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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
April 9, 2011

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Nonceliac Gluten Intolerance?
HDL and Colorectal Cancer Risk
FDA Issues Reminder on Risk for Methemoglobinemia with Topical Benzocaine
Community-Onset Urinary Tract Infections Caused by Fluoroquinolone-Resistant
  Escherichia coli
Religious Groups Target Rising Drug Prices
Artificial Dyes Safe to Eat
Caffeine Consumption Associated with Shorter Sleep Time in Children
New Drug Approved for Restless Legs Syndrome
Progesterone Gel Lowers Risk for Preterm Birth in Women with a Short Cervix
Elevated — But Still 'Normal' — Adolescent BMIs Portend CHD in Midlife
WHI Researchers Examine Risks During and After Estrogen Therapy
Long Work Hours Add to Coronary Disease Risk
Long-Term Statin Therapy Does Not Lower Risk for Atrial Fibrillation
Aspirin Discontinuation and Cerebrovascular Events
Weather and Migraine
More Insight into the Pathophysiology of Bipolar Disorder

Am J Gastroenterol 2011 Mar; 106:508
Nonceliac Gluten Intolerance?
Gluten caused gastrointestinal symptoms in some individuals without celiac disease
     Many people without celiac disease actively follow gluten-free diets and insist that gluten produces symptoms. Some of these individuals believe that they have celiac disease, despite negative test results, and many cannot be adequately tested because they are following a gluten-free diet. Can gluten cause gastrointestinal symptoms in people without celiac disease, and — if so — by what mechanism? To answer these questions, researchers in Australia conducted a double-blind, randomized, placebo-controlled, dietary rechallenge trial involving individuals with irritable bowel syndrome who were proven not to have celiac disease and whose symptoms were under control on a gluten-free diet.
     Participants were recruited through advertisements. Proof that celiac disease was not present required either absence of the HLA-DQ2 and HLA-DQ8 haplotypes or a normal duodenal biopsy at endoscopy while the person was on a gluten-containing diet. Of the 39 individuals who met the inclusion criteria and were enrolled, 5 were excluded (4 because of inadequate symptom control during the 2-week baseline period and 1 because of acute psychiatric illness). All participants followed a gluten-free diet; in addition, they were asked to eat two slices of bread and one muffin daily (these foods contained gluten for the gluten group but were gluten free for the placebo group). Preliminary testing showed that the taste and texture of the gluten-free and gluten-containing products were identical.
     Nine participants stopped the study diet prematurely because of intolerable symptoms (6 in the gluten group after a median of 7 days and 3 in the placebo group after a median of 16 days). Poorly controlled symptoms were reported during more than half of the 6-week study period by more gluten-group participants than placebo-group participants (68% vs. 40%; P=0.001). During the entire study period, scores for pain, satisfaction with stool consistency, and tiredness were significantly worse in the gluten group than in the placebo group. Neither group showed significant changes in levels of fecal lactoferrin or celiac antibodies or in measures of intestinal permeability. Responses to gluten were similar between participants who had HLA-DQ2, HLA-DQ8, or both, and those who did not.
     Comment: Although this study does not identify a mechanism for nonceliac gluten intolerance, it provides the most convincing evidence yet for the existence of this condition. Certainly, getting tested for celiac disease before a gluten-free trial is still optimal, given the implications of a celiac diagnosis — including the necessity of strict adherence to a gluten-free diet, an increased cancer risk, and the need to screen family members.
Douglas K. Rex, MD Published in Journal Watch Gastroenterology April 8, 2011
MM: Conventional statin meds seem to have little or no benefit on HDL. Our Cholesterol Health supplement combined withOmega-3 fish oil and Niacin are just about the best combination to increase HDL.
     Citation(s):Biesiekierski JR et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo-controlled trial. Am J Gastroenterol 2011 Mar; 106:508. http://www.ncbi.nlm.nih.gov/pubmed/21224837?dopt=Abstract
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Gut 2011 Mar 7; [e-pub ahead of print].
MM: Conventional statin meds seem to have little or no benefit on HDL. Our Cholesterol Health supplement combined withOmega-3 fish oil and Niacin are just about the best combination to increase HDL.
HDL and Colorectal Cancer Risk
HDL levels were inversely associated with colon cancer risk but showed no association with rectal cancer risk.
     Small studies have shown an inverse association between serum levels of HDL and risk for colorectal cancer. The current investigation — a nested case-control study within the European Prospective Investigation into Cancer and Nutrition — is the largest yet to address this issue.
