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Osteochondroma / Exostoses Out Line Link (*****You should read these
papers, when you would like to understand MHE / MO / HME research
better*****)
The Center for Information Technology (CIT) makes special NIH events, seminars, and
lectures available to viewers. Click this link and view the listing and you can watch these videos
Howard Hughes Medical Institute Holiday Lectures on Science Programs. This four part lecture series
held in 2002 will give you a better insight and understanding of research that is now being
conducted in MHE now. Once you have viewed these 4 lectures you can view other illustrations on
this web-page. Click this link
Yu Yamaguchi, Ph.D.
Burnham Institute in La Jolla, California:
My laboratory has been studying the role of EXT1/heparan sulfate in mouse embryonic
development. We have created a conditional EXT1 knockout mouse model. These conditional EXT1
knockout mice are being used for genetic studies to figure out how the deficiency of EXT1/heparan
sulfate causes MHE.
These conditional knockout mice, which allow knocking out EXT1 at the site and time of researchers'
desire, are very useful for diverse studies on the function of EXT1/heparan sulfate.
Dr. Yamaguchi and his lab have been able to distribute these mice to more than 20 laboratories
around the world (US, Europe, and Japan) to help studies by other MHE investigators. Using this
model system, Dr. Yamaguchi has demonstrated that mutations of EXT1 influence not only bones
but also the nervous system. Although frequently ignored in the clinical front, MHE patients tend to
have some mental, neurological, and muscular symptoms. Such symptoms include: mild social
interaction deficits (excessive shyness, adherence to routines), heightened sensitivities to sensory
stimulation (sounds, touch, taste), difficulties to concentrate, and muscle weakness. Dr. Yamaguchi
believes these neurological symptoms can be explained by the deficiency of heparan sulfate in nerve
cells. Indeed, recent analysis of knockout mouse behavior has revealed that these mice have deficits
in certain aspects of learning and the levels of fear/anxiety, as well as alterations in nerve cell wiring.
In addition, Dr. Yamaguchi has recently discovered that knockout of EXT1 in stem cells that destined
to become bones and cartilage causes severe bone abnormalities. These findings have provided us
with a new insight into the reason why MHE patients frequently associate a variety of symptoms in
addition to exostosis/osteochondroma formation, and suggests potential novel MHE treatment
paradigms.
Jeff Esko, Ph.D.
University of California, San Diego:
“Hereditary multiple exostoses (HME) is a dominant genetic disorder resulting in the formation of
generally benign cartilage-capped tumors in various bones.
Recent work from a number of laboratories indicates that the disease results from mutations in EXT
genes involved in making a complex sugar, or polysaccharide, called heparan sulfate.
Since heparan sulfate interacts with many factors involved in cell growth, this discovery may shed
light on the cause of the disease, which in turn may suggest new treatments.
Studies of HME have relied on analysis of human exostosis samples made available when patients
have surgery to remove problematic growths.
Progress understanding the cause of the disease has been frustrated by the paucity of material
available for study and only rare opportunities to compare the exostosis to normal tissue.
Recently, we discovered that mice bearing mutations in EXT genes also develop exostoses, which
mimic many key features of the human tumors.
One finding that emerged from studies of the HME mice is that the frequency of exostoses is highly
variable and depends on other genetic traits in the mice.
Since we can breed mice rapidly, we are now in a position to identify these other genes that may
contribute to the severity of the disease.
Additionally, we need to work out methods to detect exostoses in live animals, assess treatment
strategies for reducing the frequency and growth of exostoses, and develop systems to look at
exostosis development in isolated bones."
Dominique Stickens, Ph.D.
Mice deficient in Ext2 lack heparan sulfate and develop exostoses:
Stickens D, Zak BM, Rougier N, Esko JD, Werb Z.(Dominique Stickens), Department of Anatomy,
University of California, San Francisco, CA 94143-0452, USA.
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 one-third 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.
These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise
from deficiencies in other heparan sulfate-dependent pathways.
