wim Wuyts, Ph.D., Presenting the ABC’s of MHE – Genetics.
Supervisor, DNA Diagnostics, Department of Medical Genetics, University of Antwerp,
Belgium.
Jacqueline Hecht, Ph.D.,# Sandra Darilek M.S., +
Presenting study results of
“Hereditary Multiple Exostoses and Pain”.
#
Medical Genetics, Family Studies, University of Texas Houston Medical Center and Medical
School, Department of Pediatrics, Division of Medical Genetics, Director, Genetic Counseling
+
Program, Houston, TX., Genetic Counselor.
Ashish Sinha, M.D., Ph.D., DABA., Presenting the issue of chronic pain and the need
for treatment. Department of Anesthesiology & Critical Care School of Medicine, University of
Pennsylvania Philadelphia PA.
Harish Hosalkar, M.D.,# John P. Dormans, M.D., + Presenting The ABC’s of MHE
#
Orthopaedic Resident, The Children’s Hospital of Philadelphia,
+
Chief of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Professor of Orthopaedic
Surgery University of Pennsylvania School of Medicine.
John E. Herzenberg, M.D., FRCSC, Presenting the use of Fixators.
Chief of Pediatric Orthopedics, Sinai Hospital; Co-Director, International Center for Limb
Lengthening Rubin Institute for Advanced Orthopaedics Baltimore, MD.
40. Genetic Aspects of MHE.
Wim Wuyts
Department of Medical Genetics University of Antwerp, Belgium.
MHE is a genetic disorder and therefore it not only affects the patient and his/her relatives, but
also future generations. Genetic counseling of MHE patients and their family is therefore an
important aspect and should be offered to all MHE patients. However, to understand the genetics
of MHE one should have an understanding of basic genetics. In this workshop commonly used
genetic terms and mechanisms will be explained and the specific genetic aspects of MHE will be
discussed in detail. An overview will be presented of the options and difficulties associated with
genetic screening for MHE.
41. Hereditary Multiple Exostosis and Pain
Jacqueline Hecht1 and Sandra Darilek2
1
Department of Pediatrics, University of Texas Houston Medical Center
2
Genetic Counselor Baylor College of Medicine
This study was undertaken to characterize pain in individuals with hereditary multiple exostosis
(HME). Two hundred ninety-three patients with HME completed a questionnaire designed to
assess pain as well as its impact on their life. Eighty-four percent of participants reported having
pain, indicating that pain is a real problem in HME. Of those with pain, 55.1% had generalized
pain. Two factors were found to be associated with pain outcome: HME-related complications
and surgery. Individuals who had HME-related complications were five times more likely to
have pain, while those who had surgery were 3.8 times more likely to have pain. No differences
were found between males and females with respect to pain, surgery, or HME-related
complications. The results of this study indicate that the number of individuals with HME who
have pain has been underestimated and that pain is a problem that must be addressed when
caring for individuals with HME.
42. Pediatric Pain Management
Ashish Sinha
Department of Anesthesiology & Critical Care
School of Medicine
University of Pennsylvania
Philadelphia PA 19104-4283
Pain in the pediatric patients is frequently under treated due to a variety of factors. From under
recognition of the pain itself to myths that children do not feel as much pain as adults, because of
immature peripheral and central nervous systems. Part of the problem is the mistaken belief that
pain is less harmful than the side effects of analgesic therapy. Lack of awareness of treatment
options and ignorance of analgesic pharmacology in children compound this problem.
Pain assessment in children has been mandated by JCAHO and frequently referred to as the 5th
vital sign. The need for accurate pain assessment is essential for accurate pain management.
Sometimes this is an approximation because of limited verbal communication in the younger
children population. Multiple reasons contribute to the denial of pain by children. Useful tools
for pediatric pain assessment, depending on the age of the child, include CRIES, FLACC, Wong
Baker faces scale and VAS (Visual Analog Scale) scores.
