ST. LOUIS, Mo., Jan. 25 — In a finding with potential antibioterror implications, a key protein’s absence appears to slow the deadly attack of pneumonic plague, potentially making it susceptible to antibiotic treatment, according to researchers here.

If the plasminogen activator Pla is missing or inactive, the characteristic pneumonia of the plague takes longer to develop, even though the bacteria responsible, Yersinia pestis, continues to grow and spread, found William Goldman, Ph.D., of Washington University School of Medicine here.

The prolonged survival offers “a therapeutic option to extend the period during which antibiotics are effective,” Dr. Goldman and colleagues reported in the Jan. 25 issue of Science.

“By the time most doctors recognize an infection as plague, rather than the flu, it’s already too late to begin antibiotic treatment,” Dr. Goldman said.

“That makes pneumonic plague a concern both because of its rare natural outbreaks, one of which began in the Congo in 2005, and because of its potential use as a bioweapon,” he said.

Dr. Goldman said that medications to inhibit Pla might be useful in future human outbreaks, although the current study used experimental mice that develop a disease similar to pneumonic plague when given the bacterium intranasally.

Depending on how it is introduced to the body, Y. pestis can result in pneumonic plague, bubonic plague, and septicemic plaque. During the Middle Ages — as bubonic plague — the pathogen depopulated Europe, killing an estimated one person in three.

Because of its rapid killing power in the pneumonic form, it is widely feared as a possible bioterror weapon, Dr. Goldman and colleagues said.

The researcher had suspected that Pla was used by the bacterium to break up blood clots surrounding pockets of infection. The clotting mechanism is seen as the body’s way of quarantining the bacteria and keeping it from the rest of the body.

To test that idea, they infected mice with three different variants of Y. pestis — a wild-type strain, a strain in which the gene for Pla was missing, and the same strain but with the coding sequence for the Pla gene added.

The mice that got the wild-type strain all died within 3.5 days and at much the same time after infection. In contrast, only half the mice given the non-Pla strain developed fatal plague within seven days and their deaths were more separated in time.

Finally, the addition of the Pla coding sequence restored the virulence of the bacteria, Dr. Goldman and colleagues said.

But bacterial growth in the mice that got the non-Pla strain was different from the other two groups — after 24 hours the amount of bacteria in the lungs was lower by a factor of about a million than it was in the other animals.

At the same time, Y. pestis was detected in the spleens of all three groups at about the same level, indicating that the pathogen was still finding a way out of the lungs, despite the absence of Pla.

One of the hallmarks of pneumonic plague is edema in the lungs, which can be measured by weighing the organs. Interestingly, the researchers said, the lungs of mice given the non-Pla strain showed no change in weight although the lungs of the other groups were significantly heavier.

The implication is that “the death of mice infected with this strain is not due to pneumonia but rather is caused by systemic infection,” the researchers said.

In fact, Dr. Goldman and colleagues concluded, Pla controls the ability of the Y. pestis to cause pneumonic plague, possibly by promoting bacterial growth and inflammation.

To test that idea, they created a strain of Y. pestis in which the Pla gene was masked, but could be made active by a dose of the antibiotic tetracycline.

Mice given this variant initially had the non-pneumonic variant of the disease, but a dose of the antibiotic turned the disease into the full-blown pneumonic version, Dr. Goldman and colleagues reported.

Moreover, if the mice are infected and also given some tetracycline, the disease begins as pneumonic plague, but as the antibiotic is cleared — and the Pla is again masked — the disease reverts to the less-deadly systemic plague.

That implies, Dr. Goldman colleagues said, that blocking Pla in the course of the disease “may indeed prolong the survival of the affected individual.”

The study was supported by a grant from the National Institutes of Health. The researchers did not report any relevant financial conflicts.

Primary source: Science

Source reference:
Lathem WW et al. “A Plasminogen-Activating Protease Specifically Controls the Development of Primary Pneumonic Plague.” Science 2007;315:509-13.

