• British Medical Journal to Require More Details on Drug Trials
• Obesity Interventions Most Effective in Young Children
• Obese Teens at Increased Risk for End-Stage Renal Disease in Adulthood
• Metabolic Consequences of Insufficient Sleep
• Oral Cannabinoids for Muscle Stiffness in Multiple Sclerosis
• Mental Decline May be Helped by Daily Low-dose Aspirin
• Fish Rich in Omega-3s Associated with Moderate Reduction in Cerebrovascular Events
• Causes of Death in Men with Prostate Cancer
• A Possibly Treatable Type of Autism
• Antibiotic Exposure Linked with Development of IBD in Children
• Rising Incidence of Stroke Among Young Adults
• Synthetic Cannabinoids ("Spice") — Relatively New Drugs of Abuse
• Single Dose of Topical Ivermectin Kills Head Lice
British Medical Journal to Require More Details on Drug Trials
Beginning in January, the British Medical Journal (BMJ) will no longer publish the results of clinical trials unless drug companies and researchers agree to provide detailed study data when requested. This action is meant to induce pharmaceutical companies to reveal their data collected in researching new drugs, very little of which is ever made public. Critics complain that the drugs are presented in the best possible light and do not permit independent researchers to evaluate the data.
http://www.nytimes.com/2012/11/01/business/british-medical-journal-to-require-detailed-clinical-trial-data.html
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Obesity Interventions Most Effective in Young Children
Two studies in the Archives of Pediatrics and Adolescent Medicine highlight the importance of treating obesity early in childhood.
In the first, 75 overweight or obese children aged 3 to 5 years in the Netherlands were randomized to either usual care or to a multidisciplinary intervention (25 sessions on dietary advice, physical activity, and psychological counseling for parents) over 4 weeks. At 12 months, the intervention group had greater reductions in BMI and waist circumference, relative to usual care.
In the second study, researchers examined registry data on roughly 650 obese children aged 6 to 16 years in Sweden who underwent behavioral treatment. After 3 years, children who started treatment before age 10 had greater reductions in BMI standard deviation scores than those who started treatment later. Adolescents aged 14 to 16 who were severely obese when they started treatment did not have any reduction in BMI. Most severely obese adolescents were already obese by age 7.
Editorialists write: "The studies ... provide evidence that intervening on obesity at an early age is effective and may have sustained effects on weight and adiposity."
http://archpedi.jamanetwork.com/article.aspx?articleid=1387377
http://archpedi.jamanetwork.com/article.aspx?articleid=1387375
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Obese Teens at Increased Risk for End-Stage Renal Disease in Adulthood
Overweight and obese teens face increased risk for end-stage renal disease (ESRD) years later, according to a retrospective cohort study in the Archives of Internal Medicine.
Researchers studied nearly 1.2 million Israelis who underwent medical assessments, including BMI measurements, at age 17 years. Those with diagnoses suggesting potentially increased risk for ESRD were excluded.
During roughly 25 years' follow-up, 874 participants developed ESRD. In adjusted analyses, those who were overweight at age 17 had three times the ESRD risk — and those who were obese had nearly seven times the risk — as those who were normal weight. The risk increase was much higher for diabetic than nondiabetic ESRD, but even the increase in nondiabetic disease was statistically significant.
The authors and a commentator suggest several possible mechanisms for the observed association, including leptin-related renal fibrosis, elevated plasma renin and aldosterone levels, and underlying focal segmental glomerulosclerosis in obese individuals.
http://archinte.jamanetwork.com/article.aspx?articleid=1387591
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Ann Intern Med 2012 Oct 16; 157:549
Metabolic Consequences of Insufficient Sleep
A small, randomized, controlled crossover study demonstrates changes in a critical insulin-signaling pathway in peripheral tissue.
Small experimental studies have revealed adverse effects of reduced sleep duration on glucose tolerance and insulin sensitivity. To explore the effects of sleep restriction on metabolic activity in peripheral tissue, investigators randomized seven lean, healthy young adults (aged 18–30) to undergo 4 weeks each of normal and restricted sleep (8.5 and 4.5 hours, respectively), in random order and under controlled conditions, 4 weeks apart. The primary endpoint was change in levels of phosphorylated Akt — an important step in the insulin-signaling pathway — in abdominal subcutaneous adipocytes.
Phosphorylation of Akt was 30% lower after restricted sleep than after normal sleep (P=0.01). This reduction coincided with a 16% reduction in total-body insulin sensitivity, as measured by frequently sampled intravenous glucose tolerance tests.
