High intake of processed meat linked to cancer deaths

Bacon, sausage, and ham are once again being singled out as key culprits driving the association between meat consumption and the world's most common diseases.

One of the largest studies to address this question, published online March 7 in BMC Medicine, found a moderate positive association between processed meat consumption and mortality. This was particularly true for cardiovascular diseases (CVDs), but was also true for cancer.

Over a mean of 12 years, high consumption of processed meat was associated with a near doubling of the risk for all-cause mortality in adults, compared with low consumption. The risk for cancer death was 43% higher and the risk for cardiovascular death was 70% higher in people eating more than 160 g/day of processed meats than in those eating 10.0 to 19.9 g/day.

"The clinical message [is] to limit consumption of processed meat — not every day and not in high amounts," said lead author Sabine Rohrmann, PhD, MPH, head of the Department of Epidemiology and Prevention at the University of Zurich in Switzerland, in an interview.

EPIC data
The new data come from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which involved 10 countries and almost half a million men and women.

A signal of increased mortality was seen in the highest consumers of red meat in general; however, the risk was much lower with red meat than with processed meats, and lost statistical significance after correction for measurement error, the researchers report. In fact, the high consumption of processed meat was associated with an 18% increased risk for all-cause mortality.

After multivariate adjustment, the consumption of more than 160 g/day of red meat was related to higher all-cause mortality than the consumption of 10.0 to 19.9 g/day (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01 to 1.28). The HR was higher for more than 160 g/day of processed meat (1.44; 95% CI, 1.24 to 1.66).

After correction for measurement error, all-cause mortality remained significantly higher only for the consumption of 50 g/day of processed meat (HR, 1.18; 95% CI, 1.11 to 1.25).

A very high consumption of red meat was nonsignificantly associated with increased cancer mortality, but not with deaths caused by CVD or respiratory diseases, diseases of the digestive tract, or any other disease.

As the researchers point out, processed meats tend to contain more saturated fat than unprocessed meat (where the fat is often trimmed off) and more cholesterol and additives (which are part of the smoking or curing process). Some of these are believed to be carcinogenic or precursors to carcinogenic processes.

When the researchers re-examined the association between processed meat intake and cancer risk using the lowest consumption category (0.0 to 9.9 g/d) as a reference, they observed a statistically significantly increased risk for cancer mortality in people who consumed 80.0 to 159.9 g/day (HR, 1.12; 95% CI, 1.01 to 1.24). There was also a nonsignificantly increased risk in the highest consumption category (HR, 1.19; 95% CI, 0.93 to 1.51).

"Another factor is the salt in processed meat products, which is linked to hypertension — a CVD risk factor," noted Dr. Rohrmann. Heme iron also links meat consumption to CVD risk, "but that's not limited to processed meat," she explained.

Dr. Rohrmann and colleagues point out that the high consumption of processed meat typically goes hand in hand with other unhealthy behaviors, including smoking, low levels of physical activity, and low consumption of fruit and vegetables.

"Overall, we estimate that 3% of premature deaths each year could be prevented if people ate less than 20 g of processed meat per day," she said in a press statement.

What about red meat?
Other studies have singled out processed meats as being particularly hazardous to health. Two large long-running American studies have documented the link between meat consumption and CVD and cancer deaths. However, the stronger association with processed meats that Dr. Rohrmann and colleagues found in their European cohort is somewhat at odds with the American data.

A number of studies have examined the link between meat consumption and cancer. For example, one large prospective trial linked the consumption of processed meat to an increased risk for bladder cancer. Another study found that the consumption of red and processed meats increases the risk for colorectal cancer.

"Although we did not find a statistically significant association between unprocessed red meat consumption and mortality in our studies, we would not say that there is definitely no association" between red meat consumption and CVD, Dr. Rohrmann explained.

"Our studies show it that it's okay to eat a moderate amount of meat (300 to 600 g per week), as recommended by many nutrition societies," she said. However, "a balanced vegetarian diet is okay as well," she added.

Significant association with processed meat
In their study, Dr. Rohrmann and colleagues examined the association between risk for early death and the consumption of red meat, processed meat, and poultry. The 448,568 study participants were 35 to 69 years of age, and had no prevalent cancer, stroke, or myocardial infarction, and had complete information on diet, smoking, physical activity, and body mass index.

A total of 26,344 study participants (11,563 men and 14,781 women) died during the median follow-up period of 12.7 years; 5556 died of CVD, 9861 of cancer, 1068 of respiratory diseases, 715 of digestive tract diseases, and 9144 of other causes.

The researchers note that, according to their estimates, "3.3% (95% CI, 1.5% to 5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g/day."

The consumption of poultry was not related to all-cause mortality.

Source: http://www.medscape.com/viewarticle/780553?nlid=29163_1301&src=wnl_edit_dail

Domperidone under scrutiny in Europe for cardiac risks

European Union (EU) drug regulators announced yesterday that they have begun a review of domperidone, an antiemetic, because of concerns about adverse cardiac events, including QT prolongation and arrhythmias.

Domperidone-containing antiemetics, sold under brand names such as Motilium (Janssen), Mirax (Berlin), and Domper(Opalia, YSP, and Yung Shin), are widely available over the counter or by prescription in a number of European countries. The drugs also have been used on an off-label basis to increase lactation in breast-feeding mothers.

The US Food and Drug Administration (FDA) has not approved domperidone for any indication. In 2004, the FDAwarned clinicians and breast-feeding mothers not to use domperidone to boost milk production because of the risk for adverse events. The agency cited reports of cardiac arrhythmias, cardiac arrest, and sudden death in patients receiving an intravenous form of domperidone that has been discontinued in several countries. However, the European Medicines Agency (EMA) — the EU equivalent of the FDA — continued to receive reports of these adverse events with other forms of the drug.

