A single session of submaximal grip strength training with or without high-definition anodal-TDCS produces no cross-education of maximal force

BACKGROUND: Previous studies suggest that cross-education of strength may be modulated by increased corticospinal excitability of the ipsilateral primary motor cortex (M1) due to cross-activation. However, no study has examined the influence of bilateral TDCS of both M1 and how it affects corticospinal excitability, cross-activation and cross-education of muscle strength.METHOD: Twelve participants underwent three conditions in a randomized crossover design: (1) submaximal grip training and single-site unilateral-high definition-TDCS (2) submaximal grip training and bilateral anodal-high definition-TDCS, and (3) submaximal grip training and sham-high definition-TDCS. Submaximal gripping task involved a single-session of unilateral training which was squeezing the transducer at 70% of maximum voluntary isometric contraction (MVIC) grip force and performing four sets of 10 isometric contractions. Anodal-high definition-TDCS was applied for 15 min at 1.5 mA over right M1 or left and right M1s, and in a sham condition. Participants were pseudorandomized to receive either single-site or bilateral M1 stimulation with each session separated by one-week. Before and after each session, MVIC force of ipsilateral and contralateral gripping, ipsilateral stimulus-response curve, short-interval intracortical inhibition, cortical silent period, intracortical facilitation, long-interval intracortical inhibition, and cross-activation were measured.RESULTS: MVIC of the trained arm decreased by 43% (P=0.04) after training. We observed no changes in MVIC of the untrained hand and in any of the TMS measures (all P>0.05).CONCLUSION: A single session of submaximal grip training with or without anodal-high definition-TDCS produces no cross-education of maximal grip force nor does it affect the excitability of the ipsilateral M1

Assessment of RNAlater® as a Potential Method to Preserve Bovine Muscle Proteins Compared with Dry Ice in a Proteomic Study

peer-reviewedRNAlater® is regarded as a potential preservation method for proteins, while its effect on bovine muscle proteins has rarely been evaluated. Bovine muscle protein samples (n = 12) collected from three tender (Warner–Bratzler shear force: 30.02–31.74 N) and three tough (Warner–Bratzler shear force: 54.12–66.25 N) Longissimus thoracis et lumborum (LTL) samples, preserved using two different sampling preservation methods (RNAlater® and dry ice), at two post mortem time points (day 0 and day 14), were characterized using one-dimensional electrophoresis. Fourteen bands with molecular weights ranging from 15 to 250 kDa were verified, both in the dry ice and RNAlater® storage groups, at each time point, using image analysis. A shift from high to low molecular weight fragments, between day 0 and day 14, indicated proteolysis of the muscle proteins during post mortem storage. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses and database searching resulted in the identification of 10 proteins in four bands. Protein profiles of muscle preserved in RNAlater® were similar to those of muscle frozen on dry ice storage, both at day 0 and day 14. The results demonstrate that RNAlater® could be a simple and efficient way to preserve bovine muscle proteins for bovine muscle proteomic studie

Post-operative monitoring of intestinal tissue oxygenation using an implantable microfabricated oxygen sensor

Anastomotic leakage (AL) is a common and dangerous post-operative complication following intestinal resection, causing substantial morbidity and mortality. Ischaemia in the tissue surrounding the anastomosis is a major risk-factor for AL development. Continuous tissue oxygenation monitoring during the post-operative recovery period would provide early and accurate early identification of AL risk. We describe the construction and testing of a miniature implantable electrochemical oxygen sensor that addresses this need. It consisted of an array of platinum microelectrodes, microfabricated on a silicon substrate, with a poly(2-hydroxyethyl methacrylate) hydrogel membrane to protect the sensor surface. The sensor was encapsulated in a biocompatible package with a wired connection to external instrumentation. It gave a sensitive and highly linear response to variations in oxygen partial pressure in vitro, although over time its sensitivity was partially decreased by protein biofouling. Using a pre-clinical in vivo pig model, acute intestinal ischaemia was robustly and accurately detected by the sensor. Graded changes in tissue oxygenation were also measurable, with relative differences detected more accurately than absolute differences. Finally, we demonstrated its suitability for continuous monitoring of tissue oxygenation at a colorectal anastomosis over a period of at least 45 h. This study provides evidence to support the development and use of implantable electrochemical oxygen sensors for post-operative monitoring of anastomosis oxygenation

Genetic and functional characterization of putative Ras/Raf interaction inhibitors in C. elegans and mammalian cells

