Medical Research Blog

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases, and one of the least understood. Smoking is the major known environmental risk factor for RA, though little is known about the mechanisms involved. HLA-DR shared epitope (SE) genes are a widely recognized genetic risk factor for RA, though little is known about how these genes affect autoimmune reactions that lead to chronic inflammation and progressive joint and organ damage.

To better understand the interactions between smoking and HLA-DR SE genes in RA, a team of researchers in Sweden focused on the disease’s distinctive autoimmune hallmark: citrulline, an amino acid not normally present in protein. While extremely rare in healthy individuals and relatively rare in other inflammatory conditions, citrulline-modified proteins are common in about two-thirds of RA patients and may be an underlying factor in the development of the disease. To investigate whether smoking and SE genes trigger immune reactions to citrullinated proteins, the team conducted a case-control study involving patients with recent-onset RA. The results, featured in the January 2006 issue of Arthritis & Rheumatism, suggest that smokers with SE genes are more susceptible to anticitrulline antibody-positive RA.

The study’s 930 early RA patients, drawn from the Epidemiological Investigation of Rheumatoid Arthritis Study Group, ranged in age from 18 to 70 years. 383 healthy controls, drawn from the blood bank of northern Sweden, were matched for age, gender, and residential area. All participants completed questionnaires about their past and present smoking habits, as well as genotyping profiles. In addition, bronchial fluid was obtained from a representative sample of RA patients, including both current heavy smokers and lifelong non-smokers, and tested with immunostaining for the presence of citrullinated protein in cells.

Based on their series of experiments and comparisons, the researchers found that a history of smoking increases the risk for RA, but only for individuals who test positive for anticitrulline antibodies, regardless of the presence of SE genes. Similarly, inheriting HLA-DR SE genes in a single copy, as well as in double copies, increases the risk for RA, but only for individuals who test positive for anticitrulline antibodies, including individuals who have never smoked. Yet, for individuals who test positive for anticitrulline antibodies, the interaction of smoking and carrying 2 copies of the SE gene dramatically increases the risk for developing RA–by 21 times.

A promising new therapy pioneered by University of Kentucky gastroenterology specialists may offer improved lives to patients suffering from moderate to severe forms of the disease.

Ulcerative colitis causes inflammation and ulcers in the colon, leading to abdominal pain and such frequent trips to the bathroom that normal routines can be disrupted. Finding the right treatment can be difficult, with therapies that may include steroids and anti-inflammatory drugs, or possibly surgery in as many as 25 to 40 percent of ulcerative colitis patients.

A drug already used for other inflammatory diseases, including Crohn’s and rheumatoid arthritis, has received FDA approval for treatment of ulcerative colitis after performing well in clinical trials. UK was a primary investigator of infliximab, brand name Remicade®, and enrolled the largest study group in North America.

The medication is administered intravenously, with an initial regimen of three doses of infliximab, followed by maintenance infusions every eight weeks. Nearly 70 percent of patients receiving the drug experienced clinical response and remission early in the trial, and nearly all had significant results after one year of therapy.

Although cystic fibrosis patients in clinical trials had more severe illness, worse lung function, a lower weight level and more respiratory infection than non-participants, their involvement in research studies resulted in less lung function decline over a 7-year period.

The research results appeared in the first issue for January 2006 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Christopher H. Goss, M.D., M.Sc., of the Departments of Medicine and Pediatrics at the University of Washington Medical Center in Seattle, along with three associates, looked at data from 13,041 patients in the Cystic Fibrosis Foundation Registry between 1992 and 1998.

Despite their worse clinical status at the beginning of the study, participants’ lung function declined at 1.33 percent per year, as compared with 1.52 percent for non-participants.

Of the 8,375 patients followed for the entire 7-year study period, 2,635 individuals (30.2 percent) were enrolled in at least 1 of 32 Institutional Review Board clinical trials.