The FDA noted in 2004 that breast-feeding women in the United States were buying the drug from Internet pharmacies and US compounding pharmacies. The FDA sent warning letters to 6 such compounding pharmacies about the illegal trade in domperidone. A similar letter was issued in 2010 to a compounding pharmacy in Virginia. However, Internet pharmacies still continue to advertise the drug.

The EMA said yesterday that it began its review of domperidone at the request of drug regulators in Belgium, who learned of new cases of cardiotoxicity. Those regulators have proposed that the drug be contraindicated for patients with QT prolongation, significant electrolyte disturbances, or underlying cardiac diseases such as congestive heart failure.

The EMA said that its Pharmacovigilance Risk Assessment Committee will study domperidone-containing drugs, assess whether their benefits outweigh their risks, and recommend possible regulatory action, which could include withdrawing the drugs from the market or revising their label instructions.

Male-pattern baldness linked with heart disease

Vertex baldness, more commonly known as male-pattern baldness, is associated with an increased risk of coronary heart disease, according to the results of a new meta-analysis[1]. The severity of male pattern baldness increased the risk of coronary disease even in younger subjects, report investigators.

A receding hairline, on the other hand, was not associated with an increased risk of heart disease (relative risk 1.11, 95% CI 0.92–1.32; p=0.28).

"These findings suggest that vertex baldness is more closely associated with systemic atherosclerosis than . . . frontal baldness [is]," say Dr Kazuo Hara (University of Tokyo, Japan) and colleagues in their report, published online April 3, 2013 in BMJ Open. "Thus, cardiovascular risk factors should be reviewed carefully in men with vertex baldness, especially younger men, and they probably should be encouraged to improve their cardiovascular risk profile."

The researchers included six studies with 36 990 participants in the meta-analysis, including three cohort studies and three case-control studies. In the three cohort studies, the adjusted risk of coronary heart disease was 32% higher among individuals with severe vertex baldness compared with men with full hair. In the case-control studies, the risk of coronary heart disease was 70% higher among bald subjects compared with those without baldness. The increased relative risk of coronary disease was statistically significant in both analyses. When the analysis was restricted to younger subjects, those <55 or <60 years at baseline, the association between vertex baldness and coronary heart disease remained.

Three studies classified the severity of baldness. In this analysis, the risk of coronary heart disease was 48%, 36%, and 18% higher among subjects with severe, moderate, and mild vertex baldness compared with subjects without baldness. "When baldness was classified by the Hamilton-Norwood scale, which is the most commonly used classification of pattern baldness worldwide, the relationship between coronary heart disease and baldness was shown to be dependent on the severity of baldness," state the researchers.

The reason for the association between vertex baldness and coronary heart disease is not known. The current working hypothesis is that insulin resistance can impair the supply of nutrients to the hair follicles or a proinflammatory state could increase the inflammatory cytokines in the hair follicles. The researchers state that further studies are needed to confirm these findings, as well as to identify mechanisms for the association.

Source: http://www.medscape.com/viewarticle/781931?nlid=30099_1301&src=wnl_edit_dail

Omega-3 plasma levels predict mortality and heart disease

The highest levels of plasma phospholipid omega-3 polyunsaturated fatty acids (PUFA), as measured in over 2,500 older adults initially without coronary heart disease or a history of stroke, predicted the lowest mortality in the observational, prospective Cardiovascular Health Study(CHS)[1].

In comparisons of the highest quintile of omega-3 PUFA levels vs the lowest quintile, all-cause mortality fell by 27%, with most of the benefit due to a reduction in cardiovascular death. The rate of arrhythmic death, in particular, fell by nearly one-half.

Such cardiovascular-outcome effects are consistent with abundant evidence from laboratory and clinical studies that omega-3 PUFA intake may benefit heart rate, blood pressure, myocardial contractile function and electrical stability, and endothelial, autonomic, and hemostatic function, write the study's authors, led by Dr Dariush Mozaffarian (Harvard School of Public Health, Boston, MA). Their analysis was published in the April 2, 2013 issue of the Annals of Internal Medicine.

The CHS longitudinal data allowed the group not only to link plasma omega-3 PUFA levels with survival, Mozaffarian told heartwire , it allowed them to estimate the benefit: in this population, starting at age 65, he said, about 2.2 extra years for people in the highest compared with the lowest plasma-level quintile.

Outcomes also varied by individual omega-3 PUFAs. For a number of end points, importantly heart-disease mortality and arrhythmic mortality, there was a pattern of greater benefit from highest levels of docosahexaenoicacid (DHA) vs highest levels of eicosapentaenoic acid (EPA) and an even greater benefit from highest levels of total omega-3 PUFA.

For the end point of heart-disease death, "DHA seems to have stronger association" than EPA, according to Mozaffarian; the effect, he noted, appears to be dominated by a difference in arrhythmic death. But EPA at the highest levels vs the lowest levels showed a weakly significant trend (p=0.04) of benefit for nonfatal MI, while DHA and total omega-3 PUFA were unquestionably nonsignificant. Still, he said, given the "borderline" p value for EPA, "maybe none of them are significantly associated" with respect to nonfatal MI.

That outcomes varied by type of omega-3 PUFA has implications for dietary recommendations as well as therapeutic preparations of omega-3 PUFA.

