• Proton-Pump Inhibitors Inhibit Absorption of Levothyroxine in Tablet Form
• L-carnitine for Muscle Cramps in Patients with Cirrhosis
• Testosterone Gel not associated with Subclinical Atherosclerosis Progression,
Study Suggests
• Cutting Dietary Fat leads to Greater Body Fat Loss than Cutting Carbs,
Small Study Suggests
• Regular Consumption of Sugar-Sweetened Beverages is associated with
Excess Risk for Type 2 Diabetes
• Topical Lidocaine for Dyspareunia in Women with Breast Cancer
• Music appears to reduce Postoperative Pain, Anxiety
• Does Autoimmune Encephalitis underlie Postpartum Psychosis?
• Risks from Trans Fat confirmed in Meta-Analysis — Saturated Fat seems Innocent
• Stimulants do not Increase Tic Risk
• Mortality Benefit of lower-than-recommended Physical Activity levels in Older Adults
• Coca-Cola under fire for Funding Controversial Obesity Research
• Exercise Training Improves Vascular Function in Overweight Kids, Meta-Analysis Finds
• Menstrual Status and Fracture risk in Young Athletes
• Another Benefit of Split-Dose Bowel Preparation?
• Leptin Receptors: New Players in our understanding of Antidepressant
Medication Response
• Mismatch between Timing of Medications and Circadian Rhythms might
alter Drug Effectiveness
MM: Clinical failures are a frustration to patients and clinicians. The use of acid suppressing agents such as PPI's are frequently used by thyroid patients yet this is drug interaction that is infrequently noted. Here is an example of why it is so important to let both your doctor and your pharmacist know what prescription and OTC products you are taking. If a PPI or other acid suppressing product must be taken then this is a good opportunity to utilize the services of your compounding pharmacist at Mark Drugs! With a prescription we can prepare a liquid levothyroxine or provide a non-prescription natural alternative such as our Heart Burn Away chewable tablets as a healthy alternative to PPI's or H2 blockers.
J Clin Endocrinol Metab 2014 Dec; 99:4481
Proton-Pump Inhibitors Inhibit Absorption of Levothyroxine in Tablet Form
A levothyroxine solution appears to circumvent this problem.
Studies have shown that gastric acidity enhances the dissolution of levothyroxine tablets. Thus, proton-pump inhibitors (PPIs), which suppress gastric acid secretion, might be expected to inhibit absorption of levothyroxine delivered as a tablet, but not as liquid.
To examine this issue, Italian researchers identified 24 patients who took both levothyroxine tablets and a PPI daily and whose thyroid-stimulating hormone (TSH) levels were around the upper limit of normal (mean level, 4.1 mU/L). All patients were switched from levothyroxine in tablet form to the same dose in an oral solution (while PPIs were continued), and TSH was remeasured 8 weeks later. After the switch, the mean TSH level fell markedly, to 0.9 mU/L.
Comment: Simultaneous treatment with levothyroxine tablets and a PPI should be on the list of considerations when a patient requires higher-than-expected doses of levothyroxine to suppress TSH into a desired range. An oral solution appears to circumvent the absorption problem, but levothyroxine solution is not marketed in the U.S.; however, a soft-gel liquid-containing capsule that reportedly is unaffected by acid suppression is available (albeit at a much higher cost than generic levothyroxine tablets). Perhaps crushing tablets into a powder would accomplish the same thing, but this approach has not been studied in patients taking acid-suppressive medication.
Citation(s): Vita R et al. Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab 2014 Dec; 99:4481.
(http://dx.doi.org/10.1210/jc.2014-2684)
http://www.ncbi.nlm.nih.gov/pubmed/25259910?access_num=25259910&link_
type=MED&dopt=Abstract
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MM: Muscle cramps are very common problems and often a frustrating problem because there is no apparent reason for the cramps. Although cirrhosis is a severe condition, it may be possible that many cramp patients are suffering from livers that are not optimally functional. The use of the nutritional product, L-carnitine may be a safe and effective means of treating these less severe liver associated muscle cramps. Mark Drugs has high quality, reasonable priced L-carnitine available from cGMP and other reliable manufacturers.
