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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
May 14, 2011

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Vitamin D Deficiency and Death?
Physical Activity and Glucose Control: Some Is Good, More Is Better
Diet, Exercise, or Both in Obese Older Adults
Calcium, With or Without Vitamin D, Raises Risk for Adverse Cardiovascular Events
Study Suggests NSAIDs Shouldn't Be Prescribed After MI, Even Briefly
FDA Alert: Topiramate Increases Risk for Birth Defects
Vitamin B for PMS?
Beta-Blockers Might Reduce Mortality, Disease Exacerbations in COPD
Most Parents Would Agree to Test Their Kids for Smoke Exposure
Bisphosphonate-Related Jaw Osteonecrosis — Back on the Radar Screen
Prevention of Falls in Elders
Curbing the Risk for Stillbirth
Omega-3s May Oppose Child Obesity
Cocoa May Boost Eyes and Brain
Acute and Preventive Treatments for Cluster Headache
Topical Antiandrogen
Chantix Lawsuit Claims It Caused Murder-Suicide
Food Quality Feared in China
Early HIV Treatment Associated with Greatly Reduced Transmission to Partners
Antibiotic Prophylaxis for Dental Procedures
Physiological Effects of Water-Pipe Tobacco Smoking
New Genes Associated with Alzheimer Disease

Crit Care Med 2011 Apr; 39:671
Vitamin D Deficiency and Death?
In an 11-year observational study among critically ill patients, hypovitaminosis D was a risk factor for positive blood cultures, sepsis, and mortality.
     Although 25-hydroxyvitamin D (cholecalciferol) was once believed to be involved only in calcium metabolism and bone growth, we now know that it has pleiotropic effects on immune, endothelial, and mucosal functions. In a recent retrospective study, investigators examined the effect of vitamin D deficiency on disease course in critically ill patients. Participants were 2399 adults treated in an intensive care unit (ICU) at either of two Boston medical centers between November 1997 and April 2009. All had vitamin D levels measured ≤1 year before admission.
     Mean age was 64.9, and mean vitamin D level was 26.4 ng/mL. Most of the vitamin D measurements occurred ≤6 months before admission (29.8% ≤1 month, 51.6% ≤3 months, and 73.3% ≤6 months). Vitamin D levels were categorized as deficient (≤15 ng/mL), insufficient (16–29 ng/mL), or sufficient (>30 ng/mL).
     Sepsis or positive blood cultures were significantly more common in patients with vitamin D deficiency than in those with vitamin D sufficiency. The adjusted 30-day mortality risk was 1.4-fold higher in patients with vitamin D insufficiency — and 1.7-fold higher in those with vitamin D deficiency — than in patients with vitamin D sufficiency. Similar results were obtained for in-hospital, 90-day, and 365-day mortality.
     Comment: Hypovitaminosis D, an easily correctable yet very common condition, appears to significantly increase the risk for infection and death in critically ill patients. This link could be explained by results from previous in vitro analyses, which suggested an association between vitamin D deficiency and defects in macrophage functions (phagocytosis, chemotaxis, and proinflammatory cytokine production; Immunology 1991; 73:466), as well as impaired toll-like receptor–mediated activation of innate immune responses (J Immunol 2007; 179:2060).
Thomas Glück, MD Published in Journal Watch Infectious Diseases May 11, 2011
     Citation(s): Braun A et al. Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. Crit Care Med 2011 Apr; 39:671.
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JAMA 2011 May 4; 305:1790
Physical Activity and Glucose Control: Some Is Good, More Is Better
In a meta-analysis, structured exercise programs showed a dose–response association with improvement in glycosylated hemoglobin levels in patients with diabetes.
     That exercise improves glucose control in patients with type 2 diabetes is well known; however, the effects of physician advice regarding physical activity and the relative benefits of particular types and durations of exercise remain unclear. To assess the effects of various interventions on glycosylated hemoglobin (HbA1C) levels, investigators reviewed more than 4000 articles and performed a meta-analysis of data from 47 clinical trials of at least 12 weeks' duration involving 8538 patients with type 2 diabetes.
     Patients participating in structured exercise programs (aerobic, resistance, or combined training) had a decline in mean HbA1C level of more than 0.67%, compared with controls. All types of structured exercise were associated with significant decreases in HbA1C level; however, mean HbA1C reductions in participants who performed >150 minutes of exercise per week were nearly three times greater than those in participants who performed ≤150 minutes of exercise per week (0.89% vs. 0.36%). Interventions consisting of advice about unsupervised physical activity were associated with a decline in HbA1C levels of 0.43% compared with controls; however, the greatest reduction in HbA1C level (0.58%) occurred with combined physical activity and dietary advice, whereas the drop in HbA1C level was nonsignificant with advice only on physical activity.
     Comment: These findings suggest that a structured exercise program, whether aerobic, resistance, or both, is best; physician advice about unsupervised physical activity was also associated with HbA1C reductions, but only when combined with dietary advice. Notably, longer total weekly durations of exercise were associated with greater HbA1C reductions than shorter durations. Clinicians should encourage their patients with diabetes to participate in any type of structured exercise for at least 150 minutes per week. For those patients who have substantial barriers to exercising, we should emphasize that every increment of increase in physical activity helps when coupled with dietary changes.
JoAnne M. Foody, MD Published in Journal Watch Cardiology May 11, 2011
     Citation(s):Umpierre D et al. Physical activity advice only or structured exercise training and association with HBA1C levels in type 2 diabetes: A systematic review and meta-analysis. JAMA 2011 May 4; 305:1790.
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N Engl J Med 2011 Mar 31; 364:1218
Diet, Exercise, or Both in Obese Older Adults
Combining dieting and exercise improved physical performance — but so did dieting or exercise alone.
     Because obesity predisposes older adults to disability, we often advise such patients to diet and get exercise. To determine the relative contributions of these two interventions, researchers randomized 107 obese older adults (age, ≥65; body-mass index, >30 kg/m2) with mild-to-moderate frailty to receive a diet intervention, exercise intervention, both, or neither. The diet intervention consisted of individualized weight-loss diets targeted to 10% reduction of baseline weight and weekly group sessions with dieticians. The exercise intervention consisted of 90-minute, thrice-weekly group sessions that included aerobic exercise and resistance training.
     At 1 year, mean weight loss was about 9 kg in both the diet-only and diet–exercise groups but was negligible in the exercise-only and control groups. Mean improvement on a 9-task, 36-point physical performance test (the primary outcome) was best in the diet–exercise group (5.4 points), intermediate in the exercise-only and diet-only groups (4.0 and 3.1 points, respectively), and negligible in the control group.
     Comment: Unsurprisingly, a combination of dieting plus exercise improved physical performance more than dieting or exercise alone. However, the exercise-only intervention improved physical performance nearly as much as the combined intervention; that's an important message to convey to older patients who successfully engage in exercise but are frustrated by inability to lose weight. The interventions in this study were labor-intensive (from the healthcare system's perspective) and required substantial commitment (from the patient's perspective).
Allan S. Brett, MD Published in Journal Watch General Medicine April 12, 2011
     Citation(s):Villareal DT et al. Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med 2011 Mar 31; 364:1218. (http://dx.doi.org/10.1056/NEJMoa1008234)
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BMJ 2011 Apr 19; 342:d2040
Calcium, With or Without Vitamin D, Raises Risk for Adverse
Cardiovascular Events

