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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
June 2, 2012

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Lactobacilli vs. TMP/SMX to Prevent Recurrent Urinary Tract Infections
BMI Associated with Lumbar Disk Degeneration
Incident Hypertension in Patients with Obstructive Sleep Apnea
Should Antibiotics Be Given with Probiotics to Prevent Antibiotic-Associated Diarrhea?
Clearing the Thicket of Misdiagnosed Multiple Sclerosis
USPSTF Reviews Evidence on Menopausal Hormone Therapy for Chronic Conditions
Consequences of Early Menopause
Challenges in Glycemic Control for Adolescents with Type 2 Diabetes
Eating Certain Fish Might Prevent Liver Cancer
Maternal Obesity May Increase Risk for Autism
Prenatal Antibodies to Gluten Protein, but Not Casein, Linked to Psychosis
Prenatal PPI Exposure and Childhood Asthma
Preventing Torn Earlobes
Osteoporosis Drug Link to Uncommon Breaks Confirmed
Generic Drugmakers' Complaints Over Brand-name Access Prompt Investigations
Does Azithromycin Raise Risk for Cardiovascular-Related Death?
Acupuncture Improves Symptoms and Function in COPD Patients
Simple Warm-Up Program Prevents Anterior Cruciate Ligament Injuries
Atorvastatin Monotherapy Not Beneficial for Delaying Multiple Sclerosis
Combined Ibuprofen/Famotidine Tablet Might Reduce Ulcers

MM: We have been touting the advantages of probiotics for a long time but how about relative superiority compared to antibiotics? This is an incredible study and the results go beyond surprising. Practitioners must take a new view of the potential for probiotics and at least give them a trial run; especially with uncomplicated UTI’s
Arch Intern Med 2012 May 14; 172:704
Lactobacilli vs. TMP/SMX to Prevent Recurrent Urinary Tract Infections
Effectiveness was similar to trimethoprim-sulfamethoxazole, and Lactobacilli did not cause antibiotic resistance.
Lactobacilli use can restore normal vaginal flora and thwart colonization by pathogenic bacteria. To assess its value in preventing urinary tract infections (UTIs), Dutch researchers conducted a randomized placebo-controlled trial that involved 252 postmenopausal women with histories of at least three symptomatic UTIs in the previous year; the women received either nightly trimethoprim-sulfamethoxazole (TMP-SMX; 80 mg/400 mg) or standard doses of Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 twice daily.
During the next 12 months, the mean numbers of symptomatic UTIs were 2.9 in the TMP-SMX group and 3.3 in the Lactobacilli group (compared with roughly 7 UTIs in the preceding year for both groups); the difference was not statistically significant, but Lactobacilli treatment did not meet prespecified criteria for noninferiority. After the first month of treatment, TMP-SMX resistance rose from about 20% to 80% in the antibiotic group and climbed to 100% by the end of the study. On sensitivity testing, bacterial isolates in the TMP-SMX group also showed increased resistance to amoxicillin. No increase in resistance to any antibiotic was noted in the Lactobacilli group. Adverse events were similar between groups.
Comment: The difference between TMP-SMX and Lactobacilli in the rate of recurrent UTI was minimal, and Lactobacilli have an important advantage in not causing antibiotic resistance. At the very least, Lactobacilli are an acceptable alternative for women who prefer not to take antibiotics.
Thomas L. Schwenk, MD Published in Journal Watch General Medicine May 22, 2012
Citation(s): Beerepoot MAJ et al. Lactobacilli vs antibiotics to prevent urinary tract infections: A randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med 2012 May 14; 172:704.
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Arthritis Rheum 2012 May; 64:1488
BMI Associated with Lumbar Disk Degeneration
The findings help explain the link between obesity and low back pain.
Whether body-mass index (BMI) is associated with lumbar intervertebral disk degeneration is unclear. This possible association was explored in a population-based Hong Kong study of 2600 volunteers (age range, 21–63), each of whom underwent magnetic resonance imaging (MRI) of the lumbar spine.
According to standard MRI criteria, 73% of participants had at least minimal evidence of disk degeneration. The prevalence and severity of disk degeneration increased progressively across four BMI categories (underweight, normal, overweight, obese). Compared with underweight or normal-weight subjects, obese participants were significantly more likely (odds ratio, 1.7) to have at least one level of degeneration with the highest grade of abnormality (hypointense nucleus pulposus with disk space narrowing) and to have multilevel involvement. These findings were independent of age and history of lumbar injury.
Comment: In this cross-sectional study, BMI was associated with intervertebral disk degeneration. Because previous studies have shown both disk degeneration and BMI to be associated with elevated risk for chronic low back pain, the current study allows us to infer that degenerative disk disease might — at least in part — mediate the relation between BMI and back pain. This study should not be invoked to endorse routine MRI in overweight patients with uncomplicated chronic low back pain; rather, it helps us understand a possible mechanism for low back pain in overweight people.
