How Excess Alcohol Depresses Immune Function

Alcoholism suppresses the immune system, resulting in a high risk of serious, and even life-threatening infections. A new study shows that this effect stems largely from alcohol’s toxicity to immune system cells called dendritic cells. These cells play a critical role in immune function, responding to danger signals by searching for unfamiliar antigens within the body that would be coming from invading microbes, and presenting such antigens to T cells, thus activating them to seek and destroy cells containing these antigens. The research is published in the July 2011 issue of the journal Clinical and Vaccine Immunology.

Earlier studies in mice had shown that excessive drinking of alcohol impaired T cell function, and subsequently that this impairment could be reversed by exposure to dendritic cells (so named for their shape) from non-alcoholic mice, and that poor function in CD4 and CD8 T cells could be improved through exposure to cytokines produced by non-alcoholic dendritic cells. (Cytokines are immune regulatory cells.) In this study, Jack R. Wands and colleagues of Brown University, Providence, RI, compared dendritic cells produced by alcoholic and non-alcoholic mice, which they first removed from the mice.  

The result: dendritic cells from the alcoholic mice had a poor ability to activate T cells, while the dendritic cells from mice on isocaloric diets containing no alcohol functioned normally. The researchers found further that the dendritic cells from alcohol-fed mice showed reduced antigen presentation compared to those from control mice, as well as less production of the regulatory cytokines. This research also confirmed earlier results showing that alcohol inhibits cytokine secretion by dendritic cells.

“This research helps us understand why alcoholics are predisposed to bacterial and viral infections, and why they do not respond well to vaccines,” says Wands. Understanding this, he says, will help in the development of ways to improve dendritic cell function in people with alcohol syndromes. 

More information: A. Eden, et al., 2011. Ethanol inhibits antigen presentation by dendritic cells. Clin. Vaccine Immunol. 18:1157-1166.)

Provided by American Society for Microbiology

Tattoos linked to rare skin infection in US

One 44-year-old man was confirmed to have a case of Mycobacterium haemophilum after getting a tattoo on his arm in the western US city in August 2009, the Centers for Disease Control and Prevention said.

The infection, which showed up as a bumpy red rash and a pus infection on the skin's surface, resisted treatment with several antibiotics but eventually disappeared after nine months.

A second suspected case was reported in a 35-year-old man who got a tattoo at the same place two months later, but tests were inconclusive. The CDC said it considered it a "suspected" instance of infection.

The source of the bacteria remains a mystery. Authorities said the tattoo parlor was in compliance with safety regulations but told the owner to use sterilized water for rinsing skin and diluting ink instead of tap water.

(c) 2011 AFP

Assessment tool appears to effectively evaluate quality of life in patients with sinus inflammation

According to background information in the article, acute rhinosinusitis often causes patients to feel sick and anxious, miss work or school and face treatment costs. Therapy for acute rhinosinusitis focuses on helping patients feel better and continue to function. "Because there are no clinical objective measures of disease resolution for use in clinical trials, tools to assess outcomes that are meaningful for patients are needed," write the authors. They point out that QOL questionnaires which serve this need have been evaluated for use in chronic rhinosinusitis (lasting longer than four weeks), but not in acute cases (lasting for shorter periods of time).

Jane Garbutt, M.B., Ch.B., and colleagues from Washington University, St. Louis, sought to evaluate how reliable, valid and responsive (able to detect small but important changes over time) the modified SNOT-16 was in adult patients with acute rhinosinusitis treated in a primary care setting. Their study was conducted during a randomized, controlled trial of antibiotic treatment for the condition. The modified SNOT-16, which gathers information on 16 sinus-related symptoms, was completed in person and by telephone on the first day of the study, and by telephone on days three, seven and 10. The questionnaire asked how severe and frequent symptoms were and how much they bothered patients. Participants were between 18 and 70 years old, had a diagnosis of acute rhinosinusitis from a primary care physician and initially reported their symptoms as moderate to very severe.

Of the 166 patients randomized in the treatment study, 78 percent were white and 36 percent were male. Statistically significant differences in terms of symptom severity and how bothered patients felt were identified by the modified SNOT-16, demonstrating the instrument's validity. Analysis of results demonstrated the questionnaire's internal consistency and sensitivity to clinical changes in patients' conditions. Researchers noted that the tool was quick and easy to use, and that scores were lower when the questionnaire was conducted by telephone on the same day following completion during a face-to-face interview.

"In conclusion, we found the modified SNOT-16 to be valid, responsive, and easy to use, and we recommend its use to assess change in disease-related QOL in interventions targeting patients with acute rhinosinusitis," the authors write. "It is important to note that if the planned mode of administration is by telephone interview, then the baseline assessment must also be by telephone interview."

More information: Arch Otolaryngol Head Neck Surg. 2011;137[8]:792-797.

