When a patient's first symptoms of rheumatoid arthritis (RA) occur in winter, the severity of their RA (as measured by the modified Total Sharp Score, mTSS, an assessment of erosion and joint space narrowing) was rated more severe at six months, when compared to patients whose RA first became symptomatic in summer (Odds Ratio (OR) =2.82 [1.14;7], p=0.0255). Furthermore, RA patients with their first symptoms in spring showed poorer radiographic outcome compared to summer-onset patients (OR=2.83 [1.10;7.37], p=0.0322), according to the results of a new study presented today at EULAR 2009, the Annual Congress of the European League Against Rheumatism in Copenhagen, Denmark.
Similarly, patients' mTSS after six months was worse if their first symptoms had occurred in winter (OR=2.61 [1.20; 5.71], p=0.0158) or in spring (OR=2.63 [1.13; 6.14], p=0.0025) versus autumn as the reference season. This effect was not however observed at 12 month follow up, which the study authors suggest could suggest that these initial environmental factors exert less of an effect on longer term radiographic progression.
Dr Ga?«l Mouterde, Immuno-Rheumatology Department, Lapeyronie Hospital, Montpellier, France who led the research, said: "During our study of predictors of radiographic progression, we have unveiled a distinct relationship between RA progression and seasonal onset and postulate that this could be as a result of either a vitamin D deficiency or environmental factors, such as winter viruses, influencing protein citrullination. Anti-citrullinated protein antibodies (ACPAs) are often found in the immune systems of RA patients. This finding may assist towards the identification of RA patients at a higher risk of developing structural damage, in order to propose early intensive therapy and minimise disease progression."
Of the 736 patients from the multicentre French ESPOIR cohort analysed in the study (48?±12 years of age, females 77%, mean disease duration 103+/-53 days, DAS28 5.11?±1.31, HAQ score 0.97?±0.68, CRP 21.9?±32 mg/l, HLA-DRB1*01 or 04 57.5%), those found to have anti-CCP antibodies (total n=290) were also likely to have experienced increased radiographic disease progression (defined by an increase of at least 1 point of the mTSS), than those without anti-CCP antibodies, both after six months (OR=3.73 [2.04;6.82], p
пятница, 28 октября 2011 г.
вторник, 25 октября 2011 г.
U-M Study Offers New Perspective On Nitric Oxide Signaling In Rheumatoid Arthritis
Scientists at the University of Michigan Medical School have found evidence that challenges current thinking about the cause of rheumatoid arthritis (RA), a chronic inflammatory disease that damages joints, causes pain, loss of movement, and bone deformities in 2.1 million Americans.
Published in the November 2006 issue of Arthritis and Rheumatism, results from the study could help answer questions that have puzzled scientists for more than 20 years:
Why do nearly 95 percent of RA patients have a common sequence of DNA, which scientists call a shared epitope, and why do patients with this DNA sequence have more severe forms of the disease than patients without it?
Most researchers believe that RA is an autoimmune disorder, because the shared epitope is located in an area of the human genome that codes for proteins involved in the immune system's recognition of antigens.
Antigens are like little name tags on the surfaces of cells. They help the immune system recognize what belongs in our bodies and what doesn't. The immune system will attack foreign antigens. For example, without closely matched antigens, a transplant patient's immune system will reject a donated organ.
"Although the hypothesis that RA is an autoimmune disorder is widely accepted, there is no convincing evidence that it is correct," says Joseph Holoshitz, M.D., associate professor of internal medicine at U-M Medical School who directed the study. "We see this same type of association with HLA genes in other diseases, which we know are not autoimmune diseases."
Holoshitz and his colleagues discovered that the shared epitope can trigger a signaling cascade that leads to increased production of nitric oxide in other cells. A gas produced by several types of cells in the body, nitric oxide is an important signaling molecule.
"Our findings suggest this activity is unrelated to antigen presentation," says Holoshitz. "This is the first direct evidence that the shared epitope may be responsible for the overproduction of nitric oxide seen in patients with RA."
Overproduction of NO inhibits apoptosis - the natural process that leads to cell death. Resistance to apoptosis is a common trait found in cells lining the joints of RA patients, and is believed to lead to disease symptoms.
In the U-M study, cells from individuals with the shared epitope were completely resistant to cell death when compared to samples from individuals without the shared epitope.
"It was previously postulated that nitric oxide plays a role in RA, since patients have higher levels of it in their joint tissue. When we looked at the rate of NO generation in these patients, we found that it was significantly higher for people with the shared epitope," says Holoshitz.
The findings offer scientists a new way of viewing other diseases, in addition to RA. For example, narcolepsy and certain types of leukemia are strongly associated with HLA genes, yet there is no convincing evidence that they are autoimmune diseases. According to Holoshitz, further research into HLA genes and their function could offer new insights into the cause of these diseases.
Holoshitz cautions that, although the association between the shared epitope and RA is consistently found among many ethnic groups, five to 10 percent of all RA patients are shared epitope-negative. Further studies are needed to examine other possible causes of nitric oxide overproduction in RA.