Allan S. Brett, MD Published in Journal Watch General Medicine May 24, 2012
Citation(s): Samartzis D et al. The association of lumbar intervertebral disc degeneration on magnetic resonance imaging with body mass index in overweight and obese adults: A population-based study. Arthritis Rheum 2012 May; 64:1488.
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MM: Obstructive Sleep Apnea is frequently related to being overweight and correcting this issue may show a host of other benefits including pain relief, hypertension, diabetes, depression and a host of others. The HCG Metabolic Syndrome treatment approach may be the best choice to battle this condition long term.
JAMA 2012 May 23/30; 307:2169
Incident Hypertension in Patients with Obstructive Sleep Apnea
Treatment with continuous positive airway pressure attenuated risk in severely affected patients.
Cross-sectional studies show a relation between obstructive sleep apnea (OSA) and hypertension, but prospective studies of incident hypertension have yielded conflicting results. OSA patients who receive continuous positive airway pressure (CPAP) experience short-term reductions in blood pressure, but CPAP's long-term effects are unknown, as are its cardiovascular (CV) benefits for patients with mild OSA. In two related studies from Spain, investigators explored these issues.
In one study (median follow-up, 12 years), researchers recruited 1889 patients (mean age, 50; mean body-mass index [BMI], 30 kg/m2) without hypertension who were referred for polysomnography. Of 1579 with OSA, 1117 (71%) were eligible for CPAP. In analyses adjusted for CV risk factors, BMI, and other variables, risk for incident hypertension in OSA patients who adhered to CPAP therapy was 29% lower than in non-OSA participants. In contrast, risk for incident hypertension was higher in OSA patients who were ineligible for CPAP (+33%), in those who declined CPAP (+96%), and in those who did not adhere to CPAP therapy (+78%) than in non-OSA participants.
In another study from the same investigators (median follow-up, 4 years), 725 patients (mean age, 52; mean BMI, 31 kg/m2) with OSA but without daytime sleepiness were randomized to CPAP or no therapy. No difference was found between the CPAP and control groups in incident hypertension or adverse CV events.
Comment: OSA should be explored as a possible comorbidity or cause of new-onset hypertension, with a particular focus on those who experience daytime sleepiness. Editorialists suggest that subgroups should be identified who would benefit most from CPAP so we can target adherence efforts, because nonadherence is a major problem in primary care practices. We also should remember that other therapeutic approaches are available, including weight loss (JW Gen Med Jan 14 2010) and oral appliances (JW Gen Med Jan 17 2012).
Thomas L. Schwenk, MD Published in Journal Watch General Medicine May 31, 2012
Citation(s): Marin JM et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA 2012 May 23/30; 307:2169.
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MM: It’s unfortunate that this study demonstrates a fundamental lack of understanding of probiotics and their use by the reviewers. The most studied probiotic for antibiotic associated diarrea in the world is Saccharomyces Boulardii (SB), a non-bacterial probiotic. It is effective, relatively inexpensive and resistant to the effects of antibiotics. For more information about this outstanding product, please contact Mark Drugs at info@MarkDrugs.com.
JAMA 2012 May 9; 307:1959
Should Antibiotics Be Given with Probiotics to Prevent Antibiotic-Associated Diarrhea?
A recent meta-analysis suggests that probiotics work, but it leaves us with more questions than answers.
Probiotics have increasingly been studied for the treatment and prevention of antibiotic-associated diarrhea. In a review of 12 databases, these investigators identified 63 randomized controlled trials of probiotic use with antibiotics that reported the number of participants with diarrhea; the trials included 11,811 participants. The most commonly used probiotics were Lactobacillus and Saccharomyces.
The pooled relative risk of antibiotic-associated diarrhea when probiotics were given with antibiotics was 0.58 (95% confidence interval, 0.50–0.68; P<0.001). The number of participants needed to treat to prevent one case of antibiotic-associated diarrhea was 13. The results did not differ among age groups (0–17, 18–65, and >65 years). The investigators were not able to determine whether the choice of antibiotics, the indication for antibiotics, or the choice of probiotics affected the outcome.
Comment: Although the quality of studies included in the meta-analysis varied, the consistent finding of decreased risk for antibiotic-associated diarrhea with probiotic use in every subgroup analysis is striking. Still not clear are the most effective probiotic and the optimal dose and duration of therapy. Based on findings of numerous studies of probiotics, I am confident that, at a minimum, this therapy in healthy people falls in the realm of doing no harm. In my experience, many families and young adults express an interest in taking probiotics, and I am certainly willing to agree with their use.
Peggy Sue Weintrub, MD Published in Journal Watch Pediatrics and Adolescent Medicine May 23, 2012
Citation(s):Hempel S et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: A systematic review and meta-analysis. JAMA 2012 May 9; 307:1959.