Provided by JAMA and Archives Journals (news : web)

New drug aids gout patients not helped by standard treatments August 16, 2011

In two controlled clinical trials, pegloticase rapidly lowered high levels of uric acid, the biochemical abnormality in gout, and kept it in the normal range for six months or more in 42 percent of patients receiving the drug every two weeks. Forty percent of patients had complete resolution of at least one of the painful swollen joint nodules, known as tophi, a hallmark of severe gout.

"This represents the first effective therapy for a group of patients who previously had no options at all," said the study's senior author, Michael A. Becker, MD, professor of medicine at the University of Chicago. "This is for patients with severe gout, including major disabilities and high levels of pain. Many of these people had dramatic responses within months, some with complete resolution of tophi, as well as reduced levels of pain and disability. The rapidity of these outcomes is unheard of."

"People are dramatically helped by the drug," said rheumatologist John S. Sundy, MD, PhD, director of the Duke Clinical Research Unit and lead author of the study. The drug's response among patients who have failed common therapies is typically an "all-or-nothing result," he added, "providing marked relief for those who benefit."

Becker cautioned that "it's not curative, but it resets the clock, moving the hands back on a patient's struggle with a progressive disease."

Once associated with European royal families, gout is increasingly a middle-class American disease, with connections to obesity, hypertension, diabetes, heart disease and alcohol abuse. An estimated 6 million people, about 2 percent of the U.S. adult population, have gout, a number that has increased by about 50 percent since 1990.

The disease is caused by a gradual accumulation of uric acid. When levels exceed the saturation point, uric acid forms tiny urate crystals, like thousands of little needles, that deposit in the lining of joints and other tissues. The crystals can cause inflammation, swelling and intense pain. A favorite target is at the base of the big toe, a common site for acute arthritic attacks and tophi. 

There are medications for chronic gout that block the synthesis of uric acid or help the kidneys remove it. For about 3 percent of people with gout, however, these drugs either are ineffective or cause intolerable side effects. This leaves about 120,000 to 180,000 patients in the United States with chronic disabling disease and, until recently, no effective therapy.

Pegloticase—approved by the FDA in September 2010 for the treatment of severe, refractory gout—was designed to meet that need, filling a gap left by nature. Most species, except for humans and a few other primates, produce the enzyme urate oxidase (also know as uricase). This enzyme converts uric acid to allantoin, which is far more soluble in fluids and can be easily excreted. "It essentially digests uric acid," Becker said.

Scientists at Duke, led by Michael Hershfield, MD, developed the compound and spent decades to fine tune the drug and usher it to market. They modified the version of the enzyme from pigs and wrapped it in polyethylene glycol to protect it from being degraded or attacked by the patient's immune system. The coating extends the half-life of the enzyme from eight hours to 10 to 12 days, so patients need an injection just once every two weeks, making this drug suitable for long-term treatment.

When pegloticase is injected into patients with severe gout, their uric acid levels return to normal within 24 hours. This can lead to gradual dissolution of uric-acid crystals and eventual resolution of gout symptoms.

The two parallel clinical trials focused on 212 patients from 56 rheumatology practices in the United States, Canada and Mexico. They enrolled patients with severe gout and high uric-acid levels who were not helped by or couldn't tolerate standard treatments. Patients were divided into three groups. One group was injected with 8 milligrams of pegloticase every two weeks, one group received pegloticase every month and one group got a placebo—injections of saline but no actual drug. All participants were enrolled for six months of treatment.

Although uric-acid levels fell to normal ranges within 24 hours in all patients who received the drug, for some patients the drug soon lost its beneficial effect. In 42 percent of patients who got the drug every two weeks, however, uric-acid levels stayed within normal ranges for at least 80 percent of the six-month period. In 35 percent of those who got injections once a month, uric-acid levels remained low for 80 percent of the trial period. Patients who received a placebo had no change in levels.

Forty percent of biweekly injection patients and 21 percent of those getting monthly injections had complete resolution of one or more tophi within six months, compared with 7 percent of patients receiving placebo. Patients who received the drug also reported improved physical function and quality of life.

Nine out of 10 patients, however, had at least one adverse event. The most common were gout flares—brief, treatable attacks of pain and inflammation. These declined after the first three months of treatment.

The second most common side effect, and the primary reason for patients to withdraw from the study, was an infusion-related reaction; 26 percent of treated patients, most of whom had already stopped responding to the drug, developed an immune response to injection of the foreign protein. Although patients were given medications to reduce the risk and severity of an immune response, about 5 percent of biweekly and 8 percent of monthly patients had a serious reaction. These all resolved completely.

Nearly all of the patients in the study had multiple cardiovascular risk factors and seven patients died during the trial period. The authors recommend "measures to stabilize cardiovascular problems prior to and during treatment."

Most patients eventually developed antibodies against the drug, which suggests that it may be difficult to repeat treatment months or years later. Additional research is aimed at learning the optimum duration of treatment and bolstering the drug's response in more patients.

Despite the risks, "this is an advance – a significant advance," Becker said.