The research was supported by the National Institutes of Health, the Arthritis Foundation, and the University of Michigan Biotechnology Development Fund.
Contributing authors include first author Song Ling, Ph.D., a research investigator in the departmental of internal medicine, U-M Medical School; Angela Lai, a U-M undergraduate student; and Olga Borschukova and Paul Pumpens from the Biomedical Research and Study Center, University of Latvia.
Citation: Arthritis & Rheumatism: (54) 11, pp. 3423-3432, November 2006
Written by Rossitza Iordanova
Contact: Sally Pobojewski
University of Michigan Health System
Published in the November 2006 issue of Arthritis and Rheumatism, results from the study could help answer questions that have puzzled scientists for more than 20 years:
Why do nearly 95 percent of RA patients have a common sequence of DNA, which scientists call a shared epitope, and why do patients with this DNA sequence have more severe forms of the disease than patients without it?
Most researchers believe that RA is an autoimmune disorder, because the shared epitope is located in an area of the human genome that codes for proteins involved in the immune system's recognition of antigens.
Antigens are like little name tags on the surfaces of cells. They help the immune system recognize what belongs in our bodies and what doesn't. The immune system will attack foreign antigens. For example, without closely matched antigens, a transplant patient's immune system will reject a donated organ.
"Although the hypothesis that RA is an autoimmune disorder is widely accepted, there is no convincing evidence that it is correct," says Joseph Holoshitz, M.D., associate professor of internal medicine at U-M Medical School who directed the study. "We see this same type of association with HLA genes in other diseases, which we know are not autoimmune diseases."
Holoshitz and his colleagues discovered that the shared epitope can trigger a signaling cascade that leads to increased production of nitric oxide in other cells. A gas produced by several types of cells in the body, nitric oxide is an important signaling molecule.
"Our findings suggest this activity is unrelated to antigen presentation," says Holoshitz. "This is the first direct evidence that the shared epitope may be responsible for the overproduction of nitric oxide seen in patients with RA."
Overproduction of NO inhibits apoptosis - the natural process that leads to cell death. Resistance to apoptosis is a common trait found in cells lining the joints of RA patients, and is believed to lead to disease symptoms.
In the U-M study, cells from individuals with the shared epitope were completely resistant to cell death when compared to samples from individuals without the shared epitope.
"It was previously postulated that nitric oxide plays a role in RA, since patients have higher levels of it in their joint tissue. When we looked at the rate of NO generation in these patients, we found that it was significantly higher for people with the shared epitope," says Holoshitz.
The findings offer scientists a new way of viewing other diseases, in addition to RA. For example, narcolepsy and certain types of leukemia are strongly associated with HLA genes, yet there is no convincing evidence that they are autoimmune diseases. According to Holoshitz, further research into HLA genes and their function could offer new insights into the cause of these diseases.
Holoshitz cautions that, although the association between the shared epitope and RA is consistently found among many ethnic groups, five to 10 percent of all RA patients are shared epitope-negative. Further studies are needed to examine other possible causes of nitric oxide overproduction in RA.
The research was supported by the National Institutes of Health, the Arthritis Foundation, and the University of Michigan Biotechnology Development Fund.
Contributing authors include first author Song Ling, Ph.D., a research investigator in the departmental of internal medicine, U-M Medical School; Angela Lai, a U-M undergraduate student; and Olga Borschukova and Paul Pumpens from the Biomedical Research and Study Center, University of Latvia.
Citation: Arthritis & Rheumatism: (54) 11, pp. 3423-3432, November 2006
Written by Rossitza Iordanova
Contact: Sally Pobojewski
University of Michigan Health System
суббота, 22 октября 2011 г.
Autoantibodies Precede Disease in Lupus Patients
CONTACT:
Susan Bettendorf
301-496-8190
A new study funded largely by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reveals that people diagnosed with systemic lupus erythematosus (lupus) - an autoimmune disease in which the body attacks its own tissues - have autoantibodies in their blood years before the symptoms of lupus appear.
The early detection of autoantibodies - proteins that attach to the body's healthy tissues by mistake - may help in recognizing those who will develop the disease and allow physicians to monitor them before they might otherwise be noticed.
Senior author John Harley, M.D., Ph.D., of the Oklahoma Medical Research Foundation and the University of Oklahoma, and his colleagues there and in other institutions, tested blood from 130 U.S. armed forces servicemen and women, without knowing their identities, who were once healthy but later developed lupus.
Using many years of previously collected samples from the Department of Defense Serum Repository, the researchers compared samples from the lupus patients to samples from those who never developed lupus.
When testing early samples from both groups, they found that those with lupus had the autoantibodies in their blood for months to years before symptoms appeared. Some of the autoantibodies, such as antinuclear antibody, had been present longer than others.
The lupus autoantibodies, say the authors, tend to accumulate in the blood in a predictable pattern up until diagnosis, when the rate of new autoantibodies slows.