"I think that our results support DHA, in particular, being important for heart-disease death and leaves open the question of whether EPA . . . [has] additional benefit." Consuming both together is probably wise, as there appear to be "complementary effects," Mozaffarian said. Based on the current analysis, "If you're going to consume omega-3s, you should at least be sure you're getting DHA. EPA alone might not have the same benefit; I think that's fair to say."

The CHS enrolled 5201 adults aged >65 years in four US communities, two in the East and one in California from 1989 to 1990, plus 687 additional African Americans from 1992 to 1993. The current analysis includes 2692 without CHD, stroke, or heart failure at baseline who were not taking fish-oil supplements and in whom levels of plasma phospholipid omega-3 PUFA were measured in 1992–1993. Their mean age at baseline was 74 years, 64% were women, and 88% were white; they were followed until 2000.

The adjusted hazard ratio (HR) for total mortality was 0.83 for the highest quintile of EPA vs the lowest quintile (p=0.005), 0.80 for DHA (p=0.006), and 0.73 for total omega-3 PUFA (p<0.001).

Decreases in HR for total heart-disease mortality were significant only for DHA (p=0.003) and total omega-3 PUFA (p=0.002). The same was true for arrhythmic death: DHA (p=0.028) and total omega-3 PUFA (p=0.008).

Acknowledging that "this is an observational study--it doesn't prove cause and effect," Mozaffarian said that it at least supports high plasma levels of omega-3 PUFAs as directly affecting survival. "If there was confounding--if it was just that people were more educated or had healthy lifestyles--you'd expect that higher [omega-3 PUFA plasma levels] would relate very similarly to a lower risk of every kind of death: [including] respiratory death, infectious death, cancer death, and stroke death. But the bulk of the association seems to be from heart-disease death, and [especially] heart disease death from arrhythmia."

As for the possible advantage high plasma DHA levels may have over high EPA levels with respect to total and heart-disease mortality, which would conceivably conflict with the higher elevations in LDL cholesterol observed with DHA vs EPA supplementation, Mozaffarian said doesn't see a paradox.

"The LDL-raising effect of omega-3s is very modest." If there is any such effect, he said, "it's to make the particles larger and fluffier and therefore potentially less atherogenic." According to Mozaffarian, "it's just hype" to say that an omega-3 PUFA supplement that delivers only EPA should be preferred over a mixed EPA/DHA supplement because of a difference in LDL effects.

In addition to many brands of nonprescription mixed EPA/DHA supplements on the market, in the US there is the prescription-only mixed formulation Lovaza (GlaxoSmithKline); and just last year, the FDAapproved the synthetic EPA-only preparation Vascepa (Amarin), which contains ethyl eicosapentaenoic acid.

Source: http://www.medscape.com/viewarticle/781931?nlid=30099_1301&src=wnl_edit_dail

Dietary nitrate in beet lowers blood pressure

A small, proof-of-principle study has demonstrated that the blood-pressure lowering effects of dietary nitrates--already documented in normotensives--are also seen in subjects with established hypertension[1].

Dr Amrita Ahluwalia (Barts and the London School of Medicine and Dentistry, UK) and colleagues have a track record of studying the interaction between dietary sources of biologically inert nitrate (NO3) and oral microflora, which converts the NO3 into bioactive nitrite (NO2). Circulating NO2 is known to cause vasodilation and lower blood pressure. Ahluwalia et al have previously proposed a pathway for nitrate-nitrite conversion, showing that beet juice, after coming into contact with human saliva, increases levels of plasma nitrate and nitrite, and leads to significant blood-pressure decreases in healthy volunteers.

In their latest study, published online April 15, 2013 in Hypertension, Ahluwalia and colleagues, including senior author Dr Suborno Ghosh (Queen Mary University of London, UK) turned again to beetroot, which, along with green leafy vegetables, has high concentrations of inorganic nitrate. In a mouse model of hypertension, investigators first established a threshold nitrite dose at which blood pressure decreased in the hypertensive mice, but not in normotensive control mice. At higher doses, however, both strains of mice saw blood-pressure decreases.

The authors then tested the beet-juice effects in 15 hypertensive, drug-naive patients, randomized to either 250ml of inorganic nitrate-rich beetroot juice or an equal volume of water. The "dose" of juice elevates nitrite levels approximately 1.5 fold--a rise previously shown to have no significant BP-lowering effect in subjects with normal blood pressure.

In patients who drank the juice, systolic blood pressure dropped by a mean of 11.2 mm Hg between three and six hours after consumption (vs 0.7 mm Hg in subjects who drank water). By 24 hours, clinic systolic BP remained significantly lower in the beet-juice group and roughly 7.2 mm Hg lower than baseline. Peak drop in diastolic BP also occurred within the first six hours, dropping by a mean of 9.6 mm Hg. Pulse-wave velocity also decreased in the beet-juice group, but not in the controls.

"Our observations . . . support the concept of dietary nitrate supplementation as an effective, but simple and inexpensive, antihypertensive strategy," the authors conclude.

Ahluwalia underscored the finding that nitrate in beets appears to be even more potent in hypertensives than in normotensives. "In this new study we used a dose that had little to no effect upon blood pressure in healthy volunteers; in contrast, this dose caused a substantial decrease in blood pressure (~12 mm Hg) in the patients, suggesting that dietary nitrate is more potent, and therefore potentially one needs less to produce an important blood-pressure–lowering effect."

She added: "It is also true that while we all know that eating fruits and vegetables is good for the cardiovascular system, exactly why this is the case is not certain. Studies have shown that of all the different fruit and vegetables out there it is the green leafy vegetables that provide the greatest protection against heart attacks and strokes. What is true about these vegetables is that they represent the major source of nitrate in our diet."