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MM: A misdiagnosis of MS may be related to failure to measure Vitamin D blood levels. We have had numerous patients who have been diagnosed with MS who have responded well to a simple daily regimen of Vitamin D supplementation. Many of them had previously been taking daily doses of 1000IU or less vitamin D3 but when we changed them to our Vitamin D 5000IU/Probiotic capsules, their MS symptoms almost universally improved.
Neurology 2012 May 11
Clearing the Thicket of Misdiagnosed Multiple Sclerosis
Neurologists report discomfort in telling patients that they do not actually have MS.
Efforts to diagnose multiple sclerosis (MS) earlier, using simplified criteria, sometimes lead to misdiagnosis. To learn about how physicians handle this dilemma, investigators e-mailed surveys to 242 neurologists with an active MS practice.
Most of the 122 respondents had long-standing experience in treating MS, had completed an MS fellowship, and worked at a U.S. academic MS center. Of the 95% of respondents who within the past year had evaluated a patient they "strongly felt did NOT in fact have MS," a plurality had seen three to five such patients. Alternative diagnoses included nonspecific white-matter abnormalities, small-vessel ischemic disease, migraine, psychiatric disease, neuromyelitis optica, and fibromyalgia.
Most respondents found removing a misdiagnosis to be more challenging than giving a new MS diagnosis. Sixteen respondents said they sometimes do not inform the patient of the misdiagnosis; as reasons, most cited no current use of disease-modifying therapy, the risk for psychological harm, a benign alternative diagnosis, and potential damage to the patient's support system.
Comment: The McDonald criteria for diagnosing MS are diagnostic research criteria derived from a relatively young population with typical demyelinating syndromes (JW Neurol Jan 25 2011). The criteria are useful in clinical practice but can be difficult to apply to patients who are older or who have nonspecific neurological symptoms, cardiac risk factors, or nonspecific magnetic resonance imaging (MRI) findings. In such individuals, objective exam findings with positive ancillary testing (such as cerebrospinal fluid analysis, evoked potentials, or spinal imaging) are critical to building a case for diagnosis. The neurologist must personally review the MRI films to determine whether the lesions are typical for demyelination. When a preponderance of the evidence does not suggest demyelinating disease, the diagnosis should be withheld in favor of judicious monitoring.
A particular challenge is that in many cases, one can almost never be absolutely certain that MS has been misdiagnosed. Patients often have had the diagnosis for years and have endured the burden of treatment, and the alternative diagnosis is frequently for a functional disorder. Sometimes it takes several visits to determine that MS is extremely unlikely to be the culprit.
Robert T. Naismith, MD Published in Journal Watch Neurology May 29, 2012
Citation(s): Solomon AJ et al. "Undiagnosing" multiple sclerosis: The challenge of misdiagnosis in MS. Neurology 2012 May 11; [e-pub ahead of print].
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MM: We must remember that these studies used synthetic progestin and not progesterone. The synthetic progestins are well known for all of the potential risk factors described. Progesterone is not.
USPSTF Reviews Evidence on Menopausal Hormone Therapy for Chronic Conditions
A new evidence review from the U.S. Preventive Services Task Force reaffirms that menopausal hormone therapy offers fracture-prevention benefits — but at the cost of increased risks for venous thromboembolism, stroke, and other adverse outcomes.
The review, appearing in the Annals of Internal Medicine, included nine trials published since 2002 on hormone therapy for the primary prevention of chronic conditions. Most results came from the Women's Health Initiative, including:

The review will inform a forthcoming guideline update from the USPSTF. (In 2002, the task force advised against estrogen-progestin use to prevent chronic conditions; in 2005, it issued the same advice against estrogen alone.)
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BJOG 2012 Jun; 119:810
Consequences of Early Menopause
In a 34-year prospective study, early menopause led to more osteoporotic fractures and earlier death.
Although early menopause has been linked to osteoporosis and fragility fractures, most studies have been cross-sectional and retrospective, raising concerns about recall bias. In 1977, investigators began a study of white North European women residing in Malmö, Sweden who were born in 1929. The 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups: early menopause (before age 47) and late menopause (at or after age 47). In all, 198 of the 298 surviving participants underwent BMD reassessment at age 77. Fracture history and mortality were assessed at the study's end in 2011.
BMD measurements at age 77 indicated osteoporosis in 56% and 30% of those with early and late menopause, respectively (P=0.01). Incidence of fragility fractures per 1000 person-years was 19.4 and 11.6 in the early and late groups (P=0.01), respectively, and mortality during the 34-year follow-up was 52.4% and 35.2% (P=0.01), respectively. Ever-use of menopausal hormone therapy occurred in 22% and 10% of women in the early and late groups (P=0.05), respectively.
Comment: The prospective, population-based design of this Swedish study and its almost universal tracking of health and mortality over multiple decades make its findings particularly credible. Use of hormone therapy was uncommon among the overall cohort. However, given our current knowledge of HT's efficacy in lowering risk for osteoporotic fractures in menopausal women and in reducing coronary heart disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause; JW Womens Health May 3 2007), these data underscore the importance of advising women who experience early menopause to use HT unless they have specific contraindications.