'We don't know whether the virtual halt in the accumulation of new autoantibodies is a result of therapy now typically used or whether the relative stability in the autoantibodies found after diagnosis is a feature of the natural history of lupus,' said Dr. Harley. 'Certainly, this observation reminds us of how important diagnosis is for what subsequently happens in the immune system of the patient.'
NIAMS Director Stephen I. Katz, M.D., Ph.D., said 'Identifying such patterns in disease progression may lead researchers to understand what causes autoantibodies to appear when they do and how they contribute to the disease.' NIAMS researcher Gregory Dennis, M.D., a coauthor of the study, said, 'Lupus and other autoimmune diseases often go untreated for years and are diagnosed only after damage to the body tissues has occurred. Findings such as these, which will help us identify and monitor people who may develop these diseases, are extremely valuable.'
Lupus can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels and brain. People who have lupus may have many different symptoms, but some of the most common ones include extreme fatigue, painful or swollen joints (arthritis), unexplained fever, skin rashes and kidney problems. Many more women than men have lupus.
It is three times more common in African American women than in Caucasian women and is also more common in women of Hispanic, Asian and Native American descent.
Other institutions taking part in the study included NIAMS, the Department of Veterans Affairs, Walter Reed Army Medical Center and the U.S. Army Center for Health Promotion and Preventive Medicine.
Funding was also provided by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources, both part of the Department of Health and Human Services' National Institutes of Health.
To contact Dr. Harley, call Adam Cohen at the Oklahoma Medical Research Foundation at (405) 271-7159.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases.
For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at niams.nih.
Susan Bettendorf
301-496-8190
A new study funded largely by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reveals that people diagnosed with systemic lupus erythematosus (lupus) - an autoimmune disease in which the body attacks its own tissues - have autoantibodies in their blood years before the symptoms of lupus appear.
The early detection of autoantibodies - proteins that attach to the body's healthy tissues by mistake - may help in recognizing those who will develop the disease and allow physicians to monitor them before they might otherwise be noticed.
Senior author John Harley, M.D., Ph.D., of the Oklahoma Medical Research Foundation and the University of Oklahoma, and his colleagues there and in other institutions, tested blood from 130 U.S. armed forces servicemen and women, without knowing their identities, who were once healthy but later developed lupus.
Using many years of previously collected samples from the Department of Defense Serum Repository, the researchers compared samples from the lupus patients to samples from those who never developed lupus.
When testing early samples from both groups, they found that those with lupus had the autoantibodies in their blood for months to years before symptoms appeared. Some of the autoantibodies, such as antinuclear antibody, had been present longer than others.
The lupus autoantibodies, say the authors, tend to accumulate in the blood in a predictable pattern up until diagnosis, when the rate of new autoantibodies slows.
'We don't know whether the virtual halt in the accumulation of new autoantibodies is a result of therapy now typically used or whether the relative stability in the autoantibodies found after diagnosis is a feature of the natural history of lupus,' said Dr. Harley. 'Certainly, this observation reminds us of how important diagnosis is for what subsequently happens in the immune system of the patient.'
NIAMS Director Stephen I. Katz, M.D., Ph.D., said 'Identifying such patterns in disease progression may lead researchers to understand what causes autoantibodies to appear when they do and how they contribute to the disease.' NIAMS researcher Gregory Dennis, M.D., a coauthor of the study, said, 'Lupus and other autoimmune diseases often go untreated for years and are diagnosed only after damage to the body tissues has occurred. Findings such as these, which will help us identify and monitor people who may develop these diseases, are extremely valuable.'
Lupus can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels and brain. People who have lupus may have many different symptoms, but some of the most common ones include extreme fatigue, painful or swollen joints (arthritis), unexplained fever, skin rashes and kidney problems. Many more women than men have lupus.
It is three times more common in African American women than in Caucasian women and is also more common in women of Hispanic, Asian and Native American descent.
Other institutions taking part in the study included NIAMS, the Department of Veterans Affairs, Walter Reed Army Medical Center and the U.S. Army Center for Health Promotion and Preventive Medicine.
Funding was also provided by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources, both part of the Department of Health and Human Services' National Institutes of Health.
To contact Dr. Harley, call Adam Cohen at the Oklahoma Medical Research Foundation at (405) 271-7159.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases.
For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at niams.nih.
среда, 19 октября 2011 г.
Discovery Hints At How Autoimmune Disease May Develop Late In Life
A St. Jude Children's Research Hospital study shows that T cells, the body's master immune regulators, do not use simple on/off switches to govern the cellular machinery that regulates their development and function. Rather, they possess sophisticated molecular controls that enable them to adjust their function with exquisite precision. Such subtle adjustment enables T cells to modulate their development and function, including avoiding autoimmunity.
In autoimmune disease, rather than attacking invading microbes, the immune system attacks the body's own organs, tissues or cells. Some 80 autoimmune diseases are known, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
"Among the many mysteries surrounding autoimmune diseases is why they can sometimes take decades to manifest themselves," said Dario Vignali, Ph.D., associate member in the St. Jude Department of Immunology. "Our findings hint that this delayed onset could be explained by subtle defects in the molecular controls on T cells." Such T cells are white blood cells whose duties include shutting down the immune system when it has done its job and suppressing T cells that can attack the body.