She also stressed the limitations of the study: while "impressive," the BP-lowering effects of beet juice consumption were measured only over 24 hours and in very small numbers. "Whether this effect can be sustained in the long term is not yet known, and further clinical studies that assess the effects over longer periods of time and in larger cohorts are needed," she said.

Source: http://www.medscape.com/viewarticle/782590?nlid=30483_1301&src=wnl_edit_dail

Carnitine in red meat ups atherosclerosis risk via gut flora

Research in mice and human volunteers has suggested a mechanism that may contribute to an association between eating red meat and increased risk of cardiovascular disease[1]. It involves microbes in the gut.

People who regularly eat red meat have an increased colonization of intestinal bacteria that break down the carnitine in red meat into a metabolite that promotes increased cholesterol deposition in the artery wall, the researchers report. Their study was published online April 7, 2013 inNature Medicine.

Energy drinks are another major source of carnitine. If someone regularly eats red meat or drinks energy drinks, "microbes that like carnitine become more abundant [in the gut], and now you are much more capable of making this metabolite . . . trimethylamine-N-oxide (TMAO)," he said. "This paper showed [that TMAO] . . . essentially leads to an enhanced capacity to deposit cholesterol on the cells of your artery wall."

Previously, the researchers showed that dietary choline and phosphatidylcholine (lecithin) are metabolized in mice and humans by intestinal microbes to produce trimethylamine, which is rapidly metabolized to TMAO, which is linked to accelerated atherosclerosis. Hypothesizing that carnitine, which has a similar molecular structure to choline, behaves this way, the researchers performed a series of experiments.

Carnitine linked to TMAO levels
First, they showed, for what they believe is the first time, that humans need gut microbes to form TMAO from dietary carnitine. After an overnight fast, volunteer omnivores were given a carnitine challenge--they were fed a capsule of carnitine plus an 8-oz sirloin steak--and their TMAO plasma and urine levels were measured. The volunteers were then given oral, broad-spectrum antibiotics for a week to suppress their gut microbes, after which they received a second carnitine challenge. Then after three weeks to allow their gut organisms to repopulate, they received a third carnitine challenge. Their TMAO levels were almost undetectable after the antibiotic regimen, but the levels rebounded after their gut flora repopulated.

The researchers also showed that after ingesting carnitine capsules, vegans and vegetarians produced markedly lower levels of TMAO than omnivores.

TMAO, not carnitine, drives CVD
Next, in a cohort of 2595 subjects undergoing elective cardiovascular evaluation, the researchers determined that increased plasma carnitine was associated with increased risk of having or soon developing CAD, peripheral artery disease (PAD), or other CVD. However, after adjustment for traditional cardiovascular risk factors, an elevated carnitine concentration predicted a higher three-year risk of MI, stroke, or death only in subjects with high plasma TMAO levels. Thus TMAO, not carnitine, drives the cardiovascular outcomes, the researchers conclude.

Their mouse studies suggest a possible, multifaceted mechanism for the development of atherosclerosis. In mice, dietary carnitine promoted cholesterol buildup in the artery wall, which was completely inhibited after treatment with an antibiotic cocktail. In other mice with intact intestinal microbes, receiving TMAO and carnitine or lecithin led to inhibition of the reverse cholesterol transport pathway.

For now, eat well; in future, also take a pill?
Does this mean that physicians should advise all their patients to become vegetarians and avoid drinking energy drinks? Hazen says that people need to be aware that "a can of an energy drink can have more carnitine than a porterhouse steak." Carnitine is obtained from many sources, since it is derived from lysine, the most abundant amino acid in animal and vegetable protein in the diet, he noted.

For now, "it makes sense to adhere to a lower-cholesterol, lower-saturated-fat diet [that will be] more heart healthy in terms of decreasing the nutrients that give rise to forming TMAO, [since] this may be one of the hidden contributors to heart disease."

In the future, there might be a TMAO test and a drug that targets TMAO, Hazen speculated. "Measuring TMAO can be a very strong predictor of cardiovascular risk, and it will become a test that is available for clinical use in the future," he hypothesized. "Down the road, we think we are going to be able to go after this, just like we take a statin . . . to decrease the [risk of] development of heart disease."

Source: http://www.medscape.com/viewarticle/782236?nlid=30183_1301&src=wnl_edit_dail

Green tea and coffee protects against stroke

Green tea and coffee consumption may help protect against stroke, according to a large Japanese population-based study.

The study showed that people who drank green tea or coffee regularly had about a 20% lower risk for stroke than their peers who seldom drank these beverages.

"This is the first large-scale study to examine the combined effects of both green tea and coffee on stroke risks," Yoshihiro Kokubo, MD, PhD, head of the Department of Preventive Cardiology, National Cerebral and Cardiovascular Center in Osaka, said in a statement.

Their findings were published online March 14 in Stroke.

Inverse link
The study involved 82,369 Japanese adults aged 45 to 65 years without cardiovascular disease or cancer at baseline who were followed for a mean of 13 years. "Green tea and coffee consumption was assessed by self-administered food-frequency questionnaire at baseline," Dr. Kokubo toldMedscape Medical News.

During more than 1 million person-years of follow-up, the researchers documented 3425 strokes (1964 cerebral infarctions, 1001 intracerebral hemorrhages, and 460 subarachnoid hemorrhages) and 910 coronary heart disease (CHD) events (489 definite myocardial infarctions and 28 sudden cardiac deaths).