The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the
complex molecular mechanisms underlying the development of exostoses.
Dan Wells, Ph.D.
University of Houston:
Multiple Hereditary Exostoses (MHE) is an autosomal dominant skeletal disorder most frequently
caused by mutations in the EXT1 gene.
MHE affects proper development of endochondral bones, such that all affected individuals present
with exostoses adjacent to the growth plate of long bones, while some individuals exhibit additional
bone deformities. EXT1 functions as a heparan sulfate (HS) co-polymerase, and when defective
causes improper elongation of glycosaminoglycan side chains on core proteins of HS proteoglycans.
Although analysis of heterozygous EXT1-deficient mice has failed to reveal any significant gross
morphological variations in skeletal development, significant alterations in molecular signaling occur in
the developing long bones.
Our results indicate that defects in EXT1 and the resulting reduction in HS lead to enhanced Indian
Hedgehog diffusion causing an increase in chondrocyte proliferation and delayed hypertrophic
differentiation.
Andrea Vortkamp, P.h.D.
Propagation of Ihh signaling:
One important question to understand the IhhP/THrP feedback loop is how the Ihh signal is
transported through the growth plate. In Drosophila the glycosyltransferase ‘tout velu’ (ttv) is
necessary to transport the hedgehog signal in the developing embryo.
Mutations in the human homologues, Ext-1 and Ext-2, result in, Heritable multiple exostoses’ (HME),
disease characterized by benign bone tumors and short stature.In the developing bone we found
Ext-1 and Ext-2 both expressed in domains flanking the Ihh expression domain.
Using transgenic mice and a gene trap line targeting the Ext1 locus we aim to analyze the role of
Ext1 during bone devolopment and to identify a potential function in Ihh transport.
Marion Kuche-Gullberg, Ph.D.
Characterization of enzymes involved in heparan sulfate biosynthesis:
Our area of interest is the structure and function of heparan sulfate (HS). HSs play dynamic
functional roles in a diverse number of biological events related to intracellular signaling, cell-cell
interactions and tissue morphogenesis.
HS execute its function by the binding to a variety of molecules including growth factors, serine
protease inhibitors and extracellular matrix proteins.
The biological activities of HS largely depend on the amount and distribution of its sulfate groups
that provide specific binding sites for proteins.
Our overall goal is to understand the mechanisms generating specific saccharide structures and to
provide insight into the link between cell type specific expression of HS modifying enzymes and the
biological function of the polysaccharide.
Our research focus on
1. UDP-glucose dehydrogenase, which converts UDP-glucose to UDP-glucuronic acid providing one
of the building blocks for chain elongation
2. heparan sulfate polymerases (EXT1 and EXT2) giving rise to the polysaccharide backbone(mice
with a gene trap mutation in Ext)
3. 2-O- and 6-O-sulfotransferases, incorporating sulfate groups in specific positions, generating
biological active heparan sulfate.
4. Sulfs, cell associated HS 6-O endosulfatases, that remove sulfate groups in specific positions,
thus modulating HS dependent growth factor signaling.
papers, when you would like to understand MHE / MO / HME research
better*****)
The Center for Information Technology (CIT) makes special NIH events, seminars, and
lectures available to viewers. Click this link and view the listing and you can watch these videos
Howard Hughes Medical Institute Holiday Lectures on Science Programs. This four part lecture series
held in 2002 will give you a better insight and understanding of research that is now being
conducted in MHE now. Once you have viewed these 4 lectures you can view other illustrations on
this web-page. Click this link
Yu Yamaguchi, Ph.D.
Burnham Institute in La Jolla, California:
My laboratory has been studying the role of EXT1/heparan sulfate in mouse embryonic
development. We have created a conditional EXT1 knockout mouse model. These conditional EXT1
knockout mice are being used for genetic studies to figure out how the deficiency of EXT1/heparan
sulfate causes MHE.