SAN DIEGO, May 22 — Fecal incontinence, common in patients undergoing bariatric surgery, appears to worsen for many after the procedure, a researcher said here.When surveyed a mean of two years after gastric bypass or banding, 51.2% of 194 patients who had liquid fecal incontinence prior to the procedure said it had gotten worse, said Erica N. Roberson, M.D., of the University of Wisconsin in Madison, Wis., at Digestive Disease Week sessions.Similarly, about half of patients who had solid fecal incontinence before the surgery also said it had worsened afterwards.

Only about 10% of patients with pre-surgery fecal incontinence reported improvement over time.

“This is an underdetected population,” Dr. Roberson said. “Nobody really talks about incontinence enough in these patients. They don’t tell their doctors about it, and their doctors don’t ask them about it.”

Urinary incontinence was also frequent, reported by 73.4% of the respondents, but three-quarters said it had either improved or not changed after surgery.

The findings came from a survey of 194 patients who had undergone bariatric surgery at the University of Wisconsin from 2002 to 2006. A total of 405 surveys were sent, for a response rate of 48%.

Dr. Roberson said the study was inspired by research published several years ago that found obese women had substantially higher rates of urinary and fecal incontinence than women who were not obese. She and colleagues wanted to investigate how this phenomenon would be affected by bariatric surgery.

Significant predictors of fecal incontinence in the new study included a history of vaginal birth in women and concurrent urinary incontinence, she said.

The mean time since surgery for the women was 757 days. About 82% of respondents were women, with a mean weight loss of 48.4 kg (SD 20.4) and current body mass index of 32.9 (SD 7.4).

Gastric bypass had been performed in 159 respondents with the rest undergoing laparoscopic banding.

Dr. Roberson said the mechanism was unclear. “Is their diet different?” she asked. “Does the fact they might have some obesity around their belly affect their incontinence, or is there something else going on? We really don’t know.”

Mark DeLegge, M.D., a gastroenterologist and nutrition specialist at the Medical University of South Carolina in Charleston, commented that he agreed that the issue of fecal incontinence is not discussed enough between patients and physicians.

“I see a lot of patients, and most of my patients have never mentioned that to me,” he said.

He speculated that the worsening incontinence seen in Dr. Roberson’s survey may stem from permanent damage beginning when the patients were still obese.

John M. Morton, M.D., Ph.D., a gastric surgeon at Stanford University, said if that’s the case, “it’s going to be difficult to overcome even with weight loss.”

He added that diarrhea following bariatric surgery is a known issue. “It probably relates to the diet. Patients are completely changing what they’re eating, more protein-based and certainly more of a liquid consistency afterward.

“We always do a rectal exam before surgery, but this study may prompt us to take a little closer look at it and maybe find different ways to help people afterwards,” Dr. Morton said.

Dr. Roberson and Dr. Morton reported no potential conflicts of interest.

Dr. DeLegge reported a relationship with Nestle Home Care.

Primary source: Gastroenterology

Source reference:
Roberson E, et al “Prevalence of fecal incontinence (Fi) and urinary incontinence (Ui) after bariatric surgery” Gastroenterology 2008; 134: A65.

PRAGUE — Adding the nutritional supplement alpha-lipoic acid to ursodeoxycholic acid (UDCA, ursodiol) reduced the major symptoms of non-alcoholic steatohepatitis (NASH) in a small controlled trial, it was reported here.

Measures of fibrosis, liver transaminase levels, and overall disease severity were all improved significantly relative to diet-based treatment in a six-month, 20-patient study, according to Vincenzo Gianturco, MD, of the University of Rome “La Sapienza” in Italy.

UDCA is already an FDA-approved treatment for NASH, one of the major complications of diabetes and obesity, but many patients fail to show substantial improvement on the treatment.

Gianturco, speaking here at the World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension, said about 2% to 3% of the population in Western countries suffers from NASH, an advanced stage of non-alcoholic fatty liver disease.