Comment: We know that partial sleep restriction is associated with marked adverse changes in insulin sensitivity and glucose tolerance; now, this small study shows a correlation between sleep restriction and significant changes in molecular metabolic pathways in subcutaneous abdominal fat. I wonder if this line of research will lead us to recognize sleep deprivation as a precursor risk factor for metabolic abnormalities that lead to vascular disease — and whether we might eventually prescribe more sleep to our high-risk patients.
— Harlan M. Krumholz, MD, SM Published in Journal Watch Cardiology October 31, 2012
CITATION(S): Broussard JL et al. Impaired insulin signaling in human adipocytes after experimental sleep restriction: A randomized, crossover study. Ann Intern Med 2012 Oct 16; 157:549.
http://www.ncbi.nlm.nih.gov/pubmed/23070488?dopt=Abstract
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J Neurol Neurosurg Psychiatry 2012 Nov; 83:1125.
Oral Cannabinoids for Muscle Stiffness in Multiple Sclerosis
A randomized, placebo-controlled study suggests a benefit, but insufficient blinding and lack of objective or functional outcome measures are serious flaws.
Cannabis has been advocated for treatment of pain, spasticity, and spasms by patients with multiple sclerosis (MS). Pharmacologic therapies are available for these troubling symptoms, but relief remains unsatisfactory for many. To assess the effects of cannabis on muscle stiffness caused by MS, investigators randomized 279 patients with MS and at least 3 months of muscle stiffness to receive oral 
-9-tetrahydrocannabinol (THC) or placebo for 12 weeks. The dosage was titrated during the initial 2 weeks, from 2.5-mg capsules twice daily to a maximum of 25 mg per day or until intolerable adverse effects occurred. The primary outcome was participant response, on an 11-point scale, to the question, "Compared with before the study started, my muscle stiffness over the last week has been. . ." Ratings ranged from 0 (very much better) to 5 (no difference) to 10 (very much worse). A score of 0–3 was considered clinically relevant.
Significantly more THC recipients than placebo recipients reported scores of 0–3 for the primary outcome (29% vs. 16%). However, placebo was maximally titrated in 87%, whereas THC was maximally titrated in only 47%, and 11.2% of the THC group discontinued treatment versus 3.0% of the placebo group. The most common adverse effects of THC were dizziness and fatigue. The THC group showed greater improvements than the placebo group on some secondary measures, including the MS walking scale.
Comment: The authors implemented a subjective, patient-reported, 11-point rating of change scale, citing the difficulty in establishing an objective or functional improvement with cannabinoids. However, the adverse effect profile of THC is such that patients often know which treatment they receive. This problem is further compounded by a dose titration in which more than half the THC group could not tolerate the maximum dose. Because patients know what they are receiving, objective corroboration of signs and functional improvement is critical. Improvement observed on the walking scale should be confirmed in future trials with objective ambulatory testing.
Fatigue and cognitive issues are relevant for MS, so cannabis has potential to exacerbate those symptoms (JW Neurol Jun 7 2011). At present, the evidence remains insufficient to support a recommendation of cannabinoids as an effective therapy for spasticity.
— Robert T. Naismith, MD Published in Journal Watch Neurology October 30, 2012
CITATION(S): Zajicek JP et al. MUltiple Sclerosis and Extract of Cannabis: Results of the MUSEC trial. J Neurol Neurosurg Psychiatry 2012 Nov; 83:1125.
http://www.ncbi.nlm.nih.gov/pubmed/22791906?dopt=Abstract
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Mental Decline May be Helped by Daily Low-dose Aspirin
Aspirin 81 mg (low-dose aspirin) that millions take to help prevent heart attacks and strokes may also help slow down age-related mental decline, a new study suggests. The study involved almost 700 Swedish women aged 70 to 92, most of whom had heart disease. The women that took low-dose aspirin every day to prevent a heart attack showed a less pronounced slide in mental functioning after five years than their counterparts who did not take aspirin. The study showed that tests of memory, verbal fluency, and other mental capabilities showed some loss of brain power, but the decline was significantly less and occurred at a slower pace among the women who received aspirin continuously or even for a period of time compared to those who never took it. Sixty-six of the women taking the drug for all five years even saw some of their scores improve, the researchers said. The low-dose aspirin utilized was between 75 and 160 milligrams.
http://consumer.healthday.com/Article.asp?AID=670053
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Fish Rich in Omega-3s Associated with Moderate Reduction in
Cerebrovascular Events
Adults who eat several servings of omega-3-rich fish per week may have a reduced risk for cerebrovascular events, according to a BMJ meta-analysis. Omega-3 supplementation, however, does not appear to confer the same benefit.