Andrew M. Kaunitz, MD Published in Journal Watch Women's Health May 24, 2012
Citation(s): Svejme O et al. Early menopause and risk of osteoporosis, fracture and mortality: A 34-year prospective observational study in 390 women. BJOG 2012 Jun; 119:810.
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N Engl J Med 2012 Apr 29
Challenges in Glycemic Control for Adolescents with Type 2 Diabetes
Metformin plus rosiglitazone bested metformin monotherapy, but failure rates for all tested regimens were disappointingly high.
To address the persistent challenge of maintaining glycemic control in adolescents with type 2 diabetes, researchers compared three treatment options. The participants were 699 teenagers (age range, 10–17 years) with type 2 diabetes, body-mass index (BMI) in the 85th percentile, a negative test for diabetes-related autoantibodies, and a fasting C-peptide level >0.6 ng/mL.
After maintaining a glycated hemoglobin level <8% for ≥2 months on metformin monotherapy, participants were randomized to continue receiving metformin alone, to receive metformin plus rosiglitazone (a thiazolidinedione that increases fat cells' sensitivity to insulin), or to receive metformin plus a lifestyle intervention. Mean follow-up was about 4 years.
Treatment failure — defined as a persistently elevated glycated hemoglobin level (≥8%) for at least 6 months — occurred in 52% of the metformin-alone group, 39% of the metformin–rosiglitazone group, and 47% of the metformin–lifestyle group. Only the difference between the rosiglitazone group and the monotherapy group was statistically significant. The change in BMI over time differed significantly among the groups but was not a significant determinant of treatment failure.
The overall failure rate was somewhat higher in boys than girls (48% vs. 44%), and metformin plus rosiglitazone was significantly more effective in girls than boys. Non-Hispanic blacks had the highest failure rate overall (53%) and, in particular, with metformin monotherapy (66%).
Comment: Metformin plus rosiglitazone was superior to metformin monotherapy for achieving glycemic control in teenagers with type 2 diabetes. Rosiglitazone has been shown to be associated with myocardial infarction and heart disease in adults (JW Gen Med Apr 7 2011). Regardless of the therapy protocols used in this trial, the lack of success in maintaining glycemic control (an overall failure rate of 46%) is nonetheless disappointing.
F. Bruder Stapleton, MD Published in Journal Watch Pediatrics and Adolescent Medicine May 23, 2012
Citation(s): TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012 Apr 29; [e-pub ahead of print].
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Gastroenterology 2012 Feb 16
Eating Certain Fish Might Prevent Liver Cancer
In a large prospective study in Japan, higher consumption of fish with n-3 polyunsaturated fatty acids translated to lower risk for hepatocellular carcinoma.
Dietary n-3 polyunsaturated fatty acids (PUFAs) have been demonstrated to protect against several cancers. However, their protective benefit against hepatocellular carcinoma (HCC) has been inconsistent in the mostly retrospective studies conducted.
To investigate the association between fish and n-3 PUFA consumption and HCC, researchers analyzed data from a large-scale, population-based, prospective cohort study involving 90,296 people in Japan (aged 45–74). A validated food intake questionnaire — including items on fish rich in n-3 PUFAs (salmon or trout, sea bream, horse mackerel or sardine, mackerel pike or mackerel, and eel) — was completed at baseline by 84% of the cohort. Only 0.4% of subjects were lost to follow-up. During an average follow-up of 11.2 years (1,008,595 person-years), 398 cases of HCC were newly diagnosed.
Total fish consumption was not significantly associated with lower risk for HCC. However, in multivariate analysis, consumption of n-3 PUFA-rich fish showed a dose-dependent, inverse association with risk for HCC (hazard ratio, 0.64; P for trend=0.04). Similar dose-dependent, inverse associations with HCC were demonstrated for consumption of the individual n-3 PUFAs eicosapentaenoic acid (HR, 0.56; P for trend=0.01), docosapentaenoic acid (HR, 0.64; P for trend=0.05), and docosahexaenoic acid (HR, 0.56; P for trend=0.03). These associations remained in a subgroup analysis of 17,500 participants with data on hepatitis C and B viruses.
Comment: In this large, population-based cohort study, consumption of fish rich in n-3 polyunsaturated fatty acids reduced the risk for hepatocellular carcinoma, perhaps through anti-inflammatory effects or improvement in insulin sensitivity. These results should be confirmed in other settings and with more robust dietary information (not just that collected at baseline), but it is reasonable to advocate a diet rich in n-3 PUFA — especially for patients with cirrhosis who are at high risk for HCC.
Atif Zaman, MD, MPH Published in Journal Watch Gastroenterology May 11, 2012
Citation(s): Sawada N et al. Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology 2012 Feb 16; [e-pub ahead of print]. (http://dx.doi.org/10.1053/j.gastro.2012.02.018)
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Pediatrics 2012 May; 129:e1121
Maternal Obesity May Increase Risk for Autism
More evidence that maternal metabolic conditions during pregnancy are associated with neurodevelopmental disorders in children.