Both conditions are most common in middle-age, obese women with diabetes. However, according to Gianturco, NASH may be seen in individuals of any age or gender.

Alpha-lipoic acid is an antioxidant compound found naturally in human cells and in many foods — and, in capsule form, in health food stores. It is used in complementary medicine to treat various diabetic complications and some neurologic conditions, on the theory that it has cytoprotective effects.

UDCA also appears to have cytoprotective effects, by a different mechanism; hence the idea to combine the two agents as a one-two punch against NASH.

Gianturco and colleagues randomly assigned 10 patients to receive ALAURSO — 400 mg of alpha-lipoic acid plus 300 mg UDCA — daily for six months. Ten other patients were randomized to a placebo group that was treated only with a low-calorie diet plan.

Patients with hepatitis B or C virus infection, alcohol drinkers, and those with gallbladder stones were excluded. Patients underwent liver biopsy at baseline, confirming the diagnosis, and again at the end of treatment.

Essentially no change in mean liver enzyme levels were seen in the control group, whereas the ALAURSO group showed substantial and statistically significant reductions (P=0.001) relative to controls, even with the small number of patients involved: Aspartate acetyltransferase: baseline 47.0 mg/dL (SD 6.0); 30.6 mg/dL (SD 4.0) after treatment Alanine acetyltransferase: baseline 50.9 mg/dL (SD 5.7); 33.4 mg/dL (SD 3.1) after treatment Gamma-glutamyl acetyltransferase: baseline 57.7 mg/dL (SD 7.0); 34.2 (SD 3.5) after treatment

In the control group, none of the liver enzymes changed by more than 1 mg/dL with treatment.

Fibrosis scores increased in the control group, from 1.4 at baseline to 1.52, whereas scores declined significantly in the ALAURSO group, from 1.2 at baseline to 1.01 (P=0.04), Gianturco said.

Both compliance and tolerability were good, he told attendees here.

However, he cautioned that detailed histological analyses had not been performed. The small number of patients and the relatively short follow-up were also limitations, Gianturco said.

Session moderator Robert Niecestro, PhD, of the drug development firm Accelapharm in New York City, commented that alpha-lipoic acid is a chiral molecule, with both R- and S- enantiomers contained in commercially sold versions.

He said the R- enantiomer is responsible for the compound’s beneficial effects, whereas the S- version tends to offset them somewhat.

Niecestro suggested that using only the R- form might further boost the effectiveness of the ALAURSO combination.

No commercial funding for the study was reported.

Gianturco reported no potential conflicts of interest. Niecestro is owner and managing director of Accelapharm. He reported no other potential conflicts.

SAN ANTONIO, Dec. 13 — The anthracycline drugs — long a mainstay of breast cancer chemotherapy — only benefit a minority of women and should be mostly scrapped, a researcher said here.The continued use of the drugs “on a one-size-fits-all approach is just crazy and it’s medically dangerous,” said Dennis Slamon, M.D., Ph.D., of the University of California at Los Angeles.Both retrospective and prospective data show that the anthracyclines only benefit women with amplification of both the HER2 receptor and the topoisomerase IIa gene (Topo IIa), Dr. Slamon told an oral session at the San Antonio Breast Cancer Symposium.

The amplification of Topo IIa appears only to occur when HER2 is amplified, but not always, he said, so that women with both changes account for about 8% of all women with breast cancer.

“When we didn’t have an alternative and when we didn’t know how to identify the women who would benefit, it made sense to use the drugs,” he said.

Now, he said, anthracycline-based adjuvant treatment should be reserved for women who don’t have access to therapy targeted to the HER2 receptor, which doesn’t apply to women in the U.S.

The anthracyclines — notably doxorubicin (Adriamycin) — yield about a 5% improvement in survival overall, Dr. Slamon said, but they are also associated with cardiac and bone marrow morbidity and mortality.

“The reality is that there’s probably a 25% to 30% benefit for a small subgroup” while the remaining patients do not benefit, Dr. Slamon said.