Vascular calcification is one proposed mechanism.
     A recent meta-analysis showed that calcium supplementation without vitamin D elevates cardiovascular (CV) risk (JW Gen Med Aug 31 2010). However, whether calcium and vitamin D taken together elevate CV risk is unclear. Although the Women's Health Initiative (WHI) previously reported that calcium and vitamin D supplements taken together did not elevate CV risk, about half the 36,000 participants were taking nonprotocol calcium and vitamin D at randomization — potentially obscuring the association. To determine whether calcium and vitamin D taken together elevate CV risk, investigators reanalyzed WHI data according to personal use of calcium and incorporated these data in a meta-analysis of eight additional studies.
     In the reanalysis of WHI data, women who did not report baseline calcium use who were randomized to daily calcium (1 g) and vitamin D (400 IU) had significantly elevated risks for myocardial infarction, MI or revascularization, and MI or stroke (hazard ratio, 1.2 for each outcome), compared with placebo recipients. In contrast, users of calcium at baseline who were randomized to calcium and vitamin D did not have excess CV risk compared with placebo recipients.
     In a meta-analysis of three randomized trials with 20,000 participants, calcium and vitamin D supplementation raised risks for MI, stroke, and a composite of MI or stroke, compared with placebo (relative risk, 1.2 for each outcome). A meta-analysis of nine trials that involved 28,000 participants showed that calcium or calcium and vitamin D supplementation significantly raised risks for MI and a composite of MI or stroke compared with placebo (RR, 1.2 for each outcome). The average duration of the trials was about 6 years.
Comment: These results suggest that calcium supplements, with or without vitamin D, raise risk for adverse CV events. The authors note "calcium supplements acutely increase serum calcium concentration . . . an effect that is sustained during long term treatment, as evidenced by lower levels of parathyroid hormone" and might promote vascular calcification. That baseline users of calcium in the WHI study who were randomized to calcium and vitamin D did not have excess CV risk suggests a dose-response relation does not exist. The authors speculate "the abrupt change in plasma calcium after supplement ingestion" rather than total calcium load causes the adverse effect. What should clinicians do until these results are confirmed or refuted by additional research? One approach would be to advise patients to increase calcium intake through food sources (e.g., milk products), as the aforementioned studies say nothing about this type of calcium intake. Another approach would be to avoid calcium supplementation in patients at high CV risk.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine May 12, 2011
     Citation(s):Bolland MJ et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: Reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ 2011 Apr 19; 342:d2040. (http://dx.doi.org/10.1136/bmj.d2040)
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Study Suggests NSAIDs Shouldn't Be Prescribed After MI, Even Briefly
     In patients with a history of myocardial infarction, use of nonsteroidal anti-inflammatory drugs — even for brief periods — increases risks for death and recurrent infarction, according to a Circulation study.
     Using Danish national healthcare registries, researchers identified more than 80,000 patients who'd been treated for a first MI and then tracked subsequent NSAID prescriptions. Over 40% of patients received at least one prescription for an NSAID during follow-up.
Risks for death or reinfarction were significantly higher during treatment with all NSAIDs studied. Diclofenac was associated with the greatest risk, which began immediately and persisted throughout treatment. (Naproxen was the least problematic.)
     The authors say their results "indicate that there is no apparent safe therapeutic window for NSAIDs in patients with prior MI and challenge the current [American Heart Association] recommendations of low-dose and short-term use of NSAIDs as being safe."
MM: Topiramate is one of the two components that is being touted as the “new diet drug wonder” seeking FDA approval. Could this be another Phen-Fen Disaster in the making?
AHA scientific statement on NSAIDs:
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MM: Topiramate is one of the two components that is being touted as the “new diet drug wonder” seeking FDA approval. Could this be another Phen-Fen Disaster in the making?
FDA Alert: Topiramate Increases Risk for Birth Defects