These conditional knockout mice, which allow knocking out EXT1 at the site and time of researchers'
desire, are very useful for diverse studies on the function of EXT1/heparan sulfate.
Dr. Yamaguchi and his lab have been able to distribute these mice to more than 20 laboratories
around the world (US, Europe, and Japan) to help studies by other MHE investigators. Using this
model system, Dr. Yamaguchi has demonstrated that mutations of EXT1 influence not only bones
but also the nervous system. Although frequently ignored in the clinical front, MHE patients tend to
have some mental, neurological, and muscular symptoms. Such symptoms include: mild social
interaction deficits (excessive shyness, adherence to routines), heightened sensitivities to sensory
stimulation (sounds, touch, taste), difficulties to concentrate, and muscle weakness. Dr. Yamaguchi
believes these neurological symptoms can be explained by the deficiency of heparan sulfate in nerve
cells. Indeed, recent analysis of knockout mouse behavior has revealed that these mice have deficits
in certain aspects of learning and the levels of fear/anxiety, as well as alterations in nerve cell wiring.
In addition, Dr. Yamaguchi has recently discovered that knockout of EXT1 in stem cells that destined
to become bones and cartilage causes severe bone abnormalities. These findings have provided us
with a new insight into the reason why MHE patients frequently associate a variety of symptoms in
addition to exostosis/osteochondroma formation, and suggests potential novel MHE treatment
paradigms.
Jeff Esko, Ph.D.
University of California, San Diego:
“Hereditary multiple exostoses (HME) is a dominant genetic disorder resulting in the formation of
generally benign cartilage-capped tumors in various bones.
Recent work from a number of laboratories indicates that the disease results from mutations in EXT
genes involved in making a complex sugar, or polysaccharide, called heparan sulfate.
Since heparan sulfate interacts with many factors involved in cell growth, this discovery may shed
light on the cause of the disease, which in turn may suggest new treatments.
Studies of HME have relied on analysis of human exostosis samples made available when patients
have surgery to remove problematic growths.
Progress understanding the cause of the disease has been frustrated by the paucity of material
available for study and only rare opportunities to compare the exostosis to normal tissue.
Recently, we discovered that mice bearing mutations in EXT genes also develop exostoses, which
mimic many key features of the human tumors.
One finding that emerged from studies of the HME mice is that the frequency of exostoses is highly
variable and depends on other genetic traits in the mice.
Since we can breed mice rapidly, we are now in a position to identify these other genes that may
contribute to the severity of the disease.
Additionally, we need to work out methods to detect exostoses in live animals, assess treatment
strategies for reducing the frequency and growth of exostoses, and develop systems to look at
exostosis development in isolated bones."
Dominique Stickens, Ph.D.
Mice deficient in Ext2 lack heparan sulfate and develop exostoses:
Stickens D, Zak BM, Rougier N, Esko JD, Werb Z.(Dominique Stickens), Department of Anatomy,
University of California, San Francisco, CA 94143-0452, USA.
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 one-third 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.
These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise
from deficiencies in other heparan sulfate-dependent pathways.
The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the
complex molecular mechanisms underlying the development of exostoses.
Dan Wells, Ph.D.
University of Houston:
Multiple Hereditary Exostoses (MHE) is an autosomal dominant skeletal disorder most frequently
caused by mutations in the EXT1 gene.
MHE affects proper development of endochondral bones, such that all affected individuals present
with exostoses adjacent to the growth plate of long bones, while some individuals exhibit additional
bone deformities. EXT1 functions as a heparan sulfate (HS) co-polymerase, and when defective
causes improper elongation of glycosaminoglycan side chains on core proteins of HS proteoglycans.
Although analysis of heterozygous EXT1-deficient mice has failed to reveal any significant gross
morphological variations in skeletal development, significant alterations in molecular signaling occur in
the developing long bones.
Our results indicate that defects in EXT1 and the resulting reduction in HS lead to enhanced Indian
Hedgehog diffusion causing an increase in chondrocyte proliferation and delayed hypertrophic
differentiation.
