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Phase 2 enzyme inducers appear to stop harmful inflammation

Johns Hopkins researchers have discovered that plant-derived compounds known for their ability to protect tissue also appear to block the activity of an enzyme that triggers inflammation in joints.

Their findings, based on experiments with human cells in a lab, could lead to new arthritis treatments and better methods of making artificial cartilage.

The discovery was detailed in a paper published in the Sept. 27 edition of Proceedings of the National Academy of Sciences.

The findings came to light while the researchers were studying the wildly different ways in which cells in human blood vessels and joints respond to pressure gradients generated from liquid moving along their surface, a force called shear stress.

In cells that line blood vessels, the reaction to shear stress is beneficial: the boosting of phase 2 enzymes that may protect the cells from cancer-causing chemicals and other toxic agents. Yet in joints, the response to high shear stress is potentially harmful: an increase in the levels of COX-2 enzyme, which triggers inflammation and pain, and suppresses the activity of phase 2 enzymes, ultimately causing the death of chondrocytic cells. Healthy chondrocytes are responsible for the smooth functioning of joints. When chondrocytes stop functioning properly, the result can be arthritis.

The divergent responses to shear stress prompted a series of experiments in a Johns Hopkins lab supervised by Konstantinos Konstantopoulos, associate professor of chemical and biomolecular engineering and Agarwal-Masson Faculty Scholar. His team knew that strenuous exercise or heavy exertion of muscles can cause joints to increase the levels of harmful COX-2 enzyme. What would happen, the researchers wondered, if the vulnerable chondrocyte cells in human joints were first exposed to the beneficial phase 2 enzymes?

To find out, the researchers obtained compounds that boost the activity of helpful phase 2 enzymes. They added these phase 2 inducers to a dish containing the chondrocyte cells that are crucial to maintaining healthy joints. After 24 hours, the cells were subjected to a stress test designed to mimic aspects of strenuous exercise on a joint as well as the hydrodynamic environment in a bioreactor designed to generate artificial cartilage.

The results were surprising. “The beneficial phase 2 enzymes somehow seemed to prevent the activation of the inflammatory COX-2 enzyme,” said Zachary R. Healy, a doctoral student in Konstantopoulos’ lab and lead author of the journal paper. “The phase 2 enzymes inhibited the inflammation and the apoptosis — the cellular suicide we’d observed.”

Some prescription drugs like Vioxx keep COX-2 enzyme at bay by temporarily blocking its ability to send the biochemical signals that set off pain and inflammation. When the medication is stopped, however, the stockpiled COX-2 enzyme can resume its damaging ways. Unlike these traditional pain killers, Healy said, the phase 2 enzyme inducers seemed to stop the increasing activity of COX-2 enzyme.

“That means these compounds could be useful as a preventive measure, perhaps before strenuous exercise,” Healy said. “This has the potential for stopping pain and inflammation before they start.”

Although these experiments appeared to be the first to determine how phase 2 enzyme inducers affect chondrocytes, these compounds have been studied extensively by researchers at the Johns Hopkins School of Medicine. Paul Talalay, the medical school’s John Jacob Abel Distinguished Service Professor of Pharmacology, has shown that phase 2 enzymes can detoxify certain cancer-causing agents and damaging free radicals in tissue, including cells that line blood vessels. He has isolated compounds in edible plants that boost production of phase 2 enzymes. These phytochemicals can be found in cruciferous plants, including broccoli.

Talalay provided one of the phase 2 inducers used in Healy’s experiments. “This was the first work done in applying these phytochemicals to chondrocytes, which are constantly under the influence of forces because of the way we move our joints,” Talalay said. “The phase 2 inducers seemed to counteract the effects of that stress by inhibiting the expression of COX-2 enzyme. It’s interesting to think that people may be able to obtain this benefit through dietary components.”

By showing a way to ward off inflammation and by providing insights into the effects of shear stress, the new chondrocyte research may also aid tissue engineers who are trying to grow artificial cartilage or seeking to revitalize human cartilage in the lab. This is important because human bodies cannot make new cartilage to replace tissue that’s lost to injury or disease.

“More research is needed,” said Konstantopoulos, who directed and supervised the experiments. “But these discoveries could provide guidelines for designing an ideal hydrodynamic environment in bioreactors for generating functional cartilage as well as for the treatment of osteoarthritis.”

