Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.

Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt-/-) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt-/- mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt-/- mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt-/- mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.

Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation.

Understanding the role of astrocytes in the development of the nervous system and neurodegenerative disorders implies a necessary knowledge of the oxidative metabolism of proliferating astrocytes. The electron flux through mitochondrial respiratory complexes and oxidative phosphorylation may impact the growth and viability of these astrocytes. Here, we aimed at assessing to which extent mitochondrial oxidative metabolism is required for astrocyte survival and proliferation. Primary astrocytes from the neonatal mouse cortex were cultured in a physiologically relevant medium with the addition of piericidin A or oligomycin at concentrations that fully inhibit complex I-linked respiration and ATP synthase, respectively. The presence of these mitochondrial inhibitors for up to 6 days in a culture medium elicited only minor effects on astrocyte growth. Moreover, neither the morphology nor the proportion of glial fibrillary acidic protein-positive astrocytes in culture was affected by piericidin A or oligomycin. Metabolic characterization of the astrocytes showed a relevant glycolytic metabolism under basal conditions, despite functional oxidative phosphorylation and large spare respiratory capacity. Our data suggest that astrocytes in primary culture can sustainably proliferate when their energy metabolism relies only on aerobic glycolysis since their growth and survival do not require electron flux through respiratory complex I or oxidative phosphorylation.

Consequences and implications of the coronavirus disease (COVID-19) on pregnancy and newborns: A comprehensive systematic review and meta-analysis.

BACKGROUND: Pregnant patients are potentially vulnerable to COVID-19. OBJECTIVES: To clarify the clinical features of COVID-19 and analyze maternal/fetal morbidity and mortality and the obstetric and neonatal outcomes of pregnant patients. SEARCH STRATEGY: Embase, PubMed, Web of Science, CINAHAL, LILACS, Google Scholar, and Scopus. SELECTION CRITERIA: Articles published from December 2019 to February 2021. DATA COLLECTION AND ANALYSIS: The reviewers extracted relevant data from the full-text. Data synthesis was performed using the R-4.1.0 Project for Statistical Computing for Windows. The meta-analysis of the included studies was carried out using the random-effects model (DerSimonian and Laird). Heterogeneity was measured using I2 analysis. RESULTS: A total of 70 studies included 10 047 pregnant women with COVID-19, of whom 71.6% were in their third trimester. The most common symptoms were fever, cough, chest pain, dyspnea, and fatigue. Most newborns were delivered preterm (24%, 95% confidence interval [CI] 0.17-0.34, I2  = 93%) and via cesarean delivery (42%, 95% CI 0.38-0.47, I2  = 92%). There were 108 maternal mortalities (2%, 95% CI 0.01-0.03, I2  = 54%) and 50 abortions (5%, 95% CI 0.03-0.09, I2  = 73%). The neonatal outcomes included fetal distress (11%, 95% CI 0.06-0.19, I2  = 91%), birth weight (15%, 95% CI 0.10-0.21, I2  = 76%), APGAR <7 (19%, 95% CI 0.12-0.28, I2  = 43%), admission to the neonatal intensive care unit (28%, 95% CI 0.17-0.43, I2  = 90%), and fetal mortality (2%, 95% CI 0.01-0.03, I2  = 46%). CONCLUSION:  There was no evidence of severe acute respiratory syndrome coronavirus-2 in the placenta, breast milk, umbilical cord, and amniotic fluid of pregnant patients. PROSPERO registration number: CRD42020181519.

Physical methods for the treatment of genitourinary syndrome of menopause: A systematic review.

BACKGROUND: Genitourinary syndrome of menopause (GSM) negatively affects sexual function and quality of life. Techniques like laser and radiofrequency are being used to manage GSM, particularly in women with contraindications for hormone therapy. OBJECTIVES: To verify whether the physical methods of laser and radiofrequency can be recommended as safe and effective options for the treatment of GSM/urinary urgency or incontinence in pre- and postmenopausal women. SEARCH STRATEGY: Databases were comprehensively searched using combinations of the following keywords in any language: "postmenopause"; "genitourinary syndrome of menopause"; "vaginal atrophy"; "radiofrequency"; and "laser." SELECTION CRITERIA: Full articles of case-control, cross-sectional, cohort, randomized clinical trials, and quasi-randomized or controlled clinical trials were included. DATA COLLECTION AND ANALYSIS: All authors independently evaluated the design of the studies for quality of reporting, risk of bias, and quality of evidence. MAIN RESULTS: Of the included 49 studies, 37 were on the CO2 laser, 10 on the Erbium laser, and two on radiofrequency. CONCLUSIONS: Laser and radiofrequency therapy could be promising and safe therapeutic options for GSM/urinary incontinence. However, the study findings cannot be generalized until new randomized clinical trials are performed that confirm the strength of the evidence. This review has been registered with PROSPERO: CRD42020141913.

Influence of the SPECT calibration source position on the absorbed dose calculation for 131I-NaI therapy using GATE simulations.