In multivariate analysis, higher coffee and green tea consumption were inversely associated with risk for cardiovascular disease (CVD) and stroke.

For example, people who drank at least 1 cup of coffee daily had a 20% lower risk for any stroke (adjusted hazard ratio [aHR], 0.80; 95% confidence interval [CI], 0.72 - 0.90) compared with those who seldom drank coffee.

People who drank 2 to 3 cups of green tea daily had a 14% lower risk for any stroke (aHR, 0.86; 95% CI, 0.78 - 0.95), and those who consumed at least 4 cups had a 20% lower risk (aHR, 0.80; 95% CI, 0.73 - 0.89), compared with those who seldom drank green tea.

The risk reduction for intracerebral hemorrhage was 17% (aHR, 0.83; 95% CI, 0.68 - 1.02) with consumption of at least 1 cup of coffee daily and 23% (aHR, 0.77; 95% CI, 0.63 - 0.92) for 2 cups of green tea daily compared with rare consumption of either beverage.

There was no significant association between coffee and tea consumption and CHD, largely mirroring findings from other studies.

Experts weigh in
Victoria J. Burley, PhD, senior lecturer in nutritional epidemiology, School of Food Science and Nutrition, University of Leeds, United Kingdom, who wasn't involved in the study, called it "very interesting."

She noted that "both high-fiber foods and these particular beverages may have anti-inflammatory properties. Whole grains, fruit and vegetables, and these beverages are all rich in polyphenols, which appear to have multiple potential actions on markers of CVD risk: blood pressure, glucose homeostasis, lipid metabolism, and so on."

"This appears to be a well-conducted study," Dr. Burley said, "with good power (plenty of cases), with long follow-up and a respectable method of assessing green tea and coffee intake (for these dietary aspects I think an FFQ [food-frequency questionnaire] is likely the best approach)."

She cautioned, however, that the intakes of green tea in this Japanese cohort "far exceed" usual consumption in western populations and that, conversely, intakes of coffee may generally be somewhat lower in Japan.

"The highest coffee intake category was 2-3 cups per day, which is not particularly high. Other studies (eg, conducted in Sweden) have reported elevated CVD risk in people with much higher intakes ( > 7 cups per day), so in setting their highest category this low these study authors may not have been able to pick up evidence of increased CVD risk with greater intakes," Dr. Burley said.

"Overall, it's encouraging data that suggest people who incorporate coffee and green tea in their diet may experience lower CVD risk in later life," she added.

Commenting on the coffee findings, Susanna C. Larsson, PhD, from the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, found it "interesting that such a small amount as 1 cup of coffee per day reduces the risk of stroke by 20% (quite a large reduction in risk)."

"Otherwise, this Japanese study confirms results from studies conducted in the US and Europe showing an inverse association between coffee consumption and stroke risk. This study adds further support that moderate coffee consumption may lower the risk of stroke," said Dr. Larsson, who was not involved in the study.

Physical therapy as effective as surgery for meniscal tear

Patients with knee osteoarthritis and a meniscal tear who received physical therapy without surgery had good functional improvement 6 months later, and outcomes did not differ significantly from patients who underwent arthroscopic partial meniscectomy, a new clinical trial shows.

In the Meniscal Tear in Osteoarthritis Research (METEOR) trial, both groups of patients improved substantially in function and pain.

This finding, presented here at the American Academy of Orthopaedic Surgeons 2013 Annual Meeting and published online simultaneously in the New England Journal of Medicine, provides "considerable reassurance regarding an initial nonoperative strategy," the investigators report.

Patients with a meniscal tear and osteoarthritis pose a treatment challenge because it is not clear which condition is causing their symptoms," principal investigator Jeffrey Katz, MD, from Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.

"These data suggest that there are 2 reasonable pathways for patients with knee arthritis and meniscal tear," Dr. Katz explained. "We hope physicians will use these data to help patients understand their choices."

In an accompanying editorial, clinical epidemiologist Rachelle Buchbinder, PhD, from the Monash University School of Public Health and Preventive Medicine in Victoria, Australia, said that "these results should change practice. Currently, millions of people are being exposed to potential risks associated with a [surgical] treatment that may or may not offer specific benefit, and the costs are substantial."

These results should change practice.

The METEOR trial enrolled 351 patients from 7 medical centers in the United States. Eligible patients were older than 45 years, had osteoarthritic cartilage change documented with magnetic resonance imaging, and had at least 1 symptom of meniscal tear, such as knee clicking or giving way, that lasted at least 1 month despite drug treatment, physical therapy, or limited activity.

In this intent-to-treat analysis, investigators randomly assigned 174 patients to arthroscopic partial meniscectomy plus postoperative physical therapy and 177 to physical therapy alone.

The physical therapy in both regimens was a standardized 3-stage program that allowed patients to advance to the next intensity level at their own pace, Dr. Katz explained. The program involved 1 or 2 sessions a week for about 6 weeks and home exercises. The average number of physical therapy visits was 7 in the surgery group and 8 in the nonsurgery group.

Investigators evaluated patients 6 and 12 months after randomization. The primary outcome was the between-group difference in change in physical function score from baseline to 6 months, assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). At baseline, demographic characteristics and WOMAC physical function scores were similar in the 2 groups.

At 6 months, improvement in the WOMAC function score was comparable in the 2 groups. The mean between-group difference of 2.4 points was not statistically significant after analysis of covariance. There was also no significant difference between groups in pain improvement or frequency of adverse events.

There was 1 death in each group, and 8 patients in the nonsurgery group and 13 in the surgery group withdrew in the first 6 months of the study.