Because of a topiramate-associated risk for oral clefts, the FDA has now designated topiramate as a pregnancy category D drug.
     On March 4, 2011, the FDA reported an increased risk for oral clefts in infants born to women taking topiramate during pregnancy.
Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry revealed that mothers taking topiramate during the first trimester of pregnancy had an increased risk for infants born with oral cleft palate or lip. According to the registry data, 1.4% of infants exposed to topiramate in utero were born with a cleft lip or palate, compared with a range of 0.38% to 0.55% of infants born to mothers taking other antiepileptic medications during pregnancy and with 0.07% of infants born to mothers who neither had epilepsy nor took antiepileptic medications.
     Topiramate has now been designated as a category D drug ("positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks").
     Comment: Oral clefts form in the first trimester, during the earliest phases of development, often before many women even know they are pregnant. Clinicians treating women of childbearing potential should carefully weigh the risks and benefits of topiramate and must inform their patients of the increased risk for oral clefts in a baby gestated while they are on this medication. As topiramate can also reduce the efficacy of estrogen-containing contraceptives, physicians should discuss with these patients reliable options for contraception while on topiramate to avoid unplanned pregnancies.
     These findings underscore the importance of prenatal counseling for all women of childbearing potential who are considering treatment with medications that have an unknown effect in pregnancy. Most frequently-used medications in migraine have an unknown risk in pregnancy (FDA pregnancy category C). Clinicians prescribing drugs classified by the FDA as anything other than category A or B to women of childbearing potential should counsel them regarding the use of safe and effective forms of birth control.
— Ana Recober, MD, and Rashmi Halker, MD Dr. Recober is Assistant Professor, Department of Neurology, University of Iowa Hospitals and Clinic, Iowa City. Dr. Halker is Assistant Professor of Neurology, Mayo Clinic, Phoenix.
Published in Journal Watch Neurology May 3, 2011
     Citation(s):Food and Drug Administration. FDA drug safety communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate). Mar 4 , 2011. (http://www.fda.gov/Drugs/DrugSafety/ucm245085.htm
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Am J Clin Nutr 2011 May; 93:1080.
Vitamin B for PMS?
Higher dietary intake of thiamine (B-1) and riboflavin (B-2) was associated with lower risk for new-onset premenstrual syndrome.
     The etiology of premenstrual syndrome (PMS) remains elusive. To evaluate possible associations between dietary B vitamin intake and development of PMS, investigators conducted a case-control study nested within the Nurses' Health Study, a longitudinal cohort of women who provide biennial reports of diet and lifestyle factors and health outcomes. During 10 years of follow-up, PMS was diagnosed in 1057 participants (36%); 1968 women were identified who did not have PMS or other menstrual symptoms.
     Women in the highest quintile of thiamine intake were 25% less likely to develop PMS than were those in the lowest quintile, and women in the highest quintile of riboflavin intake were 35% less likely to develop PMS. Intake of B vitamins from supplements did not lower risk for PMS — probably a reflection that such supplements often are prescribed for management of PMS.
     Comment: Several studies have shown benefits, albeit inconsistent, of using vitamin B supplements to treat PMS. This study suggests that high dietary intake of thiamine and riboflavin is associated with diminished risk for PMS. However, my enthusiasm for the findings is dimmed by the lack of correction for multiple comparisons, strong correlations among intake of individual B vitamins, and exclusion of women without PMS who reported any menstrual symptoms besides PMS. In general, women should be counseled to consume a wide variety of foods that contain high levels of B vitamins, such as seafood, legumes, and green leafy vegetables, as part of a healthy diet.
Anna Wald, MD, MPH Published in Journal Watch Women's Health April 28, 2011
     Citation(s): Chocano-Bedoya PO et al. Dietary B vitamin intake and incident premenstrual syndrome. Am J Clin Nutr 2011 May; 93:1080.
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BMJ 2011; 342:d2549
Beta-Blockers Might Reduce Mortality, Disease Exacerbations in COPD
Beta-blockers might reduce mortality and disease exacerbations in patients with chronic obstructive pulmonary disease, according to a retrospective cohort study in BMJ.
     Researchers in Scotland used national databases to examine prescriptions and outcomes among some 6000 COPD patients aged 50 and older; about 13% were using beta-blockers in addition to other COPD therapies (e.g., long-acting beta-agonists).
     During 4 years' follow-up, beta-blocker use was associated with a 22% reduction in all-cause mortality, as well as significant reductions in oral corticosteroid use and hospital admissions for respiratory disease. Beta-blockers appeared beneficial when added to step-up inhaled treatment regimens, even after adjustment for use of other cardiovascular drugs and history of cardiovascular disease. The drugs did not show any deleterious effects on pulmonary function testing.
     The authors say their data "suggest that beta-blockers have effects on reducing mortality in COPD in addition to the benefits gained by reducing cardiovascular risk."
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Pediatrics 2011 Apr; 127:628
Most Parents Would Agree to Test Their Kids for Smoke Exposure
Even parents who smoke
     On the basis of biochemical measures of cotinine, a metabolite of nicotine, more than two thirds of children are exposed to second-hand and so-called third-hand (residual contamination on surfaces and people) tobacco smoke. Researchers examined the acceptability to parents of testing children for tobacco smoke exposure in a nationally representative telephone survey of 477 parents (19% were current smokers).
     Sixty percent of all parents and 62% of parents who smoke said they would have their children tested for tobacco smoke exposure if a test were available from their pediatricians. More than 70% would have their children tested if the test could be performed on blood already collected for other reasons (e.g., screening for anemia or lead exposure). Parent factors that were associated with wanting smoke exposure testing were lower parental education level, allowing smoking in the home, nonwhite race, and being a mother.
    Comment: Tests that detect tobacco smoke exposure in children might appeal to parents, but would they encourage parents to quit or remove children from smoky environments? The authors note that a rapid test would provide real-time feedback and potentially encourage parents who smoke to stop. The only commercially available test is for urine cotinine, which reliably detects nicotine exposure during the prior 3 days. How smoke exposure testing would work in clinical practice remains to be seen, but it is noteworthy that most parents are interested in having their children tested.
Cornelius W. Van Niel, MD Published in Journal Watch Pediatrics and Adolescent Medicine
May 11, 2011
    Citation(s):Winickoff JP et al. Acceptability of testing children for tobacco-smoke exposure: A national parent survey. Pediatrics 2011 Apr; 127:628.
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J Dent Res 2011 Apr; 90:439.
Bisphosphonate-Related Jaw Osteonecrosis — Back on the Radar Screen
Studies support a link between oral bisphosphonate use and jaw osteonecrosis, but absolute risk is very low.
     Controversy about jaw osteonecrosis in oral bisphosphonate users was a hot topic several years ago (JW Gen Med Apr 8 2008), but it faded into the background when attention shifted to a possible connection between atypical femoral fractures and bisphosphonates (JW Womens Health May 4 2011). Now, two new NIH-funded studies, conducted in dental practice–based research networks, put the spotlight back on bisphosphonate-related osteonecrosis of the jaw (BRONJ).
     In a case-control study that involved 119 dental practices in four U.S. metropolitan areas, 191 patients with BRONJ were compared with 573 control patients. About half the BRONJ patients had used oral bisphosphonates. In multivariate analysis, oral bisphosphonate use was strongly associated with BRONJ (odds ratio, 12.2).
     In another retrospective study, researchers identified 23 BRONJ cases during roughly 10 years in two health maintenance organizations that provided dental benefits. Six BRONJ patients (26%) used oral bisphosphonates, compared with 4% of non-cases (adjusted OR for association between oral bisphosphonates and BRONJ, 15.5). The overall incidence of BRONJ was 0.63 cases per 100,000 person-years, but, among oral bisphosphonate users, it was 4.1 per 100,000 person-years.
     Comment: BRONJ is recognized widely as a complication of high-dose intravenous bisphosphonate use for cancer treatment, but its association with oral use for osteoporosis is controversial. These observational studies have many limitations, but they suggest that oral use is a rare cause of BRONJ. Clinicians should keep this possibility in mind but should not let it deter use of bisphosphonates in osteoporotic patients who have evidence-based indications for these drugs.
Allan S. Brett, MD Published in Journal Watch General Medicine May 5, 2011
     Citation(s): Barasch A et al. Risk factors for osteonecrosis of the jaws: A case-control study from the CONDOR Dental PBRN. J Dent Res 2011 Apr; 90:439.
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Arch Intern Med 2011 Mar 28; 171:525
Prevention of Falls in Elders
Effects of different interventions vary in different populations.
     Researchers have evaluated a wide range of interventions to prevent falls in older people with a wide range of outcomes. Two randomized studies illustrate this issue.
     Swiss researchers enrolled 134 community-dwelling older people (mean age, 76) at elevated risk for falling to evaluate the effects of a music-based program that involved progressively more difficult multitask exercises. For 6 months, intervention patients attended weekly 1-hour sessions of music and movement training; delayed-intervention control patients were asked to continue their usual activities. During the second 6 months of the study, assignments were reversed. Overall attendance in the exercise program was 78% in both groups. During the first 6 months, the intervention group had 51% fewer falls than the control group; this benefit persisted into the second 6-month period.
     In Australia, 1206 hospitalized older patients (mean age, 75) were assigned to one of three fall-prevention programs: one-on-one counseling by a physical therapist who used written and video materials (median duration, 25 minutes), materials alone, or a usual-care control group. Falls during hospitalization (median stay, 11–14 days) were reduced roughly 50% in the counseling group compared with the materials-only or usual-care groups, but only among cognitively intact patients. Unexpectedly, falls among cognitively impaired patients were more common in the intervention group (7.5 injurious falls/1000 patient-days vs. 2.9 in the usual-care group).
     Comment: These studies have two main messages. First, fall-prevention programs are labor-intensive. Second, prevention programs can have unintended consequences among some patient populations — in one study, hospitalized, cognitively impaired patients had more falls after intervention, perhaps because they were encouraged to walk.
Thomas L. Schwenk, MD Published in Journal Watch General Medicine April 12, 2011
     Citation(s): Trombetti A et al. Effect of music-based multitask training on gait, balance, and fall risk in elderly people: A randomized controlled trial. Arch Intern Med 2011 Mar 28;
171:525. (http://dx.doi.org/10.1001/archinternmed.2010.446)
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Lancet 2011 Apr 16; 377:1331
Curbing the Risk for Stillbirth
Modifiable risk factors for stillbirth in high-income countries include maternal overweight and obesity, advanced age, and smoking.
     The rate of stillbirth in high-income countries has stabilized at 1 per 200 pregnant women who reach 22 weeks' gestation. To examine risk factors for stillbirth in high-income countries, researchers conducted a meta-analysis of studies in which at least one risk factor was assessed and stillbirth was defined as death after ≥20 weeks' gestation or birth weight ≥400 g. Of 22,691 identified studies, 96 from 13 countries (29 from the U.S.) met inclusion criteria (6 prospective and 70 retrospective cohort studies and 20 case-control studies). Most studies excluded women with multiple pregnancies and stillbirths with congenital abnormalities.
     The most critical and potentially modifiable risk factors for stillbirth were maternal weight, smoking, age, preexisting diabetes or hypertension, primiparity, placental abruption, and small-for-gestational-age fetus. The top modifiable risk factor was combined maternal prepregnancy overweight and obesity (body-mass index >25 kg/m2. Odds of stillbirth rose by 23% for overweight, 60% for obesity, 36% for smoking during pregnancy, and 65% for age >35. Heavy smoking (≥10 cigarettes/day) doubled the odds of stillbirth (odds ratio, 1.86) as did maternal age >40 (OR, 2.29). Growth restriction (gestational size <10%) was associated with four times higher risk for stillbirth. Interestingly, gestational diabetes was not associated with excess risk for stillbirth.
     Comment: Most risk factors for stillbirth in high-income countries are modifiable and can be addressed with better educational programs. Strategies to lower incidence of obesity before and after pregnancy could have the greatest effect. Although results of meta-analyses are limited (particularly by the effects of residual confounding), the data identify modifiable risk factors that can be targeted to prevent stillbirth.
Diane J. Angelini, EdD, CNM, FACNM, FAAN, NEA-BC Published in Journal Watch Women's Health May 12, 2011
     Citation(s): Flenady V et al. Major risk factors for stillbirth in high-income countries: A systematic review and meta-analysis. Lancet 2011 Apr 16; 377:1331
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Omega-3s May Oppose Child Obesity
Clinical study supports growing evidence that maternal and infant diets influence children’s future health
by Craig Weatherby
Do maternal and infant diets affect people’s health throughout life?
     Although it may seem somehow unfair, a growing body of evidence suggests the answer is “yes”. Surprisingly, connections between infant diets and adult disease were not closely examined until the 1990s, when a series of papers by Britain’s David Barker, M.D., Ph.D., started the ball rolling. Further research has led to increasingly wide acceptance of the “Barker Theory”, which holds that poor – or unbalanced – maternal nutrition leads to later heart disease, diabetes, breast and ovary cancers, osteoporosis, and other disorders.
     Poor maternal nutrition appears to change the child’s “phenotype” … a term that refers to physiological attributes that arise from the interactions between a person’s genes and their lifestyle, including their diet in the womb and during infancy. For example, a Swedish study published two years ago showed that children born to mothers who ate vegetables only three to five times per week were 71 percent more likely to develop type 1 diabetes, compared to children of women who ate vegetables daily during pregnancy (Brekke HK et al. 2010). Now, the findings from a novel Harvard clinical study adds to growing evidence that maternal nutrition can influence a child’s health prospects.