The reason, he said, is that the Topo IIa protein is a “major target” of the anthracyclines and the Topo IIa gene is amplified only in a minority of women who are also HER2-positive.

Dr. Slamon said data from the registrational trial of trastuzumab (Herceptin), which he led, showed clearly that patients with co-amplified Topo IIa were the only ones who benefited from anthracyclines.

Among HER2-positive women treated with doxorubicin and cyclophosphamide (Cytoxan), those with a normal or deleted Topo IIa gene had a median survival of 18.2 months. In contrast, women with amplified Topo IIa had a median survival of 38.5 months — a difference that was significant at P=0.004.

When trastuzumab was added in the experimental arm of the study, the difference disappeared, he said.

Similar results have been seen in eight other studies, he said, leading to his conclusion that HER2-positive women with amplified Topo IIa are a “unique niche” in which the anthracycline drugs can be used.

But it may be too soon to consign the drugs to the scrap heap, countered Eric Winer, M.D., of Boston’s Dana-Farber Cancer Center, who moderated the session and was not involved in Dr. Slamon’s research.

“It will make me very happy if we can get rid of Adriamycin and its inherent cardiac toxicity,” Dr. Winer said. “But I’m not ready to say that this is an agent that doesn’t have a role — yet.”

Dr. Winer said the debate doesn’t signal a “rift in the breast cancer community.”

Instead, he said, it’s a question of timing: “Most people feel they’ll be using a lot less in the way of anthracycline-based therapy in the years ahead,” he said, “and there are some people who are running to that goal post.”

Others, he said, are waiting for more than “a bunch of retrospective studies and one prospective trial.”

The research was supported by the Revlon Foundation, Genentech, and Amgen. Dr. Slamon reported financial relationships with Genentech and sanofi-aventis.

Primary source: Breast Cancer Research and Treatment

Source reference:
Slamon DJ, et al “Role of anthracycline-based therapy in the adjuvant treatment of breast cancer: efficacy analyses determined by molecular subtypes of the disease” Breast Cancer Res Treat 2007; 106 (Supp1): Abstract 13.

NEW ORLEANS — Acute infection appears to be associated with an increased likelihood of ischemic stroke in children, although the rarity of pediatric stroke means that most parents shouldn’t worry, researchers said.

In a large healthcare system, there were 126 ischemic strokes identified over a 15-year period in children and teens who were at least 29 days old, according to Nancy Hills, PhD, of the University of California San Francisco.

Having an outpatient visit for infection prior to stroke was associated with greater odds of ischemic stroke, with the likelihood increasing when the infection occurred in the month before the stroke, Hills reported at the American Stroke Association’s International Stroke Conference here.

But because pediatric stroke is so rare — occurring in an estimated 2.4 to 5 per 100,000 U.S. children each year — the observed relationship is “not something that parents of healthy children need to worry about,” she said.

“We really believe that it is not the infection that is causing the stroke,” she said. Rather, it appears that the infection acts as a trigger and that “these children probably have some underlying predisposition that causes them to have this very unusual response to a very common infection.”

Such a susceptibility could result from conditions causing a prothrombotic state or an underlying arteriopathy, Hills said.

A large percentage of strokes in children have an unknown cause, and even when a cause can be identified, it is generally thought to be an incomplete explanation, he added.

In adults, minor acute infection is considered a risk factor for stroke, but the issue had not been thoroughly explored in a pediatric population.

Hills and colleagues conducted a retrospective cohort study of children and teens ages 29 days to 19 years who received treatment in the Kaiser Permanente system. From 1993 to 2007, the database contained a base population of about 2.5 million children and teens.

During that period, there were 126 ischemic strokes identified by a search of the medical records in that age group. The median age of the patients was 10.5.

Each patient was matched to three randomly selected controls by birth year and primary care facility.

The researchers searched through the patients’ records for outpatient visits related to infection in the two years prior to the stroke. Having three or more visits during that time period was associated with more than double the odds of having a stroke (OR 2.32, 95% CI 1.28 to 4.18).