Vignali is the senior author of a report on this work that appears in the advance online publication of the journal Nature Immunology.
The researchers explored the function of T cell receptors, proteins that span the cell membrane of T cells. These receptors receive outside signals that instruct T cells to develop, proliferate and transmit those signals into the cell. The St. Jude investigators sought to understand why T cell receptors need many copies of switch-like components called immunoreceptor tyrosine-based activation motifs (ITAMS). ITAMs are components of the CD3 adaptor proteins that attach to the T cell receptor and help transmit the control signals from the T cell receptor into the cell.
"The ITAMs we studied are little molecular tags inside the cell by which the T cell receptor communicates to the rest of the cell," Vignali said. "The mystery we wanted to address was why the T cell receptor needs 10 ITAMs to do its job. Why not just have a simple on/off switch?"
To explore the role of multiple ITAMs, Jeff Holst, Ph.D., the paper's first author and a St. Jude postdoctoral scientist, used a technique developed in the Vignali lab to produce mice whose T cells have variations in the number and type of functional ITAMs. The technique involved using a virus as a genetic cargo-carrier to transport genes for different combinations of normal and mutant non-functional ITAMs into the mouse cells.
The researchers found that reducing the number of normal ITAMs caused the mice to develop autoimmune disease. However, the investigators also found that some mice with fewer than normal functional ITAMs did not become sick with autoimmune disease. Vignali said this finding suggests that it is not just the number of ITAMs, but also their type that may influence T cell function.
"We theorized that there were two possibilities why the immune system needs so many ITAMs," he said. "One is that the requirement was purely quantitative, and that the ITAMs were there for signal amplification. The second possibility is that different ITAMs do slightly different things - they do have slightly different structures, so maybe they bind to some signaling molecules better than others; and their positions in the T cell receptor are different. So, while our primary observation is that quantity is more important than ITAM type, we also found that type has some influence."
The researchers' analyses of the immune systems of the altered mice indicated that reducing the number of normal ITAMs crippled a process called "negative selection." In this process, the immune system rids itself of immature T cells that might attack the body's own cells, causing autoimmune disease. Vignali said that these findings might provide insight into how autoimmune diseases start.
"One implication of our findings is that a relatively small defect in the efficiency of signal transduction through the T cell receptor could give rise to a subtle failing in negative selection, which gives rise over a long period of time to a few overly active T cells that might initiate autoimmunity," Vignali said. "Clearly from our studies there is the possibility that you don't really need a very big reduction in T cell receptor signal strength to have a defect in negative selection."
The study also showed that different T cell functions required different numbers of functional ITAMs. "We were surprised to find that many ITAMs were required to make T cells divide and expand, but only one or two was required to make T cells secrete cytokines," Vignali said. Cytokines are soluble proteins used by cells of the immune system to communicate and send messages to one another. Vignali said these basic findings represent only the beginning of more detailed studies of the role of ITAMs in T cell function.
"We believe this idea that T cell signaling acts more like a rheostat than an on/off switch offers significant new insights into how T cell development and function is controlled," Vignali said.
Other authors include Haopeng Wang, Kelly Durick Eder, Creg Workman, Kelli Boyd, Zachary Baquet, Karen Forbes and Richard Smeyne (St. Jude); Harvir Singh, Andrzej Chruscinski and Paul Utz (Stanford University School of Medicine, Stanford, Calif.); and Nicolai van Oers (The University of Texas Southwestern Medical Center, Dallas).
This work was supported by the National Institutes of Health, a Cancer Center Support CORE grant and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit stjude/.
Source: Summer Freeman
St. Jude Children's Research Hospital
In autoimmune disease, rather than attacking invading microbes, the immune system attacks the body's own organs, tissues or cells. Some 80 autoimmune diseases are known, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis and lupus.
"Among the many mysteries surrounding autoimmune diseases is why they can sometimes take decades to manifest themselves," said Dario Vignali, Ph.D., associate member in the St. Jude Department of Immunology. "Our findings hint that this delayed onset could be explained by subtle defects in the molecular controls on T cells." Such T cells are white blood cells whose duties include shutting down the immune system when it has done its job and suppressing T cells that can attack the body.
Vignali is the senior author of a report on this work that appears in the advance online publication of the journal Nature Immunology.
The researchers explored the function of T cell receptors, proteins that span the cell membrane of T cells. These receptors receive outside signals that instruct T cells to develop, proliferate and transmit those signals into the cell. The St. Jude investigators sought to understand why T cell receptors need many copies of switch-like components called immunoreceptor tyrosine-based activation motifs (ITAMS). ITAMs are components of the CD3 adaptor proteins that attach to the T cell receptor and help transmit the control signals from the T cell receptor into the cell.
