Combined Dietary Nitrate and Exercise Intervention in Peripheral Artery Disease: Protocol Rationale and Design

Background: Peripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects approximately 8-12 million people in the United States alone, one-third of whom suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. Patients with IC suffer a markedly impaired quality of life and a high perception of disability. Improving pain-free walking time is a primary goal of rehabilitation in this population. Objective: The nitric oxide (NO)-PAD trial is designed to compare the effects that 12 weeks of supervised exercise training, in combination with a high inorganic nitrate-content (beetroot [BR] juice) beverage or placebo (PL) beverage, has on clinical outcomes of exercise and functional capacity in two groups of PAD+IC patients: exercise training plus beetroot (EX+BR) and exercise training plus placebo (EX+PL). The primary aims of this randomized controlled, double-blind pilot study are to determine group differences following 12 weeks of EX+BR versus EX+PL in the changes for (1) exercise capacity: pain-free walking time (claudication onset time, COT), peak walk time (PWT), and maximal exercise capacity (peak oxygen uptake, VO2peak) during a maximal-graded cardiopulmonary exercise test (max CPX) and (2) functional capacity: 6-minute walk (6MW) distance. The secondary aims will provide mechanistic insights into the exercise outcome measures and will include (1) gastrocnemius muscle oxygenation during exercise via near-infrared spectroscopy (NIRS); (2) gastrocnemius muscle angiogenesis: capillaries per unit area and per muscle fiber, and relative fraction of type I, IIa, IIb, and IId/x fibers; and (3) vascular health/function via brachial artery flow-mediated dilation, lower-limb blood flow via plethysmography, and pulse wave velocity and reflection. Methods: A total of 30 subjects between 40 and 80 years of age with PAD who are limited by IC will undergo exercise training 3 days per week for 12 weeks (ie, 36 sessions). They will be randomized to either the EX+BR or EX+PL group where participants will consume a beverage high in inorganic nitrate (4.2 mmol) or a low-nitrate placebo, respectively, 3 hours prior to each training session. Results: Data collection from this study has been completed and is in the process of analysis and write-up. While the study is too underpowered—EX+BR, n=11; EX+PL, n=13—to determine between-group differences in the primary outcomes of COT, PWT, and 6MW, preliminary observations are promising with Cohen d effect sizes of medium to large. Conclusions: Exercise training is currently the most effective therapy to increase functional capacity in PAD+IC. If the addition of inorganic nitrate to an exercise regimen elicits greater benefits, it may redefine the current standard of care for PAD+IC

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

Open Access ArticleBACKGROUND: Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health. RESULTS: One hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83-0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is 'up-regulated' in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case-control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA 'disease signature', the healthy ageing RNA classifier is diagnostic for AD. CONCLUSIONS: We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.European CommissionAlzheimer’s Research UKJohn and Lucille van Geest FoundationNational Institute for Health Research (NIHR)European Medical Information Framework (EMIF)Medical Research Council (MRC)Wallenberg FoundationKarolinska InstitutetSwedish Medical Research CouncilSwedish Society for Medical Research (SSMF

Gene expression profiles link respiratory viral infection, platelet response to aspirin, and acute myocardial infarction

Background Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. Methods A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. Results In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2%(69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). Conclusions A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection

Rationale and design of the Exercise Intensity Trial (EXCITE): A randomized trial comparing the effects of moderate versus moderate to high-intensity aerobic training in women with operable breast cancer

<p>Abstract</p> <p>Background</p> <p>The Exercise Intensity Trial (EXcITe) is a randomized trial to compare the efficacy of supervised moderate-intensity aerobic training to moderate to high-intensity aerobic training, relative to attention control, on aerobic capacity, physiologic mechanisms, patient-reported outcomes, and biomarkers in women with operable breast cancer following the completion of definitive adjuvant therapy.</p> <p>Methods/Design</p> <p>Using a single-center, randomized design, 174 postmenopausal women (58 patients/study arm) with histologically confirmed, operable breast cancer presenting to Duke University Medical Center (DUMC) will be enrolled in this trial following completion of primary therapy (including surgery, radiation therapy, and chemotherapy). After baseline assessments, eligible participants will be randomized to one of two supervised aerobic training interventions (moderate-intensity or moderate/high-intensity aerobic training) or an attention-control group (progressive stretching). The aerobic training interventions will include 150 mins.wk^-1of supervised treadmill walking per week at an intensity of 60%-70% (moderate-intensity) or 60% to 100% (moderate to high-intensity) of the individually determined peak oxygen consumption (VO_2peak) between 20-45 minutes/session for 16 weeks. The progressive stretching program will be consistent with the exercise interventions in terms of program length (16 weeks), social interaction (participants will receive one-on-one instruction), and duration (20-45 mins/session). The primary study endpoint is VO_2peak, as measured by an incremental cardiopulmonary exercise test. Secondary endpoints include physiologic determinants that govern VO_2peak, patient-reported outcomes, and biomarkers associated with breast cancer recurrence/mortality. All endpoints will be assessed at baseline and after the intervention (16 weeks).</p> <p>Discussion</p> <p>EXCITE is designed to investigate the intensity of aerobic training required to induce optimal improvements in VO_2peakand other pertinent outcomes in women who have completed definitive adjuvant therapy for operable breast cancer. Overall, this trial will inform and refine exercise guidelines to optimize recovery in breast and other cancer survivors following the completion of primary cytotoxic therapy.</p> <p>Trial Registration</p> <p>NCT01186367</p