Clin Gastroenterol Hepatol 2015 Aug; 13:1540
L-carnitine for Muscle Cramps in Patients with Cirrhosis
Preliminary data show significant reduction of cramps in 88% of patients after 8 weeks of therapy.
Muscle cramps occur commonly in patients with cirrhosis and are associated with diminished quality of life. They are typically described as involuntary painful contractions of muscle groups during rest or sleep that last for seconds or minutes and are self-limiting. The mechanism is unclear but includes impairment in energy metabolism, derangement in electrolyte and volume status, and possibly nerve dysfunction. Carnitine deficiency might affect energy metabolism, thereby causing muscle cramps.
In an uncontrolled study, investigators assessed the efficacy of an 8-week course of L-carnitine (300 mg, 3 or 4 times daily) in 42 consecutive patients with cirrhosis and symptoms of muscle cramps occurring more than twice during the preceding 4 weeks. Patients reported the frequency and duration of cramps in questionnaires and the severity of cramps using a visual analog scale (VAS).After 8 weeks of therapy, the mean frequency of muscle cramps was significantly reduced from 5.1 (standard deviation, 5.9) to 1.7 (SD, 3.0) times per week. Cramps were reduced in 88.1% of patients and completely eliminated in 28.6%. The VAS score (evaluated in 31 patients) at baseline was 69.9 (SD, 22.5) and was significantly reduced to 26.2 (SD, 29.1) after 8 weeks. Patients receiving the higher daily dose of L-carnitine had a significantly higher rate of muscle cramp elimination (43.5% vs. 10.5%) and lower VAS scores (P=0.003).
Comment: Although this is a small uncontrolled pilot study, the results are compelling; patients with cirrhosis experienced improvement not only in the frequency but also in the intensity of muscle cramps, and a dose-response relationship was evident. Larger placebo-controlled studies are needed, but until then, a trial of L-carnitine would be a reasonable option in clinical care of patients with debilitating muscle cramps.
Citation(s): Nakanishi H et al. L-carnitine reduces muscle cramps in patients with cirrhosis. Clin Gastroenterol Hepatol 2015 Aug; 13:1540.
(http://dx.doi.org/10.1016/j.cgh.2014.12.005)
http://www.ncbi.nlm.nih.gov/pubmed/25496816?access_num=25496816&link_
type=MED&dopt=Abstract
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MM: The FDA and the medical literature have attacked the use of supplemental Testosterone (T) in men as being unnecessary and dangerous. This study demonstrates that those dangers may not be as significant as previously postulated. We have hundreds of male patients at Mark Drugs who use and have used transdermal or intramuscularly injected testosterone. Their physicians monitor their levels and their general health. In general our male "T" patients tell us that they enjoy life more and have better energy and an overall better outlook on life than when their T levels were diminished. And we have not noted an increase of adverse cardiovascular events in this population.
Testosterone Gel Not Associated with Subclinical Atherosclerosis Progression, Study Suggests
By Kelly Young, Edited by Lorenzo Di Francesco, MD, FACP, FHM
Use of a testosterone gel in older men with lower testosterone levels was not associated with progression of subclinical atherosclerosis in an industry-funded study published in JAMA.
Roughly 300 men aged 60 and older with low or low-normal testosterone (total testosterone 100–400 ng/dL or free testosterone <50 pg/mL) were randomized to receive either placebo gel or 7.5 g of 1% testosterone gel daily for 3 years.
Both total and free testosterone levels were higher in the testosterone than placebo group throughout the study. However, the groups did not differ in terms of change in common coronary artery intima-media thickness or total coronary artery calcium. Sexual function and health-related quality of life also did not differ between the groups.
The authors caution: "Because this trial was only powered to evaluate atherosclerosis progression and not cardiovascular events, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men such as those enrolled in this trial."
http://jama.jamanetwork.com/article.aspx?articleid=2425744
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MM: Cutting unhealthy fats or cutting simple, empty carbohydrates will both help a person lose weight. The long term problem is altering habits and lifestyle. Without this modification people may lose weight but will simply gain it back and typically exceed the point that they started at. This change in lifestyle approach is a central tenet of the HCG Metabolic Syndrome and Weight Loss Protocol. Mark Drugs can help you find a physician or will communicate with your clinician so that you can possibly benefit from this program. Just call us and our friendly staff will assist you!