“Subjects who were involved in clinical trials were more likely to be older, have commercial health insurance, be white, be colonized with a bacterial infection like Pseudomonas aeruginosa, have worse lung function and have more office visits,” said Dr. Goss.

Cystic fibrosis (CF), one of the most common inherited life-shortening illnesses, is characterized by the production of thick, sticky mucus that eventually blocks the small airways, leading to inflammation and infection. Mucus also affects the pancreatic ducts, preventing normal digestion and weight gain. Respiratory failure is the primary cause of early death. CF incidence runs from 1 in 2,000 to 1 in 3,200 live births.

According to the authors, access to better health care through more office visits appeared to be the reason explaining less lung function decline for clinical trial participants.

“Given that there may be potential benefits to study participation, CF clinicians need to ensure adequate opportunities for participation in studies for all eligible subjects,” said Dr. Goss.

He added that the persons most likely to participate in the study were those without a high school education who worked full-time.

According to the authors, this CF study was the first to compare clinical trial participants against a majority in a disease category within a specific country.

Taking 1,000 international units (IU) of vitamin D3 daily appears to lower an individual’s risk of developing certain cancers – including colon, breast, and ovarian cancer – by up to 50 percent, according to cancer prevention specialists at the Moores Cancer Center at the University of California, San Diego (UCSD) Medical Center. The researchers call for prompt public health action to increase intake of vitamin D3 as an inexpensive tool for prevention of diseases that claim millions of lives each year.

The paper, to be published on-line December 27, 2005 and printed in the February 2006 issue of The American Journal of Public Health, associates the same risks to breast and ovarian cancers, and underscores the researchers’ call to action.

“For example, breast cancer will strike one in eight American women in their lifetime. Early detection using mammography reduces mortality rates by approximately 20 percent. But use of vitamin D might prevent this cancer in the first place,” said co-author Cedric F. Garland, a professor with UCSD’s Moores Cancer Center and the Department of Family and Preventive Medicine at the UCSD School of Medicine.

In the paper, the authors conclude: “The high prevalence of vitamin D deficiency, combined with the discovery of increased risks of certain types of cancer in those who are deficient, suggest that vitamin D deficiency may account for several thousand premature deaths from colon, breast, ovarian and other cancers annually.”

The study also found that residents of the northeastern United States, and individuals with higher skin pigmentation were at an increased risk of vitamin D deficiency. This is because solar UVB is needed for the human body to make vitamin D. The increased skin pigmentation of African-Americans reduces their ability to synthesize vitamin D.

“African-American women who develop breast cancer are more likely to die from the disease than White women of the same age,” said Garland. “Survival rates are worse among African-Americans for colon, prostate and ovarian cancers as well.” Even after adjustments that removed the effect of socioeconomic status and access to care, blacks were shown to have substantially poorer survival rates, a difference that the authors link with the decreased ability of blacks to make Vitamin D.

The findings are based upon an extensive systematic review of scientific papers on the relationship of blood serum levels or oral intake of vitamin D with risk of certain types of cancers published worldwide between January 1966 and December 2004. Sixty-three observational studies of vitamin D status in relation to cancer risk, including 30 of colon cancer, 13 of breast cancer, 26 of prostate cancer and seven of ovarian cancer, were assessed.

This complex analysis of virtually every observational study written on the subject, called a systematic review, paints a clearer picture than any single study and is recognized by scientists as an important tool for establishing a consensus of findings.

“A preponderance of evidence, from the best observational studies the medical world has to offer, gathered over 25 years, has led to the conclusion that public health action is needed,” Garland said. “Primary prevention of these cancers has largely been neglected, but we now have proof that the incidence of colon, breast, and ovarian cancer can be reduced dramatically by increasing the public’s intake of vitamin D.”

Since the safety of daily intake of vitamin D3 in the recommended range has been thoroughly assessed and confirmed by the National Academy of Sciences, and the benefits found so far in observational studies are considerable, expanded use of vitamin D as a public health measure should not be delayed, according to the authors.

