Atypical intrinsic neural timescale in the left angular gyrus in Alzheimer's disease.

Alzheimer's disease is characterized by cognitive impairment and progressive brain atrophy. Recent human neuroimaging studies reported atypical anatomical and functional changes in some regions in the default mode network in patients with Alzheimer's disease, but which brain area of the default mode network is the key region whose atrophy disturbs the entire network activity and consequently contributes to the symptoms of the disease remains unidentified. Here, in this case-control study, we aimed to identify crucial neural regions that mediated the phenotype of Alzheimer's disease, and as such, we examined the intrinsic neural timescales-a functional metric to evaluate the capacity to integrate diverse neural information-and grey matter volume of the regions in the default mode network using resting-state functional MRI images and structural MRI data obtained from individuals with Alzheimer's disease and cognitively typical people. After confirming the atypically short neural timescale of the entire default mode network in Alzheimer's disease and its link with the symptoms of the disease, we found that the shortened neural timescale of the default mode network was associated with the aberrantly short neural timescale of the left angular gyrus. Moreover, we revealed that the shortened neural timescale of the angular gyrus was correlated with the atypically reduced grey matter volume of this parietal region. Furthermore, we identified an association between the neural structure, brain function and symptoms and proposed a model in which the reduced grey matter volume of the left angular gyrus shortened the intrinsic neural time of the region, which then destabilized the entire neural timescale of the default mode network and resultantly contributed to cognitive decline in Alzheimer's disease. These findings highlight the key role of the left angular gyrus in the anatomical and functional aetiology of Alzheimer's disease.

Assessing freedom from chronic wasting disease in semi-domesticated reindeer in Norway and Sweden.

Establishing freedom from disease is a key component of surveillance and may have direct consequences for trade and economy. Transboundary populations pose challenges in terms of variable legislation, efforts, and data availability between countries, often limiting surveillance efficiency. Chronic wasting disease (CWD) is a contagious prion disease of cervids. The long incubation period and slow initial epidemic growth make it notoriously difficult to detect CWD in the early phase of an epidemic. The recent emergence of CWD in wild reindeer in Norway poses a threat to approximately 250,000 semi-domesticated reindeer in Norway and 250,000 in Sweden, including transboundary populations. Here, we provide a first analysis of surveillance data (2016-2022) from all reindeer districts in Norway and Sweden to determine the probability of freedom from CWD infection. During the six years, 6017 semi-domesticated reindeer were tested in Sweden and 51,974 in Norway. Most samples came from healthy slaughtered animals (low risk). Reindeer use large and remote areas and (high risk) samples from fallen stock and animals with clinical signs were difficult to obtain. A scenario tree model was run for seven different set of values for the input parameters (design prevalence within and between districts, probability of introduction, and relative risks) to determine the effect on surveillance sensitivity. At the national level, the mean probability of disease freedom was 59.0 % in Sweden and 87.0 % in Norway by 2021. The most marked effect on sensitivity was varying the design prevalence both within and between districts. Uncertainty about relative risk ratios affected sensitivity for Sweden more than for Norway, due to the higher proportion of animals in the high-risk group in the former (13.8 % vs. 2.1 %, respectively). A probability of disease freedom of 90 % or higher was reached in 8.2 % of the 49 districts in Sweden and 43.5 % of the 46 districts in Norway for a design prevalence of 0.5 %. The probability of freedom remained below 60 % in 29 districts (59.2 %) in Sweden and 10 districts (21.7 %) in Norway. At the national level, only Norway had a sufficiently large number of samples to reach a probability of more than 95 % of disease freedom within a period of 10 years. Our cross-border assessment forms an important knowledge base for designing future surveillance efforts depending on the spatial pattern of prevalence of CWD and risk of spread.

A dual-color PAX7 and MYF5 in vivo reporter to investigate muscle stem cell heterogeneity in regeneration and aging.