"The ITAMs we studied are little molecular tags inside the cell by which the T cell receptor communicates to the rest of the cell," Vignali said. "The mystery we wanted to address was why the T cell receptor needs 10 ITAMs to do its job. Why not just have a simple on/off switch?"
To explore the role of multiple ITAMs, Jeff Holst, Ph.D., the paper's first author and a St. Jude postdoctoral scientist, used a technique developed in the Vignali lab to produce mice whose T cells have variations in the number and type of functional ITAMs. The technique involved using a virus as a genetic cargo-carrier to transport genes for different combinations of normal and mutant non-functional ITAMs into the mouse cells.
The researchers found that reducing the number of normal ITAMs caused the mice to develop autoimmune disease. However, the investigators also found that some mice with fewer than normal functional ITAMs did not become sick with autoimmune disease. Vignali said this finding suggests that it is not just the number of ITAMs, but also their type that may influence T cell function.
"We theorized that there were two possibilities why the immune system needs so many ITAMs," he said. "One is that the requirement was purely quantitative, and that the ITAMs were there for signal amplification. The second possibility is that different ITAMs do slightly different things - they do have slightly different structures, so maybe they bind to some signaling molecules better than others; and their positions in the T cell receptor are different. So, while our primary observation is that quantity is more important than ITAM type, we also found that type has some influence."
The researchers' analyses of the immune systems of the altered mice indicated that reducing the number of normal ITAMs crippled a process called "negative selection." In this process, the immune system rids itself of immature T cells that might attack the body's own cells, causing autoimmune disease. Vignali said that these findings might provide insight into how autoimmune diseases start.
"One implication of our findings is that a relatively small defect in the efficiency of signal transduction through the T cell receptor could give rise to a subtle failing in negative selection, which gives rise over a long period of time to a few overly active T cells that might initiate autoimmunity," Vignali said. "Clearly from our studies there is the possibility that you don't really need a very big reduction in T cell receptor signal strength to have a defect in negative selection."
The study also showed that different T cell functions required different numbers of functional ITAMs. "We were surprised to find that many ITAMs were required to make T cells divide and expand, but only one or two was required to make T cells secrete cytokines," Vignali said. Cytokines are soluble proteins used by cells of the immune system to communicate and send messages to one another. Vignali said these basic findings represent only the beginning of more detailed studies of the role of ITAMs in T cell function.
"We believe this idea that T cell signaling acts more like a rheostat than an on/off switch offers significant new insights into how T cell development and function is controlled," Vignali said.
Other authors include Haopeng Wang, Kelly Durick Eder, Creg Workman, Kelli Boyd, Zachary Baquet, Karen Forbes and Richard Smeyne (St. Jude); Harvir Singh, Andrzej Chruscinski and Paul Utz (Stanford University School of Medicine, Stanford, Calif.); and Nicolai van Oers (The University of Texas Southwestern Medical Center, Dallas).
This work was supported by the National Institutes of Health, a Cancer Center Support CORE grant and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit stjude/.
Source: Summer Freeman
St. Jude Children's Research Hospital
воскресенье, 16 октября 2011 г.
Protein Involved In Causing Gum Disease, Osteoporosis, Arthritis Identified
Investigators at Hospital for Special Surgery, collaborating with researchers from other institutions, have contributed to the discovery that a gene called interferon regulator factor-8 (IRF-8) is involved in the development of diseases such as periodontitis (gum disease), rheumatoid arthritis and osteoporosis. The study, which was published online August 30, ahead of print, in the journal Nature Medicine, could lead to new treatments in the future.
"The study doesn't have immediate therapeutic applications, but it does open a new avenue of research that could help identify novel therapeutic approaches or interventions to treat diseases such as periodontitis, rheumatoid arthritis or osteoporosis," said Baohong Zhao, Ph.D., lead author of the study and a research fellow in the Arthritis and Tissue Degeneration Program at Hospital for Special Surgery located in New York City.
Dr. Zhao initiated the study while working in the laboratory led by Drs. Masamichi Takami and Ryutaro Kamijo at Showa University, Tokyo, where much of the work was performed. Dr. Zhao completed the study and extended the work to human cells during the past year at Hospital for Special Surgery working with Dr. Lionel Ivashkiv.
Specifically, the researchers discovered that downregulation of IRF-8 (meaning that the gene produces less IRF-8 protein) increases the production of cells called osteoclasts that are responsible for breaking down bone. An osteoblast is a type of cell that is responsible for forming bone and an osteoclast is a type of cell that breaks down bony tissue (bone resorption). In humans and animals, bone formation and bone resorption are closely coupled processes involved in the normal remodeling of bone. Enhanced development of osteoclasts, however, can create canals and cavities that are hallmarks of diseases such as periodontitis, osteoporosis and rheumatoid arthritis.
Previous researchers have spent time identifying genes that are upregulated during enhanced development of osteoclasts, such as NFATc1, but few studies have identified genes that are downregulated in the process. To fill this knowledge gap, scientists at Hospital for Special Surgery, collaborating with researchers at other institutions, used microarray technology to conduct a genome-wide screen to identify genes that are downregulated during the formation of osteoclasts. They found that expression of IRF-8 was reduced by 75 percent in the initial phases of osteoclast development.
