Muscular HSP70 content is higher in elderly compared to young, but is normalized after 12 weeks of strength training.

PURPOSE: Aging is associated with increased myocellular stress and loss of muscle mass and function. Heat shock proteins (HSPs) are upregulated during periods of stress as part of the cells protective system. Exercise can affect both acute HSP regulation and when repeated regularly counteract unhealthy age-related changes in the muscle. Few studies have investigated effects of exercise on HSP content in elderly. The aim of the study was to compare muscular HSP levels in young and elderly and to investigate how training affects HSP content in muscles from aged males and females. METHODS: Thirty-eight elderly were randomized to 12 weeks of strength training (STG), functional strength training (FTG) or a control group (C). To compare elderly to young, 13 untrained young performed 11 weeks of strength training (Y). Muscle biopsies were collected before and after the intervention and analyzed for HSP27, αB-crystallin and HSP70. RESULTS: Baseline HSP70 were 35% higher in elderly than in young, whereas there were no differences between young and elderly in HSP27 or αB-crystallin. After the training intervention, HSP70 were reduced in STG (- 33 ± 32%; P = 0.001) and FTG (- 28 ± 30%; P = 0.012). The decrease in HSP70 was more pronounced in the oldest. In contrast, Y increased HSP27 (134 ± 1%; P < 0.001) and αB-crystallin (84 ± 94%; P = 0.008). CONCLUSION: Twelve weeks of STG or FTG decreased the initial high levels of HSP70 in aged muscles. Thus, regular strength training can normalize some of the increases in cellular stress associated with normal aging, and lead to a healthier cellular environment in aged muscle cells.

Impact of HIV on inpatient mortality and complications in stroke in Thailand: a National Database Study.

The co-existence of stroke and HIV has increased in recent years, but the impact of HIV on post-stroke outcomes is poorly understood. We examined the impact of HIV on inpatient mortality, length of acute hospital stay and complications (pneumonia, respiratory failure, sepsis and convulsions), in hospitalized strokes in Thailand. All hospitalized strokes between 1 October 2004 and 31 January 2013 were included. Data were obtained from a National Insurance Database. Characteristics and outcomes for non-HIV and HIV patients were compared and multivariate logistic and linear regression models were constructed to assess the above outcomes. Of 610 688 patients (mean age 63·4 years, 45·4% female), 0·14% (866) had HIV infection. HIV patients were younger, a higher proportion were male and had higher prevalence of anaemia (P < 0·001) compared to non-HIV patients. Traditional cardiovascular risk factors, hypertension and diabetes, were more common in the non-HIV group (P < 0·001). After adjusting for age, sex, stroke type and co-morbidities, HIV infection was significantly associated with higher odds of sepsis [odds ratio (OR) 1·75, 95% confidence interval (CI) 1·29-2·4], and inpatient mortality (OR 2·15, 95% CI 1·8-2·56) compared to patients without HIV infection. The latter did not attenuate after controlling for complications (OR 2·20, 95% CI 1·83-2·64). HIV infection is associated with increased odds of sepsis and inpatient mortality after acute stroke.

Acute and long-term effects of blood flow restricted training on heat shock proteins and endogenous antioxidant systems.

Blood flow restricted exercise (BFRE) with low loads has been demonstrated to induce considerable stress to exercising muscles. Muscle cells have developed a series of defensive systems against exercise-induced stress. However, little is known about acute and long-term effects of BFRE training on these systems. Nine previously untrained females trained low-load BFRE and heavy load strength training (HLS) on separate legs and on separate days to investigate acute and long-term effects on heat shock proteins (HSP) and endogenous antioxidant systems in skeletal muscles. BFRE and HLS increased muscle strength similarly by 12 ± 7% and 12 ± 6%, respectively, after 12 weeks of training. Acutely after the first BFRE and HLS exercise session, αB-crystallin and HSP27 content increased in cytoskeletal structures, accompanied by increased expression of several HSP genes. After 12 weeks of training, this acute HSP response was absent. Basal levels of αB-crystallin, HSP27, HSP70, mnSOD, or GPx1 remained unchanged after 12 weeks of training, but HSP27 levels increased in the cytoskeleton. Marked translocation of HSP to cytoskeletal structures at the commencement of training indicates that these structures are highly stressed from BFRE and HLS. However, as the muscle gets used to this type of exercise, this response is abolished.

Vitamin C and E supplementation alters protein signalling after a strength training session, but not muscle growth during 10 weeks of training.