Many research groups have studied nuclear medicine image quantification to improve its accuracy in dose estimation. This work aims to evaluate the influence of the source calibration position for absorbed dose calculation for a 131I-NaI therapy using Monte Carlo (MC) simulations. The calibration approach consisted of a cylindrical phantom filled with water. A cylindrical 131I source with 361.1 ± 3.6 kBq ml-1 was positioned at the center of the phantom and its outer part. Images were acquired with 150 00 counts per projection image acquired with SPECT detector (high counts density-HCD) and 3000 counts per projection (low counts density-LCD). MC simulations, performed with GATE code, were validated by comparing the S values of a water sphere uniformly filled with 131I, as from the sphere model of OLINDA/EXM 1.1. Calibration factors deviation between central and peripheral calibrations is more significant for HCD (18.3%) than for LCD images (3.7%). The 3D dose distribution map obtained from GATE resulted in a dose factor equal to 1.5 × 10-3 mGy/(MBq.s). For both HCD and LCD images, the commonly used approach, which employs the central source calibration to obtain the dose from a peripheral source, resulted in dose overestimation. Results suggest that organ dose calculation can be improved considering the organ position in the field of view. Finally, patients' radiation protection in dosimetry studies could be improved considering the calibration source position, due to the superior accuracy in dose calculation.

TCF7L2 polymorphism is associated with low nitric oxide release, endothelial dysfunction and enhanced inflammatory response after myocardial infarction.

BACKGOUND: The favorable effects of insulin during myocardial infarction (MI) remain unclear due to the divergence between mechanistic studies and clinical trials of exogenous insulin administration. The rs7903146 polymorphism of the transcription factor 7-like 2 (TCF7L2) gene is associated with attenuated insulin secretion. METHODS: In non-diabetic patients with ST-elevation MI (STEMI), using such a model of genetically determined down-regulation of endogenous insulin secretion we investigated the change in plasma insulin, C-peptide, interleukin-2 (IL-2), C-reactive protein (CRP), and nitric oxide (NOx) levels between admission (D1) and the fifth day after MI (D5). Coronary angiography and flow-mediated dilation (FMD) were performed at admission and 30 days after MI, respectively. Homeostasis Model Assessment estimated insulin secretion (HOMA2%ß) and insulin sensitivity (HOMA2%S). RESULTS: Although glycemia did not differ between genotypes, carriers of the T-allele had lower HOMA2%ß and higher HOMA2%S at both D1 and D5. As compared with non-carriers, T-allele carriers had higher plasma IL-2 and CRP at D5, higher intracoronary thrombus grade, lower FMD and NOx change between D1 and D5 and higher 30-day mortality. CONCLUSION: In non-diabetic STEMI patients, the rs7903146 TCF7L2 gene polymorphism is associated with lower insulin secretion, worse endothelial function, higher coronary thrombotic burden, and higher short-term mortality. GENERAL SIGNIFICANCE: During the acute phase of MI, a lower capacity of insulin secretion may influence clinical outcome.

Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.

OBJECTIVE: Chronic dysglycemia was recently identified as a predictor for adverse outcomes in patients with ST-elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention. Data for non-diabetic patients who underwent thrombolysis is scarce. In this context, we aimed to study the effect of HbA1c on cardiovascular outcome after STEMI. METHODS: A prospective cohort of 326 non-diabetic STEMI individuals was used for the analyses. We measured plasma glucose, hemoglobin A1c [HbA1c], lipid profile, C-reactive protein (CRP), and nitrate/nitrite (NOx) upon admission and five days after STEMI (D5). Flow-mediated dilation (FMD) was performed 30 days after STEMI. During clinical follow-up, we assessed patients for incident diabetes (progression to HbA1c ≥ 6.5%) and major adverse cardiac events (MACE), defined as a composite of fatal and non-fatal MI, sudden cardiac death, and angina requiring hospitalization. RESULTS: Using ROC-curve analysis, a 5.8% HbA1c best predicted MACE with a sensitivity of 75% and specificity of 53% (AUC 0.673, p = 0.001). Patients were categorized as high HbA1c if ≥ 5.8% and low HbA1c if <5.8%. Compared with patients with low HbA1c, those with high HbA1c presented with 20% higher CRP-D5 (p = 0.009) and 19% higher ΔCRP (p = 0.01), a 32% decrease in ΔNOx (p < 0.001), and 33% lower FMD (p < 0.001). After a median follow-up of 1.9 (1.1-2.8) years, patients with high HbA1c had more incident diabetes (HR 2.3 95% CI 1.01-5.2; p = 0.048) and MACE (HR 3.32 95% CI 1.09-10.03; p = 0.03). CONCLUSION: Non-diabetic STEMI patients with high HbA1c present with decreased endothelial function and increased inflammatory response and long-term risk of MACE.

Effect of gastric bypass on spontaneous growth hormone and ghrelin release profiles.

OBJECTIVE: The purpose of this study was to analyze growth hormone (GH) concentrations in obese women before and after Roux-en-Y gastric bypass (RYGBP) and how resulting changes in weight, fat mass, ghrelin levels, and insulin sensitivity affect GH secretion. RESEARCH METHODS AND PROCEDURES: Blood was sampled at 20-minute intervals for 24 hours in 10 non-diabetic premenopausal severely obese women before and 6 months after RYGBP. GH concentrations were measured in all samples, and serum ghrelin was collected at five time-points. RESULTS: After a 27% BMI drop (55.9 +/- 6.2 to 40.7 +/- 5.8 kg/m2), blunted GH profiles underwent partial recovery. Basal, postprandial, and mean ghrelin concentrations were not changed. A negative correlation was found between mean GH levels and insulin and homeostasis model assessment (p < 0.01). BMI accounted for 54% of GH variation. DISCUSSION: Partial recovery of GH secretion after RYGBP-induced weight loss suggests that a blunted secretion is not a causal factor of obesity but a consequence of the obese state and does not seem to be ghrelin-level dependent.