Red wine chemical extends life - in yeast

18:00 24 August 03

NewScientist.com news service

A chemical found in red wine can mimic the life-extending effect of calorie-restricted diets in yeast, researchers have found.

The findings could provide a new explanation for beneficial effects of red wine. And replication of the results in mammals - although still a long way off - would raise hopes that the compound could one day be used to slow age-related diseases in humans.

"Seventy years ago we found that caloric restriction in rats increased lifespan. And over the last 70 years people have been looking for ways to explain it," says lead researcher David Sinclair, at Harvard Medical School in the US. "Now we have shown we can control the longevity pathway with a small molecule."

The compound is a polyphenol called resveratrol, and is found in grapes. Previous research has shown it can protect against heart disease in humans, but whether the life-extending properties it shows on yeast will extend to mammals is unknown. "It's a long way from yeast to humans," says David Finkelstein, at the US National Institute on Aging in Washington DC. "But it points the way to go."

Potent polyphenol

Caloric restriction in yeast activates an enzyme called SIR2, which is thought to extend lifespan by stabilising DNA. Sinclair and his colleagues found a group of polyphenols that activated this gene in yeast and extended the organisms' life. The most potent was resveratrol, which increased average survival time by 70 per cent.

Scientists have suggested that resveratrol acts as an anti-oxidant, mopping up harmful free radicals that damage the cell. But Sinclair found the compound does not have strong antioxidant effects in yeast.

"The lifespan enhancing properties seem to depend more on SIR2 activation," he says. Sinclair also believes this process is responsible for the human health benefits of drinking red wine.

Unpublished preliminary results show resveratrol also extends lifespan in worms and flies, says Sinclair. But while caloric restriction, acting via the same SIR2 pathway, can cause worms and mice to live longer, no one knows this occurs in higher mammals. Primate studies are underway, but the results from the long-lived animals will not be available for years.

In the meantime, people may continue to enjoy a drink with dinner, but Finkelstein notes: "It's silly to say that drinking a glass a day of wine a day will make you live to 150."

Journal reference: Nature (DOI: 10.1038/nature01960)

Emily Singer

Is Post-Stroke Depression Different from Post-MI Depression

Journal Watch Psychiatry
July 9, 2003

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 08/20/2003

Summary

Researchers have speculated that particular lesions caused by stroke can predispose patients to depression. To learn more about a possible association between depression and stroke, these researchers compared the incidence of depression over one year in 190 patients suffering a first cerebral infarct (mean age, 69; 47% female) with the incidence of depression in 200 patients suffering a first myocardial infarct (MI; mean age, 60; 23% female). Participants were consecutive emergency-room patients with stroke or MI. Those with prior depression, other current psychiatric disorders, dementia, aphasia, or general frailty were excluded. Standardized rating scales were used to determine depression incidence.

Cumulative one-year incidence of depression was found to be 39% in stroke patients and 28% in MI patients (P=0.06). This difference, however, disappeared when the researchers controlled for sex, age, and level of handicap. In approximately half of the depressed patients in each group, depression developed during the first month after stroke or MI.

Comment

These results raise questions about the specificity of stroke -- or of particular stroke-associated lesions -- as a cause of depression. Still, stroke and MI share many vascular risk factors (e.g., hypertension, increased serum cholesterol, and diabetes); it remains possible that the high rate of depression in both conditions represents a common cerebrovascular mechanism. The depression in both conditions could also signify a general stress-precipitated reaction.

-- Gary Tucker, MD

Might Ximelagatran Replace Warfarin in Patients with Nonvalvular Afib?

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 08/18/2003

Summary

In patients with nonvalvular atrial fibrillation (NVAF), warfarin anticoagulation limits stroke risk better than aspirin does. Ximelagatran is a new, oral direct thrombin inhibitor (DTI) with consistent pharmacokinetic properties that obviate the needs for dose titration and routine coagulation monitoring that are characteristic of warfarin use. In this European, 12-week safety study, funded by ximelagatran's manufacturer, 254 patients with persistent, verified NVAF and at least 1 stroke risk factor were randomized to 1 of 3 twice-daily doses of ximelagatran (20, 40, or 60 mg) or to dose-adjusted warfarin (target INR, 2.0-3.0).