The researchers then genetically engineered mice to be deficient in IRF-8 and gave the animals x-rays and CT (computed tomography) scans to analyze IRF-8's influence on bone. They found that the mice had decreased bone mass and severe osteoporosis. Experiments demonstrated that this was due not to a decreased number of osteoblasts, but because of an increased number of osteoclasts. The researchers concluded that IRF-8 suppresses the production of osteoclasts.
Tests in human cells confirmed these findings. This included a study that showed that silencing IRF-8 messenger RNA in human osteoclast precursors with small interfering RNAs resulted in enhanced osteoclast production. In other words, decreased IRF-8 means more osteoclasts are produced.
This led the investigators to examine the effect of IRF-8 on the activity of a protein called NFATc1 that was previously reported to interact with IRF-8. They found that IRF-8 inhibited the function and expression of NFATc1. This makes sense given that upregulation of NFATc1 is involved in triggering osteoclast precursor cells to turn into osteoclasts.
"This is the first paper to identify that IRF-8 is a novel key inhibitory factor in osteoclastogenesis [production of osteoclasts]," said Dr. Zhao. "We hope that the understanding of this gene can contribute to understanding the regulatory network of osteoclastogenesis and lead to new therapeutic approaches in the future."
Other authors involved in the study are Masamichi Takami, Ph.D., Atsushi Yamada, Ph.D., Xiaogu Wang, Ph.D., and Ryutaro Kamijo, Ph.D., from Showa University in Tokyo, Japan; Takako Koga, Ph.D., and Hiroshi Takayanagi, M.D., Ph.D., from Tokyo Medical and Dental University and the International Research Center for Molecular Science in Tooth and Bone Disease, both in Japan; Xiaoyu Hu, M.D., Ph.D., and Lionel Ivashkiv, M.D., from Hospital for Special Surgery; Tomohiko Tamura, M.D., Ph.D., and Keiko Ozato, Ph.D., from the National Institutes of Health; and Yongwon Choi, Ph.D., from the University of Pennsylvania School of Medicine.
The work was supported by in part by the High-Tech Research Center Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology in Japan; by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; and by grants from the U.S. National Institutes of Health.
Source:
Phyllis Fisher
Hospital for Special Surgery
"The study doesn't have immediate therapeutic applications, but it does open a new avenue of research that could help identify novel therapeutic approaches or interventions to treat diseases such as periodontitis, rheumatoid arthritis or osteoporosis," said Baohong Zhao, Ph.D., lead author of the study and a research fellow in the Arthritis and Tissue Degeneration Program at Hospital for Special Surgery located in New York City.
Dr. Zhao initiated the study while working in the laboratory led by Drs. Masamichi Takami and Ryutaro Kamijo at Showa University, Tokyo, where much of the work was performed. Dr. Zhao completed the study and extended the work to human cells during the past year at Hospital for Special Surgery working with Dr. Lionel Ivashkiv.
Specifically, the researchers discovered that downregulation of IRF-8 (meaning that the gene produces less IRF-8 protein) increases the production of cells called osteoclasts that are responsible for breaking down bone. An osteoblast is a type of cell that is responsible for forming bone and an osteoclast is a type of cell that breaks down bony tissue (bone resorption). In humans and animals, bone formation and bone resorption are closely coupled processes involved in the normal remodeling of bone. Enhanced development of osteoclasts, however, can create canals and cavities that are hallmarks of diseases such as periodontitis, osteoporosis and rheumatoid arthritis.
Previous researchers have spent time identifying genes that are upregulated during enhanced development of osteoclasts, such as NFATc1, but few studies have identified genes that are downregulated in the process. To fill this knowledge gap, scientists at Hospital for Special Surgery, collaborating with researchers at other institutions, used microarray technology to conduct a genome-wide screen to identify genes that are downregulated during the formation of osteoclasts. They found that expression of IRF-8 was reduced by 75 percent in the initial phases of osteoclast development.
The researchers then genetically engineered mice to be deficient in IRF-8 and gave the animals x-rays and CT (computed tomography) scans to analyze IRF-8's influence on bone. They found that the mice had decreased bone mass and severe osteoporosis. Experiments demonstrated that this was due not to a decreased number of osteoblasts, but because of an increased number of osteoclasts. The researchers concluded that IRF-8 suppresses the production of osteoclasts.
Tests in human cells confirmed these findings. This included a study that showed that silencing IRF-8 messenger RNA in human osteoclast precursors with small interfering RNAs resulted in enhanced osteoclast production. In other words, decreased IRF-8 means more osteoclasts are produced.
This led the investigators to examine the effect of IRF-8 on the activity of a protein called NFATc1 that was previously reported to interact with IRF-8. They found that IRF-8 inhibited the function and expression of NFATc1. This makes sense given that upregulation of NFATc1 is involved in triggering osteoclast precursor cells to turn into osteoclasts.