They recommend intake of 1,000 IU/day of vitamin D, half the safe upper intake established by the National Academy of Sciences. Garland said that while this study looked at all forms of vitamin D – intake through diet or supplements, and photosynthesis through modest sun exposure – as a practical matter, the majority of people will most easily achieve the target levels by eating foods containing vitamin D and taking supplements, which the authors estimated would cost about five cents per day.

“Many people are deficient in vitamin D. A glass of milk, for example, has only 100 IU. Other foods, such as orange juice, yogurt and cheese, are now beginning to be fortified, but you have to work fairly hard to reach 1,000 IU a day,” he explained. “Sun exposure has its own concerns and limitations. We recommend no more than 15 minutes of exposure daily over 40 percent of the body, other than the face, which should be protected from the sun. Dark-skinned people, however, may need more exposure to produce adequate amounts of vitamin D, and some fair-skinned people shouldn’t try to get any vitamin D from the sun. The easiest and most reliable way of getting the appropriate amount is from food and a daily supplement.”

A compound isolated from a cyanobacterium, a type of blue-green algae known as Nostoc, shows promise of becoming a natural drug candidate for fighting Alzheimer’s and other neurodegenerative diseases, according to an in vitro study by researchers in Switzerland. It is believed to be the first time that a potent agent against Alzheimer’s has been isolated from cyanobacteria, commonly known as ‘pond scum.’ The study was published in the Dec. 26 issue of the Journal of Natural Products, a monthly peer-reviewed joint publication of the American Chemical Society and the American Society of Pharmacognosy.

Cyanobacteria and other marine natural products have been increasingly found to be a promising source of drug candidates for fighting a variety of human diseases, including cancer and bacterial infections, but their chemistry has been largely unexplored, experts say. Now, a common marine organism could lead to yet another potential health benefit, says study leader Karl Gademann, Ph.D., an organic chemist at the Swiss Federal Institute of Technology (ETH) in Zürich. Gademann’s lab specializes in identifying, synthesizing and studying new bioactive compounds from natural sources.

There is no cure for Alzheimer’s at present, although cholinesterase inhibitors have shown promise for delaying or preventing the symptoms of mild to moderate forms of the disease, experts say. The newly isolated compound, nostocarboline, was shown to be a potent inhibitor of cholinesterase — a brain chemical thought to be important for memory and thinking — whose breakdown has been associated with the disease’s progression. The natural compound’s potency is comparable to galanthamine, a cholinesterase inhibitor already approved for the treatment of Alzheimer’s, the researchers say.

As with any promising structure, it could be many years before the new compound is tested as a drug candidate in humans, the scientists caution.

Howard Hughes Medical Institute researchers have discovered a molecular link between a high-fat, Western-style diet, and the onset of type 2 diabetes. In studies in mice, the scientists showed that a high-fat diet disrupts insulin production, resulting in the classic signs of type 2 diabetes.

In an article published in the December 29, 2005, issue of the journal Cell, the researchers report that knocking out a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a ) disrupts insulin production. Importantly, the scientists showed that a high-fat diet suppresses the activity of GnT-4a and leads to type 2 diabetes due to failure of the pancreatic beta cells.

The experiments point to a mechanistic explanation for why failing pancreatic beta cells don’t sense glucose properly and how that can lead to impaired insulin production, said Jamey Marth, a Howard Hughes Medical Institute investigator at the University of California, San Diego (UCSD). Marth and first author Kazuaki Ohtsubo at UCSD collaborated on the studies with researchers from the Kirin Brewery Co. Ltd., and the University of Fukui, both in Japan.

The discovery of the link between diet and insulin production offers new information that may aid in the development of treatments that target the early stages of type 2 diabetes. In its earliest phases, the disease causes failure of insulin-secreting beta cells in the pancreas, which leads to elevated blood glucose levels. As the disease progresses, the insulin-secreting beta cells overcompensate for the elevated blood glucose, and eventually pump out too much insulin. This leads to insulin resistance and full-blown type 2 diabetes.