The association appeared to be confined to outpatient visits for infection in the month before the stroke (OR 8.37, 95% CI 4.31 to 16.3).

The odds ratios for visits for infection in the two days before the stroke, from three to seven days before, and from eight to 28 days before were 182, 10, and 2, respectively (P<0.05 for all).

The results remained significant after accounting for the possibility that parents of children with chronic diseases — including hematologic, autoimmune, and cardiac conditions — might take their children to the doctor more frequently.

E. Steve Roach, MD, a pediatric neurologist at Nationwide Children’s Hospital in Columbus, Ohio, and an American Heart Association spokesperson, said that clinicians have always suspected that there is a relationship between infection and pediatric stroke, but that it was difficult to prove because of the rarity of the event.

“So this study actually provides some objective evidence that our suspicions may have been correct,” he said.

Although Roach said he doesn’t think that the study will have any immediate impact on clinical practice, he said “if this holds up and is bolstered by additional studies, I could actually see this maybe altering what we do in the future.”

He noted that the issue currently is being explored in a prospective study — the Vascular Effects of Infection in Pediatrics (VIPS) trial — with results likely to be published in a year or two.

Hills acknowledged some limitations of the current study, including the likelihood that the number of infections was underestimated, and the use of infection data that came mostly from chart review and not laboratory testing.

Hills reported that she had no conflicts of interest.

Eating a high-fiber diet may reduce your risk of colorectal cancer, especially if the fiber is from cereal and whole grains, according to a new review.

British and Dutch researchers analyzed 25 studies that included a total of nearly 2 million people. Compared with the lowest levels of fiber consumption, each 10 gram per day increase in intake of total dietary fiber and cereal fiber was associated with a 10 percent reduced risk of colorectal cancer.

Consuming 90 grams more a day (three servings, or three and one-quarter ounces) of whole grains was associated with about a 20 percent lower risk.

The review did not find significant evidence of a link between fruit or vegetable fiber and colorectal cancer risk.

A previous analysis did find that a high intake of fruit and vegetables was associated with a reduced risk of colorectal cancer, which suggests that components other than fiber in fruits and vegetables may play a role, the researchers said.

The study appears online Nov. 11 in BMJ.

“In summary, our meta-analysis suggests that a high intake of dietary fiber, particularly from cereal and whole grains, is associated with a reduced risk of colorectal cancer,” the researchers wrote in a journal news release.

They also noted that a high-fiber diet may reduce the risk of cardiovascular disease, type 2 diabetes, overweight, obesity and possibly overall risk of death.

One expert said there may be a physiological basis for the anti-cancer benefit of a high-fiber diet.

“This study highlights the importance of a diet rich in fiber,” said Dr. Anthony Starpoli, a gastroenterologist at Lenox Hill Hospital in New York City. “We know that soluble is most helpful in improving colon transit times. As the contents of the colon move at a better rate, there is thought to be less toxic exposure to the interior of the colon thereby reducing risk of developing colon cancer,” he explained.

Colorectal cancer is the third most common cancer worldwide, with 1.2 million new cases diagnosed each year, the news release noted.

The findings provide more evidence of the many health benefits of whole grains, but further research is needed to learn how this occurs, Anne Tjonneland, from the Danish Cancer Society, added in an accompanying editorial.

More information

The American Academy of Family Physicians outlines how to increase your fiber intake.

Small changes in troponin levels detected with an investigational high-sensitivity test may improve prediction of outcomes in heart failure patients, researchers reported.
In a study of 144 patients hospitalized for acutely decompensated heart failure, those with increases in troponin I were at increased risk for death within 90 days of hospital discharge, whereas B-type natriuretic peptide levels were not significantly predictive of mortality, according to Yang Xue, MD, of the University of California San Diego, and colleagues.
Results of single troponin I measurements were also significantly associated with 90-day mortality and readmission, Xue and co-authors reported online in the European Journal of Heart Failure.