Funding for the research was provided by a DuPont Young Professor Award, a National Science Foundation Graduate Research Fellowship and an Achievement Reward for College Students Fellowship. Healy’s co-authors on the PNAS paper were Talalay, Konstantopoulos, Norman H. Lee of the Institute for Genomic Research, Xiangqun Gao of the Department of Pharmacology and Molecular Sciences at the Johns Hopkins School of Medicine, Mary B. Goldring of the Harvard Institutes of Medicine, and Thomas W. Kensler of the Department of Environmental Health Sciences in the Johns Hopkins Bloomberg School of Public Health.

More than One Million Americans Helped in 6 Months by Private-Sector Drug Program Program Ranks Grow by More than 5,000 Each Day; Patients and Physicians Praise Program

WASHINGTON, Oct. 31 /PRNewswire/ — In just six months, the Partnership for Prescription Assistance (PPA), a national program dedicated to helping people in need access prescription medicines, has matched more than one million patients with assistance programs that likely meet their needs. The PPA is the largest private-sector effort to connect uninsured or underinsured patients to patient assistant programs, many of which provide medicines for free or nearly free. America’s pharmaceutical research companies launched the program on April 5th of this year in partnership with prominent health care, physician and patient advocacy organizations.

“The Partnership for Prescription Assistance is changing thousands of lives everyday,” said Billy Tauzin, president and CEO of the Pharmaceutical Research and Manufacturers of America (PhRMA). “Put it in perspective: the PPA has helped more people than live in cities like Detroit, San Francisco or Washington, D.C.”

Through a toll-free number and user-friendly Web site, the PPA provides a single point of access to more than 2,500 prescription medicines and 475 public and private patient assistance programs. The more than one million patients matched through the PPA join the millions of patients who have benefited from individual company programs directly.

“Without health insurance, my monthly drug bill was more than $1,000,” said Kendall DePascal of San Diego, California. “Now, patient assistance programs cover 100% of my prescription drug costs. The PPA is a blessing.”

Among the PPA’s 1,200 local and national member organizations are the Pharmaceutical Research and Manufacturers of America, American Academy of Family Physicians (AAFP), National Association of Chain Drug Stores, American Cancer Society, United Way and the NAACP.

“As a family physician, I am grateful that this program has helped so many patients across the country get the medicines they need and proud of the role the AAFP has played in the program’s success,” said Dr. Mary E. Frank, President of the American Academy of Family Physicians. “The ultimate goal for physicians is getting the right medication to the right patient at the right time. The PPA plays a critical role in helping make that happen.”

Study shows long-term benefits of initial combination therapy, including either prednisone or infliximab, over dmards alone or step-up combination therapy

A progressive, inflammatory disease affecting the joints and organs, rheumatoid arthritis (RA) claims more than two million Americans, mostly women over age 40, among its victims. While a cure has yet to be found, the treatment of RA patients has changed considerably over the last two decades.

Today, the goal of therapy is not simply symptom relief, but the prevention of long-term structural damage and functional decline. Toward this end, various disease-modifying antirheumatic drugs (DMARDs) have been proven effective in clinical trials, on their own and in tandem with various tumor necrosis factor (TNF) antagonists.

While the recent increase in therapeutic options offers much promise, it has left doctors grappling with the question: What is the best treatment strategy for a patient newly diagnosed with RA?

The results of a long-term study, featured in the November 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), provide clear answers. A team of researchers in the Netherlands compared the four most widely sanctioned and commonly prescribed treatment strategies for very early RA on 508 patients. Primarily women, with a mean age of 54, the patients had suffered disease symptoms for an average of 23 weeks before entering the trial. After randomly assigning the patients to one of four treatment strategies, the researchers closely monitored the effects and benefits for each group over the course of one year.

Group 1 (126 patients) received standard DMARD therapy, starting with methotrexate. Group 2 (121 patients) was assigned to step-combination therapy, starting with methotrexate only, adding other DMARDs and prednisone. Group 3 (133 patients) started with a combination of methotrexate, sulphasalazine and prednisone. Group 4 (128 patients) started with a combination of methotrexate and infliximab.

For all groups, drug dosages were increased or switched to other (combinations of) drugs according to the treatment protocol to achieve a state of low disease activity.

At the end of the year, every group demonstrated measurable improvements, with 32 percent of all the patients achieving clinical remission of their disease. However, patients who had received initial combination therapy–either with prednisone (group 3) or with infliximab (group 4)–had significantly less progression of radiographic joint damage than did patients treated with DMARDs only (group 1), or patients assigned to step-up combination therapy (group 2).