This study investigated the effects of vitamin C and E supplementation on acute responses and adaptations to strength training. Thirty-two recreationally strength-trained men and women were randomly allocated to receive a vitamin C and E supplement (1000 mg day(-1) and 235 mg day(-1), respectively), or a placebo, for 10 weeks. During this period the participants' training involved heavy-load resistance exercise four times per week. Muscle biopsies from m. vastus lateralis were collected, and 1 repetition maximum (1RM) and maximal isometric voluntary contraction force, body composition (dual-energy X-ray absorptiometry), and muscle cross-sectional area (magnetic resonance imaging) were measured before and after the intervention. Furthermore, the cellular responses to a single exercise session were assessed midway in the training period by measurements of muscle protein fractional synthetic rate and phosphorylation of several hypertrophic signalling proteins. Muscle biopsies were obtained from m. vastus lateralis twice before, and 100 and 150 min after, the exercise session (4 × 8RM, leg press and knee-extension). The supplementation did not affect the increase in muscle mass or the acute change in protein synthesis, but it hampered certain strength increases (biceps curl). Moreover, increased phosphorylation of p38 mitogen-activated protein kinase, Extracellular signal-regulated protein kinases 1 and 2 and p70S6 kinase after the exercise session was blunted by vitamin C and E supplementation. The total ubiquitination levels after the exercise session, however, were lower with vitamin C and E than placebo. We concluded that vitamin C and E supplementation interfered with the acute cellular response to heavy-load resistance exercise and demonstrated tentative long-term negative effects on adaptation to strength training.

Ballistic strength training in adults with cerebral palsy may increase rate of force development in plantar flexors, but transition to walking remains unclear: a case series.

BACKGROUND: Persons with cerebral palsy (CP) walk with reduced ankle plantar flexor power compared to typically developing. In this study, we investigated whether a ballistic strength-training programme targeting ankle plantar flexors could improve muscle strength, muscle architecture and walking function in adults with CP. METHODS: Eight adults (mildly affected CP) underwent eight weeks of ballistic strength training, with two sessions per week. Before and after the intervention preferred walking speed, ankle plantar flexion rate of force development (RFD), maximal voluntary contraction (MVC), muscle thickness, pennation angle and fascicle length were measured. Data are presented for individuals, as well as for groups. Group changes were analysed using the Wilcoxon signed-rank test. RESULTS: Data were analysed for eight participants (five women, mean age 37.9 years; six GMFCS I and two GMFCS II). Two participants increased their walking speed, but there were no significant group changes. In terms of muscle strength, there were significant group changes for RFD at 100 ms and MVC. In the case of muscle architecture, there were no group changes. CONCLUSION: In this study, we found that eight weeks of ballistic strength training improved ankle plantar flexor muscle strength but walking function and muscle architecture were unchanged. Larger studies will be needed to obtain conclusive evidence of the efficacy of this training method.

Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer.

INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.

Paper versus electronic feedback in high stakes assessment.

Tablet computers have emerged as increasingly useful tools in medical education, particularly for assessment. However, it is not fully established whether tablet computers influence the quality and/or quantity of feedback provided in high stakes assessments. It is also unclear how electronically-recorded feedback relates to student performance. Our primary aim was to determine whether differences existed in feedback depending on the tool used to record it. METHODS: We compared quantitative and qualitative feedback between paper-scoring sheets versus iPads™ across two consecutive years of a final year MBChB (UK medical degree) Objective Structured Clinical Examination. Quality of comments (using a validated five-point rating scale), number of examiner comments and number of words were compared across both methods of recording assessment performance using chi-squared analysis and independent t-test. We also explored relationships between student performance (checklist and global scoring) and feedback. RESULTS: Data from 190 students (2850 paper scored interactions) in 2015 and 193 (2895 iPad™ scored interactions) in 2016 were analysed. Overall, a greater number of comments were given with iPad™ compared to written (42% versus 20%; p < 0.001) but the quality of feedback did not differ significantly. For both written and electronic feedback, students with low global scores were more likely to receive comments (p < 0.001). CONCLUSION: The use of iPads™ in high stakes assessment increases the quantity of feedback compared to traditional paper scoring sheets. The quantity and quality of feedback for poorer performing candidates (by global score) were also better with iPad™ feedback.

Vitamin C and E supplementation does not affect heat shock proteins or endogenous antioxidants in trained skeletal muscles during 12 weeks of strength training.

BACKGROUND: Supplementation with large doses of antioxidants, such as vitamin C and E, has been shown to blunt some adaptations to endurance training. The effects of antioxidant supplementation on adaptations to strength training is sparsely studied. Herein we investigated the effects of vitamin C and E supplementation on acute stress responses to exercise and adaptation to traditional heavy load strength training. METHODS: In a double blind placebo-controlled design, twenty-eight, young, trained males and females were randomly assigned to receive either vitamin C and E (C: 1000 mg, E: 235 mg, per day) or placebo supplements, and underwent strength training for 10 weeks. After five weeks, a subgroup conducted a strength training session to investigate acute stress responses. Muscle samples were obtained to investigate changes in stress responses and in proteins and mRNA related to the heat shock proteins (HSPs) or antioxidant enzymes. RESULTS: The acute responses to the exercise session revealed activation of the NFκB pathway indicated by degradation of IκBα in both groups. Vitamin C and E supplementation had, however, no effects on the acute stress responses. Furthermore, ten weeks of strength training did not change muscle αB-crystallin, HSP27, HSP70, GPx1 or mnSOD levels, with no influence of supplementation. CONCLUSIONS: Our results showed that although vitamin C and E supplementation has been shown to interfere with training adaptations, it did not affect acute stress responses or long-term training adaptations in the HSPs or antioxidant enzymes in this study.