Patients in the nonsurgery group were allowed to cross over to the surgical group at any time. Within 6 months, 30% of patients did so.

"They were not doing very well," Dr. Katz said. His team is still analyzing the reasons these patients did not benefit from intensive physical therapy.

The 12-month results were similar to the 6-month results. In addition, by 12 months, outcomes for the crossover patients and for those in the original surgery group were similar.

Meeting delegate John Mays, MD, an orthopaedic surgeon practicing in Bossier City, Louisiana, who was asked by Medscape Medical News to comment on the findings, said most patients don't choose physical therapy. "In the real world, most people want a quick fix" and choose surgery, he noted.

Dr. Mays said he would have liked to have seen a group of patients who underwent surgery but did not receive postoperative physical therapy. He explained that his patients with osteoarthritis and meniscal tear rarely get physical therapy after arthroscopic meniscectomy; they most often do home-based exercises.

He added that "most insurance plans have limits on the number of physical therapy sessions they allow."

Source: http://www.medscape.com/viewarticle/781102?nlid=29464_1301&src=wnl_edit_dail

Women with low melatonin levels more likely to develop type 2 diabetes

Women secreting low levels of melatonin are more likely to develop type 2 diabetes than those who have higher levels of this hormone, new observational research shows.

"This case-control study is the first prospective evaluation of the link between melatonin secretion and type 2 diabetes and demonstrates an independent association between the 2," lead author Ciaran J. McMullan, MD, from Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News. He and his colleagues report their findings in the April 3 issue of the Journal of the American Medical Association.

"What's fascinating is that cases of diabetes had lower levels of melatonin secretion than controls," Dr. McMullan noted, "and when we compared the lowest category of melatonin secretion with the highest, they had double the risk of diabetes, even after adjustment for many potential confounding factors.

"We've shown that [melatonin] is a risk factor, but we are really interested to see whether it is a modifiable risk factor," he added, noting that the clinical relevance of these findings is currently "unclear; this won't change clinical practice, but it causes us to ask 2 important questions."

First, it should stimulate more research into what can influence melatonin secretion, he said, and second, "if we were to change an individual's melatonin secretion or melatonin levels, do we then change their risk of developing type 2 diabetes?"

Dr. McMullan said the next logical step would be to conduct further studies to see whether increasing melatonin levels — either endogenously via prolonged nighttime dark exposure or exogenously via supplementation — can increase insulin sensitivity and decrease the incidence of type 2 diabetes.

Melatonin levels lower in diabetes cases than controls
Dr. McMullan and colleagues explain that the pineal gland secretes melatonin in response to light exposure, following a diurnal pattern, with levels typically peaking 3 to 5 hours after sleep onset when it is dark. During daylight hours, there is almost no production of melatonin.

Melatonin receptors have been found throughout the body, including in pancreatic islet cells, and several lines of evidence — including animal work and human genomewide-association studies — suggest that the hormone may play a role in glucose metabolism. There have also been a number of cross-sectional studies in humans suggesting a protective effect of melatonin regarding diabetes development, but these have been small "and difficult to interpret," said Dr. McMullan.

In their prospective study, the researchers assessed participants in the Nurses' Health Study who, at baseline in 2000, did not have diabetes and who had provided blood and urine samples. They then identified 370 women who developed type 2 diabetes (self-reported) from 2000 to 2012 and matched them with 370 controls.

Associations between melatonin secretion at baseline — determined from morning urine samples — and incidence of type 2 diabetes were evaluated after researchers controlled for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction.

The median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg among cases of diabetes and 36.3 ng/mg among controls.

Compared with women in the highest category of 6-sulfatoxymelatonin/creatinine ratio, those in the lowest category had an odds ratio of 2.17 of developing type 2 diabetes.

In absolute terms, the estimated diabetes incidence rate was 9.27 cases/1000 person-years among those in the lowest category of melatonin secretion compared with 4.27 cases/1000 person-years among women in the highest category.

Sleep disruption did not affect association
Dr. McMullan and colleagues note that sleep disruption has also previously been associated with type 2 diabetes. In one study, men who slept less than 5 hours per night were twice as likely to develop diabetes as those who reported sleeping 7 hours a night. Similarly, women who reported snoring on a regular basis were 2.2 times more likely to develop diabetes than women who never snored, even after adjustment for adiposity.

"Consistent with these prior studies, both short sleep duration and snoring frequency were associated with incident type 2 diabetes in our case-control study. Because sleep disruption is also associated with decreased melatonin secretion, it is possible that sleep disruption could confound the association between melatonin and diabetes," they observe.

However, adjustment for sleep duration and snoring frequency in the multivariate analysis "did not significantly alter the association of melatonin secretion with incident type 2 diabetes," they note.

Also, the nurses included in this study were, on average, around 65 years of age, so few of them were still working shifts (only around 4%), Dr. McMullan pointed out. 

Source: http://www.medscape.com/viewarticle/781819

Energy drink consumption negatively affects heart health

Tossing back one to three energy drinks may result in more than just a buzz. A small-meta analysis found that immediately afterward, subjects had increased systolic blood pressure and, more troubling, they also had, on average, a 10-msec prolongation in their QT interval [1].

The study, by Dr Sachin Shah (University of the Pacific, Stockton, CA) and colleagues, was presented at EPI-NPAM 2013, the Epidemiology and Prevention/Nutrition, Physical Activity and Metabolism 2013 Scientific Sessions.

"The blood-pressure finding falls in line with what we would suspect because of the caffeine content," Shah told heartwire . "The QT prolongation that we are seeing--I was very surprised with that. It's a bit of a wake-up call for us investigators to start studying it a bit more thoroughly, and it needs to happen sooner rather than later."

The group aimed to see how energy drinks affect heart health, given that these drinks, along with dietary supplements, are not regulated as stringently as new drugs that must meet Food and Drug Administration (FDA) safety requirements, Shah said.

In a literature search, they identified seven observational and interventional trials that evaluated the impact of energy drinks on QT interval, blood pressure, and heart rate.

Three studies with a pooled sample of 93 subjects had QT/QTc data. Six studies with a pooled sample of 132 subjects had blood-pressure data, and seven studies investigated heart rate.

The patients, who were all young (aged 18 to 45) and healthy, underwent ECG and blood-pressure testing before and just after drinking one to three cans of energy drink--most commonly Red Bull, but also others such as Full Throttle and Meltdown RTD. An 8.4-oz can of Red Bull contains 80 mg of caffeine, compared with 35 mg of caffeine in a 12-oz Coke or about 100 mg of caffeine in an average cup of coffee, Shah said.

Shortly after drinking the energy drinks, the pooled subjects had a systolic blood pressure increase of an average 3.5 mm Hg. "If people are drinking energy drinks every day, that change in blood pressure could be very significant," Shah noted, adding that, as reported by heartwire , research on torcetrapibwas terminated because of a similar 3-mm-Hg increase in blood pressure.

People who don't normally drink coffee might have a heightened blood-pressure response to an energy drink, he added.

In a clinical setting, physicians are usually concerned if a patient has a QT-interval increase of about 30 msec from baseline, Shah noted. He acknowledges that this was a small study, but it did uncover a disturbing signal that needs to be further investigated.

Diastolic BP and heart rate increased nonsignificantly.

Although the 10-msec prolongation in the QT interval is a "small number, if it were consistently produced by a drug being considered by the FDA, the FDA would require more testing to make sure that there was not a liability for producing further, more serious, and life-threatening prolongation of the QT interval and associated arrhythmias," AHA spokesperson and past president Dr Gordon F Tomaselli (Johns Hopkins University, Baltimore, MD) commented.

Both Shah and Tomaselli pointed out that people who are older or who have underlying CVD might have even more heart-related side effects from energy drinks than the young, healthy people in this meta-analysis.

Soy improves lung cancer survival in women

The consumption of soy food before a lung cancer diagnosis might favorably affect disease outcomes in women, according to a longitudinal follow-up study from China.

In the Shanghai Women's Health Study, women with lung cancer who ate low levels of soy daily were at greater risk of dying from lung cancer than those who ate average or higher levels of the Asian food staple over their lifetimes.

Specifically, in 301 women with lung cancer, there was an 81% increased risk for death from lung cancer in those in the 10th percentile of soy intake, compared with those in those in the 50th percentile (the median). In contrast, there was an 11% decreased risk for death in women in the 90th percentile of intake, compared with those in the 50th percentile (P for overall significance = .004).

These effect sizes were found after adjustment for a wide variety of factors, including tumor stage and treatment.

In short, soy might have a disease-modulating effect, say the authors, led by Gong Yang, MD, from Vanderbilt University Medical Center in Nashville, Tennessee.

The study results were published online today in the Journal of Clinical Oncology.

"Plant-derived estrogens, such as isoflavones found mainly in soy food, appear to act as natural selective estrogen-receptor modulators," they write.

Thus, soy could compete with a woman's endogenous estrogens in binding to estrogen receptors, the authors explain. Soy might occupy the receptors so they cannot be stimulated by the body's estrogens.

Dr. Yang and his coauthors point out that emerging evidence suggests that female sex hormones negatively affect lung cancer survival. The evidence includes well-publicized data from the Women's Health Initiative, which showed that estrogen-plus-progestin therapy significantly increased the risk for death from lung cancer.

"Soy may have a mechanism of action similar to drugs like tamoxifen," Jyoti Patel, MD, from Northwestern University in Chicago, Illinois, told Medscape Medical News.

"This is the first scientific evidence that soy has a favorable effect on lung cancer survival," said Dr. Patel, who is a spokesperson for the American Society of Clinical Oncology, and provided independent comment on the study.

"It's really exciting," she summarized.

This study is part of a varied body of research that is seeking "hormonal clues" to lung cancer, she explained.

In 2012, Dr. Yang and colleagues found, in the same 74,000-patient cohort of Shanghai women, an approximately 40% reduction in the risk for incident lung cancer associated with the high intake of soy food. Thus, eating soy could both prevent and alter the disease course of lung cancer.

In the current study, the amount of soy consumed by the 301 women with lung cancer that was most protective (>20 g/day) was "not astronomical," said Dr. Patel. "But you have to make a concerted effort [to eat that much]," she added, referring especially to Westerners, who are less likely to include soy in their diet.

Americans typically consume what the study deemed to be a low level of soy (≤12 g/day), said Dr. Patel, who explained that the study results are "likely more applicable" in Asian countries.

More epidemiologic studies are needed to confirm these results, the authors note.

Almost all were non-smokers
There were actually 440 cases of lung cancer in the 74,000-women Shanghai cohort, but only 301 had information about both tumor stage and treatment. The hazard ratios for the 440 women were less dramatic than those for the 301 women reported above.

For example, in the 440 women with lung cancer, there was a 42% increased risk for death from lung cancer in the women who were in the 10th percentile of soy intake, compared with those in the 50th percentile (the median). In the 301 women, that increase was much larger (81%).

Nevertheless, although the effect sizes varied, the evidence in support of a possible protective effect of soy was constant.