     The study cohort, drawn from 10 western European countries, included more than 520,000 participants who completed dietary and lifestyle questionnaires, had their anthropomorphic measurements recorded, and donated blood samples for future analysis. A total of 1238 participants who developed colorectal cancer after enrollment were matched with controls —1238 cancer-free participants — by age, sex, study center, follow-up time, and details at blood collection (time, patient age, fasting status).
     Serum HDL concentration was inversely associated with risk for colon cancer but not with risk for rectal cancer. The relative risk for each one-standard-deviation (16.6 mg/dL) increase in HDL was 0.78. These results were unaffected by additional adjustments for biomarkers of systemic inflammation, insulin resistance, and oxidative stress, as well as exclusion of the first 2 years of follow-up.
     Comment: The mechanism underlying this inverse association is uncertain. Higher levels of HDL inhibit systemic inflammatory responses, and inflammation might stimulate tumor growth. Of interest and possibly relevant, obesity, metabolic syndrome, and diabetes mellitus are all associated with an increased risk for colorectal cancer, and long-term statin use has been associated with a slight decrease in risk for colorectal cancer. How all these observations are related remains unknown.
Douglas K. Rex, MD Published in Journal Watch Gastroenterology April 8, 2011
Citation(s): van Duijnhoven FJB et al. Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut 2011 Mar 7; [e-pub ahead of print]. (http://dx.doi.org/10.1136/gut.2010.225011)
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MM: This is a component found in many OTC sunburn preparations so with summer approaching, it is good to be aware of this issue. It is especially important when considering using these products on young children.
FDA Issues Reminder on Risk for Methemoglobinemia with Topical Benzocaine
     The FDA is reminding healthcare providers that benzocaine sprays, gels, and liquids carry an increased risk for methemoglobinemia. The product labels do not currently warn about this risk.
     To date, there have been 319 reported cases of methemoglobinemia, including seven fatalities, related to benzocaine sprays used to numb the oral mucosa during medical procedures. There have also been 21 cases from over-the-counter gels and liquids used to treat oral pain. Onset generally occurs from several minutes to 2 hours after application and seems to be unrelated to the dosage.
     The FDA advises clinicians to monitor for signs of methemoglobinemia — including bluish skin, lips, and nail beds; shortness of breath; reduced oxygen saturation; and tachycardia — for at least 2 hours after applying benzocaine sprays. In addition, consumers using OTC benzocaine should be made aware of these signs.
      The agency also notes that benzocaine should not be used in children younger than 2 years.

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J Antimicrob Chemother 2011 Mar; 66:650
MM: A Natural treatment option for E. coli UTI’s is D-mannose (available at Mark Drugs). This is the active extract of such fruits as cranberry, blueberry and pineapple and literally causes bacteria in the urinary tract to lose hold and simply slide out of the system. This is a great, inexpensive treatment of UTI’s and has not demonstrated any bacterial resistance to occur.
Community-Onset Urinary Tract Infections Caused by Fluoroquinolone-Resistant Escherichia coli
Fluoroquinolone use during the preceding 6 months, presence of a urinary catheter, and recent hospitalization were independent risk factors for fluoroquinolone resistance.
     Previously, fluoroquinolones (FQs) were the drugs of choice for community-onset urinary tract infections (UTIs). Escherichia coli, the most common uropathogen, was highly susceptible to these agents. Now, however, the situation is changing, with the emergence of FQ-resistant E. coli strains in the community.
     To identify patient-related and environmental risk factors for FQ resistance, researchers in the Netherlands conducted a multicenter study involving adults who presented with community-onset febrile UTIs from 2004 through 2009 (n=787). In 420 (53%) of these patients, E. coli was the causal pathogen. Fifty-one (12%) of the 420 E. coli isolates showed FQ resistance. On multivariate analysis, risk factors for FQ-resistant E. coli were FQ use during the preceding 6 months (odds ratio, 17.5; 95% confidence interval, 6.0–50.7), presence of a urinary catheter (OR, 3.1; 95% CI, 0.9–11.6), and hospitalization within the previous 6 months (OR, 2.0; 95% CI, 1.0–4.3). A case-control substudy involving 38 patients with FQ-resistant and 74 patients with FQ-susceptible E. coli isolates showed no association between FQ resistance and environmental parameters (e.g., daily contact with animals, household members with UTIs).
