Friday, August 31, 2007

Flaxseed Dims Hot Flashes in Postmenopausal Women

ROCHESTER, Minn., Aug. 30 -- A daily dose of crushed flaxseed halved hot flashes in postmenopausal women who did not want to take estrogen, according to a pilot study.
After six weeks of therapy, the mean reduction in daily hot flash frequency went from 7.3 to 3.6, Sandhya Pruthi, M.D., of the Mayo Clinic, and colleagues, reported in the summer 2007 issue of the Journal of the Society for Integrative Oncology. This represented a mean reduction of 50% and a median reduction of 50% (P<0.001), the researchers said.
The weak estrogenic properties in flaxseed seem to be the most likely mechanism of the plant's effectiveness, Dr. Pruthi said.
Effective nonhormonal therapies for hot flashes include antidepressants, such as venlafaxine (Effexor) and gabapentin (Neurontin), but not all women benefit from these agents, and toxicities may limit their use, the researchers said.
Clinical trials evaluating herbal and dietary supplements, including vitamin E, black cohosh, and soy, as well as acupuncture, have not shown convincingly that these agents outdo placebo.
Flaxseed, also known as linseed, is another popular supplement that has not been well studied for hot flashes, the researchers said.
Considered a phytoestrogen, fiber-rich flaxseed is a rich source of lignans and omega-3 fatty acids. Lignans have antioxidant properties and are thought to have estrogen agonist and antagonist properties, such as those in selective estrogen receptor modulators, such as tamoxifen, they said.
Research findings also suggest that dietary lignans have some cancer-protective effects. Therefore, Dr. Pruthi said, flaxseed is an interesting agent to study for managing vasomotor symptoms.
In the six-week study of 30 women enrolled from June 17 to Nov. 8, 2005, 23 women completed the study. Twenty-one provided complete information.
The women recorded daily hot flashes in a diary and, once a week, completed a symptom questionnaire evaluating nausea, excessive sweating, joint or muscle pain, chills, headache, nervousness, and negative mood swings.
To be enrolled, the women reported at least 14 hot flashes per week for at least one month. In the preceding four weeks, the participants had not received chemotherapy, androgen, hormonal agents, or other herbal supplements, including soy.
In the baseline week, participants took no study medication and documented the characteristics of their hot flashes. Thereafter, they took 40 g daily of crushed flaxseed.
Flaxseed, provided in a fine granulated powder, contained 26% dietary fiber, 40% triglycerides, and 1% secoisolariciresinol diglucoside (a lignan antioxidant). The high-fiber product made from flaxseed hulls provided a large percentage of lignans.
In the last week of flaxseed therapy, the mean decrease in hot flash scores was 57%, and the median decrease was 62%.
The mean number of hot flashes reported by the participants at baseline was 7.3 per day, which, after six weeks of flaxseed therapy, had decreased to 3.6 per day.
Side effect analysis revealed that 14 (50%) of the participants had abdominal distention or bloating at some time during the trial.
Of these, 12 had mild distention and two moderate distention. Eight women reported mild diarrhea, one had moderate flatulence, two had moderate headache, and one had a mild hypersensitivity reaction.
Six women (21%) did not complete all six weeks of the therapy, three because of abdominal toxicities, one because of weight gain, one because of taste intolerance, and one for unspecified reasons.
Statistically significant improvements were reported for mood, joint or muscle pain, chills, and sweating. Quality of life improved, and the women reported less anger, anxiety, and fatigue on the Self-Assessment Scale.
However, these preliminary results need to be evaluated in a larger, placebo-controlled trial, Dr. Pruthi added.
As an example, the authors pointed out that in a similar pilot trial evaluating black cohosh reported a reduction in hot flash score (frequency and severity) that exceeded 50%. A large randomized placebo-controlled study was subsequently initiated, and failed to provide evidence that black cohosh reduced hot flashes more than placebo.
Because of the various abdominal toxicities, it is possible that initiating flaxseed therapy at a lower dose and titrating the dose upward might decrease abdominal toxicities, the researchers suggested.
No financial disclosures were reported. This trial was funded by the Susan B. Komen Breast Cancer Foundation.Primary source: Journal of the Society for Integrative OncologySource reference: Pruthi S, et al "Pilot Evaluation of Flaxseed for the Management of Hot Flashes" J Soc for Integrative Oncology 2007; 5: doi 10.2310/7200.2007.007.
Stopping Statins After Stroke Raises Risk for Death, Dependence

Caroline Cassels

August 30, 2007 — Individuals who stop statin treatment after hospitalization for ischemic stroke have nearly a 5-fold increased risk for death or dependence within 3 months poststroke, a new study suggests.
In addition, patients who are withdrawn from statin therapy during the acute phase of stroke have almost a 9-fold increased risk for early neurologic deterioration (END) and larger infarct volumes.
"These results strongly support the recommendation to physicians to continue statin drugs during the acute phase of an ischemic stroke," the study's principal investigator, José Castillo, MD, PhD, from the University of Santiago de Compostela, in Santiago, Spain, said in a statement from the American Academy of Neurology.
Dr. Castillo added that while no protocols suggest patients should not receive statins after stroke, in many cases the drugs are discontinued to avoid bronchoaspiration, particularly in the most severe strokes. "This study clearly shows the benefits of continuing statin use," he said.
The study is published in the August 28 issue of Neurology.
The single-center analysis included 215 consecutive patients hospitalized for acute hemispheric ischemic stroke and admitted within 24 hours of symptom onset from October 2003 to May 2005.
Of these, 89 subjects who were on previous statin therapy were randomized to receive 20 mg daily of atorvastatin (administered orally or through a nasogastric tube) or were taken off statins for 3 days immediately following stroke.
Patients who had not been on statin therapy prior to admission were followed up as a reference group for secondary analysis.
From the fourth day onward, atorvastatin 20 mg daily was also administered to patients in the withdrawal group and in those who were not on previous statin treatment.
Greater Infarct Volume
The primary outcome was death or dependence at 3 months, defined as a modified Rankin Scale of greater than 2. Secondary outcomes were infarct volume and END, defined as an increase in National Institutes of Health Stroke Scale (NIHSS) of 4 points or more between time of admission and any time during the first 48 hours of hospitalization.
After 3 months, 60% (27) of those in the statin-withdrawal group had either died or were disabled to the point of dependence compared with 39% (16) of those who had continuous statin therapy.
The authors also report that infarct volume was greater in statin-withdrawal patients compared with those who remained on statin therapy.
In addition, secondary analysis revealed patients in the reference group had a higher frequency of atrial fibrillation and were less likely to have a previous history of hypercholesterolemia than randomized patients.
Statin Therapy Should Not Be Interrupted
Post hoc analysis showed no difference in the study's primary outcome among the statin-withdrawal group and the reference group. However, the researchers observed a 19-fold increased risk for END among patients who were withdrawn from statin therapy compared with referent subjects.
According to the authors, previous animal and clinical research has shown the neuroprotective effect of statins is related not only to the reduction of plasma cholesterol but also to their direct influence on improving endothelial function through the overexpression of nitric-oxide synthase, as well as their antithrombotic and anti-inflammatory effects.
While the optimal dose of statins for neuroprotection in ischemic stroke is not known, animal studies of cerebral ischemia indicate neuroprotection is more likely at lower doses.
"Our findings strongly support that previous statin therapy should not be interrupted during the acute phase of ischemic stroke. The recommendation to start on statin treatment as soon as ischemic stroke occurs needs to be investigated in further randomized trials," they write.
The study was partially supported by grants from the Spanish Ministry of Health. Dr. Castillo and coauthors José Vivancos, MD, PhD, and Antonio Dávalo, MD, PhD, are scientific advisors to Pfizer. The other study authors report no conflicts of interest.
Neurology. 2007;69:904-910. Abstract
Resting Heart Rate Directly Related to Risk of Cardiovascular Disease

By Will Boggs, MD
NEW YORK (Reuters Health) Aug 30 - Higher resting heart rates are associated with an increased risk of cardiovascular disease, according to a review in the August 28th Journal of the American College of Cardiology.
"I hope that as a consequence of the article physicians consider why a healthy person has a high heart rate and search for causes, such as anemia, thyrotoxicosis, etc.," Dr. Kim Fox told Reuters Health. "In an otherwise healthy person, I think we are a long way off suggesting pharmacological intervention to improve outcome."
Dr. Fox from Royal Brompton Hospital, London, and colleagues reviewed the data associating resting heart rate and mortality, the possible pathophysiological basis of this association, and the likelihood utility of therapeutic heart rate slowing in improving cardiovascular outcomes for a wide range of patients.
Epidemiological data regarding both the general population and patients with various cardiovascular diseases reveal significant associations between resting heart rate and all-cause and cardiovascular mortality, the authors report.
Lowering of resting heart rate, they note, has proven beneficial in preventing exercise-induced angina and ischemia and reducing mortality in patients with coronary artery disease and with heart failure.
Heart rate appears to have direct effects on the status of the arterial wall, the investigators say, as a result of mechanical pulsatile stress and possibly through proinflammatory actions of such stresses on the vascular endothelium. Heart rate also influences whether ischemic episodes trigger serious arrhythmias.
A relatively high heart rate is likely both causative and indicative of important pathophysiological processes, the researchers note, but exactly what heart rate is optimal remains uncertain.
"From the epidemiologic data presented previously," the investigators write, "it seems desirable to maintain heart rate in the normal rather than in the high range, and specifically, to maintain resting heart rate substantially below the traditionally defined tachycardia threshold of 90 or 100 beats per minute."
"We have designed and are running two very large-scale trials in coronary disease with various degrees of left ventricular impairment," Dr. Fox said. "We are looking at the effect of pure heart rate reduction in these patients who are otherwise well, treated with therapies such as beta blockers, ACE inhibitors/ARBs, statins, and aspirin."
"Clearly, if our studies in coronary disease are proven to show that reducing heart rate improves outcome, then this should be introduced into clinical practice," Dr. Fox concluded.
J Am Coll Cardiol 2007;50:823-830.
Isoniazid for Latent Tuberculosis Well Tolerated in Patients Taking Methotrexate