The protein was measured with a novel nanotechnology-based assay developed by Nanosphere of Northbrook, Ill., capable of 0.25-ng/mL sensitivity with a 10% coefficient of variance at 12 ng/mL.

At higher levels detectable with currently marketed assays, troponin I is used to diagnose MI and other acute cardiac conditions.

Laboratory studies have shown that troponin is increased in heart failure, but the base levels are in a range not accurately measured with these standard assays.

Among the 144 study patients, readmission or death within 90 days of discharge occurred in 38 patients, including 22 who died, Xue and colleagues wrote.

The median troponin I concentration in all measurements was 26.2 ng/mL.

Those patients with troponin I levels higher than 23.25 ng/mL at discharge were more likely to die or be readmitted, Xue and colleagues found. About 37% with values above this cutoff had one or both events, compared with 10% of those with lower levels (P=0.003).

The area under the receiver-operating characteristic curve for troponin I was nearly identical to that for B-type natriuretic peptide (BNP), a standard diagnostic and prognostic marker for heart failure (0.648 versus 0.637).

The greatest likelihood of events was seen in the 56 patients with both high troponin I and high BNP. These patients had events at a rate of 38%. Only about 3% of those with low levels of both markers suffered events.

Troponin I appeared to be the more accurate outcome predictor — patients with high levels of it but low BNP were more likely to die or be readmitted than those with low troponin I and high BNP (32% versus 23%, P not reported).

A total of 106 patients had multiple troponin I measurements. Those showing increases at some point relative to the first measurement taken at admission were at significantly increased risk for death, Xue and colleagues indicated.

Among patients with stable or decreasing levels, 10% died, compared with 20% of those showing an increase (hazard ratio 4.52, P=0.047).

Readmission was not significantly associated with changes in troponin I over time.

However, Xue and colleagues noted, blood urea nitrogen (BUN) was a significant confounding factor in the study. In multivariate analysis that took account of 40 clinical and laboratory parameters in addition to troponin I and BNP, only BUN was associated with outcomes at a statistically significant level.

“This was likely due to the limited power of our study,” the researchers wrote.

They suggested that future studies be directed to tease out the respective contributions of BUN and other confounders and those from troponin I, a direct marker of cardiac damage.

The current study “confirms that ongoing myocardial damage plays a significant role in the pathophysiology of heart failure and the presence of even a small troponin elevation during heart failure exacerbation is a strong predictor of mortality and heart failure-related readmission,” Xue and colleagues concluded.

Nanosphere filed an application with the FDA last year to market the high-sensitivity troponin I test, but the agency ruled that more clinical studies were needed before it could be approved. The company has not indicated when it may submit the additional data.

The study was funded by Nanosphere.

Study authors declared that they had no financial relationships with Nanosphere.

The incidence of invasive breast cancer declined among Canadian women ages 50 to 69 years following the publication in 2002 of the results from the Women’s Health Initiative, similar to the decrease seen among American women.

In a study published online in the Journal of the National Cancer Institute, Canadian researchers reported that the years 2002 through 2004 saw a 9.6% decrease in breast cancer among women of that age group.

That coincided with a reduction in the use of hormone replacement therapy from 12.7% (95% CI 10.1% to 14.2%) in 2002 to 4.9% (95% CI 3.4 to 6.8) in 2004, according to Prithwish De, PhD, of the Canadian Cancer Society, and colleagues.

The Women’s Health Initiative identified an increased risk of myocardial infarction, stroke, and breast cancer among users of combined hormone replacement therapy, and the resulting decrease in hormone use was accompanied by a 14.7% drop in estrogen receptor-positive breast cancer among women in their 50s and 60s.

To see if similar trends occurred in Canada, De and colleagues obtained data on the number of hormone therapy prescriptions dispensed by the country’s retail pharmacies and information on usage from the longitudinal National Population Health Survey.

Between 2002 and 2003 there was close to a 27% decline in the number of prescriptions dispensed in Canada and an accompanying 2.5-fold decrease in self-reported use of hormone products among women ages 50 to 69 years.