     Among the E. coli strains that were resistant to fluoroquinolones, 33% were also resistant to amoxicillin-clavulanate, and 65% were also resistant to trimethoprim-sulfamethoxazole.
     Comment: This study, from a country known for its prudent antibiotic use and low resistance rates, demonstrates clearly that we are running out of oral antibiotic treatment options in patients infected with FQ-resistant E. coli strains. To ensure appropriate treatment, urine cultures should be mandatory in UTI patients who have any of the identified risk factors.
Thomas Glück, MD Published in Journal Watch Infectious Diseases April 6, 2011
     Citation(s): van der Starre WE et al. Risk factors for fluoroquinolone-resistant Escherichia coli in adults with community-onset febrile urinary tract infection. J Antimicrob Chemother 2011 Mar; 66:650.
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MM: How about eliminating the need for these medications in the first place? One option may be to work on actually preventing or reversing the most common conditions such as high blood pressure, cholesterol and type 2 diabetes. Collectively these are referred to as “metabolic syndrome” and may possibly be reversed with weight loss and lifestyle changes. The HCG Diet Protocol is one such massive change in lifestyle as well as weight loss.
Religious Groups Target Rising Drug Prices
     "More and more people can't afford this, and more and more fall back on taking either less pills or half a pill," stated Sister Barbara Aires, coordinator of corporate responsibility in investments for the Sisters of Charity of Saint Elizabeth. The order's say the drugmakers haven't "made a clear case providing fiscal and moral justification for such exorbitant price increases" and they ask the companies to limit increases to the rate of inflation.
     The nuns have a point, as price increases for top-selling drugs have hit the highest levels in 10 years, and a recent study found that as many as one-fifth of patients don't fill their prescriptions because they can't afford the drugs. Others stretch their drug supplies by taking lower doses or skipping doses altogether. http://online.wsj.com/article/SB10001424052748704530204576234900744477830.html
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MM: Come on now! As parents and thinking people we know that food additives in general can be problematic. We also champion the availability of more rather than less information. After all, knowledge is power and the elimination of this info on labelling limits our knowledge and our ability for reasonable decision making,
Artificial Dyes Safe to Eat
     A government advisory panel recently voted that there is no proof that foods with artificial colorings cause hyperactivity in most children, and there is no need for these foods to carry special warning labels.
     For the first time, agency scientists have decided that while typical children may be unaffected by the dyes, those with behavior problems may see their symptoms worsen by eating foods with synthetic color additives. Artificial coloring is present in numerous popular products like Jell-O, Life Savers candy, Hostess Twinkies, and some cereals. The committee voted 8 to 6 that even a warning was not needed.
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J Pediatr 2011 Mar; 158:508
MM: Decreased sleep is associated with increased hunger and increased obesity as well as metabolic syndrome. Maybe we need to take another look at what is being made available or what is deemed acceptable for our children to consume.
J Pediatr 2011 Mar; 158:508
Caffeine Consumption Associated with Shorter Sleep Time in Children
Caffeine intake and sleep time were inversely associated, but caffeine was not associated with enuresis.
As caffeine consumption has increased in the U.S., so have concerns about the potential effect of caffeine on enuresis and child health. A convenience sample of 228 English- or Spanish-speaking parents of children aged 5 to 12 years was surveyed about their children's caffeine consumption during routine visits at an urban outpatient pediatric clinic.
     Most children in the sample (75%) consumed caffeine. Average caffeine consumption was 52 mg per day in children ages 5 to 7 years and 109 mg in children ages 8 to 12 years (a 12-oz cola drink contains about 45 mg of caffeine). Levels of caffeine consumption were significantly and inversely associated with average hours of sleep. As expected, enuresis was significantly more common in boys and younger children; however, no correlation was found between enuresis and caffeine. Enuresis was less common in children from Spanish-speaking families than English-speaking families.
     Comment: Children are participating in the caffeine craze in the U.S. Although the Food and Drug Administration has not established guidelines for caffeine intake in children, Canadian guidelines recommend upper limits of 62 mg for 7- to 9-year-olds and 85 mg for 10- to 12-year-olds. The potential negative effect of caffeine on sleep duration should prompt pediatricians to ask about caffeine consumption in children with sleep disturbances.
F. Bruder Stapleton, MD Published in Journal Watch Pediatrics and Adolescent Medicine April 6, 2011
     Citation(s): Warzak WJ et al. Caffeine consumption in young children. J Pediatr 2011 Mar; 158:508.