Researchers examined data from 26 prospective cohort studies and 12 randomized controlled trials evaluating the effects of fish consumption and omega-3 fatty acid intake on cerebrovascular risk. Some 794,000 participants and 35,000 cerebrovascular events were included.
There were small but significant reductions in cerebrovascular risk for participants who consumed 2–4 servings and 5 or more servings of fish weekly, relative to those who consumed less (relative risks: 0.94 and 0.88, respectively). The beneficial effect was limited to omega-3-rich fish. In contrast, omega-3 supplements showed no significant effect.
Findings were similar for participants with and without preexisting heart disease.
The authors conclude: "The beneficial effect of fish intake on cerebrovascular risk might be mediated through a complex interplay among a wide range of nutrients commonly found in fish."
http://www.bmj.com/content/345/bmj.e6698
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Causes of Death in Men with Prostate Cancer
In the U.S. and Sweden, men diagnosed with prostate cancer were less likely to die from the disease than from other causes.
Since the advent of prostate-specific antigen (PSA) testing, the incidence of prostate cancer has risen sharply, and the consensus has been that many patients with low-risk disease are being overtreated. Yet during the PSA era, disease-specific mortality has remained relatively stable, though data regarding outcomes for prostate cancer patients are lacking.
Now, to assess the causes of death among a modern cohort of men with prostate cancer, investigators used data from population-based databases from the U.S. and Sweden, two countries with some of the highest incidence rates of the disease. They analyzed outcomes of 490,000 men in the U.S Surveillance, Epidemiology, and End Results Program (SEER) database who were diagnosed with prostate cancer between 1973 and 2008 as well as 210,000 men in the Swedish Cancer Registry diagnosed between 1961 and 2008.
The researchers calculated the cumulative incidence of death from seven causes — prostate cancer, other cancers, ischemic heart disease, cerebrovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, and external causes (including trauma and suicide) — which accounted for more than 80% of deaths. Mortality trends were analyzed by calendar year, patient age at diagnosis, and duration of follow-up. Approximately two thirds of U.S. patients and half of Swedish patients were diagnosed during the PSA era, defined as beginning in 1991 in the U.S. and in 1994 in Sweden.
Results were as follows:
- In the U.S., 53% of patients died during a median 5.6 years of follow-up; in Sweden, 68% of patients died during a median follow-up of 3.8 years.
- The 5-year cumulative incidence of death from prostate cancer among all men was 11% in the U.S. and 29% in Sweden.
- Deaths from prostate cancer were less common in the PSA era than in the pre-PSA era among both U.S. patients (6% vs. 23%) and Swedish patients (14% vs. 39%) who had
5 years of follow-up after diagnosis. - Prostate cancer was the most common cause of death among U.S. and Swedish patients (30% and 52%, respectively), but only 16% of U.S. patients and 35% of Swedish patients diagnosed with prostate cancer died from the disease.
- Ischemic heart disease was the second most common cause of death among U.S. and Swedish patients (24% and 17%, respectively).
- In the U.S. and Sweden, men diagnosed with prostate cancer were less likely to die from the disease than from other causes.
Comment: This analysis adds to a growing body of knowledge regarding outcomes for patients with low-risk prostate cancer regardless of the effect of treatment. It provides increasing impetus for clinicians to focus on health-maintenance issues for these patients, given the likelihood that diseases other than prostate cancer will affect their longevity.
— Robert Dreicer, MD, MS, FACP Published in Journal Watch Oncology and Hematology October 30, 2012
CITATION(S): Epstein MM et al. Temporal trends in cause of death among Swedish and US men with prostate cancer. J Natl Cancer Inst2012 Sep 5; 104:1335.
(http://dx.doi.org/10.1093/jnci/djs299)
http://www.ncbi.nlm.nih.gov/pubmed/22835388?dopt=Abstract
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Science 2012 Sep 6
A Possibly Treatable Type of Autism
Genetic mutations lead to altered branched chain amino acid pathways that might be normalized with dietary supplementation.
Investigators genotyped exome regions in three consanguineous families of patients who had autism, seizures (or electroencephalographic abnormality), and intellectual impairment.