The annual percentage change in combination hormone use between 2000 and 2006 was −9.9% (95% CI −8.2 to −10.7).

And the annual percentage change in all hormone products, including those that contain estrogen alone, was −7.6% (95% CI −5.9 to −8.9).

The incidence of breast cancer fell from 296.3/100,000 women (95% CI 290.8 to 300.5) in 2002 to 268/100,000 women (95% CI 263.3 to 273.5) in 2004.

In contrast, between 1996 and 2000 there had been a 4.4% increase in combination hormone therapy use each year, along with a 1.7% annual increase in the use of all hormone-containing products.

In comparison to the nearly 10% decrease in breast cancer seen between 2002 and 2004, a change in incidence of only −0.9% was observed between 1996 and 2000.

“The results support the hypothesized link between the use of hormone replacement therapy and invasive breast cancer incidence and indicate that the sharp decline in breast cancer incidence in 2002 is likely explained by the concurrent decline in the use of hormone replacement therapy among Canadian women,” they observed.

The hypothesis was also supported by the fact that rates of mammography since 2000 have remained stable, at about 72%.

There had been a brief spike in cases shortly after the release of the Women’s Health Initiative data, the researchers noted. This likely reflected increased concerns about breast problems among women and a lower threshold among clinicians for investigating subtle changes, they explained.

Since 2005 there has again been a “noticeable increase” in breast cancer incidence among women of most age groups, according to the researchers.

This rebound in incidence provides further evidence of the association between hormone replacement therapy and breast cancer, with the greatest declines in hormone use being among women older than 50 years.

“Such a rebound might be expected if occult hormone-sensitive tumors were merely slowed by the withdrawal of hormone replacement therapy rather than prevented by it,” the authors hypothesized.

If that is the case, hormone therapy may be acting as a cancer promoter, rather than a cancer cause.

Further work will be needed, particularly on the incidence of estrogen receptor-positive cancer, to clarify this.

The authors noted that their study had limitations, including its ecological design, which permits only crude measures of trends at the population level, and absence of data about hormone-receptor status of the tumors.

Also, data on hormone replacement were self-reported and subject to bias, and did not include information on frequency or duration of use.

The authors declared that they had no financial conflicts of interest.

Although the evidence is weak, doctors should be aware that combining anti-HIV and anti-epileptic medications may lead to drug-on-drug interactions, according to a new guideline.

The issue is growing in importance as more and more people — especially in the developing world — are living with HIV as a chronic disease, according to Gretchen Birbeck, MD, of Michigan State University in East Lansing, Mich., and colleagues.

And up to 55% of people taking antiretroviral medications may need epilepsy control drugs at some point, although not for seizures in every case, Birbeck and colleagues reported online and in the Jan. 10 issue of Neurology.

But, the authors noted, there are no formal guidelines to assist physicians in making drug choices. To help fill the gap, the American Academy of Neurology and the International League Against Epilepsy convened an international panel to sift through evidence and come up with guidelines.

The bad news, the panel found, was that the data are limited; only 42 articles yielded data, most of them reporting on Class II and Class III studies. As a result, the panel’s recommendations are all level C — any effect is only “possibly” valid.

Birbeck and colleagues noted that indications for anti-epileptic drugs have expanded beyond seizures to include such conditions as peripheral neuropathy and some psychiatric disorders.

But up to 11% of HIV patients may have seizure disorders and many more will suffer some form of peripheral neuropathy, leading to “substantial” concurrent use of anti-HIV and anti-epileptic medications worldwide, they argued.