August 30, 2007 — The use of isoniazid for latent tuberculosis (LTB) was well tolerated in patients with rheumatoid arthritis (RA) who were already receiving treatment with methotrexate, according to a retrospective chart review reported in the August 20 Online First issue of the Annals of the Rheumatic Diseases.
"Reactivation of Mycobacterium tuberculosis (TB) is a significant problem with all available tumor necrosis factor (TNF) antagonists when used to treat rheumatoid arthritis (RA), psoriatic arthritis, psoriasis and other inflammatory diseases," write Adam Mor, PhD, from New York University School of Medicine in New York, and colleagues. "Concerns have been raised regarding the appropriate management of patients with latent TB (LTB) exposure (or active TB infection) before initiating TNF antagonists since the safety data of combined therapy with two potentially hepatotoxic medications, methotrexate (MTX) and isoniazid (INH), is lacking. The goal of this study was to investigate the toxicity of MTX and INH therapy in RA patients before initiating TNF antagonists."
The study authors retrospectively reviewed the medical records of 44 patients seen at the Bellevue Hospital Arthritis Clinic, New York, NY, between 2002 and 2006, and who were treated simultaneously with methotrexate and isoniazid. The main endpoint was increase in liver function tests (LFTs).
Although 11% of patients had transient increases in LFTs, this in no case exceeded twice the upper limit of normal values, and all resolved spontaneously without intervention. When isoniazid and methotrexate were given together, the incidence of abnormal findings on LFTs was no higher than that seen with either drug given alone.
"The use of INH for LTB was well tolerated in RA patients on a background regimen of MTX," the investigators write. "While the risks and benefits of all therapy must always be considered, in our experience the additive risk of INH to MTX in terms of hepatotoxicity was low. Nonetheless it is prudent to follow LFT closely on patients taking this combination."
None of the patients developed evidence of reactivation of TB reactivation.
Limitations of the study include a small sample, possible selection bias, exclusion of patients with abnormal findings on LFTs at baseline, folic acid treatment used in combination with methotrexate in all patients, and the inability to identify any subset of patients with an increased risk of developing abnormal findings on LFTs during treatment with both drugs.
This study has received no external funding, and the authors have disclosed no relevant financial relationships.
Ann Rheum Dis. Published online August 20, 2007.
See Jane Run. See Her Run Faster and Faster

ONE day, about two years ago, my son asked me a probing question. “Are you running just to run,” he asked, “or do you have some purpose in mind?” I’d been running for years but never thought to ask myself why. His question made me realize I wanted a goal. And it led me to pick one that now sounds kind of ludicrous, a five-kilometer race that was to be run in two weeks.
I started to train.
It was a revelation — I got much faster with that little bit of training. I ran the race, won my age group, came home with a trophy, and decided to race again.
Of course, there are lots of reasons to run, and not everyone cares about winning a race or winning his or her age group. There is nothing wrong with running for fun or to clear your head after a long day. But serious running is very different from the more casual running I used to do. And now that I’ve grown more committed, I am starting to notice something odd about women and running.
Men, as might be expected, get slower as they age. At a recent five-kilometer race in Pine Beach, N.J., which drew nearly 1,000 runners, the fastest man was 24 years old and the men’s times increased with each five-year age group.
But the women were different — their times were all over the place with older women beating younger women in almost every age category. The fastest woman was 37 years old; the fastest woman in the 45 to 49 age group beat the fastest woman in the 20 to 24 and the 40 to 44 age groups.
The same thing happened in another five-kilometer local race, the Eden Family Run, in Princeton, N.J.
There, the top female runner in the 50 to 54 age group beat the top females in the 20 to 24, 25 to 29, and 40 to 44 age groups.
And it’s not just a New Jersey effect. Others have noticed it elsewhere and when I did a random check of race results in California, I saw it there too. On Aug. 8, in a 10-kilometer race in Alameda, the 53-year-old woman who won in the 50 to 54 age group was faster than the woman who won in the 25 to 29 group. A 38-year-old woman beat every other woman in the race.
Results like those made me wonder, Are women really trying in these races and, if they are, why are older women beating younger women?
Mary Wittenberg, president of New York Road Runners, thinks part of the answer is that most female runners shortchange themselves. Look at them before races she said. Men warm up and do strides, short runs to prepare to take off at the starting line. A lot of women hang back, often because they are embarrassed to be out there with the men, acting like determined athletes, Ms. Wittenberg said.
“They are too inhibited to put their full passion out there,” she said. “They are almost afraid to be serious about a sport. They think that if they’re not the best, they shouldn’t care so much.”
Other women have no idea what they are capable of or how to get faster, said Dr. Vonda Wright, an orthopedic surgeon at the University of Pittsburgh Medical Center.
Dr. Wright, who holds running clinics for beginners and for those who want to compete, said women often get the impression that they should not put much effort into runs. That’s the message of some ads and magazine articles telling people to run easy, and that, Dr. Wright said, “can be negative information” for women who might like to compete. It is too tempting, she said, “to be lulled into thinking that’s enough.”
Ms. Wittenberg feels the same way. A run-easy message is fine if it helps get people started in the sport. But, she added, there is also a risk, “in that it sneers at hard work and pushing to limits.”
Dr. Wright said she knows from experience the difference between going easy and challenging training. A few years ago, Dr. Wright, 40, was living in New York and running in Central Park. “I was jogging around at 9 ½ to 10 minutes a mile,” she said, and she had been doing the same unhurried run for years.
One day, she says, she asked herself, “What am I capable of?” In a few months of training, she got much stronger and faster and ended up running a 10-kilometer race at a speed of 7:44 a mile.
“After 10 years of running at 9:30 I felt so amazing when I realized my time,” she said.
Ralph Vernacchia, who directs the Center for Performance Excellence at Western Washington University in Bellingham, Wash., has worked with elite runners including Olympians. And with elite runners, there is no question about competitive drive.
But with average runners, he said, older women may be faster because, oddly enough, they are trying harder than younger women and discovering for the first time what they are capable of.
Most middle-aged women grew up when track and cross-country teams were for men only. Some of those women, who had no opportunity to race when they were young, are just learning to be athletes and are running faster than younger women who may not care as much.
He described the experience for women as “a kind of wakening, an epiphany.”
That is not to say that training is easy, he added. Being an athlete requires dedication and training, Dr. Vernacchia explained.
“It’s a mindset and once you know the method, it’s a real achievement. It takes emotional energy, spiritual energy and physical energy. There’s a difference between being involved and being committed. To be an athlete you must be committed.”
“Commitment is a state you find yourself in when the gun goes off,” Dr. Vernacchia said.
Then, if you are lucky, you beat all those younger women.

Thursday, August 30, 2007

Five diagnoses that call for a second opinion

By Elizabeth Cohen

ATLANTA, Georgia (CNN) -- After Marci Smith was told she had a malignant brain tumor, she had surgery and then made an appointment with an oncologist to receive chemotherapy and radiation.
But Smith never kept that appointment.
A nagging voice inside her head told her to get a second opinion. In the end, that voice is the reason Smith is getting the right treatment.
The first doctor's pathologist said Smith had a type of tumor called a sarcoma. But a second opinion -- and a third and a fourth -- said she had a glioblastoma, another type of brain tumor that requires much different treatment. Further pathology tests confirmed the glioblastoma.
"You always need to ask, 'Are you sure this is what it is?' " says Smith, who's receiving treatment for her glioblastoma near her home in Tennessee.
While it's important to get second opinions for various treatments, doctors say there are certain procedures where it's especially crucial: when the diagnosis is tricky, the procedure is risky or has permanent consequences, or when there are less-invasive alternatives.
Here are five diagnoses in which patients should seek a second opinion, according to experts.
1. Heart bypass surgery
"Anytime you're considering a procedure that has a risk of dying, stroke and severe infection, you should get a second opinion," says Dr. Richard Stein, director of preventive cardiology at Beth Israel Medical Center in New York.
Stein says alternatives such as angioplasty or medications with exercise are less risky and may be better for some patients.
He says these alternatives are part of the reason fewer people are having bypass surgeries -- 249,000 had bypass surgery in 2004 compared with 314,000 in 2000, according to the Centers for Disease Control and Prevention.
2. Hysterectomy
Sometimes doctors recommend surgical removal of the uterus for bleeding or pelvic pain when the uterus isn't the problem at all.
"Almost on a monthly basis, I will see a patient whose doctor told them to get a hysterectomy, and it turns out they have myofascial pain," says Dr. Howard Sharp, vice chair of clinical affairs in the Department of Obstetrics and Gynecology at the University of Utah School of Medicine.
Myofascial pain is a type of musculoskeletal pain that can be treated with icing, stretching and anesthesia injections.
Even when the problem is in the uterus, there are alternatives to a hysterectomy. "There are lots of less-invasive options these days," says Dr. Jessica Bienstock, associate professor of maternal-fetal medicine at Johns Hopkins Medical Institutions.
For example, she says hormone treatments might be the answer to pelvic pain, and embolization -- cutting off the blood supply to the fibroids -- might be an option for uterine fibroids.
3. Pregnancy termination for fetal abnormality
Sometimes parents choose to terminate a pregnancy when the fetus has a severe abnormality -- but they should make sure they have the right diagnosis before they do it.
"I can't tell you how many times we get referrals for one diagnosis, and it actually turns out to be something different," Bienstock says.
For example, sometimes a fetus might be diagnosed with having a congenital cystic adenomatoid malformation -- an abnormal formation in the lungs -- but actually turns out to have a diaphragmatic hernia. Parents might make different decisions based on these diagnoses, Bienstock says.
4. Surgery for varicose veins
There are so many different treatment options for varicose veins, it's best to get a second opinion, according to Dr. Julie Fleishlag, chair of the department of surgery at Johns Hopkins.
Exercise, use of stockings, injections, surgery and laser treatments are all options, she says.
"Go to someone who does all these types of interventions," she suggests, since a doctor who performs only one might be biased. "If you get the wrong procedure, it won't last long."
5. Treatments for brain tumors
As Smith learned, the wrong brain tumor diagnosis could lead to the wrong treatment. The diagnosis depends largely on the pathologist reading a slide -- and mistakes can happen.
Sometimes brain tumors are diagnosed when they aren't even tumors at all, says Evan Falchuk, president of Best Doctors, a company that helps patients get second opinions. "You may not need brain surgery because what they told you was a tumor was in fact an inflammatory disease, treatable with medicines," Falchuk says.
For Smith, it all came down to that voice in her head that told her she needed a second opinion. But it wasn't easy. "People turn over their authority to the doctor the minute they get sick," she says. "You want help so desperately you say, 'Whatever you want to do, let's do it.' "
Even if it's hard, patients need to question their doctors, says Stein, the cardiologist at Beth Israel. "We need to give up the Dr. Marcus Welby model of medical care," he says. "You're the consumer who's taking the risk. As you would for any financial decisions, you should get a second opinion."
New insights into common knee injuries