The number of patients without any progression of radiographic joint damage was also higher in groups 3 and 4 than in groups 1 and 2. Furthermore, RA patients in both initial combination therapy groups experienced earlier functional improvement than did patients in either the DMARD monotherapy or step-up combination therapy group, according to scores of the Dutch version of the Health Assessment Questionnaire. Overall, patients who received initial combination therapy experienced no more side effects than patients in the other two groups.

“Patients in groups 3 and 4 had the benefit of a more rapid relief of symptoms and improvement of physical function,” observes the author, B. A. C. Dijkmans, M.D. “In addition, there is the possibility that effective suppression of disease activity during the early phases of the disease may ameliorate the long-term joint damage and poor physical function and, ideally, even induce true clinical remission without the need for ongoing DMARD treatment.”

Should any patient with newly diagnosed RA be treated with a single DMARD? Would choosing this established course always make a patient vulnerable to increased disease severity? That question can only be answered with further research.

NIAMS, Arthritis Foundation Introduce Pediatric Rheumatic Diseases CD-ROM The National Institute of Arthritis and Musculoskeletal and Skin Diseaseas (NIAMS), a part of the National Institutes of Health, in partnership with the Arthritis Foundation, announces the launch of the Pediatric Rheumatic Diseases CD-ROM and Other Related Information for You and Your Patients, a comprehensive and cost-effective educational and informational tool for doctors and other health professionals who treat children with pediatric rheumatic diseases and related conditions.

Rheumatic diseases are a group of disorders of the joints and soft tissues, causing pain and, in many cases, physical disability. While they affect people of all ages, their impact can be especially profound in children. Collectively, they are among the most common and chronic conditions of childhood. Although we have much to learn about the causes, risk factors, treatment and prevention of these diseases in children, important information already exists.

“There are unique challenges that the rheumatic diseases present in children,” says NIAMS Director Stephen I. Katz, M.D., Ph.D. “The CD-ROM will provide doctors, as well as nurses and other health professionals, with a wide range of resources and information to help them better understand these diseases and how to manage them.”

Resources on this CD-ROM include:

A collection of print-friendly PDF files of selected patient

education brochures Professional education resources, including information from the Arthritis Foundation’s Primer on the Rheumatic Diseases (12th edition)

Professional educational resources on osteogenesis imperfecta from the NIH Osteoporosis and Related Bone Diseases National Resource Center

Web links to numerous useful resources from the National Institutes of Health and other federal and nonprofit organizations.

In a prelaunch review of the new CD-ROM by a variety of healthcare professionals, reviewers overwhelming approved the content and indicated they intend to read the literature to become better informed, distribute it to patients and families of patients, share it with colleagues, and recommend it to other pediatric healthcare professionals, says Dr. Katz. Overall, the reviewers were also able to easily navigate the CD-ROM.

Although the primary audience of the CD-ROM is pediatric health professionals and Arthritis Foundation chapter staff and volunteers, copies will also be available for parents of children with rheumatic diseases, primary and secondary school teachers and counselors, faculty at health professions schools and nonprofit organizations serving individuals and families with rheumatic diseases.

“The welfare and care of children with rheumatic diseases is a priority for the Arthritis Foundation,” says John H. Klippel, M.D., Arthritis Foundation president and CEO. “We are pleased to collaborate with NIAMS to develop a product that will help health care professionals better understand these diseases in children and, thus, better enable them to provide children with rheumatic diseases the help they need.”

To order a free copy of the CD-ROM, contact the NIAMS Clearinghouse at 877-22-NIAMS (877-226-4267) (free of charge), niamsinfo@mail.nih.gov or www.niams.nih.gov.

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 additional information, call NIAMS’ Clearinghouse toll free at 1-877-22-NIAMS, or visit the NIAMS Web site at www.niams.nih.gov.

First Phase III data presented at the ACR Annual Meeting

San Diego, U.S.A.: Roche today announced the results of the first Phase III study in rheumatoid arthritis (RA) conducted by Chugai in Japan which are being presented at the American College of Rheumatology (ACR) Annual Scientific Meeting in San Diego, USA. These data conclude for the first time that Actemra in monotherapy shows superiority to conventional disease modifying anti-rheumatic drugs (DMARDs) in inhibiting radiographic progression of joint destruction.