The data analysis found that some combinations may need dose adjustments: Patients receiving phenytoin (Dilantin) may need about a 50% increase in the dosage of lopinavir/ritonavir (Kaletra) to maintain serum concentrations at the right level Patients taking valproic acid may need a lower dose of zidovudine (AZT) to keep serum concentrations unchanged Patients receiving atazanavir/ritonavir (Reyataz/Norvir) may require about a 50% increase in the dose of lamotrigine (Lamictal) to keep serum concentrations unchanged

On the other hand, the limited evidence suggests that: Using atazanavir or raltegravir (Isentress) with lamotrigine may not require lamotrigine dosage adjustment Giving raltegravir and midazolam together may not require adjusting the midazolam dosage Using valproic acid and efavirenz (Sustiva) may not require efavirenz dosage adjustment

It also may be important to avoid enzyme-inducing anti-epileptics for people whose HIV regimens include protease inhibitors or non-nucleoside reverse transcriptase inhibitors, the panel found.

While the evidence is still weak, the panel argued, those drug classes both use the cytochrome P450 system, and pharmacokinetic interactions might lead to virologic failure, with implications for disease progression and development of resistance.

“It is important that patients know exactly which drugs they are taking and provide that information to all prescribing health care providers caring for them,” Birbeck said in a statement. “Doctors may need to watch and adjust drug doses in people with HIV/AIDS who take seizure drugs.”

The guideline was developed with financial support from the American Academy of Neurology and the International League Against Epilepsy. The authors were not compensated for their work.

LITTLE FALLS, N.J., May 12 — Implementing a home-based diet and exercise program could slow functional decline in long-term cancer survivors.

A telephone-based intervention significantly halted functional decline compared with no intervention, Miriam C. Morey, Ph.D., of Duke University, and colleagues reported in the May 12 issue of the Journal of the American Medical Association.

“Even with modest change, [patients in the intervention] experienced clinically meaningful improvements in both physical function and other health-related quality-of-life domains,” the researchers said.

Long-term survival rates for many early-stage cancer patients exceed 90% and are increasing. However, these patients are at risk for accelerated functional decline.

Lifestyle interventions have benefited younger cancer survivors with more recent diagnoses, but Dr. Morey’s group wanted to know whether they’d help long-term, older cancer survivors whose diagnoses are in the distant past.

So, to determine whether a telephone counseling diet and exercise intervention is effective, the researchers randomized 641 overweight (BMI >25 and <40), long-term (> 5 years) cancer survivors ages 65 to 91 to an intervention group or a control group with no intervention.

The Reach out to Enhance Wellness (RENEW) intervention lasted 12 months over a period from July 1, 2005, to May 17, 2007.

The program consisted of a tailored workbook and a series of quarterly newsletters along with 15 sessions of telephone counseling, each 15 to 30 minutes long.

The researchers found that mean function scores declined less rapidly in the intervention group compared with the control group (-2.15 versus -4.84, P=0.03).

“A decline of 6.5 points over a four-year period is associated with a 10% higher mortality risk within a subsequent three-year window,” the researchers said. “A decline of two points is considered too small to be clinically detectable.”

Basic lower extremity function — going up and down stairs, using a step stool — changed negligibly in the intervention group. The control group, on the other hand, showed a decrease in scores (0.34 versus -1.89, P=0.005).

Advanced lower extremity function — walking a mile, running a short distance to catch a bus — followed a similar pattern, the researchers said, but didn’t reach statistical significance.

Also, there was significantly greater weight loss in the intervention group than in the control group (2.06 kg versus 0.92 kg, P<0.001).

And physical activity and dietary behaviors increased significantly in the intervention group (P<0.001). Quality-of-life scores decreased for control patients, but were sustained in the intervention group.

The researchers noted that the study was limited by self-report, and that the intervention, according to their demographics, was most likely delivered to highly motivated patients.

Still, they said the findings suggest that further efforts should be made to promote such programs among older cancer survivors, “not only in those who are well beyond their diagnosis, but also in those who are more newly diagnosed.”

The study was supported by grants from the NIH and from Veterans Affairs Research and Development.

The researchers reported no conflicts of interest.

Primary source: Journal of the American Medical Association

Source reference:

Morey MC, et al “Effects of home-based diet and exercise on functional outcomes among older, overweight long-term cancer survivors” JAMA 2009; 301(18): 1883-91.