Cutting Dietary Fat Leads to Greater Body Fat Loss Than Cutting Carbs, Small Study Suggests
By Amy Orciari Herman, Edited by André Sofair, MD, MPH
Patients may ask about a study suggesting that a reduced-fat diet leads to greater loss of body fat than a reduced-carbohydrate diet. The findings appear in Cell Metabolism.
Nineteen obese adults were admitted to the metabolic unit of the NIH Clinical Center for the study. Participants consumed an energy-balanced diet for 5 days, after which they were randomized to follow a reduced-fat or reduced-carbohydrate diet for 6 days. After a washout period, participants were readmitted and crossed over to the other diet. The two diets had similar caloric content, and participants maintained similar levels of activity.
Overall, the reduced fat diet was associated with significantly greater body fat loss than the reduced-carb diet (89 vs. 53 g/day of body fat). A mathematical model suggested, however, that differences in body fat loss between the diets would diminish over time.
The lead investigator noted in an NIH news release: "The real world is more complicated than a research lab ... it may be more important to consider which type of diet you'll be most likely to stick to over time."
http://www.nih.gov/news/health/aug2015/niddk-13.htm
http://www.cell.com/cell-metabolism/pdf/S1550-4131%2815%2900350-2.pdf
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BMJ 2015; 351:h3576
Regular Consumption of Sugar-Sweetened Beverages Is Associated with Excess Risk for Type 2 Diabetes
Adjusting for baseline adiposity attenuated, but didn't eliminate, excess risk.
Is consuming sugar-sweetened beverages, artificially sweetened beverages, and fruit juice associated with excess risk for developing type 2 diabetes? To answer this question, researchers performed a systematic review and meta-analysis of 17 multinational cohort studies (>460,000 adults; age range, 19–84). Median follow-up ranged from 3.4 to 21.1 years. About 28,000 study patients developed type 2 diabetes.
Higher consumption of sugar-sweetened beverages was associated with significantly higher risk for type 2 diabetes: 18% higher risk per 1 serving daily. After adjustment for baseline adiposity, risk was still 13% higher. Consuming artificially sweetened beverages also was associated with higher risk (25% and 8% higher risk per 1 serving daily, before and after adjusting for adiposity) as was consuming fruit juices (5% and 7% higher risk per 1 serving daily, before and after adjustment). However, the researchers could not exclude publication bias, confounding, and differential ascertainment of diabetes cases for the studies in which artificially sweetened beverages and fruit juices were assessed.
Comment: In this meta-analysis, regular consumption of sugar-sweetened beverages was associated with excess risk for type 2 diabetes, independent of adiposity. The authors estimate that, of the 20.9 million “diabetes events” predicted to occur during 10 years in the U.S., nearly 1.8 million would be attributable to consumption of sugar-sweetened beverages. Although the evidence is less clear regarding artificially sweetened beverages and fruit juices, the study authors reasonably conclude these beverages are unlikely to be healthy alternatives to sugar-sweetened beverages. The findings also lend credence to the dietary advice, “don't drink your calories.”
Citation(s):Imamura F et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: Systematic review, meta-analysis, and estimation of population attributable fraction. BMJ 2015; 351:h3576. (http://dx.doi.org/10.1136/bmj.h3576)
http://www.bmj.com/content/351/bmj.h3576?ijkey=2677213d6f139cf21d0a54e47d
0b9b7e08c0a308&keytype2=tf_ipsecsha
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J Clin Oncol 2015 Jul 27
Topical Lidocaine for Dyspareunia in Women with Breast Cancer
A small trial suggests managing pain (rather than atrophy) can relieve coital discomfort.