Abstract Background Activation of the mammalian Ras-Raf-MEK-ERK MAPK signaling cascade promotes cellular proliferation, and activating Ras mutations are implicated in cancer onset and maintenance. This pathway, a therapeutic target of interest, is highly conserved and required for vulval development in C. elegans. Gain-of-function mutations in the Ras ortholog lead to constitutive pathway signaling and a multivulva (Muv) phenotype. MCP compounds were identified in a yeast two-hybrid screen for their ability to disrupt Ras-Raf interactions. However, this had not been confirmed in another system, and conflicting results were reported regarding selective MCP-mediated blockade of Ras- and Raf-mediated biological activities in mammalian cells. Here we used the easily-scored Muv phenotype as an in vivo readout to characterize the selectivity of MCP110 and its analogs, and performed biochemical studies in mammalian cells to determine whether MCP treatment results in impaired interaction between Ras and its effector Raf. Results Our genetic analyses showed significant dose-dependent MCP-mediated reduction of Muv in C. elegans strains with activating mutations in orthologs of Ras (LET-60) or Raf (LIN-45), but not MAP kinases or an Ets-like transcription factor. Thus, these inhibitors selectively impair pathway function downstream of Ras and upstream of or at the level of Raf, consistent with disruption of the Ras/Raf interaction. Our biochemical analyses of MCP110-mediated disruption of Ras-Raf interactions in mammalian cells showed that MCP110 dose-dependently reduced Raf-RBD pulldown of Ras, displaced a fluorescently-tagged Raf-RBD probe from plasma membrane locations of active Ras to the cytosol and other compartments, and decreased active, phosphorylated ERK1/2. Conclusions We have effectively utilized C. elegans as an in vivo genetic system to evaluate the activity and selectivity of inhibitors intended to target the Ras-Raf-MAPK pathway. We demonstrated the ability of MCP110 to disrupt, at the level of Ras/Raf, the Muv phenotype induced by chronic activation of this pathway in C. elegans. In mammalian cells, we not only demonstrated MCP-mediated blockade of the physical interaction between Ras and Raf, but also narrowed the site of interaction on Raf to the RBD, and showed consequent functional impairment of the Ras-Raf-MEK-ERK pathway in both in vivo and cell-based systems

Unilateral Strength Training Imparts a Cross-Education Effect in Unilateral Knee Osteoarthritis Patients

Background: Worldwide, 86 million individuals over the age of 20 were diagnosed with knee osteoarthritis (KOA) in 2020. Hallmark features of KOA are the loss in knee extensor strength, increasing knee pain severity, and deficits in functional performance. There is a critical need for the investigation into potential cost-effective therapeutic interventions in the treatment of KOA. A potential therapeutic option is the cross-education phenomenon. Methods: This was a non-blinded randomized control trial, with a 4-week intervention, with a pre, post and follow-up assessment (3 months post intervention). Outcome measures of isometric knee extensor strength, rectus femoris muscle thickness and neuromuscular activation were assessed at all-time points. Results: Compared to age-matched KOA controls, 4 weeks of unilateral strength training in end-stage KOA patients increased strength of the untrained affected KOA limb by 20% (p < 0.05) and reduced bilateral hamstring co-activation in the KOA intervention group compared to the KOA control group (p < 0.05). Conclusions: A 4-week-long knee extensor strength training intervention of the contralateral limb in a cohort with diagnosed unilateral KOA resulted in significant improvements to knee extensor strength and improved neuromuscular function of the KOA limb. Importantly, these results were maintained for 3 months following the intervention

Feasibility study to assess the delivery of a novel isometric exercise intervention for people with stage 1 hypertension in the NHS: protocol for the IsoFIT-BP study including amendments to mitigate the risk of COVID-19.

BackgroundHypertension  (HTN) affects approximately 25% of the UK population and is a leading cause of mortality. Associated annual health care costs run into billions. National treatment guidance includes initial lifestyle advice, followed by anti-hypertensive medication if blood pressure (BP) remains high. However, adoption and adherence to recommended exercise guidelines, dietary advice and anti-hypertensive medication is poor. Four short bouts of isometric exercise (IE) performed 3 days per week (d/wk) at home elicits clinically significant reductions in BP in those with normal to high-normal BP. This study will determine the feasibility of delivering personalised IE to patients with stage 1 hypertension for whom lifestyle changes would be recommended before medication within NHS primary care.MethodsThis is a randomised controlled feasibility study. Participants were 18+ years, with stage 1 hypertension, not on anti-hypertensive medication and without significant medical contraindications. Trial arms will be standard lifestyle advice (control) or isometric wall squat exercise and standard lifestyle advice. Primary outcomes include the feasibility of healthcare professionals to deliver isometric exercise prescriptions in a primary care NHS setting and estimation of the variance of change in systolic BP. Secondary outcomes include accuracy of protocol delivery, execution of and adherence to protocol, recruitment rate, attrition, perception of intervention viability, cost, participant experience and accuracy of home BP. The study will last 18 months. Sample size of 100 participants (50 per arm) allows for 20% attrition and 6.5% incomplete data, based upon 74 (37 each arm) participants (two-sided 95% confidence interval, width of 1.33 and standard deviation of 4) completing 4 weeks. Ethical approval IRAS ID is 274676.DiscussionBefore the efficacy of this novel intervention to treat stage 1 hypertension can be investigated in any large randomised controlled trial, it is necessary to ascertain if it can be delivered and carried out in a NHS primary care setting. Findings could support IE viability as a prophylactic/alternative treatment option.Trial registrationISRCTN13472393 , registered 18 August 2020