Adherence to ximelagatran was at least 96% for all 3 doses. No subject suffered a systemic embolic event. Major bleeding occurred in no ximelagatran recipients and in 1 warfarin recipient. The minor-bleeding rate ranged from 6% to 12% in the ximelagatran groups and was 9% in the warfarin group. Rates of overall adverse events were similar with ximelagatran and warfarin, as were drug-discontinuation rates. Transient liver-enzyme abnormalities were noted in 4% of ximelagatran recipients and in no warfarin recipients. Therapeutic INRs were achieved in 57% of warfarin recipients by 12 weeks.
Comment

This study reveals that warfarin and the new, oral DTI ximelagatran have similar safety profiles in patients with NVAF. As in other studies, a low percentage of warfarin recipients achieved therapeutic INRs, emphasizing the need for better anticoagulants. If large clinical trials show that ximelagatran is as good as or better than warfarin for preventing systemic emboli in NVAF, this DTI likely will replace warfarin for this indication.

-- Howard C. Herrmann, MD
Source

Petersen P et al. for the SPORTIF II Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: A dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003 May 7; 41:1445-51.

Absolute CK-MB vs. CK-MB Relative Index for Cardiac Risk Stratification

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 08/18/2003

Summary

Nearly 7 million patients present to U.S. emergency departments annually for evaluation of possible acute coronary syndromes (ACSs). Despite hospital admission of the 25% to 30% who have atypical signs and symptoms, up to 40,000 acute MIs (AMIs) are missed. For risk stratification, both absolute CK-MB and the CK-MB relative index (CK-MB as a percentage of total CK) have been used, although neither is sufficiently sensitive to safely exclude AMI in the ED. These researchers compared the predictive values of the CK-MB relative index and the initial absolute CK-MB for diagnosing AMI, ACS, and serious cardiac events (SCEs) in consecutive adult patients who presented to the ED with chest pain and underwent electrocardiography.

Over one year, 2028 patients (mean age, 52.7; 59.9% women) were prospectively enrolled. Samples for CK-MB testing were obtained at the time of presentation. SCEs were defined as cardiac death, AMI, dysrhythmia, congestive heart failure, angioplasty, stenting, or cardiac bypass surgery within 30 days. Overall, 1256 patients (61.9%) had a chief complaint of chest pain, 105 (5.2%) had AMIs, 266 (13.1%) had ACSs, and 150 (7.4%) had SCEs. The absolute CK-MB was more sensitive but less specific than the CK-MB relative index for detecting AMI (sensitivity, 52.0 vs. 46.9; specificity, 93.2 vs. 96.1), ACS (sensitivity, 23.5 vs. 20.8; specificity, 93.1 vs. 96.1), and SCE (sensitivity, 39.6 vs. 36.0; specificity, 93.3 vs. 96.3). However, the CK-MB relative index had a higher positive predictive value for all three outcomes.
Comment

Because only patients with chest pain were enrolled in this study, some atypical presentations of AMI were excluded. The reality is that these tests are of no value in excluding ACS in the ED because they identify MI, not ACS, and because they have very low sensitivity for identifying MI in the ED time frame. A negative CK-MB test result in a patient with chest pain should not be interpreted as support for discharge.

-- Kristi L. Koenig, MD, FACEP
Source

Capellan O et al. Prospective evaluation of emergency department patients with potential coronary syndromes using initial absolute CK-MB vs. CK-MB relative index. J Emerg Med 2003 May; 24:361-7.

Obesity, HRT, and Reflux

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 08/18/2003

Summary

Results of recent population-based studies have shown little or no association between increased body-mass index (BMI) and gastroesophageal reflux symptoms. Furthermore, data on an association between weight reduction and reflux have been mixed, and studies on this topic have been flawed by observational biases. In one investigation (Scand J Gastroenterol 2002; 37:626), researchers demonstrated a strong association between increased BMI and reflux esophagitis in women -- an association further strengthened in women who were using hormone-replacement therapy (HRT). To reexamine the relation between BMI and reflux symptoms and to determine HRT's effect on this association, the same group has now performed a population-based, cross-sectional, case-control study (among 3113 adults with and 39,872 without reflux symptoms) using Norwegian public health survey data from 1984-1986 and 1995-1997.

Reflux symptoms were significantly more common in severely obese (i.e., BMI >35) men and women than in normal-weight individuals (odds ratios, 3.3 for men and 6.3 for women). Among severely obese women, risk for reflux symptoms was significantly greater before than after menopause (ORs, 6.8 and 4.2, respectively); it was also greater for women who had ever used HRT than for those who had not (ORs, 16.0 and 5.5, respectively). The effect of HRT, independent of obesity, was not statistically significant. Weight loss during the interval between the 2 surveys reduced risk for reflux compared to no weight loss (OR, 0.6 with weight loss >3.5 BMI units).