Sundy added: "This is a group of people for whom there has not been another option for a long time."

The cost of pegloticase, sold as Krystexxa by Savient Pharmaceuticals, is about $60,000 for a year of treatment. Most patients complete treatment within six to eight months.

It may also be very useful for transplant patients, Becker said. About 10 percent of transplant recipients get gout and many can't take the standard medications because they interfere with the drugs that prevent rejection.

Provided by University of Chicago Medical Center

New anti-inflammatory agents silence overactive immune response

The discovery, published Monday in the journal Proceedings of the National Academy of Sciences, offers a promising new approach to treat inflammatory auto-immune disorders such as lupus and multiple sclerosis, which are marked by an overactive immune response.

"Depending on the disease, cells that are damaged drive or perpetuate theimmune response," said Bruce A. Sullenger, Ph.D., director of the Duke Translational Research Institute and senior author of the study. "We have shown that we can inhibit that process."

Sullenger said the idea for the new approach stems from earlier findings by Duke scientists and others that dying and diseased cells spill nucleic acids – the building blocks of life that include DNA and RNA – that then circulate at high levels in the bloodstream.

While DNA and RNA inside the cell regulate important functions such as growth and division, outside of cells in the blood, these nucleic acids serve as powerful signals to the immune system that something is amiss. Once activated, the immune system launches an attack to fight whatever caused the cell damage, whether an infection or toxic substance. Under normal circumstances, this inflammatory response eventually restores order.

In some cases, however, the inflammatory response becomes persistent and out of control, leading to tissue damage and causing symptoms such as fever and pain. Chronic inflammation has been implicated in lupus, multiple sclerosis, obesity, psoriasis, irritable bowel syndrome, arthritis and numerous other maladies.

The Duke scientists, working to interrupt this cycle, focused on a set of molecules called nucleic acid binding polymers that were designed to infiltrate the nucleic acid inside of cells and deactivate specific immune triggers.

"Then we had a 'eureka moment,'" Sullenger said. "Because the inflammatory nucleic acids are outside of cells, whereas DNA and RNA normally function inside cells, we realized that the polymers could bind to the external nucleic acids without disrupting intracellular functions of DNA and RNA."

It was a simple mop-up approach, and it worked as planned in experiments on mice: "We could use the polymers as molecular scavengers - sponges to go around and soak up and neutralize those inflammatory nucleic acids so the immune system doesn't recognize them and go into the overdrive ofinflammation," Sullenger said.

David S. Pisetsky, M.D., Ph.D., a rheumatologist at Duke and co-author of the study, said the anti-inflammatory approach has numerous potential applications, not only for auto-immune disorders, but also for the acute tissue damage of severe bacterial and viral infections, shock and injuries.

"One setting to test the effects of the polymers involves acute events such as injuries, where it may be easier to measure the presence of the nucleic acids in the blood and the effects of polymer binding," Pisetsky said, adding that the long-term safety of the new anti-inflammatory approach in humans remains unknown.

Sullenger said patents have been filed on the finding, and the team is pressing ahead to develop therapies. "At some level we've opened up this huge treasure chest of opportunities and now we have to figure out which way to go," he said.

Provided by Duke University Medical Center (news : web)

BU Identifies Contributors To High Incidence of Breast Cancer In African-American Women

Investigators from the Boston University's Slone Epidemiology Center have reported findings that may shed light on why African American women have a disproportionately higher risk of developing more aggressive and difficult-to-treat breast cancers, specifically estrogen and progesterone receptor negative (ER-/PR-) cancers.

The study, which appears online in Cancer Epidemiology, Biomarkers & Prevention, found that high parity (giving birth to two or more children) was associated with an increased risk of ER-/PR- cancer, but only among women who had not breastfed.

The findings were based on the ongoing Black Women's Health Study, which has followed 59,000 African American women by biennial questionnaire since 1995.

In 14 years of follow-up, 318 women developed breast cancers negative forestrogen and progesterone receptors (ER-/PR-), while 457 developed breast cancers with estrogen and progesterone receptors (ER+/PR+). Giving birth to two or more children was associated with a 50 percent increase in the incidence of ER-/PR- breast cancer, but the association was not present among women who had breastfed.

According to the researchers, the results for ER+/PR+ breast cancer, which is more common among white women, were strikingly different. High parity was associated with a decreased risk, and breast feeding had no influence on that association.

"The higher incidence of ER-/PR- breast cancer in African American women may be explained in part by their higher parity and lower prevalence of breastfeeding relative to white women," explained lead author Julie Palmer, ScD, MPH, a senior epidemiologist at the Slone Epidemiology Center and a professor of epidemiology at Boston University School of Public Health.

"Our results, taken together with recent results from studies of triple negative and basal-like breast cancer, suggest that breastfeeding can reduce risk of developing the aggressive, difficult-to-treat breast cancers that disproportionately affect African American women," she said.

Provided by Boston University Medical Center