The data also show Actemra dramatically improves the painful and disabling symptoms of patients with rheumatoid arthritis. Actemra (tocilizumab) is a humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody that offers a novel mechanism of action and may become a new therapeutic option for the treatment of RA.

Rheumatoid arthritis is a debilitating autoimmune disease in which the lining of the joints becomes inflamed causing irreversible joint damage and destruction. Patients experience pain, stiffness, swelling and ultimately loss of mobility.

“These data show the progression of patients’ joint damage is substantially reduced over the one year period. Furthermore, the important role of IL-6 blockade is highlighted by the clinical benefits experienced in this Actemra monotherapy study. Following these impressive results, we look forward to the outcome of the large phase III programmes currently being run in Europe and the US with Actemra in combination with other anti-rheumatic drugs,” commented Dr. Eduard Holdener, Head of Global Pharma Development, Roche.

Impressive results achieved with Actemra in patients with early, aggressive disease

Of the 302 patients evaluated in this monotherapy study, patients in the Actemra arm showed significantly less radiographic joint destruction compared to patients in the DMARDs control group as measured by change in total Sharp score (2.3 ± 5.6 vs 6.1 ± 11.4; p=0.001).

Furthermore, Actemra was superior to DMARDs in preventing both erosion and joint space narrowing. Disease Activity Scores (DAS) were 6.9 and 6.8 at baseline, Actemra and DMARDs control groups respectively, indicating very active disease. Following one year of treatment, DAS in the Actemra arm fell to 2.5 and to 5.7 in the DMARDs control group. ACR2 response rates in the Actemra arm were significantly higher than those in the DMARDs control arm: percentages of Actemra patients achieving ACR20, 50 and 70 were 89%, 70% and 47% respectively compared to 35%, 14% and 6% respectively in the DMARDs group. Results of this magnitude have not been previously achieved in rheumatoid arthritis patients who have early aggressive disease.

Actemra generally well tolerated

The overall incidence of adverse events including laboratory abnormalities was 96% and 87% in the Actemra and DMARDs control arms respectively. While lipid increases were reported in the Actemra group, the mean cholesterol level stabilized around the upper limit of normal. No tuberculosis was observed and Actemra monotherapy was generally well tolerated.

Editor’s Notes

About the study

This phase III clinical trial is a randomized trial in which 306 patients with active early rheumatoid arthritis of < 5 years’ duration were allocated to receive either Actemra as a monotherapy at 8 mg/kg I.V. every 4 weeks or conventional DMARDs for 52 weeks. In the control group, the dose, type and combination of DMARDs could be varied according to disease activity, but anti-TNF agents and leflunomide were not permitted. The efficacy endpoints included change from baseline to week 52 in van der Heijde modified Sharp score, evaluated in blinded manner, and ACR response rates.

About Actemra

Actemra is a first-in-class humanized anti-IL-6 receptor monoclonal antibody whose novel mechanism of action may provide a new and effective form of treatment for adult RA. Phase II studies have been completed in Japan and Europe. Collaborative phase III clinical development in RA has been completed by Chugai in Japan and is underway outside Japan with more than 4000 patients expected to be enrolled in over 20 countries including several European countries and the USA.

Roche and Chugai are developing Actemra in collaboration with Osaka University. This co-development partnership was set up under the first licensing agreement between the two companies in 2003, where Roche was granted the right to promote in all countries except Japan, South Korea and Taiwan, and the parties would co-promote in the UK, France and Germany.

About rheumatoid arthritis

Rheumatoid arthritis is a progressive, systemic autoimmune disease characterized by inflammation of the membrane lining in joints. This inflammation causes a loss of joint shape and function, resulting in pain, stiffness and swelling, ultimately leading to irreversible joint destruction and disability. Characteristics of RA include redness, swelling, pain, and movement limitation around joints of the hands, feet, elbows, knees and neck. In more severe cases of RA the eyes, lungs or blood vessels may be involved. RA may also shorten life expectancy by affecting major organ systems and after 10 years, less than 50% of patients can continue to work or function normally on a day to day basis. RA is one of the most common forms of autoimmune disease and affects more than 21 million people worldwide.

About Roche

Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As a supplier of innovative products and services for the early detection, prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is a world leader in diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2004 sales by the Pharmaceuticals Division totalled 21.7 billion Swiss francs, while the Diagnostics Division posted sales of 7.8 billion Swiss francs. Roche employs roughly 65,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai. Additional information about the Roche Group is available on the Internet (www.roche.com).