The new studies suggest that people with an inherited predisposition to type 2 diabetes might have variations in the gene for GnT-4a, said the researchers. Worldwide, more than 200 million people have type 2 diabetes, and close to 20 million people in the United States have been diagnosed with the disorder.

Marth and his colleagues began their studies hoping to learn more about the function of protein glycosylation in the pancreas. They focused on the function of GnT-4a, in part, because it is highly expressed in the pancreas. GnT-4a is a type of enzyme known as a glycosyltransferase that attaches sugar-like molecules called glycans to proteins in a process called glycosylation. Glycans are essential for the proper function of many proteins.

GnT-4a was known to maintain glucose transporters on the surface of beta cells in the pancreas. Those transporters, such as Glut-2, play a crucial role in allowing the beta cell to sense how much glucose is in the blood. Transport of glucose across the cell membrane into pancreatic beta cells triggers insulin secretion.

The new studies showed that in the absence of sufficient GnT-4a enzyme, Glut-2 lacks an attached glycan that is required for it to be expressed at the cell membrane. Without that glycan, Glut-2 leaves the cell surface and becomes internalized, where it can no longer transport glucose into the cell. In turn, this failure impairs insulin secretion, causing type 2 diabetes in the mice.

“What was really astounding to us, however, was that when we fed normal mice a high-fat diet, we saw this same mechanism of pathogenesis with attenuation of GnT-4a enzyme levels, reduced Glut-2 glycosylation, and loss of cell surface Glut-2 expression,” said Marth. “This finding may explain the loss of Glut-2 commonly observed in type 2 diabetes. For example, transcriptional control of GnT-4a expression may underlie the pathogenesis of type 2 diabetes in human mature onset diabetes of the young (MODY), and perhaps in response to leptin signaling deficiency in db mice.”

In addition, variations in susceptibility to type 2 diabetes may result from inherited differences in the gene for GnT-4a that may ultimately affect its level or activity. These findings could have important clinical implications because reduced GnT-4a expression has been observed by other researchers in tissue samples from humans with diabetes. “If you could somehow stimulate production of this enzyme, you might be able to render animals, and perhaps humans, resistant to high-fat diet-induced diabetes,” said Marth.

To explore such possible clinical applications, Marth and his colleagues are now testing whether over-expression of the GnT-4a gene in transgenic mice makes them resistant to diabetes induced by a high-fat diet or by transcriptional factor mutations that cause MODY.

“If our findings can be applied to humans, they should give us important insights into how type 2 diabetes may be prevented and treated,” he said.

While a deficiency of insulin can cause diabetes, too much insulin can also be harmful, and has been found to contribute to the pathogenesis of cancer, cardiovascular disease, ovarian diseases, and Alzheimer’s disease. “It may be that suppressing insulin production to some degree could be beneficial in such disorders, and that could theoretically be achieved by inhibiting the GnT-4a glycosyltransferase,” Marth said.

A Mayo Clinic study has found patients report less back pain at rest and while active following vertebroplasty, a procedure in which medical cement is injected into painful compression fractures in the spinal vertebrae due to osteoporosis. Patients also reported improved function in their daily activities, such as walking, housework and getting dressed. The findings are published in the November/December issue of American Journal of Neuroradiology, http://www.ajnr.org.

“These findings give us as good evidence as there is — in a study without a group receiving another or no treatment for comparison — that patients are more functional for up to a year after vertebroplasty than before vertebroplasty,” says David Kallmes, M.D., the Mayo Clinic neuroradiologist who led the study.

The investigators conducted the study to assess vertebroplasty with a well-validated questionnaire specifically designed to measure back pain, the Roland-Morris Disability Questionnaire (RDQ). They reviewed records of 113 Mayo Clinic vertebroplasty patients. Of this group, RDQ scores were available for 108 patients before vertebroplasty treatment, and after treatment for 93 patients at one week, 73 patients at one month, 46 patients at six months and 15 patients at one year. Patients’ pain during rest and activity improved an average of seven points one week after treatment and remained improved one year following vertebroplasty. Prior to treatment, the average RDQ score was 18 on a scale of 23. The RDQ dropped to an average score of 11 immediately after treatment and remained at that level throughout the study.