Comment

This well-designed study reopens the issue of obesity as a risk factor for reflux symptoms and provides new evidence about the effects of HRT on this association. Although the authors carefully account for potential confounding effects (e.g., age, smoking, alcohol consumption), for some reason, they do not include use of reflux medications in their analysis. Also, it is extremely difficult to examine the independent effect of weight reduction without controlling for other related factors (e.g., diet, interaction with healthcare providers, physical-activity level). Hence, the results do not provide definitive answers about all aspects of the association between obesity and reflux symptoms.

-- David A. Johnson, MD
Source

Nilsson M et al. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. JAMA 2003 Jul 2; 290:66-72.

Acute Otitis Media: Do the Current Guidelines Work?

from Journal Watch
Physician-authored summaries and commentary
from the publishers of the New England Journal
of Medicine

Posted 08/19/2003

Summary

Concerns about resistant Streptococcus pneumoniae, frequent treatment failures and relapses, and lack of specific bacteriologic information for individual patients make the treatment of acute otitis media (AOM) one of the most frustrating issues in daily practice. The CDC and the AAP recommend that high-dose amoxicillin be used to treat AOM in areas with high levels of S. pneumoniae resistance. These researchers used tympanocentesis to evaluate this recommendation and to examine treatment failures.

Fifty patients with AOM and tympanocentesis-proven bacterial disease (age range, 3 months to 36 months) were treated with 80 mg/kg/day of amoxicillin for 10 days. Each patient underwent a second tympanocentesis between days 3 and 5. The overall bacterial eradication rate was 82%, and most failures involved beta-lactamase-positive Haemophilus influenzae. Only 3 patients (6%) experienced clinical failure. Seven of 35 children who were followed for 1 month (20%) experienced relapse; the middle ear fluid in these patients contained both old and new pathogens.

Comment

These authors provide excellent bacteriologic evidence that our current strategy for AOM is working. For the few patients who don't respond to high-dose amoxicillin, the logical next step is to add a beta-lactamase inhibitor to the regimen. Although S. pneumonia resistance continues to be worrisome, the bacteriologic evidence shows that most failures can be treated with amoxicillin-clavulanate and that the need to resort to ceftriaxone therapy is rare.

-- Peggy Sue Weintrub, MD
Source

Piglansky L et al. Bacteriologic and clinical efficacy of high dose amoxicillin for therapy of acute otitis media in children. Pediatr Infect Dis J 2003 May; 22:405-12.

Risk of Life-Threatening Asthma Seen With Salmeterol

Medscape Staff Report

Aug. 19, 2003 — New safety information and warnings have been added to the labeling for drug products that contain salmeterol, a long-acting bronchodilator used to treat asthma and chronic obstructive pulmonary disease (COPD), according to a U.S. Food and Drug Administration (FDA) Talk Paper released last week. The new labeling includes a boxed warning about a small, but significant, increased risk of life-threatening asthma episodes or asthma-related deaths observed in patients taking salmeterol in a recently completed large U.S. safety study.

In January, GlaxoSmithKline halted a trial of salmeterol, the Salmeterol Multi-center Asthma Research Trial (SMART), which compared the effects of salmeterol (Serevent Inhalation Aerosol, 42 µg twice daily) with placebo in patients with asthma for a period of 28 weeks. The preliminary results of an interim analysis showed an increased risk of life-threatening adverse events in those treated with the drug compared with placebo.

The trial showed a higher number of asthma-related deaths (13 vs. 4), and a higher number of asthma-related deaths or life-threatening experiences (36 vs. 23) in the salmeterol group compared with placebo. The SMART study was not prospectively designed to analyze differences in outcome based on demographic characteristics; however post-hoc subgroup analyses based on race and ethnicity were conducted. These analyses showed no increase in respiratory- or asthma-related events among white patients; but among African-American patients there was a statistically significant increase in primary events (respiratory-related death of life-threatening experience) in the salmeterol group (20 vs. 7). In addition, the occurrence of asthma-related death (8 vs. 1) and asthma-related death or life-threatening experience (19 vs. 4) was statistically significantly greater in African-American patients treated with salmeterol compared with placebo.

According to the FDA, "the benefits of treatment with salmeterol in patients with asthma and COPD continue to outweigh the potential risks when used according to the instructions contained in the product labeling."

Reviewed by Gary D. Vogin, MD