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New Drug Approved for Restless Legs Syndrome
     Gabapentin enacarbil (marketed as Horizant) has been approved for the treatment of restless legs syndrome (RLS), the FDA announced on Thursday.
     Approval was based on two 12-week clinical trials in which patients who received the once-daily tablets had better overall improvement in their RLS symptoms than those who took a placebo.
     Gabapentin enacarbil is a precursor of the antiepileptic gabapentin; therefore, it will carry the same boxed warning that all epilepsy drugs do about an increased risk for suicidality. Additionally, patients will receive a medication guide when filling their prescriptions. Common side effects include dizziness and drowsiness.
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Progesterone Gel Lowers Risk for Preterm Birth in Women with a Short Cervix
     In women with a short cervix during the second trimester of pregnancy, use of a vaginal progesterone gel essentially halves the risk for preterm birth, according to an NIH- and industry-funded study published in Ultrasound in Obstetrics & Gynecology.
     Some 450 asymptomatic women with a cervix length between 10 and 20 mm at roughly 19 to 24 weeks' gestation were randomized to use a vaginal progesterone gel or placebo daily until 37 weeks' gestation, rupture of the membranes, or delivery. Women using progesterone were significantly less likely than those using placebo to deliver before 33 weeks (9% vs. 16%), as well as before 28 weeks (5% vs. 10%).
     In addition, neonatal morbidity and mortality were lower with progesterone. Treatment side effects did not differ between the groups.
The authors calculate that 14 women with a short cervix would need to be treated to prevent one preterm birth.
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N Engl J Med 2011; 364:1315-1325 April 7, 2011
Elevated — But Still 'Normal' — Adolescent BMIs Portend CHD in Midlife
     Body-mass index at age 17 seems strongly correlated with risk for heart disease by age 40, but its association with type 2 diabetes is weaker, according to a New England Journal of Medicine study.
     Some 38,000 apparently healthy 17-year-old Israeli men had their BMI and other clinical data collected at the beginning of military service. Follow-up examinations occurred regularly thereafter. Mean adolescent BMI values ranged from 20 to 21.
     After roughly 17 years' follow-up, elevated BMIs in adolescence — including BMIs between 19 and 20, considered within normal limits — carried a higher risk for angiographically proven heart disease, even after adjusting for adult BMI (HR, 5.43 between the highest and lowest BMI deciles). For diabetes, however, only men with adolescent BMIs in the three highest deciles had significantly higher risk than those in the lowest decile.
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JAMA. 2011;305(13):1305-1314. doi: 10.1001/jama.2011.382
WHI Researchers Examine Risks During and After Estrogen Therapy
The effects of estrogen therapy on certain health outcomes seem to disappear after therapy is discontinued, according to an analysis from the Women's Health Initiative in JAMA.
The analysis involved postmenopausal women who'd had hysterectomies and were randomized to receive conjugated equine estrogens or placebo. Researchers examined health outcomes during roughly 6 years of estrogen use and 4.5 years afterward. Among the findings:

Journal Watch Women's Health Editor-in-Chief Dr. Andrew Kaunitz says the findings "provide ... reassurance to young menopausal women who are posthysterectomy and who present with bothersome vasomotor symptoms that use of estrogen therapy for as long as 6 years is safe."
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Long Work Hours Add to Coronary Disease Risk
     In estimating patients' risk for coronary heart disease, factoring in the length of their workday adds modestly, but significantly, to the sensitivity of their Framingham score, according to an Annals of Internal Medicine report.
     Using a cohort of some 7000 British civil servants without apparent coronary disease at baseline, researchers gathered information to ascertain Framingham risk scores as well as the number of hours worked in a typical day. Follow-up lasted a median of 12 years. After adjustment for Framingham scores, participants working 11 or more hours per day had a 67% increased risk for coronary disease, compared with those working the normal 7 or 8 hours.
     The authors caution that "further testing is needed to confirm the added value of information on long working hours for clinical decision making."
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BMJ 2011 Mar 16; 342:d1250
Long-Term Statin Therapy Does Not Lower Risk for Atrial Fibrillation
Several factors might explain discrepant results between short-term and long-term trials.
     Recent evidence suggests that statins lower risk for atrial fibrillation (AF). To further investigate this association, researchers conducted a meta-analysis of randomized, controlled trials in which statin treatment was compared with no statin treatment or in which high-dose statins were compared with standard-dose statins.