Affected people had various mutations in the branched chain ketoacid dehydrogenase gene (BCKDH). This gene encodes a protein that catabolizes branched chain amino acids (BCAAs; leucine, isoleucine, and valine). Mice with this gene knocked out had low BCAA levels in plasma and in the brain and exhibited neurological impairments that are observed in other autism models — including seizures, tremors, and hind-limb grasping. The knockout mice also showed perturbations in BCAA transporters (which also transport major neurotransmitters) across the blood–brain barrier, as well as elevated brain levels of other amino acids, but how these perturbations are related to phenotypic manifestations is unknown.
Bckdh-knockout mice fed a diet enriched in BCAAs showed neurological improvements. Patients had lower plasma BCAA levels than relatives and population references; after dietary supplementation, levels increased significantly immediately afterward and showed a trend toward normalization in fasting tests. Phenotypic assessments are planned.
Comment: Clinical quandaries include whether to test for plasma levels of branched chain amino acids and whether to prescribe supplements to patients with low levels. Given the current paucity of therapeutic data, clinicians need to make these decisions on a case-by-case basis. Even if plasma BCAAs are normalized, patients might be beyond the critical periods for developing social and language skills. Recent research, however, on reopening these critical periods (Nature 2012; 487:24) may eventually be applicable for skills development in older autistic individuals with treatable mutations.
— Barbara Geller, MD Published in Journal Watch Psychiatry October 1, 2012
CITATION(S):Novarino G et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 2012 Sep 6; [e-pub ahead of print].
(http://dx.doi.org/10.1126/science.1224631
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Pediatrics 2012 Oct; 130:e794
Antibiotic Exposure Linked with Development of IBD in Children
One more reason to be judicious with antibiotic use
Investigators retrospectively examined the association between antibiotic exposure and the development of inflammatory bowel disease (IBD) in children (age range, 
17 years) in 464 general practices (>3 million active patients) in a population-based database representing about 5.7% of U.K. patient visits.
Antianaerobic antibiotics were defined as penicillin, amoxicillin, ampicillin, and penicillin/ß-lactamase inhibitor combinations, as well as tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin. Patients were classified as ever (64%) or never exposed to a course of antibiotics. Antibiotic exposure during the latency period between the onset of IBD and formal diagnosis (when patients might receive antibiotics for symptoms arising from as-yet undiagnosed IBD) were excluded in the analysis regardless of outcome to address potential misclassification bias.
The analysis included data on 1,072,426 children, 748 (0.07%) of whom developed IBD. IBD incidence rates were 0.83 and 1.52 per 10,000 person-years in unexposed and exposed children, respectively (adjusted hazard ratio, 5.51; 95% confidence interval, 1.66–18.28). Any antianaerobic antibiotic exposure was significantly associated with developing IBD in a dose-response manner. Each antianaerobic course increased the risk for IBD by 6%. Results for patients with Crohn disease and ulcerative colitis were similar to the overall results.
Comment: This well-designed, retrospective study identified an association between antianaerobic antibiotic exposure and development of IBD in children. However, the causes of IBD are undoubtedly multifactorial, involving both environmental and other epigenetic phenomenon.
— Louis M. Bell, MD Published in Journal Watch Pediatrics and Adolescent Medicine October 31, 2012
CITATION(S): Kronman MP et al. Antibiotic exposure and IBD development among children: A population-based cohort study. Pediatrics2012 Oct; 130:e794.
(http://dx.doi.org/10.1542/peds.2011-3886)
http://www.ncbi.nlm.nih.gov/pubmed/23008454?dopt=Abstract
MM: Could the rising incidence of stroke in the young be associated with an increasing level of obesity in that same group? This same group is showing an increase in metabolic syndrome that may be associated with this increase stroke incidence as well. It comes back to we are what we eat and attention needs to be paid to not only weight and diet but exercise as well.
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Neurology 2012 Oct 23; 79:1781
Rising Incidence of Stroke Among Young Adults
The stroke incidence among adults aged 20 to 54 increased substantially during a 12-year period in a population-based study.
Hypothesizing that stroke in younger adults may be on the rise, researchers aimed to describe recent age-related temporal trends of stroke incidence. They identified ischemic and hemorrhagic stroke cases retrospectively through inpatient and outpatient records within a well-defined population base in Ohio and Kentucky. The investigators compared the annual incidence rates of stroke among young adults during a 12-year period, using both inpatient records and outpatient sampling to identify strokes.
The proportion of all strokes that occurred in adults aged 20 through 54 increased from 13% in the 1993–1994 period to 19% in 2005. In this age group, the incidence rate of stroke among blacks increased from 83 per 100,000 in 1993–1994 to 128 per 100,000 in 2005. Among whites in this age group, the incidence rate increased from 26 to 48 per 100,000. The authors conclude that the number of ischemic strokes diagnosed among young adults may be increasing. However, because they found that magnetic resonance imaging use also increased during this time, they speculate that the trend may be explained in part by recent improvements in diagnostic imaging.