Is your RA becoming a pain - literally? Has rheumatoid arthritis taken control of your life? If so, self-management of RA could give you your life back. Based on research by the Missouri Arthritis Rehabilitation Research and Training Center at the University of Missouri-Columbia, this research evaluation of a proven self-management program seeks to empower people with RA via the Internet.

Pain and stress reduction, interpersonal relationships, and fatigue are just a few of the important issues that RAHelp.org will address in this activity. Arthritis health professionals provide instruction and personalized one-on-one support in addition to online discussions with other people who have arthritis. This program and research study is done entirely on the web, no in person visits are needed.

The American Medical Women’s Association (AMWA) today issued physician recommendations to generate greater understanding of the role of vitamin D in bone health in women and men over 50, calling for an increase in currently recommended vitamin D intake and encouraging individualized treatment in patients.

According to an analysis published in 2004 and based on the Third National Health and Nutrition Examination Survey (NHANES III), over 70 percent of women ages 51-70 and nearly 90 percent of women over 70 are not getting the recommended adequate intake of vitamin D.

For this reason, AMWA recently convened a panel of experts to discuss the importance of vitamin D for overall bone health, the challenges of ensuring adequate vitamin D intake and how to best communicate this information to primary care physicians, specialists and patients. Vitamin D, an essential component in bone health, helps ensure that the body absorbs and retains calcium, which is critical for building strong, healthy bones. Vitamin D deficiency has often been linked to osteoporosis, a condition that affects more than 10 million Americans and threatens 34 million others.

“We agreed that there is a need for increased awareness of the role of vitamin D in osteoporosis treatment,” said Felicia Cosman, MD, clinical director of the National Osteoporosis Foundation and associate professor of clinical medicine at Columbia University School of Medicine, and chair of the expert panel. “These recommendations will serve to call attention to the high prevalence of vitamin D deficiency and help ensure that patients, particularly women and men over 50, receive optimal care for bone health.”

The panel outlined the following action points regarding vitamin D and its role in bone health for physicians treating women and men over 50, including:

* Optimum treatment for bone health should be individualized and may include a combination of exercise, healthy diet, vitamin D and calcium supplements, and potentially, prescription medications.

* Women and men over 50 receiving treatment for osteoporosis need to receive adequate vitamin D. Supplements are recommended as one of the best sources of vitamin D.

* Current daily vitamin D intake requirements for women and men over 50 should be increased to 800-1,000 International Units (IU).

An Increase in Current Vitamin D Intake

Current recommendations from the Institute of Medicine (IOM) for vitamin D intake are 400 IU for women and men ages 51-70 and 600 IU for women and men over 70. The roundtable panelists expressed concern that current recommendations do not provide for optimal bone health and recommended that intake levels be increased to 800-1,000 IU per day for patients over age 50.

In addition to the government data that found 70-90 percent of postmenopausal women are not taking the recommended adequate intake of vitamin D, an additional study found that over half of postmenopausal women already being treated for osteoporosis have inadequate levels of vitamin D, underscoring the need for more aggressive treatment guidelines and greater overall awareness of the role of vitamin D in bone health.

“The recommendations we provided are designed as a guide for primary care physicians and specialists and are sufficient for most patients. However, some patients may need to obtain serum levels of vitamin D, as determined by their physician, to ascertain vitamin D adequacy. Vitamin D deficiency should ultimately be treated on a patient-by-patient basis,” said Kimberly Templeton, MD, AMWA representative and associate professor of orthopedic surgery at the Kansas University Medical Center and fellow of the American Academy of Orthopaedic Surgeons (AAOS). “I encourage people to speak to their physicians about whether vitamin D supplementation may be appropriate. In addition, patients can access an online brochure on the AMWA web site to learn more about the role of vitamin D in overall bone health.”

Obtaining Adequate Levels of Vitamin D

Vitamin D is produced in the body after exposure to UVB rays. Indeed, individuals can obtain over 90 percent of vitamin D through sun exposure, but the panel agreed that this is becoming increasingly difficult as a result of the wide use of sunscreen and protective clothing, due to concerns about skin cancer and other skin diseases, aging and geographic limitations.