DURHAM, N.C. – The sort of swelling that occurs when a joint is damaged by injury or degeneration is normally essential to the healing process, but when it comes to the knee, that inflammation can actually interfere with healing.
These findings in experiments with pigs may lead to treatments for injuries or osteoarthritis in the knee, according to Duke University Medical Center orthopedic researchers. There are drugs that can block the action of these immune system proteins that trigger joint inflammation.
The Duke researchers report in the September issue of the journal Arthritis & Rheumatism that two immune system proteins, interleukin-1 (IL-1) and tumor necrosis factor (TNF), block the healing of the damaged pig meniscus, an important layer of buffering tissue within the joint. When agents that counteract the effects of these two proteins were administered directly to the damaged meniscus, the repair process resumed.
The primary function of the meniscus – a type of cartilage located within the knee joint between the thigh bone (femur) and the lower leg bone (tibia) -- is to act as a shock absorber and a distributor of weight within the joint. Nearly 15 percent of all athletic injuries to the knee involve the meniscus, and the breakdown and loss of this tissue ultimately leads to osteoarthritis, the so-called “wear-and-tear” form of the disease.
The researchers, led by Duke postdoctoral fellow Amy McNulty, Ph.D., said there is a need for a new approach to treat these injuries. The most common meniscus injury is a tear. If the tear is small and occurs on the outside of the meniscus, it can be repaired surgically. However, these repairs don’t often work well. If the tear is large, surgeons often have no choice but to remove the torn portion, and sometimes the entire meniscus, which leads to painful movement and ultimately osteoarthritis.
Duke researchers exposed pig knees to various concentrations of IL-1 and TNF. They found that as they increased the amounts of the proteins, the meniscus tissue was less able to repair itself. The range of concentrations of IL-1 and TNF used in the experiment match those found in the joint fluid of humans with rheumatoid arthritis and osteoarthritis, providing further evidence that these proteins could play a role in the disease process.
According to Farshid Guilak, Ph.D., senior member of the research team and director of orthopedic research at Duke, these findings should theoretically help physicians repair knee joints damaged by injury or osteoarthritis.
“There already is a drug that blocks the effects of TNF that is used widely and effectively in patients with rheumatoid arthritis, the form of the disease caused by body’s own immune system attacking the joint,” Guilak said. “Another drug also exists that blocks IL-1 that is being used for rheumatoid arthritis and is currently undergoing clinical trials for osteoarthritis.”
These drugs are administered to the entire body. However, the key to the possible new approach would be to deliver these agents directly into the site of meniscus damage, Guilak said.
Genes Promoting Lung Cancer May Not Normalize When Smoking Stops

VANCOUVER, British Columbia, Aug. 29 -- For some genes involved in the development of lung cancer, smoking may be forever, according to researchers here.
Smoking irreversibly activates some lung genes and down-regulates others, offering a possible explanation for the elevated lung cancer risk of former smokers, reported Raj Chari, Ph.D., of the British Columbia Cancer Agency, and colleagues, online in BMC Genomics.
They studied lung biopsy specimens from current, former, and nonsmokers and found that smoking induces specific changes in gene activity, some of which are permanent.
DNA repair genes are irreversibly damaged by smoking, which also turns off genes that protect against lung cancer. Down-regulated genes that regain normal function with smoking cessation are involved in xenobiotic functions, nucleotide metabolism, and mucus secretion.
"Expression levels of some of the genes related to tobacco smoking return to levels similar to never-smokers upon cessation of smoking, while expression of others appears to be permanently altered despite prolonged smoking cessation," the authors concluded. "These irreversible changes may account for the persistent lung cancer risk despite smoking cessation."
Recent gene microarray studies revealed differences in gene expression among current, former, and nonsmokers. The studies linked smoking's genetic effects to specific functions and showed that some smoking-induced changes are not reversed by smoking cessation.
Despite the recent findings, relatively little is known about genes involved in smoking-induced airway remodeling.
Dr. Chari and colleagues used serial analysis of gene expression (SAGE) to examine gene expression profiles in lung tissue. SAGE determines expression profiles by analyzing the types and concentration of short sequence tags. The investigators compared bronchial epithelial transcriptomes of current, former, and never smokers.
The study involved eight current smokers, 12 former smokers, and four never-smokers. Analysis of bronchial specimens from the participants resulted in 3,111,471 SAGE tags, representing 110,000 potentially unique transcripts. The investigators also identified 1,733 constitutively expressed genes in the transcriptomes of current, former, and never-smokers.
Further analysis revealed 609 SAGE transcript tags that were differentially expressed between current and never smokers. Chari and colleagues subsequently found that the tags classified current, former, and never smokers.
Additional comparisons of current, former, and never-smokers separated the tags and their associated genes into categories of reversible, partly reversible, and irreversible. Examples included:
Completely reversible with smoking cessation-increased expression of TFF3, CABYR, and ENDPD8, which are involved in xenobiotic metabolism and airway mucosal response.
Partly reversible-increased expression of MUC5AC, also involved in airway mucosal response.
Irreversible-decreased expression of GSK3B, which regulates expression of cyclooxygenase-2.
These finding were validated using quantitative reverse transcriptase-polymerase chain reaction on a secondary cohort of nine current smokers, seven former smokers, and six never-smokers.
The identification of reversible changes in gene expression in response to smoking cessation may help guide future studies of polymorphisms, the authors stated. Genes and functions that do not revert to normal upon smoking cessation may provide insight into former smokers' ongoing risk of developing lung cancer.
The authors had no disclosures.Additional source: BMC GenomicsSource reference: Chari R et al. "Effect of active smoking on the human bronchial epithelium transcriptome." BMC Genomics 2007; 297: doi:10.1186/1471-2164-8-297
Glucose-Sensing Neurons May Play Role in Diabetes

BOSTON, Aug. 29 -- The development of type 2 diabetes -- or at least part of it -- may be in your head, researchers here said.
The idea of neurons as a third-party player in the pathogenesis of diabetes -- in addition to improper functioning of pancreatic beta cells and impairment of insulin activity in tissue -- was revealed today by Bradford Lowell, M.D., Ph.D., of Beth Israel Deaconess Medical Center and Harvard, and colleagues.
They have identified a population of glucose-sensing neurons in the arcuate nucleus of the hypothalamus whose function is disrupted by obesity, Dr. Lowell and colleagues reported online in Nature.
These glucose-excited pro-opiomelanocortin (POMC) neurons, they wrote:
Play a role in controlling systemic glucose homeostasis.
Lose their glucose-sensing activity in obese animals fed a high-fat diet.
Appear to be turned off by the same protein -- uncoupling protein 2 (UCP2) -- that turns off pancreatic beta-cells.
Taken together, the evidence suggests that obesity-induced and OCP2-mediated loss of glucose sensing in the neurons "might have a pathogenic role in the development of type 2 diabetes," Dr. Lowell and colleagues postulated.
"For many years we've known that subpopulations of neurons in the brain become 'excited' by glucose," Dr. Lowell said. "But we haven't understood exactly how or why this is significant.
"With this study, we show that these neurons sense increases in glucose and then initiate responses aimed at returning blood-glucose levels to normal," they said. "This is the first demonstration that glucose-sensing by neurons plays an important role in responding to rising blood glucose levels."
In electrophysiology studies in mice, the researchers first showed that about half of the pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus become excited by surges in glucose equivalent to those seen after eating a meal.
The mechanism of excitement was thought to involve the closing of ATP mediated potassium channels, so the researchers created transgenic mice whose pro-opiomelanocortin neurons were 250 times less sensitive to ATP.
In these mice, almost none of the pro-opiomelanocortin neurons were excited by glucose, Dr. Lowell and colleagues reported.
In whole-body experiments, the researchers then showed that the transgenic mice -- although of normal weight -- had impaired glucose tolerance, compared to wild-type animals.
Another piece of the puzzle came from experiments on wild-type animals fed a normal chow diet or a high-fat diet to induce obesity for eight weeks, the researchers said.
In the chow-fed mice, 46% of pro-opiomelanocortin neurons were excited by glucose, but only 10% of the pro-opiomelanocortin neurons in the obese high-fat diet mice had the same response.
Since UCP2 is expressed in pro-opiomelanocortin neurons, the researchers hypothesized that it might play a similar role there as it does in the pancreas -- turning off glucose sensing.
To test that idea, they used a molecule dubbed genipin that blocks the activity of UCP2. Pancreatic beta-cells incubated with the molecule have their ability to secrete insulin restored.
In wild-type mice fed a normal chow diet, blocking UCP2 with genipin had no effect on the response to increased glucose. But in the same mice fed a high-fat diet -- whose glucose response was impaired -- the molecule completely remedied the defect.
In another test, they created transgenic mice lacking the gene for UCP2. The pro-opiomelanocortin neurons of these mice had a normal glucose response regardless of diet and did not respond differently when treated with genipin, the researchers said.
"An increase in the activity of the mitochondrial uncoupling protein 2 is behind the loss of glucose-sensing ability in the pro-opiomelanocortin neurons," said co-author Laura Parton, Ph.D., also of Beth Israel.
"Increased activity of UCP2 is known to cause loss of glucose-sensing and defective insulin secretion by pancreatic beta cells and this study now shows that a similar phenomenon also occurs in neurons."
The findings "add to our understanding of type 2 diabetes," Dr. Lowell said, "at a critically important time. The discovery that defects in glucose-sensing by the brain may also be contributing to Type 2 diabetes could help lead to new therapeutic strategies for this widespread problem."
The research was supported by the NIH, the American Diabetes Association, the National Natural Science Foundation of China, the National Basic Research Program of China, the '111' Project, and the Natural Science Foundation of Jiangsu Province. The authors said they had no competing financial interests.Primary source: NatureSource reference: Parton LE et al. "Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity." Nature 2007; doi:10.1038/nature06098.
After Oophorectomy, Cognitive Impairment Risks Rise