To examine whether metabolic conditions (diabetes, hypertension, and obesity) during pregnancy are associated with neurodevelopmental disorders in children, researchers in California performed a population-based, case-control study of children aged 2 to 5 years with autism spectrum disorder (ASD; 517 children), developmental delay without ASD (172 children), or with typical development (315 controls from the general population matched to the ASD group for age and sex). Maternal demographic and medical information was obtained from medical records, structured interviews, and an environmental exposure questionnaire. Validated instruments were used to diagnose ASD and developmental delay. Children with major motor and sensory impairments (blindness or deafness) were excluded.
All three metabolic conditions were more prevalent in case mothers than in control mothers. In analyses adjusted for covariates, mothers with diabetes were 2.3 times more likely than control mothers to have a child with developmental delay but were not significantly more likely to have a child with ASD. However, obese mothers (prepregnancy body-mass index >30 kg/m2) were 2 times more likely than control mothers to have a child with developmental delay and 1.7 times more likely to have a child with autism. Maternal diabetes was associated with greater deficits in expressive language among children with and without ASD.
Comment: This carefully executed study adds to increasing evidence indicating that maternal metabolic health during pregnancy affects neurodevelopmental health in children. The high prevalence of both obesity and diabetes among U.S. women of child-bearing age might contribute to increasing risk for autism, developmental delay, and other developmental impairments.
Louis M. Bell, MD Published in Journal Watch Pediatrics and Adolescent Medicine May 16, 2012
Citation(s):Krakowiak P et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 2012 May; 129:e1121.
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Am J Psychiatry 2012 Apr 25
Prenatal Antibodies to Gluten Protein, but Not Casein, Linked to Psychosis
Very high levels of maternal antibodies that cross the placenta are associated with elevated risk for nonaffective psychosis.
Maternal antibodies to gluten in wheat products and casein in cow's milk cross the placenta during the third trimester; theoretically, these antibodies could affect development of childhood-onset nonaffective psychosis. To test this hypothesis, researchers conducted a follow-up study of infants born in Sweden during 1975–1985 from whom dried blood-spot samples had been obtained as newborns. Registry data were used to identify individuals with nonaffective psychosis up to 28 years later. The investigators compared blood-spot antibody levels of gliadin (a protein in gluten) and casein in 211 participants with nonaffective psychosis and 553 unaffected individuals matched by age, sex, and location.
Very high percentiles of gliadin antibody levels (Gluten) were significantly associated with a high rate of nonaffective psychosis (odds ratio for 90th percentile, 1.7). Casein antibody levels were not associated with psychosis. Both higher maternal age and immigrant status also predicted higher rates of nonaffective psychosis, but controlling for these variables and for gestational factors did not change the gliadin findings. Study limitations included the lack of maternal dietary and medical histories, including comprehensive assessment for celiac disease.
Comment: These data are important clinically. Reducing maternal dietary gluten decreases maternal gliadin antibodies, which are capable of crossing the placenta. Studies of the effects of reducing maternal gliadin levels during pregnancy and investigations into preclinical gliadin pathways are warranted. Until these are forthcoming, whether to institute gluten-free diets will need to be decided by physicians and patients on a case-by-case basis.
Barbara Geller, MD Published in Journal Watch Psychiatry May 25, 2012
Citation(s): Karlsson H et al. Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. Am J Psychiatry 2012 Apr 25; [e-pub ahead of print].
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Aliment Pharmacol Ther 2012 May; 35:1190
Prenatal PPI Exposure and Childhood Asthma
Maternal PPI use during pregnancy or the year thereafter is associated with an increased risk for asthma in the offspring but may not be causal.
The prevalence of childhood asthma is increasing in developed countries. The reason for this effect is not clear, but prenatal exposure to a variety of environmental or medicinal agents has been speculated to play a role. A recent study suggested a potential association between asthma and prenatal exposure to acid-reducing drugs, including proton-pump inhibitors (PPIs).
To explore this possibility, researchers conducted a population-based cohort study, using data previously collected for all singleton births from 1996 through 2008 in northern Denmark. Maternal use of acid-reducing medications — PPIs or histamine-2 receptor antagonists (H2RAs) — was determined from the prescription database that tracks outpatient medication dispensation in the same geographic area. Presence of asthma in the children was defined as a hospital diagnosis of asthma or at least two prescriptions of both a β-agonist and an inhaled glucocorticoid.
Among 197,060 eligible children, 2238 (1.1%) had prenatal exposure to a PPI and 24,506 (12.4%) developed asthma (median follow-up, 6.8 years). The adjusted incidence rate ratio (aIRR) of asthma among children with prenatal PPI exposure was 1.41 (95% confidence interval, 1.27–1.56). The risk did not vary by trimester of exposure, and PPI use initiated during the year after birth was also associated with an increased risk for asthma in offspring (aIRR, 1.32; 95% CI, 1.20–1.46). In a secondary analysis, prenatal H2RA exposure was also associated with an increased risk for asthma (aIRR, 1.47; 95% CI, 1.32–1.65).