     Analysis of data from 13 short-term trials (average follow-up range, 1 week to 5 months; 4400 patients) showed that statins, compared with placebo, significantly lowered risk for AF (odds ratio, 0.6). In contrast, analysis of data from 22 long-term trials (average follow-up range, 1.0 to 5.3 years; 106,000 patients) showed that compared with placebo, statins did not lower risk for AF (OR, 0.95). Likewise, seven long-term trials (average follow-up range, 0.7 to 4.9 years; 29,000 patients) showed that high-dose statins, compared with standard-dose statins, did not lower risk for AF (OR, 1.0).
     Comment: Long-term statin therapy does not lower risk for AF. The authors reasonably attribute the discrepant results between the short-term and long-term trials to different AF detection methods (e.g., short-term trials used more-sensitive AF detection methods), characteristics of trial participants (e.g., short-term trials involved patients undergoing heart surgery or electrical cardioversion), and publication bias.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine April 7, 2011
Citation(s): Rahimi K et al. Effect of statins on atrial fibrillation: Collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ 2011 Mar 16; 342:d1250. (http://dx.doi.org/10.1136/bmj.d1250)
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Neurology 2011 Feb 22; 76:740
Aspirin Discontinuation and Cerebrovascular Events
Does discontinuation increase the risk for stroke or transient ischemic attack?
Treatment with antiplatelet drugs — most often aspirin — for an indefinite period is a cornerstone of secondary vascular prevention, but concerns of care providers about its long-term safety and of patients about the need for long-term use have contributed to suboptimal long-term adherence rates. However, mounting evidence suggests that discontinuation of aspirin may boost the risk for cardiovascular events.
    To assess the extent of this risk, researchers tracked hospitalizations for ischemic stroke or transient ischemic attack (TIA) over an average of 3.4 years among 39,512 patients aged 50 to 84 who were registered in a U.K. primary care database. The investigators compared the rates of discontinuation of an initial low-dose (75–300 mg/day) aspirin prescription for secondary prevention of cerebrovascular and cardiovascular events among 673 case patients (those hospitalized for stroke or TIA) and among 5000 age-, sex-, and year-matched controls. Aspirin discontinuation was defined as a period of >30 days after the end of the last prescription. Reasons for discontinuation were preclassified as provider-initiated drug switch, provider-documented safety concern, suggestion/documentation of over-the-counter rather than prescription aspirin use, or nonadherence (i.e., absence of the previously listed reasons).
     Of the 673 case patients, 71% were receiving low-dose aspirin on the day of the event, 10% were recent discontinuers, and 4% were past (>180 days after last prescription) discontinuers. Compared with current users, recent discontinuers had a significant, 40% greater risk for ischemic stroke or TIA (regardless of exact dose or treatment duration), and past discontinuers had a nonsignificant, 25% greater risk. Patient nonadherence (7.7% among patients with ischemic stroke or TIA) was the major reason for discontinuation of aspirin therapy and was the primary driver of the increased cerebrovascular risk.
     Comment: Limitations of this study include the use of prescription information alone to assess adherence, potentially incomplete data on over-the-counter aspirin use, no information on discontinuation of other cardiovascular drugs (e.g., statins; see Neurology 2007; 69:904), and an inability to show that aspirin discontinuation is not simply a marker of other unhealthy practices that may affect stroke outcome (Cerebrovasc Dis 2010; 29:146). However, as the authors note, the results accord with experimental data on the timing of rebound platelet activity and with other clinical observations. As such, this analysis should provide further impetus for clinicians to strongly encourage their patients at risk for primary or recurrent stroke (with no contraindications) not to discontinue their aspirin treatment.
Bruce Ovbiagele, MD, MS Published in Journal Watch Neurology April 5, 2011
     Citation(s): García Rodríguez LA et al. Increased risk of stroke after discontinuation of acetylsalicylic acid: A UK primary care study. Neurology 2011 Feb 22; 76:740.
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Cephalalgia 2011 Mar; 31:391
MM: Specific weather conditions may not induce migraines but it seems that weather changes can have an effect on induction. We can’t simply ignore what patients describe. Perception is a very important factor of healthcare and if a patient perceives that a problem may occur, then they are more susceptible to the effect(s) of an incident. The inverse is also true. If a person perceives a benefit may occur from a particular activity or condition, then they may benefit from that as well. Ther is nothing wrong with the notion of a “placebo effect” and it should not be ignored.
Weather and Migraine
An analysis of objective weather parameters and subjective weather perception in patients with migraine suggests that weather has little if any effect on headache and migraine.