Andrea Vortkamp, P.h.D.
Propagation of Ihh signaling:
One important question to understand the IhhP/THrP feedback loop is how the Ihh signal is
transported through the growth plate. In Drosophila the glycosyltransferase ‘tout velu’ (ttv) is
necessary to transport the hedgehog signal in the developing embryo.
Mutations in the human homologues, Ext-1 and Ext-2, result in, Heritable multiple exostoses’ (HME),
disease characterized by benign bone tumors and short stature.In the developing bone we found
Ext-1 and Ext-2 both expressed in domains flanking the Ihh expression domain.
Using transgenic mice and a gene trap line targeting the Ext1 locus we aim to analyze the role of
Ext1 during bone devolopment and to identify a potential function in Ihh transport.
Marion Kuche-Gullberg, Ph.D.
Characterization of enzymes involved in heparan sulfate biosynthesis:
Our area of interest is the structure and function of heparan sulfate (HS). HSs play dynamic
functional roles in a diverse number of biological events related to intracellular signaling, cell-cell
interactions and tissue morphogenesis.
HS execute its function by the binding to a variety of molecules including growth factors, serine
protease inhibitors and extracellular matrix proteins.
The biological activities of HS largely depend on the amount and distribution of its sulfate groups
that provide specific binding sites for proteins.
Our overall goal is to understand the mechanisms generating specific saccharide structures and to
provide insight into the link between cell type specific expression of HS modifying enzymes and the
biological function of the polysaccharide.
Our research focus on
1. UDP-glucose dehydrogenase, which converts UDP-glucose to UDP-glucuronic acid providing one
of the building blocks for chain elongation
2. heparan sulfate polymerases (EXT1 and EXT2) giving rise to the polysaccharide backbone(mice
with a gene trap mutation in Ext)
3. 2-O- and 6-O-sulfotransferases, incorporating sulfate groups in specific positions, generating
biological active heparan sulfate.
4. Sulfs, cell associated HS 6-O endosulfatases, that remove sulfate groups in specific positions,
thus modulating HS dependent growth factor signaling.
Heparan Sulfates - Regulators of Cell Functions
Heparan sulfates (HS): are glycans (complex
sugars) found on all cell surfaces which act by
binding selectively to a variety of proteins and
pathogens and are critically relevant to many
disease processes (eg. , inflammation,
neurodegeneration, angiogenesis, wound healing,
cancer, cardiovascular disordersand infectious
diseases). Many of these activities have been
detected using heparin, which is a subclass of the
HS family of glycans .
Heparan sulfates (HS): are glycans (complex
sugars) found on all cell surfaces which act by
binding selectively to a variety of proteins and
pathogens and are critically relevant to many
disease processes (eg. , inflammation,
neurodegeneration, angiogenesis, wound healing,
cancer, cardiovascular disordersand infectious
diseases). Many of these activities have been
detected using heparin, which is a subclass of the
HS family of glycans .
Heparin and heparan sulphates act by binding
to proteins and regulating their biological activities.
The picture shows the interaction of a small
heparin hexasaccharide (6 sugar units) with the
growth factor called basic FGF that controls the
growth and differentiation of many cell types.
The HS family of sugars are composed of long
chains of repeating disaccharide units of uronic acid
and glucosamine residues, decorated by variable
patterns of sulphate and carboxyl groups, giving
them very strong negative charge.
They are produced in living cells by a complex
multi-step enzymatic biosynthetic process.
Heparin is a highly sulphated and relatively
structurally homogenous molecule compared to
cellular heparan sulphates, which have increased
sequence diversity and fulfil many complex biological
functions by interacting with proteins and
influencing their biological activities.
chains of repeating disaccharide units of uronic acid
and glucosamine residues, decorated by variable
patterns of sulphate and carboxyl groups, giving
them very strong negative charge.
They are produced in living cells by a complex
multi-step enzymatic biosynthetic process.
Heparin is a highly sulphated and relatively
structurally homogenous molecule compared to
cellular heparan sulphates, which have increased
sequence diversity and fulfil many complex biological
functions by interacting with proteins and
influencing their biological activities.
Animated picture shows an extended helical
heparin sequence with sulphate groups
(yellow/red) decorating the backbone (image
courtesy of Dr Barbara Mulloy, National
Institiute of Biological Standards, Herts, UK)
heparin sequence with sulphate groups
(yellow/red) decorating the backbone (image
courtesy of Dr Barbara Mulloy, National
Institiute of Biological Standards, Herts, UK)
HS/heparin structure
HS and heparin are long, linear chains of sugars,
composed of repeating disaccharide units made
up of alternating uronic acid (glucuronic or
iduronic acid) and glucosamine residues. The
backbone structure is then decorated with
complex patterns of sulphate groups at various
positions.
HS and heparin are long, linear chains of sugars,
composed of repeating disaccharide units made
up of alternating uronic acid (glucuronic or
iduronic acid) and glucosamine residues. The
backbone structure is then decorated with
complex patterns of sulphate groups at various
positions.
HS and heparin are produced on cells by a
complex process involving the sequential action
of multiple enzymes which knit together the
repeating disaccharide units (polymerases) and
then modify them with exquisitely complex
patterns of sulphate groups (sulfotransferases).
The resulting structural motifs bind to specific
proteins and influence their biological activities.
complex process involving the sequential action
of multiple enzymes which knit together the
repeating disaccharide units (polymerases) and
then modify them with exquisitely complex
patterns of sulphate groups (sulfotransferases).
The resulting structural motifs bind to specific
proteins and influence their biological activities.
Heparan sulphate binds proteins
Heparin and heparan sulphates act by binding to
proteins and regulating their biological activities.
The picture shows the interaction of a small
heparin hexasaccharide (6 sugar units) with the
growth factor called basic FGF that controls the
growth and differentiation of many cell types.
Heparin and heparan sulphates act by binding to
proteins and regulating their biological activities.
The picture shows the interaction of a small
heparin hexasaccharide (6 sugar units) with the
growth factor called basic FGF that controls the
growth and differentiation of many cell types.
This information was provided by intellthep
We are grateful for the use of this information
We are grateful for the use of this information
|
heparan sulfate proteoglycans (HSPGs), are ubiquitous glycoproteins present at the cell surface and
in the extracellular matrix, and have their roles in neuron migration, process outgrowth and
guidance and in synapse formation. HSPGs contain a protein core substituted with heparan sulphate
(HS) polysaccharide chains, which encode complex sugar sequences with variant sulfation patterns
that confer biological functions as protein regulators. HS/HSPGs play essential roles in controlling cell
differentiation, tissue morphogenesis and homeostasis. In the nervous system, HS and HSPGs have
been implicated in neuron migration, axon guidance, synapse formation and maturation and control
of physiological responses such as feeding, learning and memory.
in the extracellular matrix, and have their roles in neuron migration, process outgrowth and
guidance and in synapse formation. HSPGs contain a protein core substituted with heparan sulphate
(HS) polysaccharide chains, which encode complex sugar sequences with variant sulfation patterns
that confer biological functions as protein regulators. HS/HSPGs play essential roles in controlling cell
differentiation, tissue morphogenesis and homeostasis. In the nervous system, HS and HSPGs have
been implicated in neuron migration, axon guidance, synapse formation and maturation and control
of physiological responses such as feeding, learning and memory.
| What is a chondrocyte |
Chondrocytes (from Greek chondros cartilage + kytos cell) are the only cells found in cartilage. They
produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans.
To view a short video of what is chondrocyte is please click the tab
produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans.
To view a short video of what is chondrocyte is please click the tab
Slide: Jeffrey D Esko, Phd
Joseph R. Bishop, Manuela Schuksz, Jeffrey D. Esko
Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells studied so far and
are a major component of extracellular matrices. Studies of model organisms and human diseases
have demonstrated their importance in development and normal physiology. A recurrent theme is
the electrostatic interaction of the heparan sulphate chains with protein ligands, which affects
metabolism, transport, information transfer, support and regulation in all organ systems. The
importance of these interactions is exemplified by phenotypic studies of mice and humans bearing
mutations in the core proteins or the biosynthetic enzymes responsible for assembling the heparan
sulphate chains.
SUMMARY: Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells
studied so far and are a major component of extracellular matrices. Studies of model organisms and
human diseases
CONTEXT: hereditary multiple exostoses, an autosomal dominant disease characterized by the
formation of cartilage-capped bony outgrowths (osteochondromas or exostoses) on growth plates
throughout the body. Heterozygous mice also develop...
Nature 446, 1030 - 1037 (25 Apr 2007) Insight
Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells studied so far and
are a major component of extracellular matrices. Studies of model organisms and human diseases
have demonstrated their importance in development and normal physiology. A recurrent theme is
the electrostatic interaction of the heparan sulphate chains with protein ligands, which affects
metabolism, transport, information transfer, support and regulation in all organ systems. The
importance of these interactions is exemplified by phenotypic studies of mice and humans bearing
mutations in the core proteins or the biosynthetic enzymes responsible for assembling the heparan
sulphate chains.
SUMMARY: Heparan sulphate proteoglycans reside on the plasma membrane of all animal cells
studied so far and are a major component of extracellular matrices. Studies of model organisms and
human diseases
CONTEXT: hereditary multiple exostoses, an autosomal dominant disease characterized by the
formation of cartilage-capped bony outgrowths (osteochondromas or exostoses) on growth plates
throughout the body. Heterozygous mice also develop...
Nature 446, 1030 - 1037 (25 Apr 2007) Insight
|
For more detailed information concerning the Perichondrium, chondrocytes, PTHrP, Ihh
and other signaling pathways affected by the defect in the EXT genes please view the video.
April 25–28, 2007, the 2nd Conference on Skeletal Biology and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai
School of Medicine, was organized and chaired by Mone Zaidi, professor of endocrinology,
geriatrics and adult development, and structural and chemical biology at Mount Sinai. Cochairs were
Gerard Karsenty of Columbia University and Steven Teitelbaum of the Washington University School
of Medicine.
The MHE Research would like to thank all for the use of the presentation on the MHE
Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
and other signaling pathways affected by the defect in the EXT genes please view the video.
April 25–28, 2007, the 2nd Conference on Skeletal Biology and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai
School of Medicine, was organized and chaired by Mone Zaidi, professor of endocrinology,
geriatrics and adult development, and structural and chemical biology at Mount Sinai. Cochairs were
Gerard Karsenty of Columbia University and Steven Teitelbaum of the Washington University School
of Medicine.
The MHE Research would like to thank all for the use of the presentation on the MHE
Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click
the link tab
| Jeffrey D Esko, Ph.D. "What is MHE Research" Click Here to view this video presentation |
This presentation will open in a new browser window
The MHE Research Foundation is proud to be working with the EuroBoNeT consortium, a European Commission
granted Network of Excellence for studying the pathology and genetics of bone tumors.
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Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
By the Health On the Net Foundation. Click here to verify.# HON Conduct 282463 and is linked on the NIH
National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
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Disclaimer: While many find the information useful, it is in no way a substitute for professional medical care.
The information provided here is for educational and informational purposes only. This website does not engage in the practice
of medicine. In all cases we recommend that you consult your own physician regarding any course of treatment or medicine.
The information provided here is for educational and informational purposes only. This website does not engage in the practice
of medicine. In all cases we recommend that you consult your own physician regarding any course of treatment or medicine.
This website is regularly reviewed by members of the Scientific and Medical Advisory Board of the MHE Research Foundation.
This web page was updated last on 2/20/08, 4:00 pm Eastern time