ROCHESTER, Minn., Aug. 29 -- There is evidence of a neuroprotective effect of estrogen from two studies that found women were at an increased risk for dementia and parkinsonism after their ovaries were removed before natural menopause.
Unilateral or bilateral oophorectomy was associated with a 46% increase in risk of cognitive impairment or dementia, and a 68% increase in risk for parkinsonism, reported Walter A. Rocca, M.D., M.P.H., of the Mayo Clinic, and colleagues.
The effect of estrogen deprivation on neural function appeared to be age dependent, with risk increasing significantly for women who were younger at the time of oophorectomy, the authors reported in the studies, both published online in Neurology.
The findings support laboratory studies that have pointed to a neuroprotective effect of estrogen, and indicate that physicians and patients should carefully consider the consequences of pre-menopausal hormonal deprivation.
"Although almost 60% of women received some estrogen treatment after both of their ovaries were removed, only 20% of them received estrogen treatment until at least age 50," the median age when women reach menopause, Dr. Rocca said.
The investigators conducted two retrospective studies of women who took part in the Mayo Clinic Cohort Study of Oophorectomy and Aging, which included 1,433 women living in Olmsted County, Minn., who underwent unilateral oopherectomies and 1,824 who underwent bilateral ovary excision for non-cancer indications from 1950 through 1987. The patients were compared with age-matched referents from the same population who had their ovaries intact.
In the study of potential associations between oophorectomy and cognitive function, the authors looked at 813 women with unilateral oophorectomy, 676 women with bilateral excision, and 1,472 controls. The women were followed through death or study end with either direct or proxy interviews.
They found in an analysis adjusted for education, type of interview, and history of depression that women who underwent either unilateral or bilateral excision had a hazard ratio for cognitive impairment or dementia of 1.46 (95% confidence interval, 1.13 to 1.90).
When they stratified patients by age at the time of oophorectomy, they saw a trend of increasing risk with younger age (test for linear trend in the adjusted log hazard ratio, P<0.001). This effect was seen regardless of the indication for surgery.
Many of the women in the dementia study were also included in the cohort of the study looking for possible associations between oophorectomy and parkinsonism.
In that study, the authors looked at 1,252 women with unilateral oophorectomy, 1,075 women with bilateral oophorectomy, and 2,368 controls. As in the dementia study, the women were followed through death or end of study with direct or proxy interviews, plus the addition of neurologic examinations, medical records in a records-linkage system, and death certificates.
The researchers found that, compared with women in the referent sample, women who underwent either unilateral or bilateral oophorectomy before the onset of menopause had an increased risk of parkinsonism, with a hazard ratio of 1.68 (95% CI 1.06 to 2.67; P=0.03).
Here too, the risk increased with younger age at oophorectomy (test for linear trend, P=0.01), and again the findings were similar regardless of the indication for the procedure, as well as for unilateral or bilateral oophorectomy considered separately.
"The observed trends of increased risk of parkinsonism with younger age at oophorectomy suggest that the neuroprotective effect of estrogen on the nigrostriatal pathway may be age-dependent and may have a critical age window," the authors wrote. "A similar concept of a critical age window for neuroprotection has been proposed for cognitive decline and dementia."
The authors proposed three possible mechanisms for the effects they saw: loss of estrogen neuroprotection, loss of neuroprotecion from progesterone and/or testosterone, and genetic predisposition to conditions requiring oophorectomy and to cognitive impairment, dementia or parkinsonism.
They acknowledged that the studies were limited by potential inaccuracies in the diagnoses of the neural disorders, cognitive impairment, dementia, and parkinsonism, reliance on telephone or proxy interviews rather than face-to-face interviews, and, in the case of parkinsonism, by potentially confounding socioeconomic factors.
Both studies were supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported no conflicts of interest. Primary source: NeurologySource reference: Rocca WA et al. "Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause." Neurology 2007; 69: 1074-1083.
New Asthma Guidelines Emphasize Disease Control and Patient Empowerment

BETHESDA, Md., Aug. 30 --Emphasizing that asthma affects different patients in different ways, the National Asthma Education and Prevention Program has issued new evidence-based guidelines on the disease.
The guidelines include a new emphasis on patient involvement and control of environmental triggers of asthma.
The guidelines are based on evidence from research and clinical experience over the past decade into the mechanisms underlying airway inflammation and into better methods for control, said William Busse, M.D., of the University of Wisconsin at Madison, chairman of the expert panel that drew up the guidelines.
Regarding medication, the guidelines continue the established stepwise approach to asthma control, but with revised and expanded management charts based on three age groups: birth to four years, five to 11, and 12 and older.
The addition of the five to 11 group is a recognition of differing drug responses between children and adults, Dr. Busse said.
The report reaffirms that patients with persistent asthma require both long-acting control medications and acute rescue therapies as needed, with inhaled corticosteroids recognized as the most effective agents for chronic control in all age groups.
The guidelines also include new recommendations on the use of leukotriene receptor antagonists and cromolyn sodium for chronic asthma control, long-acting beta agonists as adjunctive therapy with inhaled corticosteroids; omalizumab (Xolair) for severe asthma, and on the use of albuterol, levalbuterol, and corticosteroids for acute exacerbations.
The guidelines, weighing in at 487 pages, build on earlier iterations from 1991, 1997 and a 2004 update, but with several key differences, Dr. Busse said. These differences include:
Further substantiation of the role of inflammation in asthma, with recognition of phenotypic differences resulting in variability in patterns of inflammation
Recognition of genetic and environmental interactions in asthma expression, with allergic reactions identified as an important environmental factor. Emerging evidence also points to the role of viral respiratory infections.
Understanding that "the onset of asthma for most patients begins early in life with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma."
A finding that anti-inflammatory therapy as currently practiced does not appear to prevent progression of the underlying disease severity.
"The new scientific evidence that makes up the guidelines that we're releasing today point to one truth: asthma control is achievable for nearly every patient," said Elizabeth Nabel, M.D., director of the National Heart, Lung, and Blood Institute.
"With appropriate medical care, healthy environments, and well-informed and empowered patients asthma can be controlled and patients can lead full active lives," she said in a media briefing.
The Expert Panel Report 3, as the guidelines are known, focus on four key areas of asthma diagnosis and treatment: assessment and monitoring, patient education, control of environmental factors and other modifiable conditions that can affect asthma, and medications.
The guidelines call for assessing and monitoring asthma with multiple measures of asthma severity, including frequency and intensity of symptoms, lung function, and limitations of daily activities as well as future risk (risk of exacerbations, progressive loss of lung function, or adverse effects from medications). The guidelines emphasize that some patients with intermittent asthma may still be at high risk for frequent severe exacerbations.
The guidelines also stress the importance of educating patients about self-assessment of symptoms and management of asthma, including use of a written action plan with instructions for daily treatment as well as acute and chronic symptoms. New recommendations emphasize bringing asthma education into community setting such as schools, pharmacies, and homes.
The report includes recommendations on control of environmental asthma triggers, with an emphasis on multiple approaches to achieving control, and expands information on treatment of co-morbidities such as rhinitis and sinusitis, gastroesophageal reflux, overweight or obesity, obstructive sleep apnea, stress, and depression.
The report also describes promising new avenues for research into improving asthma management, including tailoring treatment to the asthma phenotype and genotype of individual patients.
"Research is beginning to help us identify genes that influence how well certain patients respond to certain asthma medications," said James Kiley, Ph.D., director of the NHLBI Division of Lung Diseases. "This information is helping us move toward providing personalized treatment for asthma based on a patient's individual characteristics."
A summary report will be released on Oct. 17.
The report, titled Expert Panel Report 3:Guidelines for the Diagnosis and Management of Asthma, is available free of charge at the NHLBI web sitePrimary source: National Heart, Lung, and Blood InstituteSource reference: Expert Panel Report 3:Guidelines for the Diagnosis and Management of Asthma
FDA Issues Proposed Rule for Sunscreen