"This is the first paper to identify that IRF-8 is a novel key inhibitory factor in osteoclastogenesis [production of osteoclasts]," said Dr. Zhao. "We hope that the understanding of this gene can contribute to understanding the regulatory network of osteoclastogenesis and lead to new therapeutic approaches in the future."
Other authors involved in the study are Masamichi Takami, Ph.D., Atsushi Yamada, Ph.D., Xiaogu Wang, Ph.D., and Ryutaro Kamijo, Ph.D., from Showa University in Tokyo, Japan; Takako Koga, Ph.D., and Hiroshi Takayanagi, M.D., Ph.D., from Tokyo Medical and Dental University and the International Research Center for Molecular Science in Tooth and Bone Disease, both in Japan; Xiaoyu Hu, M.D., Ph.D., and Lionel Ivashkiv, M.D., from Hospital for Special Surgery; Tomohiko Tamura, M.D., Ph.D., and Keiko Ozato, Ph.D., from the National Institutes of Health; and Yongwon Choi, Ph.D., from the University of Pennsylvania School of Medicine.
The work was supported by in part by the High-Tech Research Center Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology in Japan; by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; and by grants from the U.S. National Institutes of Health.
Source:
Phyllis Fisher
Hospital for Special Surgery
четверг, 13 октября 2011 г.
Association Between Rheumatoid Arthritis And Poor Sleep In Women
According to a research abstract that will be presented on Wednesday, June 10, at SLEEP 2009, the 23rd Annual Meeting of the Associated Professional Sleep Societies, symptoms of Rheumatoid Arthritis (RA) negatively affect women's sleep. Sleep is further impaired by pain, depression and poor adherence to RA medications.
Results indicate that length of time since RA diagnosis, RA disease activity, level of pain, depression symptoms and adherence to medications for RA may cause women suffering from the disease to have poor sleep quality.
According to lead author Faith Luyster, PhD, of the University of Pittsburgh, Pa., findings emphasize the need for further research concerning poor RA medication adherence and sleep quality.
"Treating depression in women with RA may not only improve sleep but may also improve pain and adherence to medications," said Luyster.
The study involved 133 women with RA; their average age was 56 years, and they were primarily Caucasian, married, had at least a high school education, were not depressed and had RA for 14.76 years. A majority of participants (71 percent) reported poor sleep quality. Pain and depression were measured through subjective reports, and medication adherence was measured objectively with an electronic medication monitor on medication bottle caps.
Sleep disturbances and depression are more prevalent in women in the general population. According to the American Academy of Sleep Medicine (AASM), women face many challenges that interfere with their sleep quality and duration.
More information about how sleep affects women can be found at sleepeducation/Topic.aspx?id=67
Abstract Title: Sleep Quality in Women with Rheumatoid Arthritis
Presentation Date: Wednesday, June 10
Category: Sleep in Medical Disorders
Abstract ID: 1007
Source:
Kelly Wagner
American Academy of Sleep Medicine
Results indicate that length of time since RA diagnosis, RA disease activity, level of pain, depression symptoms and adherence to medications for RA may cause women suffering from the disease to have poor sleep quality.
According to lead author Faith Luyster, PhD, of the University of Pittsburgh, Pa., findings emphasize the need for further research concerning poor RA medication adherence and sleep quality.
"Treating depression in women with RA may not only improve sleep but may also improve pain and adherence to medications," said Luyster.
The study involved 133 women with RA; their average age was 56 years, and they were primarily Caucasian, married, had at least a high school education, were not depressed and had RA for 14.76 years. A majority of participants (71 percent) reported poor sleep quality. Pain and depression were measured through subjective reports, and medication adherence was measured objectively with an electronic medication monitor on medication bottle caps.
Sleep disturbances and depression are more prevalent in women in the general population. According to the American Academy of Sleep Medicine (AASM), women face many challenges that interfere with their sleep quality and duration.
More information about how sleep affects women can be found at sleepeducation/Topic.aspx?id=67
Abstract Title: Sleep Quality in Women with Rheumatoid Arthritis
Presentation Date: Wednesday, June 10
Category: Sleep in Medical Disorders
Abstract ID: 1007
Source:
Kelly Wagner
American Academy of Sleep Medicine
понедельник, 10 октября 2011 г.
News From The Annals Of Internal Medicine, 18 August 2009
1. Chinese Herbal Remedy Shows Promise for Treating Rheumatoid Arthritis
Rheumatoid arthritis is an autoimmune disease that causes painful and debilitating swelling of the joints. Physicians often prescribe anti-inflammatory drugs such as sulfasalazine for the initial treatment of rheumatoid arthritis. Despite the clinical efficacy of these types of drugs, many patients discontinue treatment due to lack of improvement or adverse events. The Chinese herbal remedy Tripterygium wilfordii Hook F (TwHF) (also known as "lei gong teng" or "thunder god vine") has shown promise in treating autoimmune and inflammatory conditions. Researchers randomly assigned 121 patients to take either TwHF root extract 60mg three times per day or sulfasalazine 1g two times per day for 24 weeks. The researchers used a standard measure of joint involvement to determine treatment outcomes. Many patients in both groups discontinued treatment. However, among those who continued treatment for 24 weeks, improvement was greater with TwHF (67%) than with sulfasalazine (36%) and adverse event rates were similar. The resulst were similar in analyses that adjusted for patient drop-out. Researchers conclude that the rapid improvement in joint symptoms may make TwHF extract an attractive and affordable alternative to anti-inflammatory drugs.