An evaluation of the hypolipidemic effect of an extract of Hibiscus Sabdariffa leaves in hyperlipidemic Indians: a double blind, placebo controlled trial

<p>Abstract</p> <p>Background</p> <p>Hibiscus sabdariffa is used regularly in folk medicine to treat various conditions.</p> <p>Methods</p> <p>The study was a double blind, placebo controlled, randomized trial. Sixty subjects with serum LDL values in the range of 130-190 mg/dl and with no history of coronary heart disease were randomized into experimental and placebo groups. The experimental group received 1 gm of the extract for 90 days while the placebo received a similar amount of maltodextrin in addition to dietary and physical activity advice for the control of their blood lipids. Anthropometry, blood biochemistry, dietary and physical activity were assessed at baseline, day 45 and day 90.</p> <p>Results</p> <p>While body weight, serum LDL cholesterol and triglyceride levels decreased in both groups, there were no significant differences between the experimental and placebo group.</p> <p>Conclusions</p> <p>It is likely that the observed effects were as a result of the patients following the standard dietary and physical activity advice. At a dose of 1 gm/day, hibiscus sabdariffa leaf extract did not appear to have a blood lipid lowering effect.</p> <p>Trial Registration</p> <p>REFCTRI2009000472</p

Impact of Tail Loss on the Behaviour and Locomotor Performance of Two Sympatric Lampropholis Skink Species

Caudal autotomy is an anti-predator behaviour that is used by many lizard species. Although there is an immediate survival benefit, the subsequent absence of the tail may inhibit locomotor performance, alter activity and habitat use, and increase the individuals' susceptibility to future predation attempts. We used laboratory experiments to examine the impact of tail autotomy on locomotor performance, activity and basking site selection in two lizard species, the delicate skink (Lampropholis delicata) and garden skink (L. guichenoti), that occur sympatrically throughout southeastern Australia and are exposed to an identical suite of potential predators. Post-autotomy tail movement did not differ between the two Lampropholis species, although a positive relationship between the shed tail length and distance moved, but not the duration of movement, was observed. Tail autotomy resulted in a substantial decrease in sprint speed in both species (28–39%), although this impact was limited to the optimal performance temperature (30°C). Although L. delicata was more active than L. guichenoti, tail autotomy resulted in decreased activity in both species. Sheltered basking sites were preferred over open sites by both Lampropholis species, although this preference was stronger in L. delicata. Caudal autotomy did not alter the basking site preferences of either species. Thus, both Lampropholis species had similar behavioural responses to autotomy. Our study also indicates that the impact of tail loss on locomotor performance may be temperature-dependent and highlights that future studies should be conducted over a broad thermal range

Ecological Guild Evolution and the Discovery of the World's Smallest Vertebrate

Living vertebrates vary drastically in body size, yet few taxa reach the extremely minute size of some frogs and teleost fish. Here we describe two new species of diminutive terrestrial frogs from the megadiverse hotspot island of New Guinea, one of which represents the smallest known vertebrate species, attaining an average body size of only 7.7 mm. Both new species are members of the recently described genus Paedophryne, the four species of which are all among the ten smallest known frog species, making Paedophryne the most diminutive genus of anurans. This discovery highlights intriguing ecological similarities among the numerous independent origins of diminutive anurans, suggesting that minute frogs are not mere oddities, but represent a previously unrecognized ecological guild

A consensus-based framework for conducting and reporting osteoarthritis phenotype research

Background The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. Methods A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. Results Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. Conclusions This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients