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Abstract | Context: Physical activity (PA) is associated with 25-hydroxyvitamin D [25(OH)D] levels. Both are associated with atherosclerotic cardiovascular disease (ASCVD), but their joint association with ASCVD risk is unknown.

Objective: To examine the relationship between PA and 25(OH)D, and assess effect modification of 25(OH)D and PA with ASCVD.

Design: Cross-sectional and prospective study.

Setting: Community-dwelling cohort.

Participants: A total of 10,342 participants free of ASCVD, with moderate- to vigorous-intensity PA assessed (1987 to 1989) and categorized per American Heart Association (AHA) guidelines (recommended, intermediate, or poor).

Main Outcome Measures: Serum 25(OH)D levels (1990 to 1992) and ASCVD events (i.e., incident myocardial infarction, fatal coronary disease, or stroke) through 2013.

Results: Participants had mean age of 54 years, and were 57% women, 21% black, 30% 25(OH)D deficient [<20 ng/mL (<50 nmol/L)], and <40% meeting AHA-recommended PA. PA was linearly associated with 25(OH)D levels in whites. Whites meeting recommended PA were 37% less likely to have 25(OH)D deficiency [relative risk, 0.63 (95% confidence interval [CI], 0.56, 0.71)]; there was no significant association in blacks. Over 19.3 years of follow-up, 1800 incident ASCVD events occurred. Recommended PA was associated with reduced ASCVD risk [hazard ratio [HR], 0.78 (95% CI, 0.65, 0.93) and 0.76 (95% CI, 0.62, 0.93)] among participants with intermediate [20 to <30 ng/mL (50 to <75 nmol/L)] and optimal [≥30 ng/mL (≥75 nmol/L)] 25(OH)D, respectively, but not among those with deficient 25(OH)D (P for interaction = 0.04).

Conclusion: PA is linearly associated with higher 25(OH)D levels in whites. PA and 25(OH)D may have synergistic beneficial effects on ASCVD risk.

Kathleen Chin, Di Zhao, Martin Tibuakuu, Seth S. Martin, Chiadi E. Ndumele …

Published: 17 February 2017


Abstract | Context: Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.

Objective: The objective was to test an interaction between genetic susceptibility and HT on fracture risk.

Design: We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRS) and 50 bone mineral density (BMD) variants (BMD-GRS). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also utilized the case-only approach to test for a multiplicative interaction.

Setting: 40 US clinical centers

Participants: 9,922 genotyped white postmenopausal women (age 50-79) from the Women’s Health Initiative HT randomized trials

Main outcome: Adjudicated fracture incidence

Results: Both GRSs were associated with fracture risk (hazard ratio (HR) (95% CI) per one-unit increment in GRS, 1.04 (1.02-1.06) for Fx-GRS and 1.03 (1.02-1.04) for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a significant additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS p-for-RERI=0.047, BMD-GRS p-for-RERI=0.046.

Conclusions: These results suggest that HT reduces fracture risk in postmenopausal women especially in those at highest genetic risk of fracture and low BMD.

Youjin Wang Jean Wactawski-Wende Lara E. Sucheston-Campbell Leah Preus Kathleen M. Hovey Jing Nie Rebecca D. Jackson Samuel K. Handelman Rami Nassir Carolyn J. Crandall

J Clin Endocrinol Metab jc.2016-2936. DOI:

Published: 06 March 2017

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Written by: Rakesh Saini, PhD

The alarming rate of increase in gluten sensitivity in recent times is due to genetic modifications of grains, like wheat, resulting in an increase in gluten content by as much as 500 times in last about 110 years, and a change in molecular structure of gluten added to some foods from water extracted to alcohol extracted. Human genetics has not evolved yet to accommodate these changes.
Two distinct forms of gluten sensitivity / intolerance are NCGS (Non-Celiac Gluten Sensitivity – Not a disease – symptoms are gas/bloating/cramping/abdominal pain/ etc.) and an immune disease – CELIAC. Since there is no prescription medication for either, the only option available to MD’s until now was to ask the patients to go Gluten Free. This is not fool proof though, because patients not only get ill from gluten but also from “hidden” gluten*, cross-reactors*, FODMAPS*, and cross-contamination* (definition of each of these *irritants is provided at end of this write-up). Strictly avoiding each of these is extremely difficult, if not impossible. Therefore, patients get hit or miss relief from gluten sensitivity, causing anxiety, stress, disappointment and frustration.
Root cause of gluten sensitivity is a high concentration of gluten in intestines (>20 PPM, Parts Per Million) and/or other irritants stated above. Therefore, a solution to the problem is to break down the gluten and irritants, to zero or near zero BEFORE FOOD LEAVES THE STOMACH.

Based upon this fundamental understanding the dietary supplement ZyGluten™ was created. This development required a gastroenterologist to work with 6 PhDs for 7 years at a total cost of about $15 million, conducting most of the Research and Development in a stomach stimulator. They first discovered the root cause of gluten sensitivity and then developed a science based product to take care of it.


Safety and efficacy of ZyGluten™ has been proven beyond doubt in a clinical trial conducted under the supervision of a physician on an unpaid patient population. The study has been published in Journal of Gluten Sensitivity, 2015, Volume 14, Page 17. Safety and efficacy got further validated via post marketing data (repeat purchases, return of symptoms if use is stopped, no negative side effects or adverse events) since product was introduced about six months ago.
ZyGluten™ is a mixture of twenty enzymes of high potency, two probiotic type microbes with gluten digesting capability, and two herbs to soothe the digestive system, all together at a high concentration of enzymes in a capsule made of tapioca. Each of the twenty enzymes, within the categories of Proteases, Lipases, Amylases, and Cellulases, in reality, contains hundreds of enzymes, some that have not been even discovered yet. Before marketing, the product was tested on following foods, using twice the concentration of gluten expected in a typical American meal: Pizza, Pasta, Bread, Bagels with cream cheese, Hamburger/fries/coke, pancakes, sandwiches, etc. An example from one of these experiments in the graph shows ZYGLUTEN is extremely fast acting, bringing the concentration of gluten from 3525 PPM to <20 PPM in < 30 minutes.
ZyGluten’s™ efficacy is 7 times to 231 times higher relative to competitive products because of high concentration of high potency ingredients. It is almost a misnomer to say ZyGluten™ has a competitor. Many products are designed to breakdown gluten only, whereas ZyGluten™ ingredients start with breaking down the protective matrix surrounding the polymer of gluten. Once this shield has been removed, gluten breaks down quickly because it is now exposed and ready to be attacked by specific enzymes (diphenyl peptidases) in the product. Moreover, the capsule is made of tapioca, dissolves much faster than gelatin allowing more time for the biological natural catalysts to do their job in achieving gluten/irritant level of zero / near zero BEFORE FOOD LEAVES THE STOMACH.

Healthcare professionals can purchase ZyGluten™ from our exclusive distributor:

Medaus Pharmacy
6801 Cahaba Valley Road
Birmingham, AL 35244


ABSTRACT | Objective: To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD).

Methods: Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47–56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999–2009). The study population included 8,195 women (227 cases of incident AD).

Results: Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68–1.2, 0.99/0.75–1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31–0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome.

Conclusions: Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use.

Received May 6, 2016.
Accepted in final form December 21, 2016.
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

A prospective cohort study

Bushra Imtiaz, MD, MPH, Marjo Tuppurainen, MD, PhD, Toni Rikkonen, PhD, Miia Kivipelto, MD, PhD, Hilkka Soininen, MD, PhD, Heikki Kröger, MD, PhD and Anna-Maija Tolppanen, PhD

Correspondence to Dr. Imtiaz:
Published online before print February 15, 2017, doi: http:/​/​dx.​doi.​org/​10.​1212/​WNL.​0000000000003696

Neurology 10.1212/WNL.0000000000003696


Abstract: The Mediterranean Diet (MD) has been associated with reduced mortality and risk of cardiovascular diseases, but there is only limited evidence on cancer. We investigated the relationship between adherence to MD and risk of postmenopausal breast cancer (and estrogen/progesterone receptor subtypes, ER/PR). In the Netherlands Cohort Study, 62,573 women aged 55–69 years provided information on dietary and lifestyle habits in 1986. Follow-up for cancer incidence until 2007 (20.3 years) consisted of record linkages with the Netherlands Cancer Registry and the Dutch Pathology Registry PALGA. Adherence to MD was estimated through the alternate Mediterranean Diet Score excluding alcohol. Multivariate case–cohort analyses were based on 2,321 incident breast cancer cases and 1,665 subcohort members with complete data on diet and potential confounders. We also conducted meta-analyses of our results with those of other published cohort studies. We found a statistically significant inverse association between MD adherence and risk of ER negative (ER−) breast cancer, with a hazard ratio of 0.60 (95% Confidence Interval, 0.39–0.93) for high versus low MD adherence (ptrend = 0.032). MD adherence showed only nonsignificant weak inverse associations with ER positive (ER+) or total breast cancer risk. In meta-analyses, summary HRs for high versus low MD adherence were 0.94 for total postmenopausal breast cancer, 0.98 for ER+, 0.73 for ER− and 0.77 for ER − PR− breast cancer. Our findings support an inverse association between MD adherence and, particularly, receptor negative breast cancer. This may have important implications for prevention because of the poorer prognosis of these breast cancer subtypes.

Piet A. van den Brandt, Maya Schulpen

First published: 5 March 2017

DOI: 10.1002/ijc.30654


Controversy exists regarding the safety of testosterone replacement therapy (TRT) following recent reports of an increased risk of adverse cardiovascular events.

To investigate the association between TRT and cardiovascular outcomes in men with androgen deficiency.

A retrospective cohort study was conducted within an integrated health care delivery system. Men at least 40 years old with evidence of androgen deficiency either by a coded diagnosis and/or a morning serum total testosterone level of less than 300 ng/dL were included. The eligibility window was January 1, 1999, to December 31, 2010, with follow-up through December 31, 2012.

Any prescribed TRT given by injection, orally, or topically.

The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD). Multivariable Cox proportional hazards models were used to investigate the association between TRT and cardiovascular outcomes. An inverse probability of treatment weight, propensity score methodology, was used to balance baseline characteristics.

The cohorts consisted of 8808 men (19.8%) ever dispensed testosterone (ever-TRT) (mean age, 58.4 years; 1.4% with prior cardiovascular events) and 35 527 men (80.2%) never dispensed testosterone (never-TRT) (mean age, 59.8 years; 2.0% with prior cardiovascular events). Median follow was 3.2 years (interquartile range [IQR], 1.7-6.6 years) in the never-TRT group vs 4.2 (IQR, 2.1-7.8) years in the ever-TRT group. The rates of the composite cardiovascular end point were 23.9 vs 16.9 per 1000 person-years in the never-TRT and ever-TRT groups, respectively. The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever-TRT group was 0.67 (95% CI, 0.62-0.73. Similar results were seen when the outcome was restricted to combined stroke events (stroke and TIA) (HR, 0.72; 95% CI, 0.62-0.84) and combined cardiac events (AMI, SCD, unstable angina, revascularization procedures) (HR, 0.66; 95% CI, 0.60-0.72).

Among men with androgen deficiency, dispensed testosterone prescriptions were associated with a lower risk of cardiovascular outcomes over a median follow-up of 3.4 years.

JAMA internal medicine. 2017 Feb 21 [Epub ahead of print]

T Craig Cheetham, JaeJin An, Steven J Jacobsen, Fang Niu, Stephen Sidney, Charles P Quesenberry, Stephen K VanDenEeden

Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena., Western University of Health Sciences, Pharmacy Practice and Administration, Pomona, California., Kaiser Permanente Southern California, Drug Information Service, Downey., Kaiser Permanente Northern California, Division of Research, Oakland.



Abstract | Introduction: The female sexual response is complex and influenced by several biological, psychological, and social factors. Testosterone is believed to modulate a woman’s sexual response and desire, because low levels are considered a risk factor for impaired sexual function, but previous studies have been inconclusive.

Aim: To investigate how androgen levels and psychosocial factors are associated with female sexual dysfunction (FSD), including hypoactive sexual desire disorder (HSDD).

Methods: The cross-sectional study included 428 premenopausal women 19 to 58 years old who completed a questionnaire on psychosocial factors and had blood sampled at days 6 to 10 in their menstrual cycle. Logistic regression models were built to test the association among hormone levels, psychosocial factors, and sexual end points.

Main Outcome Measures: Five different sexual end points were measured using the Female Sexual Function Index and the Female Sexual Distress Scale: impaired sexual function, sexual distress, FSD, low sexual desire, and HSDD. Serum levels of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate, and androsterone glucuronide were analyzed using mass spectrometry.

Results: After adjusting for psychosocial factors, women with low sexual desire had significantly lower mean levels of free testosterone and androstenedione compared with women without low sexual desire. None of the androgens were associated with FSD in general or with HSDD in particular. Relationship duration longer than 2 years and mild depressive symptoms increased the risk of having all the sexual end points, including FSD in general and HSDD in particular in multivariate analyses.

Conclusion: In this large cross-sectional study, low sexual desire was significantly associated with levels of free testosterone and androstenedione, but FSD in general and HSDD in particular were not associated with androgen levels. Length of relationship and depression were associated with FSD including HSDD.

Wåhlin-Jacobsen S, Kristensen E, Tønnes Pedersen A, et al. Androgens and Psychosocial Factors Related to Sexual Dysfunctions in Premenopausal Women. J Sex Med 2017;14:366–379.

Sarah Wåhlin-Jacobsen, MD’Correspondence information about the author MD Sarah Wåhlin-JacobsenEmail the author MD Sarah Wåhlin-Jacobsen, Ellids Kristensen, MD, Anette Tønnes Pedersen, MD, PhD, Nanna Cassandra Laessøe, MD, Arieh S. Cohen, PhD, David M. Hougaard, MD, DMSc, Marika Lundqvist, MSc, Annamaria Giraldi, MD, PhD



Abstract | Context: Findings of studies of testosterone’s effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied.

Objective: To determine the effects of testosterone administration for 3 years in older men on muscle strength, power, fatigability, and physical function.

Design, Setting, and Participants: This was a double-blind, placebo-controlled, randomized trial of healthy men ≥60 years old with total testosterone levels of 100 to 400 ng/dL or free testosterone levels <50 pg/mL.

Interventions: Random assignment to 7.5 g of 1% testosterone or placebo gel daily for 3 years.

Outcome Measures: Loaded and unloaded stair-climbing power, muscle strength, power, and fatigability in leg press and chest press exercises, and lean mass at baseline, 6, 18, and 36 months.

Results: The groups were similar at baseline. Testosterone administration for 3 years was associated with significantly greater performance in unloaded and loaded stair-climbing power than placebo (mean estimated between-group difference, 10.7 W [95% confidence interval (CI), −4.0 to 25.5], P = 0.026; and 22.4 W [95% CI, 4.6 to 40.3], P = 0.027), respectively. Changes in chest-press strength (estimated mean difference, 16.3 N; 95% CI, 5.5 to 27.1; P < 0.001) and power (mean difference 22.5 W; 95% CI, 7.5 to 37.5; P < 0.001), and leg-press power were significantly greater in men randomized to testosterone than in those randomized to placebo. Lean body mass significantly increased more in the testosterone group.

Conclusion: Compared with placebo, testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in stair-climbing power, muscle mass, and power. Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.

Topic: testosterone testosterone measurement chest lean body mass elderly muscle power muscle strength ascending stairs physical function leg press
Issue Section: Clinical Research Article

Thomas W. Storer Shehzad Basaria Tinna Traustadottir S. Mitchell Harman Karol Pencina Zhuoying Li Thomas G. Travison Renee Miciek Panayiotis Tsitouras Kathleen Hally … Show more

(2017) 102 (2): 583-593. DOI:
Published: 18 October 2016


Abstract | Context: Common concerns when using low-calorie diets as a treatment for obesity are the reduction in fat-free mass, mostly muscular mass, that occurs together with the fat mass (FM) loss, and determining the best methodologies to evaluate body composition changes.

Objective: This study aimed to evaluate the very-low-calorie ketogenic (VLCK) diet-induced changes in body composition of obese patients and to compare 3 different methodologies used to evaluate those changes.

Design: Twenty obese patients followed a VLCK diet for 4 months. Body composition assessment was performed by dual-energy X-ray absorptiometry (DXA), multifrequency bioelectrical impedance (MF-BIA), and air displacement plethysmography (ADP) techniques. Muscular strength was also assessed. Measurements were performed at 4 points matched with the ketotic phases (basal, maximum ketosis, ketosis declining, and out of ketosis).

Results: After 4 months the VLCK diet induced a −20.2 ± 4.5 kg weight loss, at expenses of reductions in fat mass (FM) of −16.5 ± 5.1 kg (DXA), −18.2 ± 5.8 kg (MF-BIA), and −17.7 ± 9.9 kg (ADP). A substantial decrease was also observed in the visceral FM. The mild but marked reduction in fat-free mass occurred at maximum ketosis, primarily as a result of changes in total body water, and was recovered thereafter. No changes in muscle strength were observed. A strong correlation was evidenced between the 3 methods of assessing body composition.

Conclusion: The VLCK diet-induced weight loss was mainly at the expense of FM and visceral mass; muscle mass and strength were preserved. Of the 3 body composition techniques used, the MF-BIA method seems more convenient in the clinical setting.

Topic: obesity weight reduction calories diet body composition ketosis fat-free mass ketogenic diet visceral fat muscle strength benefit incidence analysis
Issue Section: Clinical Research Article

Diego Gomez-Arbelaez Diego Bellido Ana I. Castro Lucia Ordoñez-Mayan Jose Carreira Cristobal Galban Miguel A. Martinez-Olmos Ana B. Crujeiras Ignacio Sajoux Felipe F. Casanueva

(2017) 102 (2): 488-498. DOI:
Published: 18 October 2016


Abstract | Context: Endothelial microRNA 126 (miR-126) attenuates the development of atherosclerosis (AS). However, there is no evidence showing the role of miR-126 in estrogen’s antiatherogenic effects.

Objective: We hypothesized that 17β-estradiol (E2) modulates miR-126 expression and thus may improve endothelial function and retard AS development.

Design/Setting/Participants: This was a prospective cohort study of 12 healthy regularly menstruating female volunteers. ApoE−/− mice were used as the atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as the cell model.

Main Outcome Measures: Serum hormones and miR-126-3p levels were measured up to 3 times for 1 cycle. Real-time polymerase chain reaction, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, cell proliferation, migration and tube formation assay, and western blot were performed.

Results: Serum concentrations of miR-126-3p in cycling women were higher at the ovulatory and luteal phases than in the follicular phase, and they were positively correlated with E2 values. Administration of miR-126-3p mimics to ApoE−/− mice-attenuated atherogenesis, and antagomir-126-3p partially reversed the protective effect of E2 on atherogenesis. In HUVECs, E2 increased miR-126-3p expression via upregulation of Ets-1 (a transcription factor for miR-126). c-Src/Akt signaling was important for E2-mediated expression of Ets-1/miR-126. E2 decreased expression of miR-126-3p target Spred1 (a protein that inhibits mitogenic signaling). Overexpression of Spred1 partially blocked enhancement of endothelial cell proliferation, migration, and tube formation by E2. Additionally, E2 regulates miR-126-3p–mediated expression of vascular cell adhesion molecule-1 to inhibit monocyte adhesion into HUVECs.

Conclusions: E2 protection against atherogenesis is possibly mediated by Ets-1/miR-126.
Topic: atherosclerosis polymerase chain reaction signal transduction western blotting cell proliferation endothelial cells estradiol adhesions apolipoprotein e endothelium fluorescent antibody technique menstrual cycle, proliferative phase luciferases monocytes vascular cell adhesion molecule-1 mice transcription factor atherogenesis protein overexpression proto-oncogene proteins c-akt micro rna spred-1 protein attenuation antagomirs
Issue Section: Clinical Research Article

Ping Li Jinzhi Wei Xiaosa Li Yang Cheng Weiyu Chen Yuhong Cui Tommaso Simoncini Zhengtian Gu Jun Yang Xiaodong Fu
(2017) 102 (2): 594-603. DOI: