Rheumatoid arthritis (part 1): general Information

Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation among joints, tissues around the joints and internal organs. Autoimmune diseases occur when body tissues are mistakenly attacked by its own immune system.
The immune system is a complex of cells and antibodies designed normally to "seek and destroy" invaders of the body, particularly infections.
Patients with autoimmune diseases have antibodies in their blood that attack their own body tissues; they can be associated with inflammation. Because it can affect other organs, rheumatoid arthritis refers to a systemic illness and is sometimes called rheumatoid disease.
When rheumatoid arthritis a chronic, which means it can take years, patients may experience a long period of time with no symptoms. Typically, rheumatoid arthritis is a progressive disease that has the ability to destroy joints.
A joint is where two bones meet to allow movement of body parts. Arthritis means joint inflammation. Joint inflammation of rheumatoid arthritis causes swelling, pain, stiffness and redness. Inflammation of rheumatoid disease can also occur in tissues around the joints, such as tendons, ligaments and muscles.
In some patients with rheumatoid arthritis, chronic inflammation leads to destruction of cartilage, bone and ligaments causing deformity of joints. Studies have shown that progressive damage to the joints does not necessarily correlate with pain, stiffness or swelling in joints.
Rheumatoid arthritis is a rheumatic disease three times more common among men than women. The condition can be triggered at any age but often occurs in people who have passed the age of 60 years.
The causes that trigger this disease are not yet known. Although infectious agents, such as viruses, bacteria and fungi have been suspected as possible causes, this assumption proved to be false. Some researchers believe that infections or environmental factors may result that immune system to attack the body tissues, resulting in inflammation among several organs of the body, such as eyes and lungs.
Whatever the cause, the result is the same: an immune system that allows joint inflammation and swelling occasionally. Surrounding factors seem to play a role in causing rheumatoid arthritis. Recently, scientists reported that smoking increases the risk of developing the disease.
Degree of joint destruction of rheumatoid arthritis varies according to each patient. Patients suffering from a mild form of rheumatoid arthritis, occur after several years of activity, can be treated with anti-inflammatory drugs and some rest. In general, joint function are improved when the patient is treated early, with slow-acting drugs.

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Amputation results from diabetes

Mr. B, age 46 years, was a physician assistant who had worked for the same internist for 10 years. He and Dr. K had an excellent relationship. Their office was in an area with a high prevalence of diabetes, and many of their patients lived with the disease. Both practitioners had an interest in conducting public outreach about the condition.
Mr. B often conducted seminars and lectures in the local pharmacy, adult education classes, and the senior center in town. His lectures covered such topics as metabolic syndrome, coping with newly diagnosed diabetes, foot and skin care for people with diabetes, and understanding medications. He also discussed lifestyle modifications that could improve health, the connection between diabetes and cardiovascular disease, and how to properly monitor blood glucose. These seminars were generally well attended, and a number of people asked interesting and sometimes challenging questions. Mr. B found this community service to be very personally rewarding, and Dr. K was supportive of his endeavors.
Both Mr. B and Dr. K brought this educational attitude into the clinic as well. They stressed the value of empowering patients by helping them understand their conditions. Both practitioners found this strategy effective, although there were always some patients that just couldn't be reached in this manner.
One such patient was Mr. X, a 64-year-old African American who had been a patient for close to 15 years. Mr. X had diabetes, and despite numerous attempts to educate him on the importance of lifestyle modifications, medication compliance, and regular checkups, he was generally noncompliant and mostly disinterested. Not surprisingly, his diabetes was not well controlled. Both practitioners had tried unsuccessfully to convey the importance of controlling his blood glucose, but Mr. X seemed less interested in managing the diabetes and staying healthy than he did in waiting until there was a problem and then coming in for a “quick fix.”

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Once-monthly treatment for arthritis

Product: Actemra
 
Company: Genentech 

Pharmacologic class: Interleukin-6 (IL-6) receptor inhibitor 


Active ingredient: Tocilizumab 20 mg/mL; solution for IV infusion after dilution; preservative-free. 


Indication: Moderately to severely active rheumatoid arthritis (RA) in patients who have had an inadequate response to one or more tumor necrosis factor (TNF) blockers. May be used with methotrexate or disease modifying antirheumatic drugs (DMARDs). 

 
Pharmacology: IL-6 is produced by monocytes and lymphocytes in the bloodstream and by synovial and endothelial cells in the joints, leading to systemic and local production of IL-6 in patients affected by inflammatory processes such as RA. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors and has been shown to inhibit IL-6-mediated signaling through these receptors. 


Clinical trials: The efficacy and safety of tocilizumab was assessed in five randomized, double-blind studies in patients >18 years with active RA. Tocilizumab was given every four weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other DMARDs (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). The primary endpoint was the proportion of patients who achieved an American College of Rheumatology (ACR) 20 response at Week 24. In all studies, patients treated with tocilizumab 8 mg/kg had statistically significant ACR20, ACR50, and ACR70 response rates versus MTX- or placebo-treated patients at Week 24. Patients with inadequate response to DMARDs or TNF antagonist therapy treated with tocilizumab 4 mg/kg had lower response rates compared with patients treated with tocilizumab 8 mg/kg. 


Adults: Give once every four weeks as a 60-minute IV infusion. Initially 4 mg/kg, may increase to 8 mg/kg based on clinical response. Do not start if absolute neutrophil count (ANC) <2,000/mm3, platelets <100,000/mm3, or alanine transaminase/aspartate transaminase (ALT/AST) >1.5 upper limit of normal (ULN). Reduce dose to 4 mg/kg if elevated liver enzymes, neutropenia, or thrombocytopenia occur (see literature). 


Children: Not recommended. 


Precautions: ANC <500 mm3, platelets <50,000 mm3, or ALT/AST >5 ULN: not recommended. Monitor neutrophils, platelets, liver function tests every four to eight weeks. Active hepatic disease or impairment: not recommended. Hepatitis B or C virus or infection. Increased risk of serious or fatal infections (e.g., TB, bacterial sepsis, invasive fungal). Active infections: do not give therapy. Chronic or history of recurring or opportunistic infections. Conditions that predispose to infection. Travel to, or residence in, areas with endemic TB or mycoses. Test for and treat latent TB prior to starting therapy. Monitor closely if new infection develops; discontinue if serious or opportunistic infection or sepsis develops. Monitor lipids four to eight weeks after initiation, then every six months. Immunosuppression. Central nervous system demyelinating disorders. Malignancies. Elderly. Pregnancy (Cat. C). Nursing mothers: not recommended. 


Interactions: Increased risk for infection with concomitant immunosuppressants (e.g., TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies, selective co-stimulation modulators). Avoid live vaccines. Caution with CYP3A4 substrate drugs (e.g., oral contraceptives, lovastatin, atorvastatin). Monitor warfarin, cyclosporine, theophylline, other drugs that are CYP450 substrates with narrow therapeutic indices. 


Adverse reactions: Upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT; infusion reactions, neutropenia, thrombocytopenia, gastrointestinal perforations, increased lipids. 


Containment: Single-use vials (80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL)—1, 4


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Role Of Gene That Causes Early Onset Alzheimer's Revealed

Researchers in the US have discovered how mutations in the presenilin 1 gene that causes early onset familial Alzheimer's Disease disrupt an essential process for recycling protein, thus allowing toxins to build up and kill brain cells. They hope their discovery will spur new treatments for both the early onset and the more common late onset form of Alzheimer's, a brain-wasting disease that affects millions of people worldwide.

A report of the study, led by Dr Ralph Nixon, professor in the Departments of Psychiatry and Cell Biology at New York University's (NYU's) Langone Medical Center, appears in the 10 June online issue of the journal Cell.

15 years ago, scientists discovered that the presenilin gene was commonly associated with the early onset familial form of Alzheimer's, which can strike people in the 30s, but little was known about how it worked until this study, when Nixon and colleagues found that presenilin 1 plays a key role in "macroautophagy", a process that digests and recycles unwanted proteins and is essential for neuron survival.

Nixon, who is also director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research, and director of the Center of Excellence on Brain Aging and the Silberstein Alzheimer's Institute at Langone, told the press that:

"In mouse models of Alzheimer's disease and in skin cells of patients with Alzheimer's disease caused by presenilin mutations, we observed that the ability to break down and reuse normal proteins and to remove potentially toxic damaged proteins and organelles is severely impaired."

He said this disruption kills nerve cells, whose loss does not appear to depend on the plaque build up of beta amyloid protein that is normally found in the brains of patients.

"Most of the drug development for Alzheimer's has been focused on removing amyloid from the brain," explained Nixon, who said their findings strongly suggest there are alternative target pathways:

"For example, therapies could be aimed at repairing the cellular mechanism that eliminates toxic proteins before they damage the brain," he added.

Ongoing observations at the Nathan Kline Institute suggest a similar disruption of cellular protein recycling occurs in late onset Alzheimer's, said Nixon, suggesting that other factors could also be involved.

So far, scientists have discovered over 160 rare mutations of presenilin 1 and two other genes cause the early onset familial form of Alzheimer's, but have only found a few genes linked to the late onset form.

Nixon said there were currently no treatments to slow or prevent the progression of Alzheimer's and he urged us to regard the disease as "multi-factorial and to approach the treatment from that perspective".

"Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations."
Ju-Hyun Lee, W. Haung Yu, Asok Kumar, Sooyeon Lee, Panaiyur S. Mohan, Corrinne M. Peterhoff, Devin M. Wolfe, Marta Martinez-Vicente, Ashish C. Massey, Guy Sovak, Yasuo Uchiyama, David Westaway, Ana Maria Cuervo, Ralph A. Nixon.
Cell, 10 June 2010
DOI:10.1016/j.cell.2010.05.008

Source: NYU.

Written by: Catharine Paddock, PhD

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Choline reduces Down syndrome dysfunction, guard against dementia

Barbara Strupp, professor of nutritional sciences and of psychology. (Credit: Alexi Wenski-Roberts)

ScienceDaily (2010-06-03) More choline during pregnancy and nursing could provide lasting cognitive and emotional benefits to people with Down syndrome. The work indicated greater maternal levels of the essential nutrient also could protect against neurodegenerative conditions such as Alzheimer's disease.

The findings, published June 2 in Behavioral Neuroscience, could help lead to increasing the maternal dietary recommendations for choline (currently 450 milligrams a day during pregnancy, 550 milligrams for lactation), a nutrient found in egg yolks, liver, nuts and such vegetables as broccoli and cauliflower. "We found that supplementing the maternal diet with additional choline resulted in dramatic improvements in attention and some normalization of emotion regulation in a mouse model of Down syndrome," said lead author Barbara Strupp, professor of nutritional sciences and of psychology. The researchers also found evidence for "subtle, but statistically significant, improvement in learning ability in the non-Down syndrome littermates." In addition to mental retardation, Down syndrome individuals often experience dementia in middle age as a result of brain neuron atrophy similar to that suffered by people with Alzheimer's disease. Strupp noted that the improved mental abilities found in the Down syndrome mice following maternal choline supplements could indicate protection from such neurodegeneration "in the population at large." Strupp and her co-authors tested Down syndrome model mice born from mothers fed a normal diet and those given choline supplements during their three-week pregnancy and three-week lactation period, as well as normal mice born from mothers with and without additional choline. The choline-supplemented mothers received approximately 4.5 times more choline (roughly comparable to levels at the higher range of human intake) than unsupplemented mothers. At six months of age, the mice performed a series of behavioral tasks for about six months to assess their impulsivity, attention span, emotion control and other mental abilities. In addition to dramatic improvements in attention, the researchers found that the unsupplemented Down syndrome model mice became more agitated after a mistake than normal mice, jumping repeatedly and taking longer to initiate the next trial, whereas the choline-supplemented Down syndrome model mice showed partial improvement in these areas. "I'm impressed by the magnitude of the cognitive benefits seen in the Down syndrome model mice," Strupp said. "Moreover, these are clearly lasting cognitive improvements, seen many months after the period of choline supplementation." Strupp noted that the results are consistent with studies by other researchers that found increased maternal choline intake improves offspring cognitive abilities in rats. However, this is the first study to evaluate the effects of maternal choline supplementation in a rodent model of Down syndrome. This is also one of the few studies that has evaluated offspring attentional function and effects in mice, rather than rats, Strupp noted. Previous studies of humans and laboratory animals have shown that supplementing the diets of adults with choline has proven to be largely ineffective in improving cognition. "Although the precise mechanism is unknown, these lasting beneficial effects of choline observed in the present study are likely to be limited to increased intake during very early development," Strupp said. The study, funded in part by the National Institutes of Health (NIH), was part of the dissertation of Jisook Moon, Ph.D. '06. Other Cornell collaborators included Myla Strawderman, research associate in nutritional sciences; David Levitsky, professor of nutrition and of psychology; May Chen '07 and Shruti Gandhy '07. Strupp and collaborators have received additional NIH funding to study the neural mechanisms underlying the positive cognitive effects of perinatal choline supplementation observed in this study.

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Brush teeth to 'prevent' heart disease

People who fail to brush their teeth twice a day are putting themselves at risk of heart disease, research suggests.

The Scottish study of more than 11,000 adults backs previous research linking gum disease with heart problems.

The researchers said more work is needed to confirm if poor oral health directly causes heart disease or is a marker of risk.

A charity added that oral hygiene was just one factor in good heart health.

Data, published in the British Medical Journal was collected on lifestyle behaviours, such as smoking, physical activity and oral health routines.

Participants were also asked how often they visited the dentist and how often they brushed their teeth.

Then nurses collected information on medical history and family history of heart disease, took blood pressure and blood samples.

Overall, six out of 10 people said they visited the dentist every six months and seven out 10 reported brushing their teeth twice a day.

Over the eight-year study there were 555 "cardiovascular events" such as heart attacks, 170 of which were fatal.

Cause and effect

Study leader Professor Richard Watt, from University College London, said future studies will be needed to confirm whether the link between oral health behaviour and cardiovascular disease "is in fact causal or merely a risk marker".

Judy O'Sullivan, senior cardiac nurse at British Heart Foundation, said: "If you don't brush your teeth, your mouth can become infected with bacteria which can cause inflammation.

"However, it is complicated by the fact that poor oral hygiene is often associated with other well known risk factors for heart disease, such as smoking and poor diet."

She added: "Good personal hygiene is a basic element of a healthy lifestyle.

"But if you want to help your heart, you should eat a balanced diet, avoid smoking and take part in regular physical activity."

Professor Damien Walmsley, scientific adviser to the British Dental Association, added it was still unclear whether there was a definite cause and effect between oral hygiene and heart disease.

"Whatever the true position is, we can say with certainty that if people brush teeth twice a day with fluoride toothpaste, visit the dentist regularly and restrict sugary snacks to mealtimes; that this will go a long way towards keeping the teeth and gums in a healthy state for life."

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New hope for better treatment for a rising cancer

Poor diet, too much alcohol, smoking and increasing obesity could be leading to an epidemic of oesophageal and upper stomach cancer, according to a leading UK team of specialists at The University of Nottingham and Nottingham University Hospitals.

The Nottingham Gastro-Oesophageal Cancer Research Group has been carrying out intensive research over the past five years to try to improve the treatment of this cancer. A major part of the research is published today in the British Journal of Cancer. The work has been prompted by a large increase in the incidence of cancer of the oesophagus (gullet) and upper stomach over the past 40 years.

According to Cancer Research UK statistics, rates of oesophageal adenocarcinoma and gastro-oesophageal (GOJ) adenocarcinoma have been increasing in the UK. Since the 1970s the incidence of this cancer has increased by 50 per cent in men and 20 per cent in women. Indeed the reported rates for white men in the UK are now the highest in the world.

Doctors believe changes in diet and lifestyle are the key factors behind the rapid rise in the number of cases. This new research is aimed at providing a better treatment and prognosis for a cancer that is historically not survivable past five years from diagnosis. Current standard treatment for potentially operable cancer consists of a 12 week intensive course of powerful chemotherapy, followed by surgery if the tumour is operable, and then a second 12 week course of chemotherapy. This prolonged, intense course of chemotherapy treatment is potentially toxic, impacts on quality of life and is likely to be beneficial only in those patients who respond to chemotherapy.

The Nottingham-based research using molecular cancer pathology and DNA protein expression techniques on tumour samples from around 250 patients after surgery has shown that only between 40 per cent and 50 per cent of these adenocarcinomas actually respond to the chemotherapy. The research has effectively tested a very promising monitoring test during treatment so that doctors can assess whether and how far the tumour is regressing during chemotherapy. In addition, the research has also identified a promising protein marker involved in DNA repair in cancer cells that predicts resistance to chemotherapy in tumours.

The new information could empower doctors to decide whether to recommend a second course of powerful chemotherapy after surgery. The research also paves the way for wider and more specialised clinical trials for this cancer which will monitor patients in real-time, rather than using past samples, and which could lead to new combinations of chemotherapy, including the new breast cancer drug, Herceptin, which has recently been proven to be effective in gastro-oesophageal cancers.

Dr Srinivasan Madhusudan, Clinical Associate Professor & Consultant in Medical Oncology at Nottingham University Hospitals and the University’s School of Molecular Medical Sciences, said: “Recent scientific advances have given real hope for patients with gastro-oesophageal cancers. The Nottingham Upper Gastrointestinal Cancer Group is a multidisciplinary research team consisting of Oncologists, Surgeons, Pathologists and Radiologists. We aim to exploit the ‘new science’ for patient benefit. This study published online today in the British Journal of Cancer provides evidence that it may be possible to tailor gastro-oesophageal cancer treatments based on ‘new’ biology. We are planning a larger prospective multicentre study to confirm these findings and we believe will have major clinical impact on how we treat these aggressive tumours in the future.”

Source:http://communications.nottingham.ac.uk/News/

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