Comment: Population studies commonly suggest an association between one or more exposures and outcomes. Because such studies cannot control for a host of potential confounding factors, the associations they uncover may raise hypotheses for further investigation, but they do not establish causation. In the present study, the acid-reducing medications could be a marker for an underlying maternal factor because even postnatal maternal use was associated with asthma in the offspring.
David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) Published in Journal Watch Gastroenterology April 27, 2012
Citation(s):Andersen ABT et al. Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: A population-based Danish cohort study. Aliment Pharmacol Ther 2012 May; 35:1190.
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Dermatol Surg 2012 May; 38:772
Preventing Torn Earlobes
Piercings should be further from the earlobe edge to avoid tears from higher-risk earring types.
Earrings can cause earlobe injuries. Investigators developed a 5-mm-thick silicon paddle model of the ear comparable to live human earlobes in the amount of force required to pull it off center by 6 mm and 10 mm. Using this model, they tested earrings of the hoop, stud, buckle, hook, and screw types. A hoop threads through the piercing in the earlobe. A stud earring is attached to a shank inserted through the lobe and into a backing on the rear of the earlobe. A buckle is similar to a hoop, with one end that goes through the ear and snaps into a groove at the other end of the hoop. Like a fish hook, a hook earring passes through the piercing and hangs behind the lobe. A screw works like a stud earring but screws into its backing. Piercings were placed 4, 8, and 12 mm from the lower margin of the model ear.
The hoop, stud, and most buckle earrings fell out before they tore through the lobe, but hook, screw, and a few buckle earrings tore through the earlobe when increasing force was applied. Earrings placed at the lowest position, 4 mm from the edge of the lobe, were most likely to tear through. Lower earring positions are customary; the authors recommend that hoop, stud, and buckle earrings may be appropriately worn this low, but hook and screw earrings should be worn higher, 8 or 12 mm from the earlobe edge.
Comment: This creative study provides practical information that can be used to counsel patients, including those with prior earlobe tears who want to avoid a recurrence of this problem. The authors found no statistically significant difference in the likelihood of tears with piercings at 8 mm or 12 mm from the lower earlobe edge, so an 8-mm distance is sufficient. Further research may clarify whether age, skin type, or ethnicity affect earlobe response to pull force or susceptibility to tearing.
Murad Alam, MD, MSCI Published in Journal Watch Dermatology May 25, 2012
Citation(s): Hwang K and Hwang PJ. Which type of earring and which piercing point is safest with regard to tearing through the ear by an external force? Dermatol Surg 2012 May; 38:772.
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Osteoporosis Drug Link to Uncommon Breaks Confirmed
According to a new study, bisphosphonate therapy appears to be associated with an increased risk of atypical fractures of the femur, and may be driven by the duration of treatment. Of 477 patients hospitalized at one center, 39 had atypical fractures and 438 had common fractures. Among those with atypical fractures, 82.1% had been taking bisphosphonates compared with just 6.4% of those with common fractures. The study was by Raphael P.H. Meier, MD, from University Hospitals of Geneva, and colleagues and reported online in the Archives of Internal Medicine.
Current reports on bisphosphonate use and atypical fractures are conflicting. A recent meta-analysis of randomized trials found no association, but a registry-based study suggested that the risk of atypical fracture was more than doubled when bisphosphonates were taken for longer than 5 years (JAMA 2011; 305: 783-789).
In 2010, the FDA confirmed that bisphosphonate drugs for osteoporosis carried a small but meaningful risk of femoral fractures and ordered an update to product labels.
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Generic Drugmakers' Complaints Over Brand-name Access Prompt Investigations
To get a generic drug approved by the FDA, a company has to test a sample of the brand-name version and show that the generic version is essentially identical and as effective. However, some companies say they are unable to create cheaper generic versions of drugs because their rivals are exploiting a legal loophole. The government has placed restrictions on distributing some drugs that are dangerous or prone to abuse. Critics say manufacturers of those brand-name drugs are using the restrictions to stop generic drugmakers from getting samples to test. It all boils down to "No samples, no generics." Some critics warn that the practice is bound to become more entrenched and widespread.
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N Engl J Med 2012 May 17; 366:1881
Does Azithromycin Raise Risk for Cardiovascular-Related Death?
Risk was most pronounced for those with the highest baseline risk for cardiovascular diseases.
Several macrolide antibiotics have proarrhythmic effects, but azithromycin is thought to be less cardiotoxic than others. Researchers at Vanderbilt University investigated this assumption using Medicaid records for 402,260 patients. They monitored deaths from heart disease and other causes during 3.3 million 5-day windows during which some patients received azithromycin and other clinically similar patients did not take antibiotics, or took amoxicillin, ciprofloxacin, or levofloxacin.