Increasing evidence suggests that the muscle stem cell (MuSC) pool is heterogeneous. In particular, a rare subset of PAX7-positive MuSCs that has never expressed the myogenic regulatory factor MYF5 displays unique self-renewal and engraftment characteristics. However, the scarcity and limited availability of protein markers make the characterization of these cells challenging. Here, we describe the generation of StemRep reporter mice enabling the monitoring of PAX7 and MYF5 proteins based on equimolar levels of dual nuclear fluorescence. High levels of PAX7 protein and low levels of MYF5 delineate a deeply quiescent MuSC subpopulation with an increased capacity for asymmetric division and distinct dynamics of activation, proliferation, and commitment. Aging primarily reduces the MYF5Low MuSCs and skews the stem cell pool toward MYF5High cells with lower quiescence and self-renewal potential. Altogether, we establish the StemRep model as a versatile tool to study MuSC heterogeneity and broaden our understanding of mechanisms regulating MuSC quiescence and self-renewal in homeostatic, regenerating, and aged muscles.

Examining variation in the relationship between disability and physical activity across Australian local government areas.

Understanding the relationship between disability and physical activity and whether it differs across local government jurisdictions may aid in the development of placed-based approaches to reducing disability-related inequalities in physical activity. The objectives of this study were to examine the association between disability and physical activity and assess whether this association varied between Australian Local Government Areas. The sample included 13,315 participants aged 18-64 years from the Household Income and Labour Dynamics Australia Survey, 2017. Participants self-reported disability and physical activity. Linear mixed-effects models estimated the association between disability and physical activity. People with disability reported less physical activity per week. We did not find evidence that this association varied across LGAs. Our findings do not add evidence towards local government-based approaches in Australia to reducing physical activity inequalities between people with and without a disability.

The Mediating Role of Kynurenine Pathway Metabolites on the Relationship Between Inflammation and Muscle Mass in Oldest-Old Men.

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ±â€…4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [n = 305] with interleukin [IL-6, IL-1ß, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%-92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se.

The moderating effects of greenspace on the association between neighbourhood disadvantage and obesity among mid-to-older aged Australian adults.

This study examined whether the association between neighbourhood disadvantage and obesity was moderated by quantity and quality of greenspace. The sample included 2848 mid-to-older aged adults residing in 200 neighbourhoods in Brisbane, Australia from the HABITAT study. Self-reported height and weight were used to calculate body mass index (BMI), neighbourhood disadvantage was measured using a census-derived composite index and greenspace was measured geospatially. We found evidence of moderation by park quality: lower average BMI at higher levels of park quality was shown in the Q3 rather than the Q1 (least disadvantaged) neighbourhood disadvantage group. The findings suggest that, for reducing socioeconomic inequalities in obesity, the quality of greenspace is imperative.

Changes in neighbourhood walkability and body mass index: An analysis of residential mobility from a longitudinal multilevel study in Brisbane, Australia.

This study examined associations between changes in neighbourhood walkability and body mass index (BMI) among 1041 residents who relocated within Brisbane, Australia between 2007 and 2016 over five waves of the HABITAT study. Measures included spatially-derived neighbourhood walkability (dwelling density, street connectivity, and land use mix) and self-reported height and weight. No associations were found between any neighbourhood walkability characteristics and BMI. Examining these associations over the life course, and the impact of residential relocation in the younger years, remains a priority for future research.

Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice.

Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2-related MD, and collagen VI-related myopathy were associated with inefficient mobilization of MuSCs after tissue damage. Using chemoinformatic analysis, we identified the 13-amino acid form of the peptide hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. Systemic administration of AP-13 using osmotic pumps generated a pro-proliferative EC-rich niche that supported MuSC function through angiocrine factors and markedly improved tissue regeneration and muscle strength in all three dystrophic mouse models. Moreover, EC-specific knockout of the apelin receptor led to regenerative defects that phenocopied key pathological features of MD, including vascular defects, fibrosis, muscle fiber necrosis, impaired MuSC function, and reduced force generation. Together, these studies provide in vivo proof of concept that enhancing endogenous skeletal muscle repair by targeting the vascular niche is a viable therapeutic avenue for MD and characterized AP-13 as a candidate for further study for the systemic treatment of MuSC dysfunction.

Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Effects of qigong exercise on physical fitness and patient-reported health outcomes in lung cancer survivors.

PURPOSE: The aim of this study was to investigate the effects of a three-month Guolin Qigong (GQ) intervention on physical fitness and patient-reported health outcomes among patients with lung cancer. METHODS: This pilot study was a non-randomized controlled trial. Eligible participants who were over 18 years of age and diagnosed with stage I-IV lung cancer were enrolled in the study and received either the GQ intervention or usual care (UC). Participants in the GQ group performed GQ at least twice a week (one hour per session) for three months. Physical fitness (chair stand, arm curl, sit and reach, back scratch, 8-foot up and go, 6-min walk test) was assessed at baseline, post-intervention, six months, and 12 months. Self-reported quality of life and sleep (European Organization for Research and Treatment of Cancer Quality of Life questionnaire and Pittsburgh Sleep Quality Index) were assessed at baseline, post-intervention, and six months. RESULTS: Forty-nine participants (65% females, 59.1 ± 7.0 years old, ranging from 39 to 71 years old) were enrolled in the study, and 25 participants completed all tests at 12-month follow-up (13 in GQ vs. 12 in UC; 68% females, 59.3 ± 5.5 years old). Compared to the UC group, results for the chair stand and arm curl tests improved significantly in the GQ group from baseline to post-intervention (P = 0.024 and P = 0.041, respectively). Similarly, the 8-foot up and go test improved in the GQ group from baseline to post-intervention and 12 months (P = 0.004 and P = 0.008, respectively) when compared to the UC group. Between-group analyses also revealed a statistically significant improvement in global health status/quality of life from baseline to six months (P = 0.018) and quality of sleep from baseline to post-intervention (P = 0.034) in favor of the GQ group. CONCLUSION: GQ had a beneficial effect on lower and upper body strength, locomotor performance (speed, agility, and balance while moving), quality of sleep, and quality of life among lung cancer survivors, but further randomized controlled trials are warranted to confirm these findings. TRIAL REGISTRATION: The trial has been registered in the Chinese Clinical Trial Registry (ChiCTR2200059145).

Nutrient Metabolites Associated With Low D3Cr Muscle Mass, Strength, and Physical Performance in Older Men.

BACKGROUND: The relationship between amino acids, B vitamins, and their metabolites with D3-creatine (D3Cr) dilution muscle mass, a more direct measure of skeletal muscle mass, has not been investigated. We aimed to assess associations of plasma metabolites with D3Cr muscle mass, as well as muscle strength and physical performance in older men from the Osteoporotic Fractures in Men cohort study. METHODS: Out of 1 425 men (84.2 ±â€…4.1 years), men with the lowest D3Cr muscle mass (n = 100), slowest walking speed (n = 100), lowest grip strength (n = 100), and a random sample (n = 200) serving as a comparison group to the low groups were included. Metabolites were analyzed using liquid chromatography-tandem mass spectrometry. Metabolite differences between the low groups and random sample and their relationships with the muscle outcomes adjusted for confounders and multiple comparisons were assessed using t-test/Mann-Whitney-Wilcoxon and partial correlations, respectively. RESULTS: For D3Cr muscle mass, significant biomarkers (p < .001) with ≥10% fold difference and largest partial correlations were tryptophan (Trp; r = 0.31), kynurenine (Kyn)/Trp; r = -0.27), nicotinamide (Nam)/quinolinic acid (Quin; r = 0.21), and alpha-hydroxy-5-methyl-tetrahydrofolate (hm-THF; r = -0.25). For walking speed, hm-THF, Nam/Quin, and Quin had the largest significance and fold difference, whereas valine (r = 0.17), Trp (r = 0.17), HKyn/Xant (r = -0.20), neopterin (r = -0.17), 5-methyl-THF (r = -0.20), methylated folate (r = -0.21), and thiamine (r = -0.18) had the strongest correlations. Only hm-THF was correlated with grip strength (r = -0.21) and differed between the low group and the random sample. CONCLUSIONS: Future interventions focusing on how the Trp metabolic pathway or hm-THF influences D3Cr muscle mass and physical performance declines in older adults are warranted.