Resuscitation decisions--when should we talk to patients?

This paper attempts to summarise the results of recent British studies in the area of resuscitation decisions, and to explain the ethical and legal framework for the use of 'do not resuscitate' decisions and to give clear guidance about involving patients and relatives.

Bioelectrical impedance analysis is more accurate than clinical examination in determining the volaemic status of elderly patients with fragility fracture and hyponatraemia.

OBJECTIVES: Management of hyponatraemia depends crucially on accurate determination of volaemic (hydration) status but this is notoriously challenging to measure in older people. Bioelectrical impedance analysis (BIA) provides a validated means of determining total body water (TBW), but its clinical utility in determining volaemic status in hyponatraemia has never been tested. This study assessed the utility of BIA in the clinical management of hyponatraemia in elderly patients with fragility fractures (EPFF), a group at high risk of hyponatraemia. DESIGN: Prospective observational study of consenting patients ≥65 years with fragility fractures (N=127). SETTING: University teaching hospital in Scotland. PARTICIPANTS: Patients ≥665 years with fragility fractures with capacity to consent to participation. MEASUREMENTS: BIA and standard clinical examination procedures (jugular venous distension, skin turgor, mouth and axillary moistness, peripheral oedema, capillary refill time, overall impression) were performed daily throughout each participant's hospital stay. Volaemic status of hyponatraemia was determined by an expert panel using clinical data (history, examination, nursing observations and laboratory tests) blinded to TBW readings. Cohen's kappa was calculated to assess the level of agreement between the expert panel and both BIA and standard clinical examination measures in determining the volaemic state of hyponatraemia. RESULTS: 26/33 (79%) cases of hyponatraemia had sufficient clinical information to allow determination of volaemic status by BIA. There was moderate level of agreement between BIA and the expert panel, kappa 0.52 (p<.001). All kappa values for standard clinical assessments of volaemic status neared zero, indicating nil to slight agreement. CONCLUSION: BIA outperformed all aspects of the standard clinical examination in determining the volaemic status of hyponatraemic EPFF, suggesting it may be useful in clinical practice.

Acute response and subcellular movement of HSP27, αB-crystallin and HSP70 in human skeletal muscle after blood-flow-restricted low-load resistance exercise.

AIM: Heat-shock proteins (HSP) are important chaperones for stressed and damaged proteins. Low-load blood-flow-restricted resistance exercise (BFRE) is generally believed not to induce significant muscle damage, but is hitherto unverified with intracellular markers. Consequently, the aim of this study was to investigate the HSP response after BFRE in human skeletal muscle. METHODS: Nine healthy volunteers performed five sets to failure of unilateral knee extension at 30% of 1RM with partial blood-flow restriction. The contralateral leg performed the same work with free blood flow. Muscle biopsies were collected before exercise, 1, 24 and 48 h after exercise and analysed for HSP27, αB-crystallin, HSP70, desmin, glycogen content and myosin heavy chain by immunohistochemistry, ELISA and western blotting. RESULTS: One hour after exercise, HSP27 and αB-crystallin levels were reduced in the cytosolic and increased in the cytoskeletal fraction in the BFRE leg. HSP70 showed a delayed response and was increased over 48 h in the BFRE leg. Immunohistochemical analyses showed higher staining intensity of HSP70 in type 1 fibres in the BFRE leg at 24 and 48 h post-exercise. PAS staining showed decreased glycogen levels after BFRE, and interestingly, glycogen was still depleted 48 h after exercise in the same fibres displaying high HSP70 staining (type 1 fibres). CONCLUSION: Translocation of HSP27 and αB-crystallin from cytosol to cytoskeletal structures indicates that cytoskeletal proteins are stressed during BFRE. However, overt signs of myofibrillar disruptions were not observed. Interestingly, the stress response was more pronounced in type 1 than in type 2 fibres and coincided with low glycogen levels.

The reliability of height measurement (the Wessex Growth Study).

The two major components of reliability are accuracy and reproducibility. Three studies of the reliability of height measurement in children are reported. In the first, a standard metre rod was used to spot check the accuracy of installation of 230 measuring instruments in one health district in Wessex, UK. The readings obtained ranged from 90.0 to 108.5 cm and showed the urgent need for the positioning of instruments to be regularly checked. In a second study, to examine the reproducibility of height measurement, two experienced observers measured 10 young children (106.0 to 152.0 cm), three times on five instruments of different design. The observations were blind and in random order. The estimated standard deviation for a single height measurement was generally in the range 0.2-0.3 cm. Over 95% of the variance was attributable to the child, very little to the instrument or observer. Finally, the conditions of the second study were modified to examine the effect on reproducibility of non-blind and non-randomised measurements, as usually occurs in the clinic. A lower but inevitably false estimate of the error was obtained. It is recommended that the error of height measurement, appropriately established and expressed in simple terms, be stated in every published growth study.