Patients who took azithromycin had significantly elevated rates of cardiovascular-related death compared with people in each of the control groups (except the levofloxacin group). For example, compared with patients who took no antibiotics or amoxicillin, patients who took azithromycin had hazard ratios of 2.9 and 2.5, respectively. The increase in absolute risk, however, was quite small. When comparing azithromycin recipients with amoxicillin recipients, the elevated absolute risk per million courses of azithromycin therapy was 47 additional cardiovascular-related deaths in patients at average cardiovascular risk and 245 in patients at greatest risk.
Comment: In this large observational study, a small but real increase in risk for cardiovascular-related death was observed for 5-day courses of azithromycin. Although such a study cannot prove that the association is causal, that people in the comparison groups were clinically similar, and that the antibiotics used in the comparison groups have similar clinical indications, suggest that the risk is real. This study provides one more reason to prescribe azithromycin for approved clinical indications only.
Anthony L. Komaroff, MD Published in Journal Watch General Medicine May 22, 2012
Citation(s):Ray WA et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012 May 17; 366:1881.
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Arch Intern Med 2012 May 14
Acupuncture Improves Symptoms and Function in COPD Patients
A controlled trial shows particular benefit in perceptions of dyspnea on exertion in patients with chronic obstructive pulmonary disease.
Uncontrolled studies of acupuncture have shown benefit in reducing dyspnea on exertion (DOE)and increasing exercise capacity in patients with chronic obstructive pulmonary disease (COPD). In this Japanese study, researchers used a sophisticated sham acupuncture procedure to conduct a controlled assessment in 68 adults with moderate-to-severe COPD and DOE who were on stable medication regimens and able to walk unassisted.
The patients were randomized to acupuncture treatments weekly for 12 weeks at 11 acupuncture points selected according to traditional Chinese theory, or to sham treatments using the same schedule and acupuncture points but performed with a blunt needle that appeared to penetrate the skin but actually telescoped with pressure. Only four patients could correctly identify the group to which they were assigned.
On a standardized assessment at 12 weeks, DOE after a 6-minute walk was statistically and clinically better in the intervention group and unchanged in the control group. The 6-minute walk distance lengthened significantly by about 60 meters (from a baseline distance of about 400 meters) in the intervention group and declined in the control group. The intervention group had significantly improved quality-of-life scores and respiratory mechanics compared with the control group.
Comment: Acupuncture might benefit COPD patients through relaxation of accessory respiratory muscles and improved rib cage mobility. These results are sufficiently positive to warrant larger and longer-term trials, and efforts also should be focused on other ways to achieve the same improvements in the many communities where acupuncture is not commonly available.
Thomas L. Schwenk, MD Published in Journal Watch General Medicine May 22, 2012
Citation(s): Suzuki M et al. A randomized, placebo-controlled trial of acupuncture in patients with chronic obstructive pulmonary disease (COPD): The COPD-Acupuncture Trial (CAT). Arch Intern Med 2012 May 14; [e-pub ahead of print].
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BMJ 2012 May 3; 344:e3042
Simple Warm-Up Program Prevents Anterior Cruciate Ligament Injuries
In adolescent female soccer players, neuromuscular training was effective.
Adolescent female soccer players experience anterior cruciate ligament (ACL) knee injuries at a rate that is more than twice that of their male counterparts. Can such injuries — which are season-ending and associated with premature arthritis — be prevented? In a randomized controlled trial, with Swedish soccer clubs as the unit of randomization, investigators evaluated the effectiveness of neuromuscular training on lowering the rate of acute knee injury in adolescent female soccer players.
Overall, 4600 adolescent players (age range, 12–17 years) participated in the study. Two thirds were instructed in how to perform a 15-minute warm-up program that focused on knee control and core stability and consisted of 5 minutes of jogging followed by six exercises (one-legged knee squat, two-legged knee squat, lunge, bench press, jump/landing technique, and pelvic lift). The program, which progressed through four levels of difficulty, was completed twice weekly during soccer season. Seven players in the intervention group (0.3%) and 14 in the usual-care control group (0.7%) experienced ACL injuries. Regression analysis of the intent-to-treat data revealed that the rate of ACL injury was 64% lower in the intervention group; the difference was statistically significant
Comment: A simple warm-up program can prevent ACL injury in young female soccer players. The authors speculate the exercises minimize lateral trunk displacement and excessive dynamic knee valgus, which are risk factors for ACL injury. Whether these results can be applied to male soccer players, other age groups, and athletes in other sports who are prone to knee injury (e.g., basketball players, softball players) is uncertain. Nevertheless, assuming the program would be effective in these settings is reasonable.
— Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine May 22, 2012
Citation(s):Waldén M et al. Prevention of acute knee injuries in adolescent female football players: Cluster randomised controlled trial. BMJ 2012 May 3; 344:e3042.