Comment: Despite an overall decline in stroke incidence rates, hospital admissions for ischemic stroke among young adults in the U.S. are thought to be on the rise. This study suggests that in addition to hospital admissions, the overall incidence of stroke in young adults may be increasing. The strengths of the study were its well-defined population base and its consistent methodology spanning more than a decade. These findings support recent literature describing stroke trends among young adults in other populations (JW Neurol Feb 7 2012). However, the cause of the apparent rising incidence of stroke in the young is still not clear. Further efforts are critical to determine why stroke risk may be increasing, so that age-appropriate stroke prevention strategies can be implemented.
— Christine Fox, MD, MAS Dr. Fox is a Vascular Neurology Fellow, University of California, San Francisco.
Published in Journal Watch Neurology October 30, 2012
CITATION(S): Kissela BM et al. Age at stroke: Temporal trends in stroke incidence in a large, biracial population. Neurology 2012 Oct 23; 79:1781.
http://www.ncbi.nlm.nih.gov/pubmed/23054237?dopt=Abstract
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Ann Emerg Med 2012 Oct; 60:435.
Synthetic Cannabinoids ("Spice") — Relatively New Drugs of Abuse
Researchers reviewed 1300 cases reported to poison control centers.
Synthetic cannabinoids (
-9-tetrahydrocannabinols; also known as "spice" or "K2") have become relatively popular drugs of abuse. Herbal mixtures are laced with these compounds and are sold in small packages at "head shops" or gas stations, or on the Internet. Synthetic cannabinoids have high affinity for cannabinoid receptors and are promoted as alternatives to marijuana.
Researchers summarized 1353 single-agent exposures to synthetic cannabinoids that were reported to the U.S. National Poison Data System between January and October 2010. Median patient age was 20. Clinical effects included tachycardia (40%), agitation (23%), vomiting (15%), lethargy (14%), confusion (12%), hallucinations or delusions (9%), and seizures (4%). One death occurred in a 58-year-old man with "intentional inhalational abuse." Treatment generally was supportive, and clinical effects nearly always subsided within 24 hours.
Comment: This report should remind clinicians to ask about "spice" use when they encounter patients — especially teenagers and young adults — who present with symptoms described above. Because these cases were evaluated in healthcare facilities and reported to a central poison data system, the findings do not necessarily represent the experience of most users of synthetic cannabinoids. Readers can learn more about synthetic cannabinoids by checking out articles on the websites of the National Institute on Drug Abuse and Forbes magazine. — Allan S. Brett, MD
Published in Journal Watch General Medicine October 11, 2012
CITATION(S): Hoyte CO et al. A characterization of synthetic cannabinoid exposures reported to the National Poison Data System in 2010.Ann Emerg Med 2012 Oct; 60:435.
http://www.ncbi.nlm.nih.gov/pubmed/22575211?dopt=Abstract
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Single Dose of Topical Ivermectin Kills Head Lice
One-time treatment with topical ivermectin effectively wipes out head lice, according to two industry-funded, phase III trials in the New England Journal of Medicine. The FDA approved topical ivermectin (brand name, Sklice) earlier this year.
The trials included 300 children aged 6 months and older with head-lice infestations who were randomized to a single, at-home application of ivermectin 0.5% or a control lotion; nit combing was not allowed. Overall, significantly more patients were louse-free with ivermectin than with control lotion at day 2 (95% vs. 31%) and day 15 (74% vs. 18%). Side effects did not differ between the groups.
Findings were similar in a larger analysis that included infected household members who also underwent ivermectin treatment.
The researchers say their findings "indicate that ivermectin is a treatment option when permethrin or pyrethrins have failed or when there is a desire to reduce the need for nit combing and increase the probability of success with a single application."
http://www.nejm.org/doi/full/10.1056/NEJMoa1200107
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Ivermectin Head Lice Lotion; Safe and Effective
Sklice wiped out head lice in a single application in a study that suggests the drug may offer a better approach than existing medications, researchers said. (Editor's note: Actually compounding pharmacists have known this for years!) Just one day after treatment, 95% of those in the Sklice group were lice free compared with 31% given a placebo, according to company funded-studies that helped gain the drug's U.S. approval earlier this year.
http://www.bloomberg.com/news/2012-10-31/sanofi-worm-pill-kills-resistant-head-lice-as-a-lotion.html
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