Patients with migraine who are asked about their headache triggers often mention weather change as a factor. However, the literature on weather and migraine is scarce, and the results are inconsistent. In this prospective study, 238 patients with diagnoses of migraine or probable migraine completed daily headache diaries for almost 90 days, thus providing about 20,550 patient-days of data. In the diaries, patients answered 59 questions that addressed occurrence and duration of headache and other features, including descriptions that allowed specific identification of migraines; 7 of the questions were related to weather perception. The authors obtained objective local weather parameters, including 11 individual meteorologic parameters and 17 synoptic conditions (weather patterns).
     The authors identified trends suggesting that ridges of high pressure influenced occurrence of headache and that lower daily mean wind speed or changes in daily sunshine duration increased risk for migraine attacks in particular. They also found a trend suggesting that an increase in minimum air temperature reduced the risk for migraine persistence. However, after correction for multiple comparisons, no individual or synoptic weather factor significantly affected the risk for headache or migraine occurrence or persistence. Patients' perceptions of weather conditions did not correlate with either headache or migraine occurrence or persistence. The authors conclude that the influence of weather on headache and migraine is marginal and that patients' self-reports of headache triggers may be unreliable.
     Comment: This elaborate work addresses a common clinical question that is exceedingly difficult to study. Weather patterns are influenced by various factors, many of which are not well understood. Climatic factors fluctuate even within short periods, and studies can only broadly address this issue. Therefore, even if it is unproven by objective means, one has to accept the subjective, almost unanimous patient perception that weather affects migraine. I doubt that more studies on single weather factors or situations will clarify the issue. We must first better understand migraine pathophysiology and trigger mechanisms by studying more-reliable and experimentally applicable triggers (e.g., nitroglycerin or alcohol) before going back to triggers such as weather with more-specific hypotheses. Focusing on modifiable triggers also seems to be a reasonable research strategy.
— Till Sprenger, MD Dr. Sprenger is Assistant Professor of Neurology and Co-Director, Neurological Outpatient Clinic, University Hospital Basel, Switzerland.
Published in Journal Watch Neurology April 5, 2011
     Citation(s): Zebenholzer K et al. Migraine and weather: A prospective diary-based analysis. Cephalalgia 2011 Mar; 31:391.
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Biol Psychiatry 2011 Feb 15; 69:344.
More Insight into the Pathophysiology of Bipolar Disorder
A polymorphism in some patients contributes to the well-characterized altered calcium ion signaling in bipolar disorder, which may become a new research focus.
Bipolar disorder is associated with greater intracellular calcium ion (Ca2+) signaling in peripheral cells such as platelets and lymphocytes. This widely replicated finding may be associated with enhanced Ca2+ release from intracellular stores. Lithium attenuates hyperactive Ca2+ signaling and induces the gene for the antiapoptotic protein Bcl-2, which is down-regulated in bipolar disorder and which interacts with the receptor on the endoplasmic reticulum (ER) and other intracellular Ca2+ storage sites that release Ca2+. To examine whether differentially active single nucleotide polymorphisms (SNPs) in the Bcl-2 gene contribute to excessive mobilization of intracellular Ca2+, researchers studied lymphoblast cell lines cultured from 18 patients with bipolar I disorder. The AA genotype is associated with deficient activity of the Bcl-2 gene.
     Cells with the AA genotype had elevated free intracellular Ca2+ concentrations and greater reduction of Ca2+ concentrations within the ER, compared with GG cells. These findings indicate that release of stored intracellular Ca2+ increased so long as extracellular Ca2+ was available to replenish stores. Therapeutic levels of lithium reversed these cellular changes. In GG cells, inhibition of Bcl-2 increased intracellular Ca2+ concentrations; the increases came from release of stored Ca2+ from the ER.
     Comment: Intracellular Ca2+ has a biphasic action: Moderate increases stimulate, whereas greater increases inhibit, cellular activity. Further increases within a physiologic range are cytotoxic. Hyperactivity of this core cellular drive in patients with bipolar disorder could explain mixed moods, rapid alternations of activation and depression, and neuronal loss. This study correlates two well-described abnormalities of cellular regulation and replicates lithium's correction of both abnormalities; the findings elucidate potential intracellular targets for more-specific medications — e.g., drugs that inhibit intracellular calcium signaling in hyperactive, but not normal, cells.
Steven Dubovsky, MD Published in Journal Watch Psychiatry April 4, 2011
     Citation(s): Machado-Vieira R et al. The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor–mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry 2011 Feb 15; 69:344.

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