As expected in an Asian population, most of the women with lung cancer (about 92%) were never smokers. Mean age at cancer diagnosis was 66.3 years.

The researchers assessed soy dietary intake with a food-frequency questionnaire, which covered soy milk, tofu, fried tofu, dried or pressed tofu, fresh green soy beans, dry soy beans, soy sprouts, and other soy products.

Mean intakes, on a dry weight basis, were 18.0 g/day for soy food and 8.8 g/day for soy protein.

The authors report that soy food intake was not related to patient characteristics such as age at diagnosis, smoking, obesity, family history of lung cancer, tumor stage, treatment regimens, or time between baseline dietary assessment and disease diagnosis.

In this study, the median follow-up time after cancer diagnosis was 36 months. During the follow-up period, 318 of the 440 women died; in 301 (94.7%), the primary cause of death was lung cancer, and in 17 (5.3%), it was another cause.

3mg melatonin may aid migraine prevention

Melatonin, which is widely available in North America as an over-the-counter supplement, is more effective than placebo for migraine prevention and has a more favorable adverse effect profile than the tricyclic antidepressant amitriptyline, new research shows.

Results from a multicenter, randomized, double-blind, placebo-controlled trial showed that 3 mg of melatonin was more effective than placebo and had efficacy similar to that of 25 mg of amitriptyline. Furthermore, it was better tolerated than amitriptyline, with lower rates of daytime sleepiness and no weight gain.

"Melatonin 3 mg was significantly better than placebo with no difference compared to amitriptyline with respect to migraine prevention," principal investigator Mario Peres, MD, PhD, told delegates here attending the American Academy of Neurology (AAN) 65th Annual Meeting.

"But if we look at the proportion of responders, then melatonin had better results than amitriptyline," added Dr. Peres, who is director of São Paulo Headache Center, professor of neurology at ABC Medical School, and senior research associate at the Albert Einstein Brain Research Institute, Brazil.

Link to headache, sleep disorders
Produced by the pineal gland, melatonin is a hormone that helps regulate the sleep/wake cycle. It has been available as a supplement in the United States since the 1990s and is often used to aid sleep and attenuate jet lag.

According to Dr. Peres, melatonin's role in regulating circadian rhythm has been linked to cluster headache, hypnic headache, and migraine.

Further, he noted, melatonin plays an important role in sleep regulation, and disruption of melatonin production has been linked to sleep disorders, including sleep apnea, insomnia, and delayed sleep phase syndrome, which, in turn, are linked to headache.

He also noted that there is a bidirectional relationship in which headache can disrupt sleep and lead to insomnia and excessive daytime sleepiness.

Finally, he pointed out that research has linked low levels of melatonin in plasma and urine and altered peak time in melatonin levels to a variety of headache types, including migraine.

According to Dr. Peres, research into melatonin as a potential treatment for headache has included several case reports and open-label studies but only 2 randomized controlled trials: 1 in cluster headache, which was positive, and 1 negative trial in migraine.

The negative migraine trial, he said, had several limitations, including a small sample size and a short duration of only 8 weeks. It also used a slow-release, 2-mg formulation of melatonin, and, although the response rate in the melatonin group was 44%, the placebo group had an exceptionally high response rate of 40%.

Surprise weight-loss finding
To test the efficacy and tolerability of melatonin and amitriptyline vs placebo for migraine prevention, the investigators recruited 178 men and women who met International Headache Society diagnostic criteria for migraine with and without aura and who had 2 to 8 migraine attacks per month.

All patients underwent a 4-week baseline phase during which each participant kept a diary of migraine frequency.

Participants were then randomly assigned to receive 3 mg melatonin (n = 60), 25 mg amitriptyline (n = 59), or placebo (n = 59) for 3 months. Medication was taken between 10 and 11 pm daily.

The study's primary outcome was a reduction in the number of headache days per month. Secondary endpoints included migraine intensity and duration and analgesic use. Tolerability was also measured in all 3 study groups.

The mean reduction in headache frequency was 2.7 in the melatonin group, 2.18 in the amitriptyline group, and 1.18 in the placebo group.

Although migraine frequency did not differ between the 2 active treatment groups, the proportion of responders was greatest in the melatonin group: 54% vs 39.1% for amitriptyline and 20.4% for placebo.

Melatonin was also "very tolerable" and had significantly fewer adverse effects compared with amitriptyline, said Dr. Peres. Daytime sleepiness was the most frequent symptom in all 3 groups but was most pronounced in the amitriptyline group (n = 24).

Although patients gained weight in both the amitriptyline (n = 3) and placebo (n = 1) groups, melatonin was associated with weight loss.

Timing of administration and formulation is also important. Ideally, said Dr. Peres, melatonin should be taken between 10 pm and 11 pm to mimic the physiologic peak. In addition, a fast-acting rather than a slow-release formula should be used.

Overall, said Dr. Peres, the study's findings are promising and warrant further research.

Worth a try?
Commenting on the study, Tobias Kurth, MD, director of research Institut national de la santé et de la recherche médicale (INSERM), University of Bordeaux in France, and associate epidemiologist, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, said the researchers "very convincingly" showed that melatonin was as effective as amitriptyline and both were superior to placebo.

"If this is true, this is great," said Dr. Kurth.

Although the study's findings are preliminary and need to be replicated, Dr. Kurth said that given its favorable adverse effect profile, melatonin may be worth a try.

"I'm not aware of any major side effects associated with melatonin. As long clinicians instruct patients appropriately and emphasize the importance of taking the recommended dose at the same time every day it may be worthwhile," he said.