Dyspareunia associated with genitourinary syndrome of menopause (GSM) is common in menopausal women, but conventional treatment with low-dose vaginal estrogen is contraindicated in breast cancer survivors. In a double-blind trial, 46 breast cancer survivors (mean age, 55) with GSM and severe penetrative dyspareunia localized to the vulvar vestibule and extinguishable with topical lidocaine were randomized to 1 month of 4% aqueous lidocaine or saline applied to vulvar vestibular tissue for 3 minutes prior to vaginal penetration. All participants were supplied with silicone-based lubricant. In an open-label trial extension, all participants used lidocaine for 2 months. Pain scores were reported on a scale of 0 to 10.
At baseline, median reported pain with intercourse was 8.0, with half of participants abstaining from intercourse because of pain. Women randomized to lidocaine or saline reported reductions in dyspareunia of 88% versus 38%, with median pain scores of 1.0 versus 5.3. After open-label use of lidocaine, 90% of participants reported comfortable penetration. In a phone interview at 6 months, all women reported that they continued to experience vestibular tenderness with penetration unless they used lidocaine. Neither study participants nor their partners reported local or systemic adverse effects from lidocaine use.
Comment: Traditional approaches to dyspareunia associated with genitourinary syndrome of menopause have focused on administration of estrogen, with the expectation that regular intercourse will also help relieve symptoms. The findings of this innovative trial should cause clinicians to rethink this conventional wisdom and explore the use of topical lidocaine for GSM in women with or without contraindications to estrogen.
Citation(s):Goetsch MF et al. A practical solution for dyspareunia in breast cancer survivors: A randomized controlled trial. J Clin Oncol 2015 Jul 27; [e-pub]. (http://dx.doi.org/10.1200/JCO.2014.60.7366)
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Music Appears to Reduce Postoperative Pain, Anxiety
By Amy Orciari Herman, Edited by Jaye Elizabeth Hefner, MD
Patients who listen to music around the time of surgery — even while under general anesthesia — reap substantial postoperative benefits, a Lancet systematic review finds.
The analysis included over 70 randomized trials in which music before, during, or after surgery was compared with usual care or non-pharmacologic interventions (e.g., white noise, bed rest). Roughly 20 to 460 adults were enrolled in each trial.
Patients who listened to music had less postoperative pain, analgesia use, and anxiety than did controls. Pain reductions corresponded to 23 mm on a 100-mm scale, and anxiety reductions corresponded to 6.4 units on a 20–80-unit scale. The greatest benefits were seen when music was played preoperatively.
Music was not associated with length of stay, however.
A commentator concludes, "Although many research questions remain, this should not inhibit implementation of a sensible choice for patients now. For my next surgery, I will bring some Mozart and a copy of this systematic review."
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60169-6/abstract
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Am J Psychiatry 2015 Jul 17; p201514101332
Does Autoimmune Encephalitis Underlie Postpartum Psychosis?
Suggestive antigen reactivity was found in 4% of cases.
Postpartum psychoses are conditions of unknown etiology that occur in 0.1% of the population, but those afflicted show relapse rates of 30% in subsequent pregnancies. Despite the almost delirium-like appearance of these conditions, they are often regarded as bipolar-spectrum disorders due to prominent affective instability. Today, there is increased awareness of cell-surface antibody-associated central nervous system (CNS) disorders, such as anti–N-methyl-d-aspartate (NMDA)-receptor encephalitis in which immunoglobulin G antibodies attack Glu-N1 NMDA receptor subunits. Given the high rates of several immunological abnormalities (e.g., autoimmune thyroiditis) in patients with acute-phase postpartum psychoses, might postpartum autoimmune encephalitis be the underlying mechanism in some?
To test this hypothesis, Dutch investigators (one with a related patent application) screened 96 consecutive patients with postpartum psychosis and 64 healthy postpartum controls for CNS autoantibodies. Serum tests used immunohistochemistry with live rat hippocampal neurons to screen for extracellular NMDA receptor antibodies and other extracellular antigens.