Treatment of chronic pain is handled differently than that of acute pain in children. Pain
treatment in the setting of chronic pain in children is multimodal as in adults and has components
of depression that should be addressed appropriately. The concept of the WHO pain ladder
being applied to children is consistent with appropriate and responsible pain management.
Pain that arises in the musculoskeletal system has issues with reluctant limb usage with its
attendant problems, of dystrophy and atrophy. An expert in physical therapy should be involved
in the handling of these issues.
43. The ABC’s of MHE
Harish Hosalkar,#; John P. Dormans,+
#
Orthopaedic Resident, The Children’s Hospital of Philadelphia
+
Chief of Orthopaedic Surgery, The Children’s Hospital of Philadelphia
Professor of Orthopaedic Surgery, University of Pennsylvania School of Medicine
Multiple hereditary exostosis (MHE) is an inherited disease causing the development of
numerous cartilaginous exostoses throughout the skeleton. It is most commonly inherited as an
autosomal dominant loss of function mutation of either the EXT1 or EXT2 genes with almost
complete penetrance. Common problems for children with MHE are pain and tenderness due to
compression of tendons and nerves by the exostoses, skeletal deformity due to altered growth of
long bones, cosmetic concerns, and rarely ischemic complication due to compression of vascular
structures. As a result, most children with MHE will undergo several procedures for removal of
painful or deforming lesions.
The ABC’S of MHE is a patient and parent-friendly manual that outlines the common skeletal
manifestations of MHE. This extensive review addresses the diagnostic tools including important
features on clinical exam, characterization of lesions, diagnostic work up including imaging
features and histology. We have attempted to outline the established patterns of involvement of
MHE in various parts of the body i.e. mainly the skeletal system and their possible treatment
options. A specific note is made in each subsection regarding what the parents should watch out
for. Finally a glossary of procedures and terminology is presented.
44. External Fixation and Stapling for Angular Deformities
and Limb Length Discrepancies in Multiple Hereditary Exostosis (MHE)
John E. Herzenberg, MD, FRCSC
Head of Pediatric Orthopaedics, Sinai Hospital of Baltimore
Co-Director, International Center for Limb Lengthening
Rubin Institute for Advanced Orthopedics
Baltimore, MD 21215
General considerations: MHE causes valgus in the knee and ankle. The cause is tethering of the
growth plates, leading to asymmetric growth and limb length discrepancy. Treatment of valgus
(knock knee) deformity improves awkward gait, and prevents abnormal joint loading that can
cause premature knee arthritis. Treating leg length discrepancy improves gait mechanics and
prevents low back pain caused by pelvic tilt. Mild angulations in growing children can be treated
with hemi-epiphyseal stapling using Blount staples (Zimmer) in pre-teens, or the new 8-plate
(Orthofix) in children as young as 3 years (where staples might dislodge). For children near
skeletal maturity, and for adults, osteotomy and gradual correction with external fixators is the
most accurate way to correct angulation and length problems. The TSF (Smith & Nephew) and
MAC (EBI) enable multiplanar correction with simultaneous lengthening. For adults without
angulation, there is an implantable telescopic lengthening nail called the ISKD (Orthofix) which
lengthens the femur or tibia without an external fixator.
Valgus knee: Assess angulation on a long standing x-ray that includes hip, knee and ankle on a
single cassette and a long lateral film. Measure the mechanical axis deviation (MAD), lateral
distal femoral angle (LDFA), medial proximal tibial angle (MPTA), posterior proximal tibial
angle (PPTA) and posterior distal femoral angle (PDFA). These tests usually localize the
problem to the proximal tibia. Consider stapling for young patients with sufficient growth. Older
children are treated with gradual correction using an external fixator and corticotomy. Consider
simultaneous peroneal nerve decompression and resection of the fibular head osteochondroma.
Valgus ankle: Assess angulation on standing films centered on the ankle. Measure the lateral
distal tibial angle (LDTA) and anterior distal tibial angle (ADTA). Evaluate for presence of
compensatory subtalar contractures. Staple the medial distal tibia for younger patients without
subtalar contractures. If there is an established subtalar contracture that makes the foot
plantigrade, then the valgus tilt of the ankle might best be left untreated.
