Key Components of Human Myofibre Denervation and Neuromuscular Junction Stability are Modulated by Age and Exercise

The decline in muscle mass and function with age is partly caused by a loss of muscle fibres through denervation. The purpose of this study was to investigate the potential of exercise to influence molecular targets involved in neuromuscular junction (NMJ) stability in healthy elderly individuals. Participants from two studies (one group of 12 young and 12 elderly females and another group of 25 elderly males) performed a unilateral bout of resistance exercise. Muscle biopsies were collected at 4.5 h and up to 7 days post exercise for tissue analysis and cell culture. Molecular targets related to denervation and NMJ stability were analysed by immunohistochemistry and real-time reverse transcription polymerase chain reaction. In addition to a greater presence of denervated fibres, the muscle samples and cultured myotubes from the elderly individuals displayed altered gene expression levels of acetylcholine receptor (AChR) subunits. A single bout of exercise induced general changes in AChR subunit gene expression within the biopsy sampling timeframe, suggesting a sustained plasticity of the NMJ in elderly individuals. These data support the role of exercise in maintaining NMJ stability, even in elderly inactive individuals. Furthermore, the cell culture findings suggest that the transcriptional capacity of satellite cells for AChR subunit genes is negatively affected by ageing

The Associations of Breastfeeding Status at 6 Months with Anthropometry, Body Composition, and Cardiometabolic Markers at 5 Years in the Ethiopian Infant Anthropometry and Body Composition Birth Cohort

(1) Background: Breastfeeding (BF) has been shown to lower the risk of overweight and cardiometabolic disease later in life. However, evidence from low-income settings remains sparse. We examined the associations of BF status at 6 months with anthropometry, body composition (BC), and cardiometabolic markers at 5 years in Ethiopian children. (2) Methods: Mother–child pairs from the iABC birth cohort were categorised into four BF groups at 6 months: 1. “Exclusive”, 2. “Almost exclusive”, 3. “Predominantly” and 4. “Partial or none”. The associations of BF status with anthropometry, BC, and cardiometabolic markers at 5 years were examined using multiple linear regression analyses in three adjustment models. (3) Results: A total of 306 mother–child pairs were included. Compared with “Exclusive”, the nonexclusive BF practices were associated with a lower BMI, blood pressure, and HDL-cholesterol at 5 years. Compared with “Exclusive”, “Predominantly” and “Almost exclusive” had shorter stature of −1.7 cm (−3.3, −0.2) and −1.2 cm (−2.9, 0.5) and a lower fat-free mass index of −0.36 kg/m2 (−0.71, −0.005) and −0.38 kg/m2 (−0.76, 0.007), respectively, but a similar fat mass index. Compared with “Exclusive”, “Predominantly” had higher insulin of 53% (2.01, 130.49), “Almost exclusive” had lower total and LDL-cholesterol, and “Partial or none” had a lower fat mass index. (5) Conclusions: Our data suggest that children exclusively breastfed at 6 months of age are overall larger at 5 years, with greater stature, higher fat-free mass but similar fat mass, higher HDL-cholesterol and blood pressure, and lower insulin concentrations compared with predominantly breastfed children. Long-term studies of the associations between BF and metabolic health are needed to inform policies

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism

correction de l'article correspondant à la notice https://prodinra.inra.fr/record/425677International audienceConcern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named "compensated hypogonadism," a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism

The Reproducibility of Lists of Differentially Expressed Genes in Microarray Studies

Reproducibility is a fundamental requirement in scientific experiments and clinical contexts. Recent publications raise concerns about the reliability of microarray technology because of the apparent lack of agreement between lists of differentially expressed genes (DEGs). In this study we demonstrate that (1) such discordance may stem from ranking and selecting DEGs solely by statistical significance (P) derived from widely used simple t-tests; (2) when fold change (FC) is used as the ranking criterion, the lists become much more reproducible, especially when fewer genes are selected; and (3) the instability of short DEG lists based on P cutoffs is an expected mathematical consequence of the high variability of the t-values. We recommend the use of FC ranking plus a non-stringent P cutoff as a baseline practice in order to generate more reproducible DEG lists. The FC criterion enhances reproducibility while the P criterion balances sensitivity and specificity

Goal-directed haemodynamic therapy during general anaesthesia for noncardiac surgery:a systematic review and meta-analysis

BACKGROUND: During general anaesthesia for noncardiac surgery, there remain knowledge gaps regarding the effect of goal-directed haemodynamic therapy on patient-centred outcomes. METHODS: Included clinical trials investigated goal-directed haemodynamic therapy during general anaesthesia in adults undergoing noncardiac surgery and reported at least one patient-centred postoperative outcome. PubMed and Embase were searched for relevant articles on March 8, 2021. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. The primary outcomes were mortality and hospital length of stay, whereas 15 postoperative complications were included based on availability. From a main pool of comparable trials, meta-analyses were performed on trials with homogenous outcome definitions. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: The main pool consisted of 76 trials with intermediate risk of bias for most outcomes. Overall, goal-directed haemodynamic therapy might reduce mortality (odds ratio=0.84; 95% confidence interval [CI], 0.64 to 1.09) and shorten length of stay (mean difference=–0.72 days; 95% CI, –1.10 to –0.35) but with low certainty in the evidence. For both outcomes, larger effects favouring goal-directed haemodynamic therapy were seen in abdominal surgery, very high-risk surgery, and using targets based on preload variation by the respiratory cycle. However, formal tests for subgroup differences were not statistically significant. Goal-directed haemodynamic therapy decreased risk of several postoperative outcomes, but only infectious outcomes and anastomotic leakage reached moderate certainty of evidence. CONCLUSIONS: Goal-directed haemodynamic therapy during general anaesthesia might decrease mortality, hospital length of stay, and several postoperative complications. Only infectious postoperative complications and anastomotic leakage reached moderate certainty in the evidence