Vitamin D is also found naturally in a limited number of foods, such as fatty fish, and in certain fortified foods such as milk, orange juice and ready-to-eat cereal. However, many of these foods are not part of most people’s diets or must be consumed in large volumes to meet the requirement. Therefore, supplements were recommended as one of the best sources of vitamin D for many older Americans.

In using supplements, the panel advised that physicians should help their patients choose the supplement that is right for them by explaining the medical terms associated with the different forms of vitamin D.

Although bone health was the primary focus of the recommendations, the panelists also reviewed other research studies published in the recent months that reflect on vitamin D’s ability to potentially protect against lymphoma and cancers of the prostate, breast, colon, ovary and other cancers, and noted that a variety of research is currently underway to examine the effects of vitamin D on other health conditions.

The Fundamentals of Vitamin D in Bone Health

Vitamin D plays an important role in building and maintaining healthy bones by promoting calcium absorption. Suboptimal levels of vitamin D are associated with reduced calcium absorption, bone loss and an increased risk for osteoporosis — a condition characterized by low bone mass, bone fragility and susceptibility to fractures, especially of the hip and spine.

In fact, the first-ever Bone Health and Osteoporosis: A Report of the Surgeon General (2004) listed vitamin D, along with calcium and physical activity, as the three key elements to maintaining optimal bone health. Based on relevant clinical practice experience and involvement in various research that highlights the role of vitamin D in bone health, the panel concluded that it is of paramount importance that vitamin D be considered in patients being treated for osteoporosis and other bone diseases.

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes.

Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3.

The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells.

An inflamed injury may increase levels of a protein responsible for persistent pain, causing the brain to mimic pain long after source has disappeared, says U of T researchers. The findings could have serious implications for the millions of Canadians who suffer from chronic pain.

The study, published in the current issue of the Journal of Neuroscience, shows how inflammation in mice increases NR2B proteins – proteins that facilitate nerve cell communication – and imprint a painful response in brain even after the stimulus is removed. “What we’re interested in uncovering are the molecular mechanisms that can turn early pain into persistent pain,” says Professor Min Zhuo of physiology, EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health and lead author of the study. “We believe that the body’s inflammatory response helps to etch the initial pain into our memory.”

Normally when a mouse or a person experiences a painful event, receptors in the injury site send an electrical impulse up the spine and to the brain. The signal triggers receptors called glutamate AMPA and kainate, which flare up initially but do not directly alter the physiology of the cells. When the painful event also triggers inflammation, the nerves send extra information to the normally dormant NR2B receptors – receptors that receive messages and then produce physiological effects in the cell.

In the study, researchers injected a chemical irritant into the hind paws of mice, causing inflammation. They then tracked brain activity in the anterior cingulate cortex (ACC) – a region of the brain associated with pain and other functions such as decision-making and emotion. In tests performed one hour, six hours and one day after injection, they found that NR2B protein levels had increased over time. Previous research had already established a link between the protein and chronic pain. In an earlier study, Zhuo demonstrated that mice initially genetically enhanced with NR2B to boost memory and learning abilities also became acutely aware of minor pain for long periods of time. “Persistent pain caused by injury, learning and memory share the same common molecular mechanisms,” Zhuo says. “By identifying these mechanisms we can greatly facilitate the treatment of chronic pain.”

Zhuo hopes the findings will one day be used to create therapeutic solutions to conditions such as allodynia – a condition where even a gentle touch produces pain. Currently, pain-blocking drugs also target other brain activity – not just NR2B receptors – and can also block acute pain that acts as a body’s warning system.

“It’s essential that therapies don’t block the body’s entire pain system as pain often plays a valuable role,” Zhuo says. “For instance, acute and immediate pain often tells us to remove ourselves from harm such as accidentally touching a hot plate. The key is to find a way to develop drugs that target only persistent pain thereby improving the patient’s quality of living.”

The research was funded by the Canadian Institutes of Health Research, the National Institutes of Health, the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, and the Canada Research Chair program.

Taking a stand against cold and flu season for you and your family is easier than you think. Woodson Merrell, MD, explains how to break the sickness cycle by taking protective measures and boosting immunity.