Leg length discrepancy: For discrepancies under 2 cm, use shoe lifts. In skeletally immature
patients, consider epiphyseodesis of the long leg. Lengthening the short leg is preferred if there is
residual angular deformity to be corrected. Predicting adult height and limb length discrepancy
with the Multiplier method helps families to decide which option to choose. In mature patients,
without angulation, lengthen either with ISKD or lengthening over nail (LON) methods to
eliminate or decrease external fixation time. Shortening the long leg in adults by up to 4 cm can
be safely done in the femur over an intramedullary nail as an alternative to lengthening.
Forearm problems: For the short ulna without angulation in young children, lengthen the ulna
with an external fixator to prevent the secondary changes of distal radius ulnar deviation and
radial head dislocation. Older children need more complex treatment: ulnar lengthening with
distal radio-ulnar fixation to gradually reduce the dislocated radial head, followed by staged
distal radial osteotomy for angular correction. Mild ulnar deviation of the distal radius may be
amenable to hemi-epiphyseal stapling techniques.
45. The American Association of Multiple
Enchondroma Diseases
Founded in 1998, incorporated in 2002 as a not-for-profit
corporation and registered as a tax exempt organization with the
US Internal Revenue Service, AAMED is comprised of individuals
with Ollier's disease, Maffucci's syndrome, enchondromatosis,
their families, and physicians.
AAMED is THE source for news and information about bone tumor
diseases, research and services for adults and children with
Enchondromatosis, Multiple Enchondroma, Ollier's disease,
Maffucci's syndrome, and their families.
Board of Directors:
President, Ellen Bregg
CEO, Director of Research, Susan Challen
Research Coordinator, Sarah Ziegler
AAMED: www.AAMED.NET
46. Houston Shriners Hospital
Family-Centered Care
Recognizing that the family plays a vital role in a child's ability to overcome an illness or
injury, the Houston Hospital helps the family provide the support the child needs by
involving the family in all aspects of the child's care and recovery. The purpose of all
Shriners Hospitals is to provide care to orthopaedically disabled and burned children to help
them lead fuller, more productive lives. By promoting the importance of the family and
helping it become a stronger support system for the child, the Houston Hospital can
accomplish its purpose more effectively.
Vision
Ours will be a place where patients and families easily access our services, partner with us
in care, and acquire the skills towards transitioning into a productive adult life. All of this is
based on education and research which provide the foundation of our care for now and in
the future.
Mission
To provide the quality of pediatric, orthopaedic care necessary to allow our children the
opportunity to be productive and involved members of their community.
To provide for the education of physicians, other health care professionals, patients,
families and the fraternity community-wide.
To engage in clinical research with a focus on patient outcomes assessment.
Research
More than 300 different and distinct diseases affect the bones, joints and supporting
structures, composed mainly of fibrous tissues such as ligaments, tendons and cartilage.
Many of these diseases are congenital, others are inherited, and a great many are both
congenital and inherited. However, very few of these diseases have identifiable causes.
Shriners Hospitals have been involved in clinical children's orthopaedic research since the
early 1920s, and in the early 1960s, Shriners Hospitals aggressively entered the structured
basic research field. Advances in research are shared widely among the 22 Shriners
Hospitals and with other hospitals throughout the country. The Houston Hospital conducts
clinical and basic research in the following areas:
Clinical research studies in gait analysis
Genetic linkage studies of club foot
Genetic and behavioral studies of spina bifida
Genetic studies of pseudoachondroplasia, a form of dwarfism
Molecular studies of hereditary multiple exostosis, a condition marked by
"spurs" or bony outgrowths on bone
Regulatory and structural studies of cartilage oligomeric matrix protein (COMP), a
key component in the growth and formation of cartilage
http://www.shrinershq.org/shc/houston/index.html
http://www.shrinershq.org/index.html