Fraction of Inspired Oxygen During General Anesthesia for Non-Cardiac Surgery:Systematic Review and Meta-Analysis

BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO(2)) in adults undergoing general anesthesia. This systematic review and meta‐analysis investigated the effect of a high versus a low FiO(2) on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO(2) levels in adults undergoing general anesthesia for non‐cardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Meta‐analyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and meta‐regression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO(2). Risk of bias was intermediate for all trials. A high FiO(2) did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81–1.02 [p = .10]). No effect was found for all other included outcomes, including mortality (OR = 1.27, 95% CI: 0.90–1.79 [p = .18]) and hospital length of stay (mean difference = 0.03 days, 95% CI −0.25 to 0.30 [p = .84). Results from subgroup analyses and meta‐regression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for non‐cardiac surgery, a high FiO(2) did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: An international multicentre analysis

Background: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. Methods: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan–Meier survival curves. Results: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients’ median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. Conclusion: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.publishedVersio

The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies

<p>Abstract</p> <p>Background</p> <p>Reproducibility is a fundamental requirement in scientific experiments. Some recent publications have claimed that microarrays are unreliable because lists of differentially expressed genes (DEGs) are not reproducible in similar experiments. Meanwhile, new statistical methods for identifying DEGs continue to appear in the scientific literature. The resultant variety of existing and emerging methods exacerbates confusion and continuing debate in the microarray community on the appropriate choice of methods for identifying reliable DEG lists.</p> <p>Results</p> <p>Using the data sets generated by the MicroArray Quality Control (MAQC) project, we investigated the impact on the reproducibility of DEG lists of a few widely used gene selection procedures. We present comprehensive results from inter-site comparisons using the same microarray platform, cross-platform comparisons using multiple microarray platforms, and comparisons between microarray results and those from TaqMan – the widely regarded "standard" gene expression platform. Our results demonstrate that (1) previously reported discordance between DEG lists could simply result from ranking and selecting DEGs solely by statistical significance (<it>P</it>) derived from widely used simple <it>t</it>-tests; (2) when fold change (FC) is used as the ranking criterion with a non-stringent <it>P</it>-value cutoff filtering, the DEG lists become much more reproducible, especially when fewer genes are selected as differentially expressed, as is the case in most microarray studies; and (3) the instability of short DEG lists solely based on <it>P</it>-value ranking is an expected mathematical consequence of the high variability of the <it>t</it>-values; the more stringent the <it>P</it>-value threshold, the less reproducible the DEG list is. These observations are also consistent with results from extensive simulation calculations.</p> <p>Conclusion</p> <p>We recommend the use of FC-ranking plus a non-stringent <it>P </it>cutoff as a straightforward and baseline practice in order to generate more reproducible DEG lists. Specifically, the <it>P</it>-value cutoff should not be stringent (too small) and FC should be as large as possible. Our results provide practical guidance to choose the appropriate FC and <it>P</it>-value cutoffs when selecting a given number of DEGs. The FC criterion enhances reproducibility, whereas the <it>P </it>criterion balances sensitivity and specificity.</p

Investigation of the direct effects of salmon calcitonin on human osteoarthritic chondrocytes

<p>Abstract</p> <p>Background</p> <p>Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteoglycans and collagen-type-II synthesis in osteoarthritic (OA) cartilage.</p> <p>Methods</p> <p>Human OA cartilage explants were cultured with salmon calcitonin [100 pM-100 nM]. Direct effects of calcitonin on articular cartilage were evaluated by 1) measurement of proteoglycan synthesis by incorporation of radioactive labeled ³⁵SO₄[5 μCi] 2) quantification of collagen-type-II formation by pro-peptides of collagen type II (PIINP) ELISA, 3) QPCR expression of the calcitonin receptor in OA chondrocytes using four individual primer pairs, 4) activation of the cAMP signaling pathway by EIA and, 5) investigations of metabolic activity by AlamarBlue.</p> <p>Results</p> <p>QPCR analysis and subsequent sequencing confirmed expression of the calcitonin receptor in human chondrocytes. All doses of salmon calcitonin significantly elevated cAMP levels (P < 0.01 and P < 0.001). Calcitonin significantly and concentration-dependently [100 pM-100 nM] induced proteoglycan synthesis measured by radioactive ³⁵SO₄incorporation, with a 96% maximal induction at 10 nM (P < 0.001) corresponding to an 80% induction of 100 ng/ml IGF, (P < 0.05). In alignment with calcitonin treatments [100 pM-100 nM] resulted in 35% (P < 0.01) increased PIINP levels.</p> <p>Conclusion</p> <p>Calcitonin treatment increased proteoglycan and collagen synthesis in human OA cartilage. In addition to its well-established effect on subchondral bone, calcitonin may prove beneficial to the management of joint diseases through direct effects on chondrocytes.</p