Exposure to Weight Management Counseling Among Students at 8 U.S. Medical Schools

INTRODUCTION: Clinical guidelines support physician intervention consistent with the Ask, Advise, Assess, Assist, Arrange framework for adults who have obesity. However, weight management counseling curricula vary across medical schools. It is unknown how frequently students receive experiences in weight management counseling, such as instruction, observation, and direct experience. METHODS: A cross-sectional survey, conducted in 2017, of 730 third-year medical students in 8 U.S. medical schools assessed the frequency of direct patient, observational, and instructional weight management counseling experiences that were reported as summed scores with a range of 018. Analysis was completed in 2017. RESULTS: Students reported the least experience with receiving instruction (6.5, SD=3.9), followed by direct patient experience (8.6, SD=4.8) and observational experiences (10.3, SD=5.0). During the preclinical years, 79% of students reported a total of \u3c /=3 hours of combined weight management counseling instruction in the classroom, clinic, doctor\u27s office, or hospital. The majority of the students (59%-76%) reported never receiving skills-based instruction for weight management counseling. Of the Ask, Advise, Assess, Assist, Arrange framework, scores were lowest for assisting the patient to achieve their agreed-upon goals (31%) and arranging follow-up contact (22%). CONCLUSIONS: Overall exposure to weight management counseling was less than optimal. Medical school educators can work toward developing a more coordinated approach to weight management counseling. Inc

Antagonism of neurosteroid modulation of native γ-aminobutyric acid receptors by (3α,5α)-17-phenylandrost-16-en-3-ol

Endogenous pregnane neurosteroids are allosteric modulators at γ-aminobutyric acid type-A (GABAA) receptors at nanomolar concentrations. There is direct evidence for multiple distinct neurosteroid binding sites on GABAA receptors, dependent upon subunit composition and stoichiometry. This view is supported by the biphasic kinetics of various neuroactive steroids, enantioselectivity of some neurosteroids, selective mutation studies of recombinantly expressed receptors and the selectivity of the neurosteroid antagonist (3α,5α)-17-phenylandrost-16-en-3-ol (17PA) on 5α-pregnane steroid effects on recombinant GABAA receptors expressed in Xenopus oocytes and native receptors in dissociated neurons. However, it is unclear whether this antagonist action is present in a mature mammalian system. The present study evaluated the antagonist activity of 17PA on neurosteroid agonists both in vivo and in vitro by examining the effects of 17PA on 5α-pregnane-induced sedation in rats, native mature GABAA receptor ion channels utilizing the chloride flux assay and further studies in recombinant α1β2γ2 receptors. The data show that 17PA preferentially inhibits 3α,5α-THP vs. alphaxalone in vivo, preferentially inhibits 3α,5α-THDOC vs. alphaxalone potentiation of GABA-mediated Cl- uptake in adult cerebral cortical synaptoneurosomes, but shows no specificity for 3α,5α-THDOC vs. alphaxalone in recombinant α1β2γ2 receptors. These data provide further evidence of the specificity of 17PA and the heterogeneity of neurosteroid recognition sites on GABAA receptors in the CNS

The Effect of the 2009 USPSTF breast cancer screening recommendations on breast cancer in Michigan: A longitudinal study

In 2009, the revised United States Preventive Services Task Force (USPSTF) guidelines recommended against routine screening mammography for women age 40â 49 years and against teaching selfâ breast examinations (SBE). The aim of this study was to analyze whether breast cancer method of presentation changed following the 2009 USPSTF screening recommendations in a large Michigan cohort. Data were collected on women with newly diagnosed stage 0â III breast cancer participating in the Michigan Breast Oncology Quality Initiative (MiBOQI) registry at 25 statewide institutions from 2006 to 2015. Data included method of detection, cancer stage, treatment type, and patient demographics. In all, 30 008 women with breast cancer detected via mammogram or palpation with an average age of 60.1 years were included. 38% of invasive cancers were identified by palpation. Presentation with palpable findings decreased slightly over time, from 34.6% in 2006 to 28.9% in 2015 (P < .001). Over the 9â year period, there was no statistically significant change in rate of palpationâ detected tumors for women age <50 years or â ¥50 years (P = .27, .30, respectively). Younger women were more likely to present with palpable tumors compared to older women in a statewide registry. This rate did not increase following publication of the 2009 USPSTF breast cancer screening recommendations.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146414/1/tbj13034.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146414/2/tbj13034_am.pd