Laurie Barclay, MD

August 29, 2007 — The US Food and Drug Administration (FDA) is issuing a proposed rule that would amend the final monograph for over-the-counter (OTC) sunscreen drug products as part of the FDA's ongoing review of OTC drug products. The proposed rule, which is published in the August 27 issue of the Federal Register, addresses formulation, labeling, and testing requirements for both ultraviolet B (UVB) and ultraviolet A (UVA) radiation protection.
Written or electronic comments concerning this proposed rule should be submitted to the FDA by November 26, 2007.
Proposed changes to the final monograph are as follows:
A. Ingredients: Permitted combinations of active sunscreen ingredients would include avobenzone with zinc oxide and avobenzone with ensulizole.
B. UVB (Sun Protection Factor [SPF]) Labeling: Specific labeled SPF values would be permitted up to, but not exceeding, an SPF of 50. OTC sunscreen drug products with SPF values greater than 50 would be labeled with the collective term "50+." The phrase "sun protection" would be changed to "sunburn protection." The term "UVB" would be included before the term "SPF" on the principal display panel (PDP), along with the product category designation (PCD). The PCD SPF ranges would reflect the current standard public health message concerning use of sunscreens. The current category descriptors of "minimal" and "moderate" would be replaced with the terms "low" and "medium," respectively.
C. UVA Labeling: The new labeling would designate the level of UVA protection on the PDP of OTC sunscreen drug products, using stars with a descriptor ("low," "medium," "high," or "highest").
D. Indications: There would be an additional indication regarding UVA protection involving selection of the appropriate descriptor ("low," "medium," "high," or "highest") to describe the level of protection.
E. Warnings: "Stop use and ask a doctor if...rash or irritation develops and lasts" would be changed to " rash occurs." A revised "sun alert" statement would be required on all OTC sunscreen drug products except lip cosmetic–drug and lip protectant–sunscreen products. This statement would read: "UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other skin damage. It is important to decrease UV exposure by limiting time in the sun, wearing protective clothing, and using a sunscreen."
F. Directions: The proposed changes should reduce the likelihood that OTC sunscreen drug products will be underapplied. One of 2 terms would be required ("liberally" or "generously"), and the word "evenly" would be included as an additional optional term. A new direction would be added: "apply and reapply as directed to avoid lowering protection."
G. UVB Testing: A padimate O/oxybenzone sunscreen standard would be required for testing sunscreen products with SPF values over 15. This padimate O/oxybenzone standard or the homosalate standard would be used to test products with SPF values of 2 to 15. A high-pressure liquid chromatography method would replace the spectrophotometric method used to assay the homosalate and padimate O/oxybenzone standards.
H. UVA Testing: A combination of spectrophotometric (in vitro) and clinical (in vivo) UVA test procedures would be used. For "water resistant" and "very water resistant" sunscreen products, the in vivo UVA test would be performed after the appropriate water immersion period for OTC sunscreen drug products.
"FDA is issuing this proposed rule after considering public comments and new data and information that have come to FDA's attention," the authors write. "FDA understands the seasonal nature of the sunscreen industry and the time required for product testing and relabeling. FDA is also aware that more than 1 year may be needed for implementation."
Fed Reg. 2007;72:49070–49122.
Biologic Therapy for Rheumatoid Arthritis Linked to Skin Cancer Risk

August 29, 2007 — Biologic therapy for rheumatoid arthritis (RA) was associated with an increased risk for skin cancer but not for other types of cancers, according to an observational study published in the August 29 Online First issue and in the September print issue of Arthritis & Rheumatism.
"Induction of malignancy is a major concern when rheumatoid arthritis (RA) is treated with biologic therapy," write Frederick Wolfe, MD, and Kaleb Michaud, PhD, from the University of Kansas School of Medicine in Wichita. "A meta-analysis of RA biologic clinical trials found a general increased risk of malignancy, but this risk was not found in a large observational study. We undertook this study to assess the risk of malignancy among biologic-treated patients in a large US observational database."
From 1998 to 2005, the authors studied incident cases of cancer in 13,001 patients who were observed for approximately 49,000 patient-years. Using the US National Cancer Institute Surveillance, Epidemiology, and End-Results (SEER) database, the investigators compared rates of cancer in the observational cohort vs those in the general population.
The risks for biologic therapy were evaluated with conditional logistic regression to calculate odds ratios (ORs) as estimates of the relative risk. Additional adjustments were made for 6 confounders: age, sex, educational level, smoking history, severity of RA, and use of prednisone.
Exposure to biologic therapy occurred in 49% of the study group. Incident cases of cancer included 623 cases of nonmelanotic skin cancer and 537 cases of other cancers.
Compared with the SEER data, the standardized incidence ratios were 1.0 for all cancers (95% confidence interval [CI], 1.0 - 1.1), 0.8 for breast cancer (95% CI, 0.6 - 0.9), 0.5 for colon cancer (95% CI, 0.4 - 0.6), 1.2 for lung cancer (95% CI, 1.0 - 1.4), and 1.7 for lymphoma (95% CI 1.3 - 2.2).
Although biologics were associated with an increased risk for nonmelanotic skin cancer (OR, 1.5; 95% CI, 1.2 - 1.8) and for melanoma (OR, 2.3; 95% CI, 0.9 - 5.4), no other cancer was associated with the use of biologic therapy. The overall risk for any cancer was 1.0 (95% CI, 0.8 - 1.2).
Limitations of the study include limited duration of biologic exposure; observational design; confounding by indication; and use of the National Death Index, which could have introduced possible bias.
"Biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies," the study authors write. "These associations were consistent across different biologic therapies."
Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, and Wyeth-Australia supported this study.
Arthr Rheum. Published online August 29, 2007.2007;56:2886-2895.
Depression Care Management May Reduce Mortality in Older Patients With Diabetes

August 29, 2007 — Depression care management may reduce 5-year mortality in older primary care patients with both depression and diabetes, according to the results of a study published in the August 23 Publish Ahead of Print issue of Diabetes Care.
"Although cohort studies document that depression is associated with increased risk of death among persons with diabetes, no known intervention study has evaluated whether treatment for depression modifies this increased risk of mortality among older primary care patients with diabetes," write Hillary R. Bogner, MD, MSCE, from the University of Pennsylvania in Philadelphia, and colleagues. "We investigated the relationship between diabetes, depression treatment, and all-cause mortality using data from the multi-site, randomized trial, PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial), supplemented with a search of the National Death Index."
PROSPECT was a practice-randomized, controlled trial with patient recruitment from May 1999 through August 2001. At 20 primary care practices from New York City, Philadelphia, and Pittsburgh, 584 participants identified from a 2-stage, age-stratified depression screening of randomly sampled patients were classified as depressed and had complete information on diabetes status.
Of the 584 participants, 123 (21.2%) reported a history of diabetes. A depression care manager as well as primary care clinicians implemented algorithm-based care, vital status was determined at 5 years, and median follow-up was 52.0 months.
During follow-up, 110 patients with depression had died. After adjustment for baseline differences in the intervention condition (IC) and usual care (UC) groups, patients in the IC group were less likely to have died during the 5-year follow-up than were those in the UC group (adjusted hazard ratio [HR], 0.49; 95% confidence interval, 0.24 - 0.98).
"Older depressed primary care patients with diabetes in practices implementing depression care management were less likely to die over the course of a 5-year interval than were depressed patients with diabetes in usual care practices," the study authors write. "We believe these findings support the integration of depression evaluation and treatment with diabetes management in primary care."
Limitations of the study include lack of generalizability to other primary care practices in the United States, diabetes mellitus based on self-report alone (some patients with impaired glucose tolerance but not diabetes may have been included), reduction in mortality in the intervention group possibly due to factors other than the specific effects of a depression management program, possible misclassification of vital status, selection of patients with diabetes from a larger intervention trial, and uncertainty regarding the effect of treatment of depression on outcomes for diabetes and other medical comorbidities.
"These results indicate that a depression care management intervention can significantly reduce all-cause mortality among depressed patients with diabetes," the study authors conclude. "These results should propel the development and dissemination of models of care that better integrate depression management for people with diabetes."
The National Institute of Mental Health supported this study. Dr. Bogner has disclosed being a faculty scholar with the Robert Wood Johnson Foundation. The remaining study authors have disclosed financial relationships with the National Institute of Mental Health.
Diabetes Care. Published online August 23, 2007.
Study Confirms 2006 Human-Human Spread of Bird Flu

WASHINGTON (Reuters) Aug 29 - A mathematical analysis has confirmed that H5N1 avian influenza spread from person to person in Indonesia in April, U.S. researchers reported on Tuesday.
Dr. Ira Longini and colleagues at the Fred Hutchinson Cancer Research Center in Seattle looked at two clusters of human H5N1 infections -- one in which eight family members died in Sumatra in 2006, and another in Turkey in which eight people were infected and four died.
"We find statistical evidence of human-to-human transmission in Sumatra, but not in Turkey," the investigators write in a report published in the journal Emerging Infectious Diseases. "This does not mean that no low-level human-to-human spread occurred in this outbreak, only that we lack statistical evidence of such spread."
In Sumatra, a 37-year-old woman appears to have infected her 10-year-old nephew, who infected his father. DNA tests confirmed that the strain the father died of was very similar to the virus found in the boy's body.
"It went two generations and then just stopped, but it could have gotten out of control," Dr. Longini said in a statement.
"The world really may have dodged a bullet with that one, and the next time, we might not be so lucky," he added.
The researchers estimated the secondary-attack rate was 20 percent. This is similar to what is seen for regular, seasonal influenza A in the United States.
The researchers developed a software product called TranStat and said they would provide it free of charge on the National Institutes of Health's Models of Infectious Disease Agent Study, or MIDAS, Web site.
"We know the key to preventing a pandemic is early detection, containment and mitigation with antiviral therapy and this tool will enable those on the front lines, such as physicians, epidemiologists and other public-health officials, to carry that out efficiently," said Elizabeth Halloran, who worked on the study.
Arsenic in Drinking Water Said to Be Rising Risk

LONDON, Aug. 29 (Reuters) — Naturally occurring arsenic in drinking water poses a growing global health risk as large numbers of people unknowingly consume unsafe levels, researchers said on Wednesday.
The problem is bigger than scientists had thought, and it affects nearly 140 million people in more than 70 countries, according to new research presented at the annual Royal Geographical Society meeting in London.
Arsenic can cause lung disease and cancers, even long after people stop drinking contaminated water, said Peter Ravenscroft, a researcher at the University of Cambridge.
“What is new is, the extent of arsenic pollution is much bigger than people realized,” Mr. Ravenscroft said in a telephone interview.
“There is a very important connection between arsenic in water and arsenic in food, especially where people grow irrigated crops.”
World Health Organization guidelines set a safe limit of 10 parts per billion of arsenic in water supplies, but tens of millions of people in the world drink unsafe water above that level, researchers said.
At present, Bangladesh has been affected the most. There, hundreds of thousands of people are likely to die from arsenic poisoning, the researchers said.
Arsenic has also been found in the water in developed countries, and industrial activities like mining can also lead to contamination.
Rising awareness has led to increased testing, which has revealed more widespread arsenic in drinking water, but other researchers said that even more must be done to address the problem.
“Most countries have some water sources with dangerous levels of arsenic, but only now are we beginning to recognize the magnitude of the problem,” Allan Smith, a researcher at the University of California, Berkeley, and an adviser to the World Health Organization on arsenic, said in a statement.
When Alzheimer's Patients Wander

1 hour, 57 minutes ago
(HealthDay News) -- Wandering -- moving about without a definite purpose in mind -- is a common trait of a person with Alzheimer's disease and other forms of dementia. This can be dangerous for the patient, and be a source of great stress for worried caregivers and loved ones.
Here are suggestions for what to do when Alzheimer's patients wander, courtesy of the Alzheimer's Association:Enroll your loved one in a nationwide identification program specifically for dementia-related wandering, which can help them return home safe. Keep contact information at hand for neighbors and local emergency services personnel, and keep them informed about the patient's condition. Install deadbolt or slide-bolt locks on all exterior doors. But never attempt to lock an Alzheimer's patient indoors without supervision. Limit access to dangerous areas, both inside and near the home. Keep in mind that Alzheimer's patients may wander in virtually any form of transportation, including bus or taxi.
Direct Anesthetic Infusion Helps Colorectal Cancer Patients

1 hour, 56 minutes ago
THURSDAY, Aug. 30 (HealthDay News) -- A technique that delivers local anesthetic directly to the surgical wound of colorectal cancer surgery patients helps control postoperative pain and shortens recovery time, a French study says.
The anesthetic is delivered through a special multi-holed catheter that's installed toward the end of the surgery.
The study of 42 patients found that those who received "continuous wound infusion" with the local anesthetic ropivacaine for 48 hours after surgery had significantly lower pain scores and required less morphine to control pain than patients who received a placebo.
The patients in the ropivacaine group also had better quality of sleep during the first two nights after surgery, and their bowel function returned to normal an average of one day earlier than those in the placebo group. Patients cannot leave hospital before resumption of normal bowel function.
The average hospital stay for patients in the ropivacaine group was five days, compared to more than six days for patients in the placebo group.
"This method offers a new way to efficiently and simply manage pain after major abdominal surgery," study author Dr. Marc Beaussier, of St.-Antoine University Hospital, Paris, said in a prepared statement.
"This technique is simple, efficient and safe," Beaussier said. "It does not need specific supervision and could be proposed to almost all patients."
The study was published in the September issue of Anesthesiology.
More information
The American Cancer Society has more about colorectal cancer.

Wednesday, August 29, 2007

Hypnosis Before Surgery Dulls Pain Later

NEW YORK, Aug. 28 -- Presurgical hypnosis may improve pain control during and after breast cancer surgery and cut costs as well, researchers said.
Women in a randomized study who underwent brief hypnosis immediately before lumpectomy or biopsy required a third less of the sedative propofol (Diprivan) and significantly less (P<0.001) anesthetic lidocaine (Xylocaine) during their procedure than controls, according to a report in the Sept. 5 issue of the Journal of the National Cancer Institute.
Hypnotized patients also reported less pain intensity after surgery (P<0.001) and their institutional cost per patient was $772.71 lower than controls, said Guy H. Montgomery, Ph.D., of Mount Sinai School of Medicine here, and colleagues.
"It has taken us a century and a half to rediscover the fact that the mind has something to do with pain and can be a powerful tool in controlling it," commented David Spiegel, M.D., of Stanford University, in an accompanying editorial.
One of the early reports of anesthetic uses of hypnosis was an 1846 account by surgeon James Esdaile of 80% surgical anesthesia using hypnosis alone during amputations in India, Dr. Spiegel noted.
Since then, it has proven effective against pain in studies of at least 20 different surgical populations, Dr. Montgomery and colleagues added.
Their study included 200 women undergoing excisional breast biopsy or lumpectomy regardless of planned axillary node dissection at two surgical practices.
Participants attended a 15-minute session with a psychologist within the hour before surgery and were randomized to either hypnosis or just undirected empathetic comments.
Hypnosis included muscle relaxation imagery, visual imagery, suggestions to experience relaxation and peace, and symptom-focused suggestions to experience reduced pain, nausea, and fatigue.
Although the researchers did not formally blind the study, interventions took place in a room away from clinical staff, and neither the psychologists nor the clinical staff collected outcome data.
Anesthesiologists followed a monitored anesthesia protocol for all patients and were blinded to group assignment.
During surgery, the hypnosis group required less analgesic and sedative medication overall than the control group (P<0.005).
Specifically, patients who had a hypnosis intervention were given less lidocaine (mean 24.23 versus 31.09 mL, P<0.001) and less propofol (mean 64.01 versus 96.64 μg, P=0.03).
But, mean intraoperative fentanyl and midazolam doses were similar between groups, which may not have been surprising, the researchers said.
"Most patients presenting for breast cancer surgery typically receive a standard dose of fentanyl and/or midazolam before the onset of the procedure and titrated doses of lidocaine and propofol as judged necessary by the anesthesiologist based on patient agitation," they wrote.
Analgesic use in the post-anesthesia care unit was similar between groups as well.
The hypnosis group spent 10.60 fewer minutes in surgery, on average, than the control group, possibly because patients were "easier to prepare for surgery and to sedate or due to less time having been spent administering medications to patients," the researcher speculated.
Less time in the OR translated into an institutional cost savings of $772.71 per patient with hypnosis (95% confidence interval $75.10 to $1,469.89, P<0.03), they added.
Patients' experiences after the procedure were also significantly better overall with hypnosis (P<0.0001). This included the following self-reported outcomes for the hypnosis versus control groups:
Less intense pain (visual analog scale mean 22.43 versus 47.83, P<0.001).
Less pain unpleasantness (mean 21.19 versus 39.05, P<0.001).
Less nausea (mean 6.57 versus 25.49, P<0.001).
Less fatigue (mean 29.47 versus 54.20, P<0.001).
Less discomfort (mean 23.01 versus 43.20, P<0.001).
Less emotional upset (mean 8.67 versus 33.46, P<0.001).
Each of these advantages had an effect size deemed clinically meaningful, the researchers said.
Further study will be needed to look at longer-term outcomes and other patient and demographic samples as well as to examine whether anesthesiologists or nurses could effectively do the hypnosis intervention, they added.
In his editorial, Dr. Spiegel speculated on reasons why hypnosis is not frequently used in the surgical setting, including the fact that there is no product to sell and that there is a "still lingering suspicion that hypnosis reeks of stage show trickery."
But, he said, hypnosis is simply a state of highly focused attention with low peripheral awareness and high responsiveness to social cues similar to "suspension of disbelief" while absorbed in a movie or book.
The study was funded by grants from the National Cancer Institute, the American Cancer Society, and the Department of Defense. The researchers and Dr. Spiegel disclosed no conflicts of interest.Primary source: Journal of the National Cancer InstituteSource reference: Montgomery GH, et al "A Randomized Clinical Trial of a Brief Hypnosis Intervention to Control Side Effects in Breast Surgery Patients" J Natl Cancer Inst 2007; 99: 1304-12. Additional source: Journal of the National Cancer InstituteSource reference: Spiegel D "The Mind Prepared: Hypnosis in Surgery" J Natl Cancer Inst 2007; 99: 1280-81.
H. pylori Cancer Risk Tracked to Specific Genotype

LYON, France, Aug. 28 -- The severity of precancerous lesions tracks to specific bacterial strains, investigators here reported, strengthening the association between Helicobacter pylori infection and gastric cancer.
Only H. pylori strains containing cytotoxin-associated (cagA) gene DNA predicted gastric dysplasia severity, Martyn Plummer, of the International Association for Research on Cancer, and colleagues reported in the Aug. 28 issue of the Journal of the National Cancer Institute.
CagA-positive lesions also were more likely to progress, they said.
The results suggest that the proportion of gastric cancers attributable to H. pylori worldwide may exceed a recent estimate of 63%, they added.
The worldwide incidence of gastric carcinoma exceeds 900,000 cases annually. However, the absolute risk of the cancer is small in comparison to the prevalence of H. pylori infection (estimated at 80-90% in developing countries).
Some evidence suggests that cancer evolves from specific genetic lineages of H. pylori, the authors noted. Potential suspects include cagA, which has been shown to increase the risk of atrophic gastritis and gastric cancer.
Data for the current study came from patients who had biopsies as part of a trial of gastric cancer control in Venezuela. Frozen biopsy specimens were available for 2,145 of the 2,200 study participants. H. pylori genotyping showed that 947 participants were cagA negative and 852 were cagA positive.
CagA-positive individuals had double the risk of chronic gastritis compared with cagA-negative study participants. The odds ratio was 7.35 for intestinal metaplasia and 16.7 for dysplasia for the cagA-positive group versus the cagA-negative participants.
"Thus, the odds ratio increased with severity of disease," the authors noted.
Using individuals with normal mucosa or superficial gastritis as control subjects, the odds ratio for dysplasia was 15.5 (95% confidence interval [CI] = 6.42 to 37.2) in cagA-positive individuals compared with uninfected individuals and 0.90 (95% CI = 0.37 to 2.17) for individuals infected with cagA-negative H. pylori compared with uninfected individuals.
Follow-up gastroscopy results were available for 1,474 participants. Evaluation of the rate of lesion progression showed that uninfected participants had a progression rate of 76.5 per 1,000 person-years, compared with 76.0 for cagA-negative participants, and 80.3 for cagA-positive individuals. Regression rates were 137.8, 149.2, and 126.9 per 1,000 person-years, respectively.
Patients with cagA-positive infection had an odds ratio of 1.21 for progression and 0.81 for regression compared with uninfected individuals, but neither difference was statistically significant.
"In this study, the risk of precancerous lesions conferred by H. pylori was specific to cagA positive strains," the authors stated. "Failure to distinguish between cagA-positive and negative strains would have led to a substantial underestimation of the relative risk."
As an example, a calculation based on H. pylori-positive versus negative patients (without genotyping) resulted in an odds ratio of 4.2 for dysplasia compared with 15.5 when cagA-positive patients were compared with uninfected patients.
"Our study adds to the emerging body of evidence that the strength of the association between H. pylori and gastric carcinoma has been underestimated," the authors concluded.
The authors disclosed no conflicts. The study was sponsored by the European Community and the U.S. National Cancer Institute.Primary source: Journal of the National Cancer InstituteSource reference: Plummer M et al. "Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions." J Natl Cancer Inst 2007; 99: 1328-1334.
Intact Cell Organization Resists Oncogenic Activity

HELSINKI, Aug. 28 -- Breast cancer may spring from the loss of cellular architecture that forms a barrier against oncogenes, found investigators here.
The loss of a cell polarity-regulating protein that helps maintain the architecture may be involved in the origin of breast malignancies, Juha Klefstrom, Ph.D., of the University of Helsinki, and colleagues, reported in the Aug. 28 issue of Proceedings of the National Academy of Sciences.
Experimental inhibition of the LKB1 cell polarity protein in mammary epithelial cells led to the formation of abnormal acini with an uneven, disorganized ultrastructure, they found. In acini with established epithelial organization, however, activation of the c-Myc oncogene failed to induce hyperproliferation.
"Our data show that an organized epithelial structure is a powerful restraint against oncogene-drive, unscheduled proliferation and apoptosis," the authors concluded.
Epithelial cells bind to each other by means of cell junctions and adhesions to form structured, polarized sheets anchored to a basement membrane. An organized epithelial architecture is essential for basic epithelial cell processes, such as proliferation, migration, differentiation, and death, the authors noted.
Recent evidence from Drosophila models indicates that an intact epithelial architecture also acts as a barrier to tumor development, they continued. Inactivation of genes linked to cell polarity can spontaneously induce neoplastic overgrowth or cooperation with active oncogenes.
"Rogue cancer genes can force epithelial cells to proliferate, and proliferation of malignant cells will certainly disrupt the organized epithelial structure," said Dr. Klefstrom. "However, there has always been this chicken-or-egg problem: Does a cancer gene initiate cell proliferation, which causes disruption of the epithelial structure, or does loss of tissue structure come first, creating a suitable environment for cancer genes to enforce the cell cycle progression?"
Data from their studies supports the view that loss of tissue structure occurs first, he added.
In the current study, investigators introduced an active form of c-Myc into mammary acini with established epithelial organization. The activated oncogene failed to induce changes in morphology or size or trigger proliferation.
Further studies revealed that five-day acinar structures were susceptible to the mitogenic effects of c-Myc but not 10-day structures. Notably, the authors stated, loss of susceptibility to c-Myc occurs during the period when the organized epithelial architecture forms.
Dr. Klefstrom and colleagues further elucidated the anticancer role on organized epithelial structure by examining mammary cells in a laboratory environment that strongly or weakly promoted cell differentiation. Activation of c-Myc promoted proliferation of immature cells in the former but not in the latter environment.
"The data underscore the importance of epithelial architecture and polarity in blocking the proliferative c-Myc function," the authors wrote.
The investigators then studied the effects of c-Myc in cells with intact LKB1 or experimentally silenced LKB1. The studies showed that "the absence of LKB1 leads to gross abnormalities in the structure and partial loss of cell polarity."
Additional experiments demonstrated that organized epithelial structures also resisted the apoptotic effects of the oncogene.
"We were amazed to find out that the formation of organized mammary epithelial architecture in three-dimensional organotypic cell culture correlated with complete loss of oncogenic activities of the c-Myc cancer gene," Dr. Klefstrom commented.
The authors had no disclosures. The study was funded by the Academy of Finland, the Finnish Funding Agency for Technology and Innovation, the Sigrid Juselius Foundation, Helsinki University Central Hospital, the Lilly Foundatin, and the Juliana von Wendt Foundation. Primary source: Proceedings of the National Academy of SciencesSource reference: Partanen JI et al. "Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization." PNAS 2007;104:epub.
Human Thrombin Gets FDA Approval

ROCKVILLE, Md., Aug. 28 -- The FDA today allowed a topical human thrombin (Evithrom) on the market to help reduce minor bleeding during surgery.
The risk of transfusion-transmitted viral infection kept human thrombin on the sidelines for more than a half-century. The alternative was bovine thrombin.
"Surgeons will now be able to choose between human thrombin and thrombin derived from cattle plasma," said Jesse L. Goodman, M.D., M.P.H., director of the FDA's Center for Biologics Evaluation and Research.
The new Israeli-made agent is derived from human plasma obtained from carefully screened and tested U.S. donors and has undergone steps to further reduce the risk for viral transmission, said the FDA.
In 1954, human thrombin was delicensed, primarily because of the risk of transmitting what was then known as non-A, non-B hepatitis (now hepatitis C). Now, according to the FDA, the human thrombin has dedicated viral inactivation and removal steps.
A recombinant-DNA product, which would be a competitor of human thrombin, is in the final stages of an FDA review.
Human thrombin was indicated as an aid to stop oozing and minor bleeding from capillaries and small veins and when control of bleeding by standard surgical techniques is ineffective or impractical, said the FDA. The product is applied to the surface of bleeding tissue and may be used in conjunction with an absorbable gelatin sponge.
The agency said human thrombin must not be injected into blood vessels, which would result in serious clinical complications and may even be fatal.
In a clinical trial involving several hundred patients, human thrombin was found comparable to cattle-derived thrombin in both safety and effectiveness, said the FDA.
Evithrom is manufactured by Omrix Biopharmaceuticals of Ramat Gan, Israel, and will be distributed by Johnson & Johnson Wound Management, a division of Ethicon, Inc., Somerville, N.J.
Calcium With or Without Vitamin D May Help Prevent Osteoporosis

August 28, 2007 — Calcium, or calcium in combination with vitamin D, may prevent osteoporosis in people aged 50 years and older, according to the results of a systematic review and meta-analysis in the August 25 issue of The Lancet.
"Calcium alone, or in combination with vitamin D, has been suggested as an inexpensive treatment to prevent osteoporotic bone loss and fractures, costing as little as €0.41 per day in one European study," write Benjamin M.P. Tang, MD, from the University of Western Sydney in New South Wales, Australia, and colleagues. "However, there has been substantial uncertainty about its efficacy in lowering the fracture rate.... We did a meta-analysis to include all the randomised trials in which calcium, or calcium in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss."
Using electronic databases, as well as a hand-search of reference lists, review articles, and conference abstracts, the study authors identified 29 randomized trials enrolling a total of 63,897 subjects. Average duration of treatment with calcium, or calcium in combination with vitamin D, was 3.5 years.
Eligibility criteria were randomized design and recruitment of people aged 50 years or older. Primary endpoints were all types of fractures and the percentage change of bone mineral density (BMD) from baseline. A random-effect model allowed pooling of data.
There were 17 trials that reported fracture as an outcome, enrolling a total of 52,625 subjects. In these trials, treatment with calcium, or calcium in combination with vitamin D, was associated with a 12% risk reduction in fractures of all types (risk ratio [RR], 0.88; 95% confidence interval [CI], 0.83 - 0.95; P = .0004).
There were 23 trials, enrolling a total of 41,419 subjects, that reported BMD as an outcome. In these trials, treatment was associated with a decrease in the rate of bone loss of 0.54% (95% CI, 0.35 - 0.73; P < .0001) at the hip and 1.19% (95% CI, 0.76 - 1.61%; P < .0001) at the spine.
In trials with high rates of compliance, the reduction in the risk for fractures was significantly greater (24%; P < .0001). Calcium doses of 1200 mg or more were associated with a greater treatment effect than were doses of less than 1200 mg (0.80 vs 0.94; P = .006), and vitamin D doses of 800 IU or more were associated with a greater treatment effect than were doses of less than 800 IU (0.84 vs 0.87; P = .03).
Subjects who were elderly, lived in institutions, had a low body weight and low calcium intake or were at a high baseline risk had a greater reduction in fracture risk than did others. The treatment effect was consistent regardless of sex, fracture sites, or history of previous fractures.
"Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older," the study authors write. "For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation)."
Limitations of the study include the scarcity of data for vitamin D doses of more than 800 IU, probable underestimation of the treatment efficacy because of poor compliance in some trials, exclusion of trials that studied calcium as part of a dietary intake or nutritional supplementation regimen, exclusion of observational studies, absence of men-only trials, and inability to determine the interaction of physical exercise on the treatment effect.
The Australian Government supported this study. The study authors have disclosed no relevant financial relationships.
In an accompanying editorial, Jean-Yves Reginster, MD, PhD, from the Bone and Cartilage Metabolism Unit, CHU Centre Ville in Liege, Belgium, notes that this study does not fully address the cost-conscious use of calcium or calcium with vitamin D supplementation.
"Tang and colleagues' contribution is important because it paves the way for future research aiming at the best clinical, pharmacological, and economic use of calcium and vitamin D in patients at increased risk of osteoporotic fractures," Dr. Reginster writes. "Various treatment options have been advocated, including systematic supplementation at the onset of menopause and restriction of calcium with or without vitamin D to patients receiving other anti-osteoporotic drugs. Tang suggests that the number needed to treat (NTT) (63 patients over 3.5 years) with calcium or calcium and vitamin D to prevent one osteoporotic fracture compares favourably with similar calculations from the cardiovascular field."
Dr. Reginster has disclosed various financial relationships with Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, Merck Sharp and Dohme, Rottapharm, IBSA, Genevrier, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, and Novo-Nordisk.
Lancet. 2007;370:632-633, 657-666.
World Health Organization Updates Guidelines for Avian Influenza Virus Management

August 28, 2007 — Oseltamivir remains the primary recommended antiviral treatment for management of avian Influenza A(H5N1) virus infection, according to guidelines updated by the World Health Organization (WHO) on August 15. The guidelines are available on the WHO Web site at:
"Experiences clearly show that to reduce mortality, patients should receive treatment with oseltamivir as early as possible, but treatment remains effective even when patients present late," John Oxford, from St. Bartholomew's and the Royal London Hospital, United Kingdom, says in a news release. "H5N1 has proven to be an extremely virulent virus in humans, and in some countries, we have seen the need to use higher and longer doses of oseltamivir to gain maximum benefit."
Beginning in late 2003, widespread infection among poultry and birds with H5N1 in several continents has increased the risk for human exposure to the virus. As of August 16, 2007, the H5N1 strain has infected 321 humans and caused 194 deaths worldwide, with a cumulative case-fatality rate of about 60%. Respiratory failure with acute respiratory distress syndrome (ARDS) is the major complication in hospitalized patients, often with rapid progression to multiorgan failure. To date, there has been no standardized approach for clinical management.
The current guidelines, which replace the 2004 WHO interim guidelines on clinical management of H5N1 infection and update recommendations on pharmacologic management published by WHO in June 2006, review pharmacologic and supportive therapies that are frequently used and offer advice on case management in humans.
The evidence base for the updated guidelines includes review of the literature and reports on cases of H5N1 presented at the first WHO Consultation on Human H5N1 Infections held in Hanoi, Vietnam, in May 2005, and at the Second WHO Consultation on Clinical Aspects of Human Infection with Avian Influenza (H5N1) Virus held in Antalya, Turkey, in March 2007.
At the second WHO consultation, a working group of experts in critical care medicine, pulmonary medicine, infectious diseases, pediatrics, and public health, as well as clinicians directly involved in treating patients infected with A(H5N1), met to develop recommendations and establish standards for clinical management of A(H5N1) infections in humans.
Because of limited data available from human infections with A(H5N1), other evidence was considered from human seasonal influenza, pertinent animal models, severe acute respiratory syndrome (SARS) and other respiratory virus infections, and ARDS from other causes.
Specific clinical recommendations for management of A(H5N1) virus infection are as follows:
To improve understanding of the disease and identify appropriate treatment, care for H5N1 infections in humans should be standardized, and clinical and treatment information should be shared promptly.
Oseltamivir is still the first-line recommendation for antiviral therapy. In early stages of H5N1 virus infection, oseltamivir reduces mortality. Oseltamivir is also indicated when the patient presents for clinical care at later stages of the disease because the A(H5N1) virus continues to replicate for a prolonged period. Oseltamivir is the only neuraminidase inhibitor previously used in clinical management of A(H5N1), and it is the only antiviral agent strongly recommended by the WHO for treatment of patients infected with the A(H5N1) virus.
Especially in patients with pneumonia or progressive disease, modified regimens incorporating treatment with oseltamivir may be considered on a case-by-case basis. These may include a 2-fold higher dosage; longer duration of treatment; and, in countries where A(H5N1) viruses are likely to be susceptible to adamantanes, possibly combination therapy with amantadine or rimantadine. Prospective data collection should continue during use of these modified regimens.
Although corticosteroids should not be used routinely, they may be considered in cases of septic shock associated with suspected adrenal insufficiency mandating use of vasopressors. However, prolonged or high-dose corticosteroids can lead to opportunistic infection or other serious adverse events in patients infected with the A(H5N1) virus.
Antibiotic chemoprophylaxis should not be given routinely except when pneumonia is present. In these cases, published evidence-based guidelines should initially be followed for antibiotic therapy of community-acquired pneumonia. Microbiologic testing, when available, should determine the best choice of antibiotics for suspected bacterial coinfection.
Whenever possible, oxygen saturation should be monitored routinely with pulse oximetry and arterial blood gases at presentation and during subsequent care. Hypoxemia should be corrected with supplemental oxygen.
Treatment of A(H5N1) virus-associated ARDS should follow published evidence-based guidelines for sepsis-associated ARDS, and it should include strategies of mechanical ventilation for lung protection.
Inhaled zanamivir has not been studied in H5N1 infection in humans. However, serious lower respiratory tract or extrapulmonary disease may impede adequate delivery of inhaled zanamivir.
"Standardization of clinical care and antiviral management is fundamental to improve understanding of the disease course and to identify the appropriate therapy," the authors of the guidelines conclude. "Developing recommendations based solely on clinical reports from humans infected with influenza A(H5N1) virus is problematic due to insufficient data currently in the public domain, and the inconsistency of data collection from A(H5N1) virus-infected individuals. Collaborative sharing of clinical and treatment data from affected patients in different regions and countries is essential to improve understanding of this disease and to refine optimal case management."
World Health Organization. Published online August 23, 2007.
Acute Myocardial Infarction: A Prediabetes Risk Equivalent?

August 28, 2007 — Physicians should consider acute myocardial infarction (AMI) to be a prediabetes risk equivalent, authors of a new study say.[1] Dr Dariush Mozaffarian (Harvard Medical School, Boston, MA) and colleagues report that compared with people who have not had an AMI, post-AMI patients have a significantly higher risk of developing diabetes or impaired fasting glucose.
"We know that diabetes is a risk factor for CAD [coronary artery disease]," senior author on the study, Dr Roberto Marchioli (Consorzio Mario Negri Sud, Chieta, Italy) told heartwire. "What was not well known is that after MI [myocardial infarction], a lot of patients are at risk of developing diabetes or disturbance of glycemic metabolism. And this is what we saw in our paper."
The results of their study appear in the August 25, 2007 issue of The Lancet.
Over a five-year period, Mozaffarian and colleagues tracked new-onset diabetes or the development of impaired fasting glucose (IFG) in a cohort of more than 8000 non-diabetic men and women who had experienced a recent AMI at baseline. Study participants were originally followed as part of the GISSI-Prevenzione trial, one of the first studies to establish the benefits of a Mediterranean diet, high in n-3 polyunsaturated fatty acids. The investigators also collected information on body mass index (BMI), cardiovascular risk factors, diet, lifestyle, and medication use at baseline and over the follow-up period.
Over a mean of 3.2 years (and a total of 26 795 person-years), 33% of the cohort developed diabetes or IFG, a number that rose to 62% when a lower cut-off for IFG was used (5.6 mmol/L). The annual incidence rate among the GISSI study group was 27.5% for IFG, using the 5.6 mmol/L cut-off, and 3.7% for diabetes. By way of comparison, Mozaffarian et al point out that studies in the general population indicate that middle-aged adults face an annual rate of developing IFG of 1.8% and of developing diabetes, 0.8-1.6%.
The authors identified older age, high blood pressure, use of beta-blockers or diuretics, higher BMI, smoking, and low Mediterranean diet score as independent risk factors for diabetes or IFG development. By contrast, use of lipid-lowering drugs, high intake of foods characteristic of Mediterranean diets, and increased physical activity levels seemed to be protective.
To heartwire, Marchioli hypothesized that lifestyle habits were likely "the most important determinant of diseased metabolism."
"We found that increased BMI was associated with the risk of developing diabetes and impaired fasting glucose and we also saw that weight gain after MI was associated with increased disease," he said. "Similarly we saw that patients who had bad dietary habits with a lower intake of fruit, vegetables, fish, and olive oil, had a higher risk of developing diabetes. The same was seen in patients who had the lowest physical activity. So there was a kind of cumulative indication saying that if you don't have good lifestyle habits, you are at high risk of becoming obese and developing diabetes."
The authors say their findings should prompt a rethinking of cardiovascular disease (CVD) and diabetes as both risk factors, and end points. "Just as diabetes can be considered a coronary heart disease risk-equivalent, acute myocardial infarction should potentially be considered a prediabetes risk-equivalent," they write.
But they are also careful to emphasize that they do not believe AMI itself increases the risk of diabetes; rather, some common pathways likely increase the risk of both MI and subsequent diabetes, including an increased likelihood of metabolic dysfunction. Indeed, in an accompanying editorial, Dr Lionel H Opie (University of Cape Town, South Africa), points out that the notion of AMI as an acute stress reaction precipitated in part by metabolic changes dates back more than 40 years.[2] If stress mediates hyperglycemia, he notes, it is "logical" to expect that AMI survivors might also be at risk of developing diabetes. Opie hypothesizes that a tendency towards prediabetes at the time of AMI might get the necessary boost towards overt diabetes or IFG over ensuing years in the form of bad lifestyle habits, or even use of beta blockers and diuretics, both known to affect insulin sensitivity.
Both Opie and the study authors highlight the apparent benefits, in this setting, of the Mediterranean diet rich in fruit, vegetables and n-3 polyunsaturated fatty acids, but low in saturated fats and refined carbohydrates. Opie speculates that the combination of these foods may have a "double benefit": protecting against both cardiovascular events and new diabetes. Likewise, Marchioli and colleagues emphasize that counseling postinfarct patients about the importance of diet and lifestyle should not be overlooked, not only for secondary CVD prevention, but also to prevent the development of diabetes.
"I think that this study should be useful to remind people, starting with the physician, that lifestyle changes should always be assessed in the physician's office," Marchioli told heartwire. "Patients believe their physicians and if the physician emphasizes the importance of diet, physical activity and stopping smoking, that could be the most important message from our study."
Mozaffarian D, Marfisi RM, Levantesi G, et al. Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors. Lancet 2007;370:667-675.
Opie LH. Acute myocardial infarction and diabetes. Lancet 2007;370:634-635.