Low maternal omega-3 intake linked to babies’ obesity risk
     Adequate intake of omega-3 fatty acids during pregnancy may lower the risk of childhood obesity by almost one-third, according to new research from Harvard Medical School (Donahue SM et al. 2011). Conversely, maternal diets high in omega-6 fatty acids (from vegetable oils) and low in omega-3s (from fish or fish oil) appeared to increase a child’s risk for obesity. Harvard researchers led by Emily Oken, M.D., determined children’s risk of obesity by measuring their body mass index (BMI) and taking skinfold measurements at the scapula and triceps. The study authors also estimated the mothers’ omega-3 intake – based on the women’s self-reported weekly fish intake – and measured the levels of omega-6 and omega-3 fatty acids in the babies’ cord blood at delivery. (Omega-3s and omega-6s compete for absorption into cell membranes, and diets high in omega-6s can limit the proportion of omega-3s.) The Harvard team concluded that higher maternal omega-3 intake and higher omega-3 blood levels in newborns reduced the risk of childhood obesity.  The Harvard group then calculated the odds for obesity in the women’s offspring at age three, and looked for links to the mother’s omega-3 fatty acid intake and/or the level of omega-6 and omega-3 fats in cord blood at delivery.  Oken and her co-workers reported the odds of obesity in three-year-olds were between two and four times higher when cord blood had a high ratio of omega-6 to omega-3 fatty acids.  In contrast, the odds of obesity were 32 percent lower when maternal consumption of omega-3s was high or if the ratio of omega-3 to omega-6 intake was at or close to the recommended 1:3 ratio.  In other words, mothers who get too few omega-3 and too many omega-6 fats during pregnancy might raise their baby’s odds of becoming obese. As they wrote, “A higher ratio of cord plasma omega-6 to omega-3 polyunsaturated fatty acids was associated with higher sub-scapular and triceps [skinfold thicknesses] and odds of obesity,” they said.