Four patients with postpartum psychosis (4%) showed extracellular antibody reactivity: two had anti-NMDA receptor reactivity, and two had autoantibodies reacting to unidentified CNS cell-surface antigens. No healthy controls showed immune reactivity to extracellular antigens. Postpartum patients with autoimmune reactivity were not clinically distinguishable from those without such reactivity. However, patients with anti–NMDA-receptor antibodies developed extrapyramidal adverse effects on low haloperidol doses (seen in 17 of 66 haloperidol-treated psychotic patients overall).
Comment These intriguing findings suggest that in some patients, autoimmune encephalitic processes — including some linked to anti-NMDA receptor autoantibodies — contribute to the pathogenesis of postpartum psychosis. However, because these associations might be coincidental, further study is required to establish clear linkages. Because anti–NMDA-receptor encephalitis is characterized by acute-onset severe psychiatric illnesses with neurological manifestations — including decreased consciousness, dyskinesias, sensitivity to medication-induced extrapyramidal signs, and seizures — patients with postpartum and other psychoses evidencing these signs might warrant antibody testing.
Citation(s):Bergink V et al. Autoimmune encephalitis in postpartum psychosis. Am J Psychiatry 2015 Jul 17; p201514101332.
(http://dx.doi.org/10.1176/appi.ajp.2015.14101332)
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Risks from Trans Fat Confirmed in Meta-Analysis — Saturated Fat Seems Innocent
By Joe Elia, Edited by Lorenzo Di Francesco, MD, FACP, FHM
Saturated fat intake doesn't translate readily into higher cardiovascular risk, but increased trans fat intake does, a BMJ meta-analysis confirms.
In an attempt to better quantify risks associated with dietary fats, researchers pooled results of several observational studies. They focused on results comparing the highest versus lowest levels of fat intake (measured, for the most part, with dietary recall).
Saturated fat wasn't associated with all-cause mortality, total coronary heart disease (CHD), stroke, or diabetes. Trans fat, on the other hand, was associated with increased risks for all-cause mortality (relative risk for highest vs. lowest intake, 1.34), CHD mortality (1.28), and total CHD (1.21) — but not stroke or diabetes.
Asked to comment, Harlan Krumholz, editor-in-chief of NEJM Journal Watch Cardiology, writes: "Caveats abound in observational studies of nutrition, but this comprehensive review not only supports policies to reduce trans fat and undermines dogma about the evil of saturated fat, but also propels the growing concerns about replacing saturated fats with carbohydrates. What this study says most clearly is that we need better and stronger evidence about what diets are best for health at the individual level."
http://www.bmj.com/content/351/bmj.h3978
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J Am Acad Child Adolesc Psychiatry 2015 Jun 30
Stimulants Do Not Increase Tic Risk
Meta-analysis results support using therapeutic doses of methylphenidate or amphetamine preparations in patients with comorbid tics and ADHD.
Use of stimulants to treat comorbid attention-deficit/hyperactivity disorder (ADHD) in patients with tics is controversial because of FDA warnings against it based on limited, case-report evidence. The contraindication is understandable because stimulants increase dopamine availability, whereas drugs used to treat tics lower dopamine activity. But in children with comorbid ADHD and tic disorders, ADHD symptoms often cause worse cognitive and social impairment than tics, thereby increasing interest in stimulant treatment.
To ascertain whether there is a data-based reason to avoid stimulants, researchers conducted a meta-analysis of tic onset or worsening among 2385 participants in 22 published, double-blind, placebo-controlled, English-language trials of stimulants in children under age 18. Onset or worsening of tics occurred in 5.7% of participants on stimulants and 6.5% of those on placebo. The pooled relative risk was 0.99 with active drug. Onset or worsening was not associated with dose, short- or long-acting preparations, duration of treatment, or patient age.
Comment This finding has far-reaching significance because about half of patients with tics have comorbid ADHD and about 20% of ADHD patients have tic disorders. These data provide strong support for using therapeutic doses of methylphenidate or amphetamine preparations in tic patients. Clinicians need to be mindful that supratherapeutic doses of amphetamine are associated with increased tics (NEJM JW Pediatr Adolesc Med Nov 2009 and J Am Acad Child Adolesc Psychiatry 2009; 48:884). Families aware of the FDA warnings can be informed that worsening of tics while on stimulants is most likely due to the natural waxing and waning of tic disorders. One proviso is that long-term effects of stimulants on tics are unknown.
Citation(s):Cohen SC et al. Meta-analysis: Risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry 2015 Jun 30; [e-pub]. (http://dx.doi.org/10.1016/j.jaac.2015.06.011)
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Br J Sports Med 2015 Aug 3
Mortality Benefit of Lower-Than-Recommended Physical Activity Levels in Older Adults
Ten-year mortality was 22% lower with low-dose moderate-to-vigorous activity than with inactivity.
Current guidelines recommend that adults get ≥150 minutes weekly of moderate-intensity physical activity or 75 minutes weekly of vigorous-intensity physical activity to gain substantial health benefits. However, many older adults find it difficult to achieve this duration of moderate-to-vigorous physical activity (MVPA). In this meta-analysis of nine cohort studies, researchers assessed the effects of lower-dose MVPA on all-cause mortality in 122,000 older adults (age, ≥60; mean age, 73). Weekly physical activity was measured in Metabolic Equivalent of Task (MET) minutes.
After mean follow-up of 10 years, 18,000 participants (15%) had died. Adjusted for multiple variables, risk for death from all causes was significantly lower among participants who engaged in low-dose MVPA (1–499 MET minutes weekly) than among inactive participants (relative risk, 0.78). All-cause mortality was even lower among those who engaged in medium-dose MVPA (500–999 MET minutes weekly; relative risk, 0.72) or high-dose MVPA (≥1000 MET minutes weekly; RR, 0.65).Comment In this meta-analysis, moderate-to-vigorous physical activity at a lower than currently recommended dose was associated with lower 10-year all-cause mortality in older adults. The results affirm that any exercise is better than none, and that health benefits accrue to adults who participate in any amount of physical activity. Furthermore, a dose-response relation was observed: Higher amounts of exercise were associated with lower risk for death from any cause.
Citation(s):Hupin D et al. Even a low-dose of moderate-to-vigorous physical activity reduces mortality by 22% in adults aged ≥60 years: A systematic review and meta-analysis. Br J Sports Med 2015 Aug 3; [e-pub].
(http://dx.doi.org/10.1136/bjsports-2014-094306)
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Coca-Cola Under Fire for Funding Controversial Obesity Research
By Amy Orciari Herman , Edited by Jaye Elizabeth Hefner, MD
Coca-Cola came into the spotlight on Monday as news spread over its investment in a new nonprofit group — the Global Energy Balance Network — that argues that Americans should be paying more attention to how much they are exercising and less attention to how much they are eating and drinking.
Last year, Coca-Cola donated $1.5 million to start the nonprofit, the New York Times reports.
On its website, the Global Energy Balance Network describes itself as being "dedicated to identifying and implementing innovative solutions — based on the science of energy balance — to prevent and reduce diseases associated with inactivity, poor nutrition and obesity." Its vice-president, exercise scientist Steven Blair, says Coke has "no control over its work or message," the Times reports.
Blair also says the group has been transparent about Coke's involvement. According to the Times, Coke was not mentioned on the organization's website until an obesity expert inquired about its funding.
http://well.blogs.nytimes.com/2015/08/09/coca-cola-funds-scientists-who-shift-blame-for-obesity-away-from-bad-diets/?_r=0
https://gebn.org/
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Exercise Training Improves Vascular Function in Overweight Kids, Meta-Analysis Finds
By Amy Orciari Herman, Edited by Susan Sadoughi, MD, and André Sofair, MD, MPH
Exercise training can help improve vascular function in overweight and obese youth, according to a meta-analysis in Pediatrics.
Researchers examined six randomized trials that compared at least 6 weeks of aerobic exercise training with a non-exercise control among 219 overweight or obese children and adolescents. Exercise training typically lasted about an hour per session, with two to five sessions per week.
Overall, exercise training was associated with significantly greater improvement in vascular function (measured by flow-mediated dilation), relative to control conditions. It also conferred significant improvements in cardiorespiratory fitness (assessed by peak oxygen consumption).
Using data from previous prognostic studies, the authors conclude that the improvement in vascular function observed among children in the current analysis "would be expected to ameliorate their cardiovascular risk profile." However, given the "heterogeneity and small sample size of this analysis, further research is warranted to establish dose-response effects together with optimal exercise modality."
http://pediatrics.aappublications.org/content/early/2015/08/05/peds.2015-0616
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Med Sci Sports Exerc 2014 Nov 13
Menstrual Status and Fracture Risk in Young Athletes
Lifetime fracture risk was higher in oligo-amenorrheic athletes than in eumenorrheic athletes or nonathletes.
Weight-bearing activities increase bone mineral density (BMD), but menstrual status may also play a role. Investigators in Boston studied the relations among menstrual status, bone density, and fracture risk in 175 teens and young women (mean age, 20). The study population included 100 oligo-amenorrheic athletes (AA), 35 eumenorrheic athletes (EA), and 40 nonathletes (NA). Oligo-amenorrhea was defined as no menarche by age ≥15 or absence of menses for ≥3 months during a 6-month period where cycle length exceeded 6 weeks. Eumenorrhea was defined as ≥9 menses yearly with no oral contraceptive use during the 3 months before enrollment. Dual-energy x-ray absorptiometry scans were used to assess bone mineral density (BMD).
AA experienced menarche significantly later than did EA or NA (14 vs. 12 years) and had lower body-mass index (20 vs. 22 kg/m2) and lower fat mass. Vitamin D levels were higher in AA (38 ng/mL) than in EA (30 ng/mL) and NA (25 ng/mL). Twenty-six percent of AA had histories of eating disorders. EA had significantly higher BMD Z-scores than did AA; however, AA and NA did not differ. Lifetime fracture risk was 47% in AA, 26% in EA, and 12% in NA. Differences in lifetime fracture risk were mostly accounted for by stress fractures (AA, 32%; EA, 6%; NA, 0%). Fracture differences among groups persisted after controlling for age at menarche and histories of eating disorders.
Comment: These results show that, although weight-bearing exercise increases bone mineral density, this effect is attenuated in athletes with menstrual dysfunction; such dysfunction also increases risk for stress fractures. Clinicians should be on the lookout for patients with the female athletic triad (low energy availability, menstrual dysfunction, poor bone health). Stressing the importance of maintaining regular menstrual function — without reflexively prescribing hormonal contraception unless indicated for birth control or other reasons — is a key component of anticipatory guidance for young athletes.
Citation(s): Ackerman KE et al. Fractures in relation to menstrual status and bone parameters in young athletes. Med Sci Sports Exerc 2014 Nov 13; [e-pub ahead of print]. (http://dx.doi.org/10.1249/MSS.0000000000000574)
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Gut 2014 Dec 19
Another Benefit of Split-Dose Bowel Preparation?
A split-dose regimen resulted in less alteration and quicker recovery of intestinal bacteria compared with a single-dose regimen.
Patients sometimes complain of altered bowel habit after bowel preparation for colonoscopy. To assess whether the dosing method affects the intestinal microbiota, investigators randomized 23 healthy participants to receive 2 L of polyethylene glycol–electrolyte lavage solution with ascorbic acid in a single dose on the morning of the study or as split doses (1 L each) on the evening before and morning of the study. The intestinal microbiota was analyzed using fecal samples taken at baseline, after bowel cleansing, and at 14 and 28 days.
Both dosing regimens decreased the microbial load dramatically, and some patients had significant alterations in the types of bacteria present. Although both groups showed full recovery of bacterial populations by 14 days, recovery was slower for the single-dose group, and these patients had more alterations of bacterial composition, including increases in bacterial species associated with irritable bowel syndrome.
Comment: I have been surprised over the years by patient reports of changes in bowel habit after colonoscopy, including development of chronic diarrhea as well as resolution of chronic diarrheal syndromes. Further study of this issue is clearly warranted, including whether probiotic administration in the postcolonoscopy period might have a favorable effect.
Citation(s): Jalanka J et al. Effects of bowel cleansing on intestinal microbiota. Gut 2014 Dec 19; [e-pub ahead of print].
(http://dx.doi.org/10.1136/GUTJNL-2014-307240)
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Transl Psychiatry 2014 Dec 2; 4:e486
Leptin Receptors: New Players in Our Understanding of Antidepressant Medication Response
In experiments using mouse models of depression, the leptin receptor regulates antidepressant effects of fluoxetine and desipramine in distinct ways.
Clinicians are well aware that serotonin, catecholamines, and their receptors are important for antidepressant activity. Other less-studied transmitters and receptors — for example, the leptin receptor — may also have important functions in antidepressants' effects. Previous studies in mice have associated lower leptin levels with models of chronic stress and depression and have suggested that the long form of the leptin receptor (LepRb) is both necessary and sufficient for antidepressant action. Now, investigators have studied the effects of fluoxetine and desipramine when LepRb capacity was knocked out either generally or in specific brain areas in genetically modified mice.
Overall, the LepRb was necessary for the antidepressant actions of both medications; neither was effective in mice that totally lacked LepRb (these mice are obese and have depression-like behaviors). However, in mice with LepRb deletions that specifically occur only in hippocampus and cortex (these mice have normal weight and depression-like behaviors), fluoxetine was ineffective, whereas desipramine retained antidepressant effects. Fluoxetine, but not desipramine, was shown to stimulate specific protein-kinase signaling pathways in hippocampus and cortex. The antidepressant effects of fluoxetine apparently hinge on these LepRb-associated processes in hippocampus and cortex, which suggests that desipramine's significant actions occur elsewhere.
Comment: The selective serotonin reuptake inhibitor fluvoxamine has been shown to reverse leptin resistance and decrease food intake in mice. Whether leptin-related processes associated with obesity and inflammation also affect depression remains to be explored. Regardless, these findings indicate that leptin and its receptors might play roles in the pathogenesis of depressive syndromes and may significantly mediate antidepressant action. The results also suggest that leptin receptor variations in distinct brain areas might account for different mechanisms of action among antidepressant medications. In the not-too-distant future, we might anticipate new drug targets based on these avenues of research.
Citation(s): Guo M and Lu X-Y.Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates. Transl Psychiatry 2014 Dec 2; 4:e486.
(http://dx.doi.org/10.1038/tp.2014.126)
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Proc Natl Acad Sci U S A 2014 Nov 11; 111:16219.
Mismatch Between Timing of Medications and Circadian Rhythms Might Alter Drug Effectiveness !
Many top-selling drugs target the products of genes whose activities cycle over 24 hours.
Circadian rhythms are governed not only by a master regulator in the brain but also by organs, tissues, and cells that have their own circadian rhythms, which “talk” back and forth with the master regulator. A new study shows that this complex process might have important effects on pharmacotherapy.
U.S. investigators looked for circadian patterns in the activation (expression) of genes in 12 different organs and tissues in mice. They measured the extent to which each of nearly 20,000 mouse genes was expressed in each organ or tissue at different times during the 24-hour day. Forty-three percent of these protein-coding genes showed circadian variation. Of potential importance to medical practice, more than half of the 100 best-selling drugs in the U.S. target the products of genes that have circadian periodicity. For example, the activity of the HMG-CoA reductase gene in the liver — the target of statin drugs — peaks in the middle of the night. Conversely, the activity of a gene associated with statin-induced myopathy peaks in the middle of the day. This might explain why taking short-acting statin drugs at night, rather than in the morning, lowers LDL cholesterol levels more effectively and causes less toxicity.
Comment: These results in mice probably apply to human biology. This study might prompt a new field that teaches us the optimal time of day to take particular medicines. We then will have to reconcile that knowledge with the fact that patient adherence to medication is best when the regimen is simplest.
Citation(s): Zhang R et al. A circadian gene expression atlas in mammals: Implications for biology and medicine. Proc Natl Acad Sci U S A 2014 Nov 11; 111:16219. (http://dx.doi.org/10.1073/pnas.1408886111)
http://www.pnas.org/content/111/45/16219?ijkey=52d4e16299e181dfb3581f5b56
be8f5279e68b8e&keytype2=tf_ipsecsha
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