Associations between changes in crime and changes in walking for transport with effect measure modification by gender: A fixed-effects analysis of the multilevel longitudinal HABITAT study (2007-2016).

Walking for transport is a potential solution to increasing physical activity in mid to older aged adults however neighbourhood crime may be a barrier. Using data from the How Areas in Brisbane Influence HealTh and AcTivity (HABITAT) study 2007-2016, this study examined associations between changes in crime (perceived crime and objectively measured crime) and changes in transport walking, and whether this association differed by gender. Fixed effects regression modelled associations between changes in crime and changes in transport walking, with interaction terms examining effect modification by gender. Positive associations were found between crimes against person and walking for transport. There was no evidence of effect modification by gender. Understanding the relationship between crime and walking for transport can inform policies aimed at promoting transport walking.

Hemoglobin A1c as a Substitute for Oral Glucose Testing in Early Pregnancy Screening.

OBJECTIVE: Current recommendations for individuals with risk factors for gestational diabetes mellitus (GDM) call for screening in early pregnancy. However, there is currently no clear consensus on a specific screening modality. This study evaluates whether a hemoglobin A1c (HbA1c) screening in individuals with risk factors for gestational diabetes (GDM) could be used instead of an early 1-hour glucose challenge test (GCT). We hypothesized that the HbA1c could replace 1-hour GCT in early pregnancy evaluation STUDY DESIGN: This is a prospective observational trial at a single tertiary referral center of women with at least one risk factor for GDM who were screened at <16 weeks of gestation with both 1-hour GCT or HbA1c. Exclusion criteria include: previous diagnosis of diabetes mellitus, multiple gestation, miscarriage, or missing delivery information. The diagnosis of GDM was made by a 3-hour 100-g glucose tolerance test, using the Carpenter-Coustan criteria (at least two results >94, 179, 154, and 139 mg/dL for fasting, 1-, 2-, and 3-hour values, respectively), 1-hour GCT > 200 mg/dL, or HbA1c > 6.5%. RESULTS: A total of 758 patients met inclusion criteria. A total of 566 completed a 1-hour GCT and 729 had an HbA1c collected. The median gestational age at testing was 91/7 weeks (range: 40/7-156/7 weeks]. Twenty-one participants were diagnosed with GDM at <16 weeks' GA. The receiver operating characteristic (ROC) curves identified the optimal valves for a positive screen for an HbA1c > 5.6%. The HbA1c had a sensitivity of 84.2%, a specificity of 83.3%, and a false positive rate of 16.7% (p < 0.001). The area under the ROC curve for the HbA1c was 0.898. Gestational age of delivery was slightly earlier with individuals with an elevated HbA1c but no other changes in delivery or neonatal outcomes. Contingent screening improved specificity (97.7%) and decreased false positive rate to 4.4%. CONCLUSION: HbA1c may be a good assessment in early pregnancy for gestational diabetes. KEY POINTS: · HbA1c is a rational assessment in early pregnancy.. · An HbA1c > 5.6% is associated with gestational diabetes.. · Contingent screening limits the need for additional testing..

The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.

Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.

Neural activation to peer acceptance and rejection in relation to concurrent and prospective depression risk in adolescent and pre-adolescent girls.