2. Elective Induction of Labor May Reduce Cesareans, Improve Fetal Outcomes
Elective induction of labor, or labor that is induced without medical necessity, is rapidly increasing in the United States. Pregnant women who are at term and their physicians may consider labor induction for several reasons including physical discomfort, scheduling issues, or concerns about maternal or fetal complications. However, many experts discourage the practice because of the widely held belief that it increases the risk for cesarean delivery and other complications. Researchers conducted a systematic review of 11 randomized trials and 25 observational studies to compare the benefits and harms of elective induction of labor and expectant management of pregnancy. The researchers found that elective induction of labor at 41 weeks of gestation and beyond was associated with an approximately 20 percent reduction in the rate of cesarean delivery and a 50 percent reduction in the presence of meconium in the amniotic fluid. These results suggest that outcomes may be better with elective induction of labor. More research should be conducted before elective induction of labor is routinely adopted.
3. China's National Free Antiretroviral Program Has Limited Success, Shows Need for Improvement
In 2002, China began the National Free Antiretroviral Program to provide highly active antiretroviral therapy (HAART) to eligible patients with HIV. To determine the long-term outcomes of the program, researchers collected information on patient deaths and CD4 cell counts for the 48,785 program participants over five years. They found that mortality was highest within the first three months after HAART initiation. After about six months of treatment, death rates decreased to levels similar to those seen in HIV-infected patients who receive HAART in other developing countries. The lower death rates remained stable through year five. However, about half of the patients in the program had CD4 cell counts that suggested treatment failure after five years. The researchers believe that treatment failure may be due to the limited number of drug choices available to these patients. Once resistance developed, patients had few options for other drugs they could take.
Source:
Angela Collom
American College of Physicians
Rheumatoid arthritis is an autoimmune disease that causes painful and debilitating swelling of the joints. Physicians often prescribe anti-inflammatory drugs such as sulfasalazine for the initial treatment of rheumatoid arthritis. Despite the clinical efficacy of these types of drugs, many patients discontinue treatment due to lack of improvement or adverse events. The Chinese herbal remedy Tripterygium wilfordii Hook F (TwHF) (also known as "lei gong teng" or "thunder god vine") has shown promise in treating autoimmune and inflammatory conditions. Researchers randomly assigned 121 patients to take either TwHF root extract 60mg three times per day or sulfasalazine 1g two times per day for 24 weeks. The researchers used a standard measure of joint involvement to determine treatment outcomes. Many patients in both groups discontinued treatment. However, among those who continued treatment for 24 weeks, improvement was greater with TwHF (67%) than with sulfasalazine (36%) and adverse event rates were similar. The resulst were similar in analyses that adjusted for patient drop-out. Researchers conclude that the rapid improvement in joint symptoms may make TwHF extract an attractive and affordable alternative to anti-inflammatory drugs.
2. Elective Induction of Labor May Reduce Cesareans, Improve Fetal Outcomes
Elective induction of labor, or labor that is induced without medical necessity, is rapidly increasing in the United States. Pregnant women who are at term and their physicians may consider labor induction for several reasons including physical discomfort, scheduling issues, or concerns about maternal or fetal complications. However, many experts discourage the practice because of the widely held belief that it increases the risk for cesarean delivery and other complications. Researchers conducted a systematic review of 11 randomized trials and 25 observational studies to compare the benefits and harms of elective induction of labor and expectant management of pregnancy. The researchers found that elective induction of labor at 41 weeks of gestation and beyond was associated with an approximately 20 percent reduction in the rate of cesarean delivery and a 50 percent reduction in the presence of meconium in the amniotic fluid. These results suggest that outcomes may be better with elective induction of labor. More research should be conducted before elective induction of labor is routinely adopted.
3. China's National Free Antiretroviral Program Has Limited Success, Shows Need for Improvement
In 2002, China began the National Free Antiretroviral Program to provide highly active antiretroviral therapy (HAART) to eligible patients with HIV. To determine the long-term outcomes of the program, researchers collected information on patient deaths and CD4 cell counts for the 48,785 program participants over five years. They found that mortality was highest within the first three months after HAART initiation. After about six months of treatment, death rates decreased to levels similar to those seen in HIV-infected patients who receive HAART in other developing countries. The lower death rates remained stable through year five. However, about half of the patients in the program had CD4 cell counts that suggested treatment failure after five years. The researchers believe that treatment failure may be due to the limited number of drug choices available to these patients. Once resistance developed, patients had few options for other drugs they could take.
Source:
Angela Collom
American College of Physicians
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