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Neurology 2012 Apr 10; 78:1171
Atorvastatin Monotherapy Not Beneficial for Delaying Multiple Sclerosis
A phase II trial does not support use of atorvastatin monotherapy after a clinically isolated syndrome, but magnetic resonance imaging measures suggest potentially beneficial immunomodulatory effects.
Statin medications have a plethora of effects, including immunomodulation, as previously demonstrated in animal models of multiple sclerosis (MS). In this phase II, investigator-initiated, NIH-sponsored trial, researchers examined whether atorvastatin could delay a second relapse in the first year after presentation with a first demyelinating event and an abnormal magnetic resonance imaging (MRI) scan consistent with a clinically isolated syndrome. The primary endpoint was a second clinical event or ≥3 new brain MRI T2 lesions; those with a second event were offered weekly interferon beta-1a.
The trial was halted because of slow recruitment after 82 of the planned 152 participants were randomized to placebo or 80 mg of atorvastatin. The groups did not differ significantly on the primary endpoint, whether measured as the proportion of people with a second demyelinating event or as time to a second event (53.1% on atorvastatin after a median of 275 days, 56.3% on placebo after a median of 284 days). However, the proportion of participants with new T2 lesions at 12 months was significantly lower with atorvastatin than with placebo (44.7% vs. 72.4%), and the median cumulative number of new T2 lesions trended toward a 27% reduction. Of those in the atorvastatin group, 22% did not tolerate the 80-mg dose; their dosage was lowered to 40 mg daily.
Comment: This study did not demonstrate a clinical benefit of atorvastatin use after a clinically isolated syndrome, potentially because of low study power caused by early study termination. The finding that atorvastatin monotherapy may have a beneficial effect on MRI outcomes in this population supports the hypothesis that atorvastatin has immunomodulatory properties aside from lowering serum cholesterol. Whether atorvastatin has beneficial or deleterious effects when combined with an interferon (IFN) has been controversial (JW Neurol Feb 24 2009). Although the number of people on combination therapy in the current study was low (15 on atorvastatin and IFN, vs. 9 on placebo and IFN), no antagonistic effect was observed. At this time, atorvastatin remains unproven in MS, either alone or in combination with another immunomodulatory therapy. For those who have MS and need a statin, clinicians may consider additional monitoring for disease activity, if it is added to an interferon, or selection of a non-interferon option.
Robert T. Naismith, MD Published in Journal Watch Neurology May 22, 2012
Citation(s):Waubant E et al. Randomized controlled trial of atorvastatin in clinically isolated syndrome: The STAyCIS study. Neurology 2012 Apr 10; 78:1171.
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Am J Gastroenterol 2012 Mar; 107:379
Combined Ibuprofen/Famotidine Tablet Might Reduce Ulcers
Patients receiving the combination tablet developed fewer upper gastrointestinal ulcers than those receiving ibuprofen alone.
Patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) have an increased risk for upper gastrointestinal (GI) ulcers (gastric and duodenal ulcers). Acid reduction with a proton-pump inhibitor (PPI) has been shown to decrease this risk. However, many patients taking NSAIDs either do not receive a prescription for PPIs or do not take them.
To investigate the efficacy of a combination tablet of 800 mg ibuprofen and 26.6 mg famotidine to reduce development of upper GI ulcers in patients requiring NSAID therapy, researchers conducted two industry-sponsored, randomized, double-blinded trials (REDUCE-1 and REDUCE-2) in which patients received the combination tablet or an 800-mg ibuprofen tablet three times daily for 24 weeks. The endpoint for the studies was upper GI ulcers identified by endoscopy during the 24-week study period.
In the REDUCE-1 trial, incidence of gastric ulcers was lower in the combination-tablet group than in the ibuprofen group (12.7% vs. 22.9%; P=0.004). In REDUCE-2, results showed a nonsignificant trend toward lower incidence of upper GI ulcers with the combination-tablet group versus ibuprofen (13.0% and 20.5%; P=0.059). In a pooled analysis of results from both trials, the combination-tablet group had lower incidence of both gastric ulcers (12.5% vs. 20.7%) and duodenal ulcers (1.6% vs. 6.9%) than the ibuprofen group. After adjustment for other potential risk factors, the risk ratio for upper gastrointestinal ulcers with the combination therapy versus ibuprofen alone was 0.46 (95% confidence interval, 0.34–0.61).
Comment: Our ability to compare these findings with data on efficacy of acid reduction with proton-pump inhibitor cotherapy is limited because this study was based on endoscopic ulcers. There were not enough complicated ulcers in the study to allow for comparison of this outcome between the two treatment groups. While some studies suggest that endoscopic ulcers are a reasonable surrogate for clinically significant events, it is impossible for us to determine how combination therapy — with its improved acid-reduction compliance — compares with standard PPI cotherapy without a head-to-head trial based on clinical events.
— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) Published in Journal Watch Gastroenterology April 20, 2012
Citation(s): Laine L et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers.
Am J Gastroenterol 2012 Mar; 107:379

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