Dr. Merrell attacks the problem with an integrative medical tool kit. “I’m a pragmatist,” he explains, “which is why I incorporate the best of Western scientific medicine and the best of complementary therapies. Even if you get a flu shot, you’re still at risk for colds and flu. However, everyone can add a few smart preventive measures to their routine and strengthen their natural immunity.” Here are Dr. Merrell’s tips and tricks for staying healthy through cold and flu season:

1. We all know the importance of hand washing in reducing the transmission of cold and flu germs. But did you know that most children do not wash their hands long enough to have a significant impact? Teach your children to recite a nursery rhyme while lathering their hands, rinsing at the completion of the poem. This technique can triple or quadruple the amount of time their hands are exposed to soap and friction — the two methods that remove the most germs from the skin.

2. When serving snacks, beware the communal snack bowl. Children (who may or may not have washed their hands first) like to touch, and may pick up three cookies before making a final selection. Better to use separate bowls, or single serving sizes.

3. Wait wisely. During peak outbreaks of viral illnesses, you might want to reconsider turning the little one loose in a children’s waiting area. These areas have tempting child-sized tables and chairs, brightly colored toys and books, which are used by many children with varying degrees of hygiene in the course of a day.

4. If you or your child is ill, be a hero and stay home. Not only is this the most effective way to protect others from your illness, you are more likely to rest and drink fluids in an unstructured home environment vs. the more rigid schedules of school and workplace. Consider canceling play dates with children who are coming down with colds.

5. After recovering from a cold or flu, treat yourself to a new toothbrush. Your old brush might still be “sick.”

6. Wash children’s scarves and mittens frequently and in hot water. Little hands in mittens wipe noses, play with outdoor toys and wrestle with playmates while scarves pick up germs from the mouth.

7. Try tea. Tea contains antioxidants and polyphenols that can boost the immune system. Substituting iced tea (decaffeinated for young ones) for soft drinks is a healthy choice anytime, but especially during cold and flu season. Choose unsweetened or lightly sweetened, which contain far less sugar than soft drinks.

8. Nutritionists tell us, and evidence has proven, the many health benefits of eating fruits and vegetables, but we know how picky children can be. Eat six daily servings of vitamin-rich dark leafy greens, yellow-orange, and red fruits and vegetables (organic is best). Use vegetables (broccoli) and fruits high in Vitamin C — experiment with banana, papaya or strawberry smoothies that young taste buds will love.

9. Some herbals work: Despite a recent report questioning the effectiveness of echinacea, there is evidence that some echinacea preparations actually work. Esberitox is a tasty, chewable product that combines two types of echinacea with the herbs baptisia and thuja, and has been clinically proven to reduce the duration and severity of colds by 50 percent. “If I only had one Western remedy to recommend during cold and flu season, I would choose Esberitox,” comments Dr. Merrell. “This herbal formula is the only one that my own children will take without a fuss because it tastes good — they even ask for it.”

10. For older kids with sore throats, gargle with disinfectant solutions, such as Listerine, tea tree oil or diluted hydrogen peroxide (the latter is not safe for young children who may swallow it).

11. Touching your eyes when inserting and removing contacts is another route for viruses to enter the body. During cold and flu season wear your glasses instead of contact lenses.

12. How sweet it isn’t: Avoid excessive amounts of sugar during cold and flu season as sugar can weaken your immune system.

13. Try some mushrooms: Many species of mushroom naturally contain substances that boost the immune system — especially maitake, reishi, and shitake — and are easy to add to your menu.

14. Garlic is good: Raw garlic has more potent immune activity than cooked, but isn’t very pleasant to eat on its own. One great trick is to crush or chop a few cloves of garlic and add them to your prepared salad dressing. Shake well before pouring so that a little garlic is contained in every serving.

15. Ease up on coffee, power-up on sleep. A caffeine buzz can rob you of precious sleep, your body’s strongest repair mechanism. Avoid late nights during flu season and take extra rest if you’re in healing mode. The maxim “early to bed early to rise makes a man healthy, wealthy and wise” is never more important than during cold/flu season.

16. Stress and anxiety boost your body’s adrenal hormone level of cortisol, which can depress the immune system. In case of a stressful event — new job, relocation, divorce, etc. — take care. Get a good night’s sleep, eat a healthy diet, allow your friends and family to pamper you, or at least, pamper yourself, and try to engage in pleasurable activities. Yoga, music, or petting a dog or cat can reduce stress in your life. Find what works for you.

17. For cold and flu prevention and treatment, consult integrative practitioners — doctors who have additional experience with mind-body practices, acupuncture, nutrition and dietary supplements, homeopathy, etc. They may have other options that may be right for you and your family. You may want to schedule a wellness visit before cold and flu season hits to develop a strong health plan for your family.