Deletion of Sod1 in Motor Neurons Exacerbates Age-Related Changes in Axons and Neuromuscular Junctions in Mice.

Whole-body knock-out of Cu,Zn superoxide dismutase (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with neuromuscular junction (NMJ) breakdown similar to sarcopenia. In order to determine whether altered redox in motor neurons underlies this phenotype, an inducible neuron-specific deletion of Sod1 (i-mnSod1KO) was compared with wild-type (WT) mice of different ages (adult, mid-age, and old) and whole-body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined. Tamoxifen-induced deletion of neuronal Sod1 from two months of age. No specific effect of a lack of neuronal Sod1 was seen on markers of nerve oxidation (electron paramagnetic resonance of an in vivo spin probe, protein carbonyl, or protein 3-nitrotyrosine contents). i-mnSod1KO mice showed increased denervated NMJ, reduced numbers of large axons and increased number of small axons compared with old WT mice. A large proportion of the innervated NMJs in old i-mnSod1KO mice displayed a simpler structure than that seen in adult or old WT mice. Thus, previous work showed that neuronal deletion of Sod1 induced exaggerated loss of muscle in old mice, and we report that this deletion leads to a specific nerve phenotype including reduced axonal area, increased proportion of denervated NMJ, and reduced acetyl choline receptor complexity. Other changes in nerve and NMJ structure seen in the old i-mnSod1KO mice reflect aging of the mice.

Genomic testing for copy number and single nucleotide variants in spermatogenic failure.

PURPOSE: To identify clinically significant genomic copy number (CNV) and single nucleotide variants (SNV) in males with unexplained spermatogenic failure (SPGF). MATERIALS AND METHODS: Peripheral blood DNA from 97/102 study participants diagnosed with oligozoospermia, severe oligozoospermia, or non-obstructive azoospermia (NOA) was analyzed for CNVs via array comparative genomic hybridization (aCGH) and SNVs using whole-exome sequencing (WES). RESULTS: Of the 2544 CNVs identified in individuals with SPGF, > 90% were small, ranging from 0.6 to 75 kb. Thirty, clinically relevant genomic aberrations, were detected in 28 patients (~ 29%). These included likely diagnostic CNVs in 3/41 NOA patients (~ 7%): 1 hemizygous, intragenic TEX11 deletion, 1 hemizygous DDX53 full gene deletion, and 1 homozygous, intragenic STK11 deletion. High-level mosaicism for X chromosome disomy (~ 10% 46,XY and ~ 90% 47,XXY) was also identified in 3 of 41 NOA patients who previously tested normal with conventional karyotyping. The remaining 24 CNVs detected were heterozygous, autosomal recessive carrier variants. Follow-up WES analysis confirmed 8 of 27 (30%) CNVs (X chromosome disomy excluded). WES analysis additionally identified 13 significant SNVs and/or indels in 9 patients (~ 9%) including X-linked AR, KAL1, and NR0B1 variants. CONCLUSION: Using a combined genome-wide aCGH/WES approach, we identified pathogenic and likely pathogenic SNVs and CNVs in 15 patients (15%) with unexplained SPGF. This value equals the detection rate of conventional testing for aneuploidies and is considerably higher than the prevalence of Y chromosome microdeletions. Our results underscore the importance of comprehensive genomic analysis in emerging diagnostic testing of complex conditions like male infertility.

An 8-year Analysis of Magnesium Status in Elite International Track & Field Athletes.