Mothers’ omega-3 intake generally inadequate
     Dr. Oken and her colleagues reported that, at mid-pregnancy, only about one-fifth of the expectant mothers in their study reported eating more than the widely recommended two fish meals per week. And only about half of these relatively frequent fish-eaters were estimated to achieve the widely recommended intake of DHA of at least 200mg per day … because they reported eating mostly lean white fish. Worse, a mere three percent of the women in the study were estimated to get the recommended 200mg of omega-3 DHA per day during their last month of pregnancy. As Oken’s team noted, the last month of pregnancy is when large amounts of omega-3 DHA are transferred from mother to baby to support brain development. Judging by their study participants’ behavior, the authors hypothesized that even pregnant women who meet the two-meals-per-week intake guideline don’t consume enough fatty, omega-3-rich fish … such as salmon, tuna, sardines, and mackerel.

Omega-3s and obesity risk: An overview
     The Harvard team’s report included an important caveat:
“These findings need to be confirmed by others. It will also be important to demonstrate that making deliberate changes to a woman’s fat intake during pregnancy has desirable effects on weight and fatness in children.” (Donahue SM et al. 2011)  Two years ago, a team at Germany’s Technical University Munich reported that they were undertaking just such a study … so we’ll keep an eye out for their findings (Hauner H et al. 2009). Although imbalances in fatty acid intake – too few omega-3s and too many omega-6s – promote the development of adipose (fatty) tissue in animals, very few clinical studies have tested this in people. Indeed, when Norwegian researchers gave pregnant mothers either omega-3-rich cod liver oil or omega-6-rich corn oil from mid-pregnancy until three months after delivery, they found no link between the infants’ omega-3 or omega-6 blood levels through the first three months of life and their BMI at age seven (Helland IB et al. 2008).

     But body mass index is not a very accurate indicator of excess body fat, since people with more muscle mass than average have a high BMI without being overweight or obese. Nor is the skinfold method used in the Harvard study perfect, because it estimates body density, not body fat percentage, which must be estimated by applying a mathematical formula … an approach with its own room for error. However, as the American Heart Association says, “… children and adolescents assessed to have a skinfold measure greater than the 95th percentile are more likely to have excess body fat as opposed to increased lean body mass or large frame size.” (AHA 2011) The Centers for Disease Control and Prevention defines overweight in children as having an age-adjusted BMI at or above the 95th percentile … and CDC recommends use of the triceps skinfold test for further evaluation when a child’s BMI exceeds this level.

     Finally, we should note that when it comes to the proposed capacity of omega-3s to help adults control their weight, the clinical evidence is mostly positive, but much too limited and mixed to be conclusive … see the “Omega-3s & Weight/Fitness” section of our news archive.

     Sources: American Heart Association (AHA). Overweight in Children. Updated March 29, 2011. Accessed at http://www.heart.org/HEARTORG/GettingHealthy/Overweight-in-Children_UCM_304054_Article.jsp.  Bermúdez Menéndez de la Granda M, Sinclair AJ. Fatty acids and obesity. Curr Pharm Des. 2009;15(36):4117-25. Brekke HK, Ludvigsson J. Daily vegetable intake during pregnancy negatively associated to islet autoimmunity in the offspring--the ABIS study. Pediatr Diabetes. 2010 Jun;11(4):244-50. Epub 2009 Sep 16.  DeFina LF, Marcoux LG, Devers SM, Cleaver JP, Willis BL. Effects of omega-3 supplementation in combination with diet and exercise on weight loss and body composition. Am J Clin Nutr. 2011 Feb;93(2):455-62. Epub 2010 Dec 15.  Donahue SM, Rifas-Shiman SL, Gold DR, Jouni ZE, Gillman MW, Oken E. Prenatal fatty acid status and child adiposity at age 3 y: results from a US pregnancy cohort. Am J Clin Nutr. 2011 Apr;93(4):780-8. Epub 2011 Feb 10. Drouillet P, Forhan A, De Lauzon-Guillain B, Thiébaugeorges O, Goua V, Magnin G, Schweitzer M, Kaminski M, Ducimetière P, Charles MA. Maternal fatty acid intake and fetal growth: evidence for an association in overweight women. The 'EDEN mother-child' cohort (study of pre- and early postnatal determinants of the child's development and health). Br J Nutr. 2009 Feb;101(4):583-91. Epub 2008 Jul 17. Hauner H, Vollhardt C, Schneider KT, Zimmermann A, Schuster T, Amann-Gassner U. The impact of nutritional fatty acids during pregnancy and lactation on early human adipose tissue development. Rationale and design of the INFAT study. Ann Nutr Metab. 2009;54(2):97-103. Epub 2009 Mar 19. Helland IB, Smith L, Blomén B, Saarem K, Saugstad OD, Drevon CA. Effect of supplementing pregnant and lactating mothers with n-3 very-long-chain fatty acids on children's IQ and body mass index at 7 years of age. Pediatrics. 2008 Aug;122(2):e472-9. Huber J, Löffler M, Bilban M, Reimers M, Kadl A, Todoric J, Zeyda M, Geyeregger R, Schreiner M, Weichhart T, Leitinger N, Waldhäusl W, Stulnig TM. Prevention of high-fat diet-induced adipose tissue remodeling in obese diabetic mice by n-3 polyunsaturated fatty acids. Int J Obes (Lond). 2007 Jun;31(6):1004-13. Epub 2006 Nov 28. Kunesová M, Braunerová R, Hlavatý P, Tvrzická E, Stanková B, Skrha J, Hilgertová J, Hill M, Kopecký J, Wagenknecht M, Hainer V, Matoulek M, Parízková J, Zák A, Svacina S. The influence of n-3 polyunsaturated fatty acids and very low calorie diet during a short-term weight reducing regimen on weight loss and serum fatty acid composition in severely obese women. Physiol Res. 2006;55(1):63-72. Epub 2005 Apr 26. Tai CC, Ding ST. N-3 polyunsaturated fatty acids regulate lipid metabolism through several inflammation mediators: mechanisms and implications for obesity prevention. J Nutr Biochem. 2010 May;21(5):357-63. Epub 2010 Feb 9. Review.
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http://newsletter.vitalchoice.com/e_article002099196.cfm?x=bjqRrGD,b1h1R7NC Jan 1; 29:54
Cocoa May Boost Eyes and Brain
British study adds more evidence for the short-term effects of cocoa’s uncommon antioxidants on brain function … and adds possible vision benefits
by Craig Weatherby
Judging by the outcome of a small clinical trial, cocoa’s uncommon antioxidants may boost brain and eye function ... at least for a few hours. If confirmed in larger, tighter trials, these short-term gains may join the growing list of health benefits attributed to cocoa’s polyphenols. And there’s sound reason to believe they would, since these apparent benefits probably flow from cocoa’s documented ability to enhance blood flow. The story began five years ago, when a small clinical study from Britain showed that “raw” cocoa increased blood flow to the gray matter in people’s brains (Francis ST et al. 2006).