Dr. Kallmes explains that in light of the wide practice of vertebroplasty for vertebral compression fractures, a study using a top-caliber back pain measurement tool like the RDQ was critical, especially in light of the often subjective nature of pain reporting by different patients.

“It’s hard to remember your pain,” he says. “Also, it’s hard to say how bad my pain is compared to your pain. I’ve had patients say their pain is no better after treatment, yet I look at them and they look 10 times better.”

Dr. Kallmes explains that ultimately, vertebroplasty needs evaluation through a study of the highest quality, a clinical trial in which patients are randomly assigned to receive treatment or no treatment and in which the patients and investigators are blinded to which patients receive the real treatment or a placebo used for comparison.

“Vertebroplasty has been promulgated by physicians who performed the procedure without quantifying the benefit,” he says. “Yet, medical literature is rife with studies that have debunked therapies that are already in use.”

Dr. Kallmes is making strides toward high-quality measurement of vertebroplasty. Currently, he is leading an international, multicenter study looking at whether the cement used in vertebroplasty is responsible for the pain relief reported by patients. Patients in this study are randomly assigned to receive treatment with the real cement used in vertebroplasty or a placebo.

Patients for whom vertebroplasty is appropriate, according to Dr. Kallmes, have osteoporosis or a similar condition and have suffered compression of their spines with no or minimal injury. For example, while bending over to tie their shoes or turning over in bed, patients’ vertebrae may fracture because their bones are weakened due to osteoporosis. Each year, 700,000 people suffer this injury. For four out of five patients, the fracture heals and the accompanying pain goes away in approximately four weeks with bed rest and analgesics. However, for one in five patients, the fracture does not heal and the pain persists, requiring treatment. Surgery is not an option for these patients, as their bones are too weak. Vertebroplasty is the only available treatment option for patients in this condition.

Vertebroplasty is not appropriate for patients with back pain due to ligament injuries, joint disease or narrowing of the spinal canal, says Dr. Kallmes.

A new procedure for the imaging of coronary veins proves to be “less invasive, have less complications, and improves the quality of diagnosis and treatment ” for individuals undergoing surgical procedures on the heart and particularly the coronary veins, a recent study found.

The study compared ECG-gated cardiac MDCT angiography to conventional angiography. “MDCT angiography is a reliable alternative to invasive conventional coronary angiography, and should be used to evaluate the coronary veins prior to pacemaker lead placement, and other procedures… MDCT angiography improves the quality of diagnosis and treatment for the patient by providing better planning of the procedure prior to surgery, such as pacemaker placement,” said Georg Mühlenbruch, MD, lead author of the study.

“Conventional angiography is of limited value for some interventional cardiac procedures,” said the authors of the study, because it is technically challenging and requires access to the central venous system. Because the coronary veins are variable in number, caliber and course, detailed knowledge of the patient’s individual anatomy is essential for optimum planning of the intended procedure. Thus, there is a need for precise imaging the cardiac venous system, Dr. Mühlenbruch said.

A team led by researchers at the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and Edith Cowan University in Joondalup, Western Australia has shown that being extremely overweight or obese increases the likelihood of developing Alzheimer’s. They found a strong correlation between body mass index and high levels of beta-amyloid, the sticky protein substance that builds up in the Alzheimer’s brain and is thought to play a major role in destroying nerve cells and in cognitive and behavioral problems associated with the disease.

“We looked at the levels of beta-amyloid and found a relationship between obesity and circulating amyloid,” says Sam E. Gandy, M.D., Ph.D., director of the Farber Institute for Neurosciences. “That’s almost certainly why the risk for Alzheimer’s is increased,” says Dr. Gandy, who is also professor of neurology, and biochemistry and molecular biology at Jefferson Medical College of Thomas Jefferson University. “Heightened levels of amyloid in the blood vessels and the brain indicate the start of the Alzheimer’s process.” The scientists reported their findings this month in the Journal of Alzheimer’s Disease.