Magnesium plays a critical role in athlete health and performance. It is involved in numerous physiological mechanisms that support energy production, immune function, pain modulation, muscle function and bone health. Athletes may be susceptible to magnesium deficiency due to an increased utilization during exercise.Objective: This study reports on the magnesium status of 192 Olympic and Paralympic athletes over the course of eight years.Methods: Athletes on the British Athletics world class performance plan undertook blood testing for Red Cell Magnesium status. Their history of tendon pain, muscle and bone injury, ethnicity, sporting event and gender were also recorded. 510 samples from 192 athletes were included in the study.Results: On at least one blood test during the study time, 22% of athletes were identified as clinically deficient (<1.19 mmol/L). The average red cell magnesium concentration was 1.34 nmol/L. Magnesium was significantly lower in female athletes and those with Black or Mixed-Race ethnicity and was higher in Throws athletes and Paralympians with Cerebral Palsy. Athletes with a history of achilles or patella tendon pain had significantly lower magnesium levels than average.Conclusions: This study highlights the importance of investigating magnesium within this population to identify deficiency and support athlete health. Several areas for future work are identified to explore the relationship between magnesium and gender, ethnicity and tendon pain and muscle injury in athletes. Furthermore, new guidelines for magnesium status within athletics populations are proposed.

HyPer2 imaging reveals temporal and heterogeneous hydrogen peroxide changes in denervated and aged skeletal muscle fibers in vivo.

To determine the role of denervation and motor unit turnover in the age-related increase in skeletal muscle oxidative stress, the hydrogen peroxide (H2O2) specific, genetically-encoded, fluorescent cyto-HyPer2 probe was expressed in mouse anterior tibialis (AT) muscle and compared with ex vivo measurements of mitochondrial oxidant generation. Crush of the peroneal nerve induced increased mitochondrial peroxide generation, measured in permeabilised AT fibers ex vivo and intra vital confocal microscopy of cyto-HyPer2 fluorescence showed increased cytosolic H2O2 in a sub-set (~24%) of individual fibers associated with onset of fiber atrophy. In comparison, mitochondrial peroxide generation was also increased in resting muscle from old (26 month) mice compared with adult (6-8 month) mice, but no age effect on fiber cytosolic H2O2 in vivo was seen. Thus ageing is associated with an increased ability of muscle fibers to maintain cytosolic redox homeostasis in the presence of denervation-induced increase in mitochondrial peroxide generation.

Associations between muscle mass, physical activity and dietary behaviour in adolescents.

BACKGROUND AND OBJECTIVES: Investigations in older individuals suggest that adequate nutrition and physical activity are particularly important to skeletal muscle health; however, data in adolescents are scant and equivocal. The objective was to determine the associations among diet, physical activity and skeletal muscle mass in adolescents. METHODS: We assessed diet with four to seven 24-h recalls and physical activity by accelerometry in 640 adolescents. Using total body measures of fat-free soft tissue mass and fat mass assessed by dual-energy X-ray absorptiometry, the skeletal muscle mass index (SMMI) was derived by adjusting fat-free soft tissue mass for fat mass in addition to height. RESULTS: Skeletal muscle mass index (SMMI) was negatively associated with consumption of sugar-sweetened beverages (standardized beta coefficient [ß] = -0.10, P = 0.001) and saturated fats (ß = -0.28, P < 0.001). SMMI was positively associated with physical activity (moderate + vigorous) (ß = 0.20, P < 0.001). In further analysis, we observed a significant interaction between physical activity and sugar-sweetened beverage intake on SMMI (P = 0.002). CONCLUSION: Our study in adolescence suggests that physical activity and consumption of both sugar-sweetened beverages and saturated fats are associated with skeletal muscle mass. More importantly, our findings suggest that sugar-sweetened beverage intake may attenuate the beneficial effects of physical activity on skeletal muscle mass.

A scoping review to explore how universal design for learning is described and implemented by rehabilitation health professionals in school settings.

BACKGROUND: Universal design for learning (UDL) is a framework that provides guidelines to support children with diverse needs in the classroom and promotes inclusion of all children. Although UDL is recognized as a promising approach for school-based rehabilitation health professionals (RHPs), there are no studies that synthesize evidence on the use of UDL by RHPs in the school setting. Therefore, the research question for this study is: How is UDL described and implemented in school settings by RHPs? This study specifically examined literature from occupational therapy, physiotherapy, and speech-language pathology. METHODS: A scoping review was completed to (a) summarize how UDL is described in the rehabilitation literature, (b) summarize the recommended and reported role of RHPs in the delivery of UDL, and (c) identify gaps in the evidence base. CINAHL, Embase, MEDLINE, PsychINFO, Sociological Abstracts, Web of Science, and ERIC electronic databases were searched. Numerical summaries and theoretical thematic analysis were used to describe the data both quantitatively and qualitatively. RESULTS: Inclusion criteria were achieved for 45 of the 3,998 screened documents. Most of the included documents lacked a definition of UDL. Analysis suggested that speech-language pathologists and occupational therapists implement UDL in a variety of ways within the school setting. No physiotherapy literature was found, and limited high-level empirical research has been conducted within rehabilitation. CONCLUSION: This scoping review provides a broad understanding of how RHPs describe and implement UDL-aligned services in school settings. UDL is a promising framework that provides RHPs with guidance on how to support children with diverse needs in the classroom, with the overall aim to promote inclusion of all children. There is a need for further research to determine the effectiveness of UDL as implemented by RHPs and to examine the role of physiotherapists in using UDL-type services.

Assessing the Burden of Clostridium difficile Infection in Low- and Middle-Income Countries.

In contrast to the significant resources invested in the diagnosis and prevention of Clostridium difficile infection (CDI) in resource-rich settings, in resource-limited settings patients with community- and hospital-acquired diarrhea may not routinely be tested for CDI. Is CDI actually less frequent or severe in resource-limited settings, or might we be missing an important opportunity to prevent CDI-related morbidity and mortality (and to promote antibiotic stewardship) in these settings? Here, we review the literature to assess the overall burden of CDI in low- and middle-income countries.

Evidence of malignant hyperthermia in patients administered triggering agents before malignant hyperthermia susceptibility identified: missed opportunities prior to diagnosis.

Malignant hyperthermia (MH) is a hypermetabolic disorder of skeletal muscle triggered almost exclusively by potent inhalational agents and suxamethonium. Signs of an MH reaction are non-specific and may be confused with the presentation of other problems such as sepsis and overheating of a patient. A high index of suspicion is needed to be aware of an early presentation of MH. Nine patients are presented who showed abnormal signs with an earlier anaesthetic where the possible diagnosis of an MH reaction was missed. These patients either presented later with an MH reaction, confirmed by DNA analysis and in some cases in vitro contracture testing, or were diagnosed by the identification of a causative mutation confirming MH susceptibility. The MH clinical grading scale is helpful in determining the likelihood that clinical indicators indicate a possible MH reaction. Masseter muscle rigidity is a known sign of MH, confirmed in this report by positive in vitro contracture testing and DNA analysis. Several uncommon muscle disorders have a high association with MH, and postoperative myalgia unrelated to suxamethonium can be a sign which is associated with MH. These reports emphasise the importance of a thorough family history (as the MH status was known by the family in four patients), a high index of suspicion for MH, and documentation of the possibility of MH susceptibility in the anaesthesia record.

Administration of anaesthetic triggering agents to patients tested malignant hyperthermia normal and their relatives in New Zealand: an update.

Testing for malignant hyperthermia in New Zealand involves two tests-in vitro contracture testing of excised lateral quadriceps muscle and DNA analysis. In vitro contracture testing is regarded as the gold standard in malignant hyperthermia diagnosis but several publications have questioned the reliability of a normal result. Analysis of 479 anaesthetic records in 280 patients or their descendants throughout New Zealand who had tested negative for malignant hyperthermia, demonstrated there was no evidence of malignant hyperthermia episodes in this group who had been administered anaesthetic triggering agents. A wide range of anaesthetics were used over the study period. Analysis of each anaesthetic record was undertaken using the malignant hyperthermia grading scale which determines the likelihood that an anaesthetic event represents a malignant hyperthermia episode. Confirmation of the negative results was further supported by normal DNA analysis of patients in 48% of anaesthetics. There are advantages to using inhalational agents in certain situations and although demonstrating a zero risk of a malignant hyperthermia episode is not statistically possible, evidence in this large series suggests that the risk of an episode in these patients is extremely low and may be negligible. We suggest that anaesthetic triggering agents can be used safely in patients with normal in vitro contracture tests, and in their descendants.

Insulin Resistance Negatively Influences the Muscle-Dependent IGF-1-Bone Mass Relationship in Premenarcheal Girls.

CONTEXT: IGF-1 promotes bone growth directly and indirectly through its effects on skeletal muscle. Insulin and IGF-1 share a common cellular signaling process; thus, insulin resistance may influence the IGF-1-muscle-bone relationship. OBJECTIVE: We sought to determine the effect of insulin resistance on the muscle-dependent relationship between IGF-1 and bone mass in premenarcheal girls. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study conducted at a university research center involving 147 girls ages 9 to 11 years. MAIN OUTCOME MEASURES: Glucose, insulin, and IGF-1 were measured from fasting blood samples. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin. Fat-free soft tissue (FFST) mass and bone mineral content (BMC) were measured by dual-energy x-ray absorptiometry. Our primary outcome was BMC/height. RESULTS: In our path model, IGF-1 predicted FFST mass (b = 0.018; P = .001), which in turn predicted BMC/height (b = 0.960; P < .001). IGF-1 predicted BMC/height (b = 0.001; P = .002), but not after accounting for the mediator of this relationship, FFST mass. The HOMA-IR by IGF-1 interaction negatively predicted FFST mass (b = -0.044; P = .034). HOMA-IR had a significant and negative effect on the muscle-dependent relationship between IGF-1 and BMC/height (b = -0.151; P = .047). CONCLUSIONS: Lean body mass is an important intermediary factor in the IGF-1-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-1-dependent muscle development in insulin-resistant children.

British athletics muscle injury classification: a reliability study for a new grading system.

AIM: To implement and validate the newly proposed British athletics muscle injury classification in the assessment of hamstring injuries in track and field athletes and to analyse the nature and frequency of the discrepancies. MATERIALS AND METHODS: This was a retrospective study analysing hamstring injuries in elite British athletes using the proposed classification system. Classification of 65 hamstring injuries in 45 high-level athletes by two radiologists at two time points 4 months apart to determine interrater variability, intrarater variability, and feasibility of the classification system was undertaken. RESULTS: Interrater Kappa values of 0.80 (95% confidence interval [CI]: 0.67-0.92; p<0.0001) for Round 1 and 0.88 (95% CI: 0.76-1.00; p<0.0001) for Round 2 of the review were observed. Percentages of agreement were 85% for Round 1 and 91% for Round 2. The intrarater Kappa value for the two reviewers were 0.76 (95% CI: 0.63-0.88; p<0.0001) and 0.65 (95% CI: 0.53-0.76; p<0.0001) and the average was 0.71 suggesting substantial overall agreement. The percentages of agreement were 82% and 72%, respectively. CONCLUSIONS: This classification system is straightforward to use and produces both reproducible and consistent results based on interrater and intrarater Kappa values with at least substantial agreement in all groups. Further work is ongoing to investigate whether individual grades within this classification system provide prognostic information and could guide clinical management.

High sodium intake is associated with short leukocyte telomere length in overweight and obese adolescents.

BACKGROUND/OBJECTIVES: Telomere shortening has an important role in cellular aging. However, the impact of high sodium intake, an important risk factor of age-related diseases, on telomere shortening remains unknown. Therefore, we examined the relationship between high dietary sodium intake and leukocyte telomere length (LTL), particularly in the context of obesity, as obesity increases salt sensitivity. SUBJECTS/METHODS: LTL was determined by a quantitative polymerase chain reaction method in 766 adolescents aged 14-18 years (50% females, 49% African Americans). Dietary sodium intake was assessed by seven independent 24-h dietary recalls. We divided the sample into low sodium (mean 2388±522 mg per day) or high sodium groups (mean 4142±882 mg per day) based on the median value (3280.9 mg per day). RESULTS: In the entire cohort, there was no significant association between sodium intake and LTL (r=-0.05, P=0.24). However, there was a significant interaction between sodium intake and obesity status (P=0.049). Further multiple linear regression analyses revealed that higher dietary sodium intake was associated with shorter LTL in the overweight/obese group (body mass index ⩾85th percentile, ß=-0.37, P=0.04), but not in the normal-weight group (ß=0.01, P=0.93) after adjusting for multiple confounding factors. In the overweight/obese group, LTL was significantly shorter in the high sodium intake subjects vs low sodium intake subjects (1.24±0.22 vs. 1.32±0.20, P=0.02), but not the normal-weight group (1.29±0.24 vs 1.30±0.24, P=0.69). CONCLUSIONS: Higher dietary sodium intake is associated with shorter telomere length in overweight and obese adolescents.

Safe duration of postoperative monitoring for malignant hyperthermia patients administered non-triggering anaesthesia: an update.

The postoperative care of malignant hyperthermia (MH) patients is subject to international variation, with a paucity of data in the literature to guide management. Over a series of three studies, our aim was to evaluate whether MH-susceptible patients (and relatives who had not yet been investigated), who had received a non-triggering anaesthetic, could be managed in the same way as the standard surgical population. Following a retrospective study, 206 anaesthetics were administered in a prospective second study to MH-susceptible/related individuals who were monitored for a minimum of one hour in the post anaesthesia care unit and a further 90 minutes in a step-down facility. No problems relating to MH were encountered. The postoperative monitoring time was subsequently changed and, in a third study, patients were managed no differently from standard surgical patients. One hundred and twenty-five anaesthetics were administered with no evidence of problems. This data shows that standard postoperative monitoring times are safe and appropriate in MH-susceptible patients.

Association of adenovirus 36 infection with adiposity and inflammatory-related markers in children.

CONTEXT: Although animal studies suggest that adenovirus 36 (Ad36) infection is linked to obesity and systemic inflammation, human data are scant and equivocal. OBJECTIVE: Associations of Ad36 infection with total body adiposity and inflammatory-related markers were determined in 291 children aged 9-13 years (50% female, 49% black). DESIGN: Fasting blood samples were measured for presence of Ad36-specific antibodies and TNF-α, IL-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). Fat mass and fat-free soft tissue mass were measured by dual-energy X-ray absorptiometry. RESULTS: The overall prevalence of Ad36 seropositivity [Ad36(+)] was 42%. There was a higher percentage of Ad36(+) children in the highest tertiles of TNF-α and IL-6 compared with their respective middle and lowest tertiles (both P < .03). There was also a trend toward a higher prevalence of Ad36(+) children in the highest tertile of VEGF compared with tertiles 1 and 2 (P = .05). Multinomial logistic regression, adjusting for age, race, sex, and fat-free soft tissue mass, revealed that compared with children with the lowest TNF-α, IL-6, and VEGF levels (tertile 1), the adjusted odds ratios for Ad36(+) were 2.2 [95% confidence interval (CI) 1.2-4.0], 2.4 (95% CI 1.4-4.0), and 1.8 (95% CI 1.0-3.3), respectively, for those in the highest TNF-α, IL-6, and VEGF levels (tertile 3). No association was observed between Ad36(+) and greater levels of fat mass or MCP-1 (all P > .05). CONCLUSIONS: In children, our data suggest that Ad36(+) may be associated with biomarkers implicated in inflammation but not with greater levels of fat mass.

Managing the health of the elite athlete: a new integrated performance health management and coaching model.

Elite athletes endeavour to train and compete even when ill or injured. Their motivation may be intrinsic or due to coach and team pressures. The sports medicine physician plays an important role to risk-manage the health of the competing athlete in partnership with the coach and other members of the support team. The sports medicine physician needs to strike the right ethical and operational balance between health management and optimising performance. It is necessary to revisit the popular delivery model of sports medicine and science services to elite athletes based on the current reductionist multispecialist system lacking in practice an integrated approach and effective communication. Athlete and coach in isolation or with a member of the multidisciplinary support team, often not qualified or experienced to do so, decide on the utilisation of services and how to apply the recommendations. We propose a new Integrated Performance Health Management and Coaching model based on the UK Athletics experience in preparation for the London Olympic and Paralympic Games. The Medical and Coaching Teams are managed by qualified and experienced individuals operating in synergy towards a common performance goal, accountable to a Performance Director and ultimately to the Board of Directors. We describe the systems, processes and implementation strategies to assist the athlete, coach and support teams to continuously monitor and manage athlete health and performance. These systems facilitate a balanced approach to training and competing decisions, especially while the athlete is ill or injured. They take into account the best medical advice and athlete preference. This Integrated Performance Health Management and Coaching model underpinned the Track and Field Gold Medal performances at the London Olympic and Paralympic Games.

The incidence and types of medication errors in patients receiving antiretroviral therapy in resource-constrained settings.

PURPOSE: This study assessed the incidence and types of medication errors, interventions and outcomes in patients on antiretroviral therapy (ART) in selected HIV treatment centres in Nigeria. METHODS: Of 69 health facilities that had program for active screening of medication errors, 14 were randomly selected for prospective cohort assessment. All patients who filled/refilled their antiretroviral medications between February 2009 and March 2011 were screened for medication errors using study-specific pharmaceutical care daily worksheet (PCDW). All potential or actual medication errors identified, interventions provided and the outcomes were documented in the PCDW. Interventions included pharmaceutical care in HIV training for pharmacists amongst others. Chi-square was used for inferential statistics and P<0.05 indicated statistical significance. RESULTS: Of 6,882 participants, 67.0% were female and 93.5% were aged ≥ 15 years old. The participants had 110,070 medications filling/refilling visits, average (± SD) of 16.0 (± 0.3) visits per patient over the observation period. Patients were followed up for 9172.5 person-years. The number of drug items dispensed to participants was 305,584, average of 2.8 (± 0.1) drug items per patient. The incidence rate of medication errors was 40.5 per 100 person-years. The occurrence of medication errors was not associated with participants' sex and age (P>0.05). The major medications errors identified were 26.4% incorrect ART regimens prescribed; 19.8% potential drug-drug interaction or contraindication present; and 16.6% duration and/or frequency of medication inappropriate. Interventions provided included 67.1% cases of prescriber contacted to clarify/resolve errors and 14.7% cases of patient counselling and education; 97.4% of potential/actual medication error(s) were resolved. CONCLUSION: The incidence rate of medication errors was somewhat high; and majority of identified errors were related to prescription of incorrect ART regimens and potential drug-drug interactions; the prescriber was contacted and the errors were resolved in majority of cases. Active screening for medication errors is feasible in resource-limited settings following a capacity building intervention.

Influence of repeated daily diving on decompression stress.

Acclimatization (an adaptive change in response to repeated environmental exposure) to diving could reduce decompression stress. A decrease in post-dive circulating venous gas emboli (VGE or bubbles) would represent positive acclimatization. The purpose of this study was to determine whether four days of daily diving alter post-dive bubble grades. 16 male divers performed identical no-decompression air dives on 4 consecutive days to 18 meters of sea water for 47 min bottom times. VGE monitoring was performed with transthoracic echocardiography every 20 min for 120 min post-dive. Completion of identical daily dives resulted in progressively decreasing odds (or logit risk) of having relatively higher grade bubbles on consecutive days. The odds on Day 4 were half that of Day 1 (OR 0.50, 95% CI: 0.34, 0.73). The odds ratio for a >III bubble grade on Day 4 was 0.37 (95% CI: 0.20, 0.70) when compared to Day 1. The current study indicates that repetitive daily diving may reduce bubble formation, representing a positive (protective) acclimatization to diving. Further work is required to evaluate the impact of additional days of diving and multiple dive days and to determine if the effect is sufficient to alter the absolute risk of decompression sickness.