By “raw” cocoa, we mean the kind not treated with alkali (Dutched), hence still rich in flavanol-type polyphenols. (Most dark chocolate is made with raw, non-Dutched cocoa, but most cocoa powder is Dutched, hence very low in flavanols.)
     The tale continued last year, when Australian scientists reported that subjects who drank either of two cocoa beverages with substantial amounts of flavanols (520 to 994 mg) performed better on tests for anxiety, “cognitive demand” and mental fatigue, compared with a flavanol-free “control” cocoa drink (Scholey AB et al. 2010). As the Aussies wrote, “This is the first report of acute cognitive improvements following CF [cocoa flavanol] consumption in healthy adults.” They seemed on the mark when they hypothesized, “While the mechanisms underlying the effects are unknown they may be related to known effects of CF [cocoa flavanols] on endothelial [artery wall] function and blood flow.” (Scholey AB et al. 2010) Now researchers from the UK’s University of Reading report that consumption of dark, flavanol-rich chocolate may improve aspects of eye and brain function.

British pilot trial sees short-term brain, eye boost
     The authors of the new study say their findings show that some aspects of vision and cognitive performance in healthy young adults were improved by cocoa containing its natural flavanols (Field DT et al. 2011). Like the Aussies, they suspect that these effects may be explained by increased cerebral and retinal blood flow caused by cocoa flavanols.  This was a randomized, single-blinded, crossover trial, involving 30 healthy adults aged between 18 and 25. One group consumed 35 grams of dark chocolate while people in a control group ate the same quantity of white (flavanol-free) chocolate. After a one-week interval between two testing sessions, the groups switched regimens. The researchers were “blinded” as to which of the two types of chocolate each test group consumed … but the participants knew (by the light or dark color of the chocolate) which of the two kinds they had eaten.

     The authors conceded the participants “may conceivably have been influenced by this knowledge.” (Field DT et al. 2011) The participants were tested for “visual contrast sensitivity”, “motion sensitivity” and cognitive performance (visual-spatial working memory and a sophisticated reaction time task). Compared with the control group, the dark chocolate group showed improved visual contrast sensitivity and reduced time required to detect motion direction. As the Brits wrote, “A reduction in the time required to integrate visual motion could be beneficial in time critical everyday tasks, such as driving. The effect on the simpler early phase of the choice reaction time task suggests that CF [cocoa flavanols] can increase response speed in simple tasks.” (Field DT et al. 2011) The researchers are conducting a follow-up study in older adults.

Cocoa’s uncommon antioxidants
     The study focused on the uncommon polyphenol-class antioxidants in cocoa, called flavanols (catechins) and procyanidins. Flavanols are the building blocks for proanthocyanidins (e.g., OPC/pycnogenol), which abound in grapes, red wine, and a few other foods and herbs. Though spelled almost the same, flavanols are distinct from flavonols (e.g., quercetin and rutin), which abound in tea, onions, citrus fruits, and many other plant foods. Flavanols also occur abundantly in green tea – with much smaller concentrations in other plant foods – while procyanidins abound in berries.

     Sources: Corti R, Flammer AJ, Hollenberg NK, Lüscher TF. Cocoa and cardiovascular health. Circulation. 2009 Mar 17;119(10):1433-41. Review. Field DT, Williams CM, Butler LT. Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. Physiol Behav. 2011 Jun 1;103(3-4):255-60. Epub 2011 Feb 12. Francis ST, Head K, Morris PG, Macdonald IA. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol. 2006;47 Suppl 2:S215-20. Galleano M, Oteiza PI, Fraga CG. Cocoa, chocolate, and cardiovascular disease. J Cardiovasc Pharmacol. 2009 Dec;54(6):483-90. Review. Rimbach G, Melchin M, Moehring J, Wagner AE. Polyphenols from cocoa and vascular health-a critical review. Int J Mol Sci. 2009 Nov 20;10(10):4290-309.
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Headache 2011 Feb; 51:272
Acute and Preventive Treatments for Cluster Headache
Several medical and surgical options are available.
     Cluster headache is an uncommon but debilitating primary headache disorder. This review provides information about acute medical therapies for cluster headache as well as preventive medical and surgical approaches to management of cluster attacks. In discussing selected trials of various treatment options, the authors refer to level-of-evidence ratings developed by the European Federation of Neurological Societies.
     Acute therapies include oxygen, sumatriptan, zolmitriptan, octreotide, lidocaine, ergotamine, and dihydroergotamine. Injectable sumatriptan and inhaled oxygen are viewed as first-line therapies for acute treatment. Preventive therapies include verapamil, lithium carbonate, topiramate, valproic acid, melatonin, baclofen, botulinum toxin, gabapentin, and clonidine. Verapamil is considered first-line prophylactic therapy. Corticosteroids often are administered for transitional prophylaxis (treatment given concurrently with preventive therapy but directed at rapid control of symptoms). Invasive treatments for refractory cluster headaches include peripheral nerve and sphenopalatine ganglion block or stimulation, hypothalamic stimulation, and ablative surgical procedures that typically involve the trigeminal nerve.
     Comment: Although this article conveys useful information about treatment of patients with cluster headaches, it was not meant to be a formal systematic review of the salient literature. Rather, the authors selectively discussed studies that, in their opinion, were most relevant. The methodologic quality of the chosen studies was not formally graded; therefore, we cannot make judgments about levels of bias in individual studies. Despite these methodologic shortcomings, the authors' recommendations are useful; furthermore, their report captures medical as well as surgical treatment options (including dosages, adverse effects, and suggestions for monitoring patients) in a single document.
— Tamara Pringsheim, MD, FRCPC (Neurology)
Dr. Pringsheim is Clinical Assistant Professor, Department of Clinical Neurosciences, University of Calgary.
Published in Journal Watch Neurology May 10, 2011
     Citation(s):Ashkenazi A and Schwedt T. Cluster headache — Acute and prophylactic therapy. Headache 2011 Feb; 51:272.
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Br J Dermatol 2011 Mar 24
Topical Antiandrogen
A new topical antiandrogen showed promise in a small, limited trial.
     Acne vulgaris results from poral occlusion, lipolysis by Pityrosporum acnes, follicular rupture, and the influence of androgenic steroids on sebaceous glands. Systemically administered antiandrogenic drugs improve acne by antagonizing the action of androgenic steroids. To evaluate the benefit of topical antiandrogen treatment of acne vulgaris, investigators enrolled 77 adult men with grade 2 to 3 acne vulgaris in a clinical, randomized, double-blind comparison of the antiandrogen cortexolone 17α-propionate (C17P) with tretinoin and with placebo. Thirty patients were randomized to receive drug, 32 to receive the retinoid tretinoin 0.05% cream, and 15 to receive placebo cream. Each formulation was applied once daily at bedtime for 8 weeks. Evaluations occurred every other week during the trial. Assessments included total lesion count, inflammatory lesion count, acne severity score, and an investigator-assessed global score on the right and left sides of the face. During the study, four patients withdrew, and six were disqualified for noncompliance.
     The C17P antiandrogen cream proved statistically superior to placebo in decreasing total lesion counts (P=0.0017) and inflammatory lesion counts (P=0.0134) and for improving acne severity scores (P=0.0090). However, no statistical superiority was observed in investigator assessments, suggesting that the overall clinical response was not as stellar. Tretinoin improved acne, too, but its efficacy was not statistically superior to the placebo's, perhaps owing to small sample sizes. Local tolerability was "good." No systemic toxicities were uncovered by laboratory tests, and no serious adverse effects were seen.
     Comment: An effective topical antiandrogen would be a novel addition to acne treatments. Worries that systemic absorption of drug might masculinize a female fetus make it unlikely that the drug would be used in women with childbearing potential. This cohort was small and did not include women. Skin types were not defined. Patients with mild or very severe acne were not enrolled, and anatomic sites other than the face were not evaluated. In my opinion, this was a successful "proof of concept" study.
Mark V. Dahl, MD Published in Journal Watch Dermatology May 13, 2011
     Citation(s):Trifu V et al. Cortexolone 17α-propionate 1% cream, a new potent anti-androgen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study versus placebo and tretinoin (Retin-A® 0.05% cream). Br J Dermatol 2011 Mar 24; [e-pub ahead of print]. (http://dx.doi.org/10.1111/j.1365-2133.2011.10332.x)
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Chantix Lawsuit Claims It Caused Murder-Suicide
     A lawsuit has been filed by the estates of a couple killed in a murder-suicide two years ago saying its stop-smoking medicine Chantix caused the rage that prompted the event. Sean Wain, 34, killed himself and his wife Natalie, 33, in an early-morning shooting in May 2009, leaving four children behind. The lawsuit states that users of Chantix were not sufficiently warned at the time that it can cause rage, hostility, and suicide.
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Food Quality Feared in China
     Two years ago, China's government was reeling from nationwide outrage over melamine-contaminated baby milk that sickened 300,000 infants and killed at least 6, and declared food safety a national priority. Subsequently, throngs of shady food processors have been threatened, raided, and arrested, and a couple of them were even executed. Despite the government's efforts to create a modern food-safety program, oversight is still haphazard and is in the hands of ill-trained, ill-equipped, and outnumbered enforcers whose quick fixes are very quickly undone.
     Recently, China's news media have reported sales of pork adulterated with clenbuterol, pork sold as beef after being soaked in borax, rice contaminated with cadmium, arsenic-laced soy sauce, popcorn and mushrooms treated with fluorescent bleach, bean sprouts tainted with an animal antibiotic, wine diluted with sugared water and chemicals, outdated rolls mixed with flour and water and repackaged and sold, and even eggs that have turned out not to be eggs at all but were fabricated concoctions of chemicals, gelatin, and paraffin. Manufacturers have found that the odds of profiting from unsafe practices far exceed the odds of getting caught.
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Early HIV Treatment Associated with Greatly Reduced
Transmission to Partners

     A 10-year study on early HIV treatment has been stopped prematurely after a monitoring board found convincing evidence that it "can have a major impact on reducing HIV transmission," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, in an NIH announcement Thursday.
     Called HPTN 052, the international study was conducted primarily among some 1800 heterosexual couples. One partner in each couple was uninfected at entry. Infected partners were randomized either to immediate treatment with a three-drug antiretroviral regimen or to deferred treatment (until CD4 counts fell below 250 per cubic millimeter or an AIDS-related event occurred).
     There were 28 new infections linked to partners, 27 of which occurred among the deferred-treatment group, giving a relative reduction in transmission of 96%.
     Dr. Carlos del Rio of Journal Watch HIV/AIDS Clinical Care commented that the findings "prove once and for all that antiretroviral therapy not only is good for the individual but it is also good for society, as it reduces HIV transmission."
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BMJ 2011 May 3; 342:d2392
Antibiotic Prophylaxis for Dental Procedures
In England, cessation of antibiotic prophylaxis for dental procedures was not associated with a significant increase in the incidence of infective endocarditis.
     The long-standing practice of antibiotic prophylaxis before dental procedures in patients at risk for infective endocarditis (IE) was recently challenged. Consequently, in March 2008, the National Institute for Health and Clinical Excellence (NICE) issued a guideline recommending the cessation of such prophylaxis in the U.K. Now, researchers have quantified the effect of this guideline.
     National monthly prescribing data were examined for all relevant prescriptions issued in England between January 2004 and April 2010. National data on inpatient hospital activity were used to determine the rates of IE and deaths from IE. Rates were compared between two 12-month periods: immediately before guideline implementation and 14–25 months afterward.
     Between the two periods, prescriptions for prophylactic doses of amoxicillin or clindamycin dropped by 78.6%. Before guideline implementation, the rates of IE and IE-related deaths were trending upward. These general upward trends showed no significant increase (defined as >15% over the expected number) after introduction of the guideline. In addition, the upward trend in the number of IE cases caused by oral streptococci (the pathogens for which dental prophylaxis was administered before the 2008 NICE guideline) showed no significant change.
     Comment: One can only be happily amazed at the compliance — primarily by dentists — with the NICE guideline. As the authors point out, these findings do not exclude the possibility that antibiotic prophylaxis might benefit some high-risk patients (e.g., those with prosthetic valves, congenital heart disease, or a history of IE, for whom prophylaxis is still recommended in Europe and the U.S.). Nor can they prove that some cases of IE might have been avoided. However, in the war against antibiotic overuse, these findings offer some rare good news.
Stephen G. Baum, MD Published in Journal Watch Infectious Diseases May 11, 2011
     Citation(s):Thornhill MH et al. Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: Before and after study.
BMJ 2011 May 3; 342:d2392.
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Chest 2011 Apr; 139:764
Physiological Effects of Water-Pipe Tobacco Smoking
Effects are similar to those of cigarette smoking.
     The American Lung Association has identified water-pipe smoking (WPS) of tobacco as "an emerging deadly trend." Common for centuries in the Middle East and Southeast Asia, WPS recently has gained popularity in western nations, particularly among college students and young professionals. Two new studies add to our very limited knowledge about its physiological effects.
     In a meta-analysis, researchers combined data from six studies of habitual water-pipe smokers, cigarette smokers, and nonsmokers. Compared with nonsmokers, water-pipe smokers exhibited significantly lower percent-predicted forced expiratory volume in 1 second (FEV1; 4% lower) and nearly significantly lower percent-predicted forced vital capacity (FVC) and FEV1/FVC (1.4% and 3.1% lower, respectively). Cigarette smokers had significantly lower percent-predicted FVC (by 2.5%) than water-pipe smokers; however, percent-predicted FEV1 and FEV1/FVC were similar between these two groups.
Israeli researchers studied 45 experienced water-pipe smokers (30 men) before and after 30-minute sessions of WPS. After sessions, carboxyhemoglobin levels rose significantly (from 1.5% to 9.5%); three people had potentially dangerous post-WPS carboxyhemoglobin levels (>20%). Significant increases were noted after WPS in blood pressure (from 120 to 132 mm Hg systolic; from 75 to 83 mm Hg diastolic), pulse (80 to 96 beats per minute), and respiratory rate (14 to 17 breaths per minute), and a significant decrease was observed in percent-predicted peak expiratory flow rate (83% to 75%).
Comment: Despite a common belief that water-pipe smoking is less harmful than cigarette smoking, early evidence suggests that the short- and long-term effects of WPS are similar to those of cigarette smoking and could contribute to development of chronic obstructive pulmonary disease.
Bruce Soloway, MD Published in Journal Watch General Medicine May 10, 2011
     Citation(s): Raad D et al. Effects of water-pipe smoking on lung function: A systematic review and meta-analysis. Chest 2011 Apr; 139:764.
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Nat Genet 2011 May; 43:436
New Genes Associated with Alzheimer Disease
Two large genome-wide association studies revealed at least four new susceptibility loci for AD.
     Although Alzheimer disease (AD) shows strong patterns of heritability, uncommon variants in three genes (APP, PSEN1, and PSEN2) account for only a small percent of AD cases (i.e., early-onset autosomal dominant disease) — and the association of the APOE genotype with development of late-onset AD does not fully account for the excess risk for disease in first-degree relatives of AD patients. In a pair of genome-wide association studies, both of which were conducted in three stages (initial identification of susceptibility variants followed by two stages of testing for associations with AD risk), researchers sought to identify other susceptibility loci.
     The first study was specific to late-onset AD. Overall, pooled data were analyzed from 12 cohorts consisting of >18,000 case patients (age >65) and >35,000 cognitively normal controls (mixed ages); some participants in stage 3 were also analyzed in the companion study discussed below. After appropriate adjustment for multiple comparisons, the results confirmed previously reported associations of APOE as well as four other genes (BIN1, CR1, CLU, and PICALM) with late-onset AD and revealed four new susceptibility loci (MS4A, CD2AP, CD33, and EPHA1).
     The companion study involved a similar three-stage approach using data from >19,000 case patients and >39,000 controls from multiple cohorts; however, the pool of participants with AD was not restricted to those with late-onset AD, and individuals in both affected and control groups were of mixed ages. Associations with AD were confirmed for the four newly discovered susceptibility genes; in addition, an association was reported for a fifth gene, ABCA7.
     Taken together, both studies indicate that the population-attributable fractions for each candidate gene other than APOE range from 2.72% to 5.97%, and the cumulative estimate for all nine non-APOE loci is as high as 35%.
     Comment: These studies demonstrate the value of investigative collaboration in unraveling complex multigenic susceptibility for common diseases. Furthermore, the putative functions of these susceptibility genes support the biological plausibility of their roles in the development of AD. Such functions include immune activity (CLU, CR1, ABCA7, CD33, and EPHA1), cell membrane processes such as endocytosis (PICALM, BIN1, CD33, and CD2AP), and lipid processing (APOE, CLU, and ABCA7). Not only have these findings opened the way for focused confirmatory investigations, but they also might provide more clues about pathogenesis and, consequently, help guide therapeutic approaches.
Brandy R. Matthews, MD Published in Journal Watch Neurology May 10, 2011
     Citation(s): Naj AC et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 2011 May; 43:436.

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