According to, Dr. Gandy, evidence has emerged over the last five years that many of the conditions that raise the risk for heart disease such as obesity, uncontrolled diabetes, hypertension and hypercholesterolemia also increase the risk for Alzheimer’s. Yet exactly how such factors made an individual more likely to develop Alzheimer’s remained a mystery.

Dr. Gandy, Ralph Martins, Ph.D., of Edith Cowan University and their colleagues measured body mass index and beta-amyloid levels in the blood. They also looked at several other factors associated with heart disease and diabetes, such as the inflammatory marker C-reactive protein, insulin, and high density lipoprotein in 18 healthy adults who were either extremely overweight or obese. They found a “statistically significant correlation” between body mass index and beta-amyloid.

“Ours is one of the first attempts to try to find out on both the pathological and the molecular levels how obesity was increasing the risk of Alzheimer’s,” says Dr. Gandy, who serves as chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

One implication of these findings could be that by losing excess weight and maintaining normal body weight, an individual might reduce the risk of developing Alzheimer’s. However, this has not been proven, notes Dr. Gandy.

“What’s especially interesting about this is that several studies are showing that even medical conditions in midlife may predispose to Alzheimer’s later on,” he says. “The baby boomers today should pay attention to this. Their medical risk factors today will play a role 30 years later. Think about weight, cholesterol, blood pressure, which could affect you long-term. In terms of Alzheimer’s, another risk factor is maintaining an active mental lifestyle.”

The next step is to follow such patients over the long term to see how many do indeed develop Alzheimer’s. “We need to first develop a medicine that is effective in humans in lowering amyloid accumulation or generation,” says Dr. Gandy. “We have those now in mice and we are testing them in humans. If we can develop such a medicine, then the question will be, if we can lower amyloid, will that in fact prevent Alzheimer’s?”

Researchers have demonstrated a technique that has the potential to reduce the toxicity of vaccines and to make smaller doses more effective, according to a study published in PLoS Pathogens.

Developing vaccines is fraught with challenges, particularly because many candidates carry a high risk of toxic side effects. For example, twenty percent of people immunized against smallpox will suffer side effects.

Boosting the production of TAP, an immune system component, can make smaller doses of vaccines more effective. Smaller vaccine doses would mean reduced side effects and the capacity to immunize more people with less material. As the approach appears to augment immune responses for different pathogens and is not limited to the genetics of the host we vaccinate, this new approach could have far reaching benefits in the field of vaccines.

Vaccines capitalize on normal immune responses. Viral infections are naturally detected with the aid of special molecules called the major histocompatibility complex (MHC), which alert immune system cells to destroy infected cells. If the same virus infects again, the system is primed and ready to respond more quickly. Vaccines, which are created from disease-causing viruses (or their relatives), provide a harmless first exposure so that future infections are thwarted before they become lethal.

In this study, Jefferies and his colleagues vaccinated mice against the viral relatives of rabies and measles viruses and simultaneously induced the overproduction of one component already part of the immune system, called TAP, which enhances MHC activity. Subsequently, specific “destroyer” cells increased fourfold, compared with traditional vaccination. Since these cells help initiate immunity, the group recognized that they were an important piece of the puzzle, according to Jefferies.

“The pathway works like a machine or factory where increasing the efficiency of one component part can lead to a massive increase in functional output,” he said.

Next, using varying doses, the team vaccinated mice against a relative of the smallpox virus. Mice immunized with just one-hundredth the standard dose and induced to overproduce TAP were still able to survive an otherwise lethal viral infection.

“We were surprised that over-expression of TAP would have such a great effect because it implies that it is in limiting amounts normally or is inefficient normally,” Jefferies said. “Combining viral antigens with a gene that is involved in their processing appears to be a solution to increasing the efficacy of vaccines in general.”