Neurobiological sensitivity to peer interactions is a proposed marker of risk for adolescent depression. We investigated neural response to peer rejection and acceptance in relation to concurrent and prospective depression risk in adolescent and pre-adolescent girls. Participants were 76 girls (Mage=13, 45% racial/ethnic minorities) varying in depression risk: 22 with current major depressive disorder (MDD), 30 at High Risk for MDD based on parental history, and 24 at Low Risk with no psychiatric history. Girls participated in the Chatroom-Interact task-involving rejection and acceptance feedback from fictitious peers-while undergoing functional magnetic resonance neuroimaging. Activation in response to peer rejection and acceptance was extracted from regions of interest. Depressive symptoms were assessed at 6- and 12-month follow-up. Girls with MDD showed blunted left subgenual anterior cingulate response to acceptance versus girls in High and Low Risk groups. Girls in the High Risk group showed greater right temporo-parietal junction (rTPJ) and right anterior insula (AI) activation to both acceptance and rejection versus girls in the MDD (rTPJ) and Low Risk (rTPJ, AI) groups. Greater rTPJ response to rejection was associated with fewer depressive symptoms at 12-months and mediated the association between High Risk group status and 12-month depressive symptoms; greater rTPJ response to acceptance mediated the association between High Risk and increased 12-month depressive symptoms. Our finding of associations between altered neural response to peer interactions and concurrent and prospective depression risk/resilience highlights the importance of neural underpinnings of social cognition as risk and compensatory adaptations along the pathway to depression.

Evidence for inefficient contraction and abnormal mitochondrial activity in sarcopenia using magnetic resonance spectroscopy.

BACKGROUND: Mitochondrial dysfunction has been implicated in sarcopenia. 31 P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function. METHODS: Twenty Chinese men with sarcopenia (SARC, age = 73.1 ± 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 ± 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations. RESULTS: Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 ± 0.59 vs. 0.57 ± 0.22, moderate: 0.93 ± 0.43 vs. 0.58 ± 0.68, high: 0.70 ± 0.57 vs. 0.43 ± 0.51 mmol L-1  min-1  bar-1  cm-2 , P = 0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3 ± 6.4 vs. 14.6 ± 6.5 mmol L-1  min-1 , P = 0.2). However, relative increases in end-exercise ADP in SARC (31.8 ± 9.9 vs. 24.0 ± 7.3 mmol L-1 , P = 0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho = -0.42, P = 0.03] and end-exercise ADP (complex III, rho = -0.52, P = 0.01; CS rho = -0.45, P = 0.02; SDH rho = -0.45, P = 0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho = -0.47, P = 0.02), and the cost of contraction at high intensity (rho = -0.54, P = 0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho = 0.5, P = 0.03), CS (rho = 0.47, P = 0.02) and SDH (rho = 0.46, P = 0.03), linking increased mitochondrial complex activity with increased ability to generate energy through oxidative pathways. CONCLUSIONS: This study used 31 P MRS to assess ATP utilization and resynthesis in sarcopenic muscle and demonstrated abnormal increases in the energy cost during exercise and perturbed mitochondrial energetics in recovery. Associations between mitochondrial complex activity and the fractional contribution to energy requirement during exercise indicate increased ability to generate energy oxidatively in those with better mitochondrial complex activity.

Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Third Trimester Ultrasound Stratifies Risk of Peripartum Complications in Pregnancies Complicated by Impaired Glucose Tolerance.

OBJECTIVE: The objective of our study was to investigate the effect of impaired glucose metabolism (IGM) and ultrasound (US) findings consistent with hyperglycemia on maternal and neonatal outcomes. STUDY DESIGN: This was a retrospective case-control study of singleton, nonanomalous pregnancies with an elevated 1-hour glucose screening test (GST) completed after 23 weeks of gestation. IGM was defined as a 1-hour GST of >130, but less than two abnormal values on 3-hour glucose tolerance test (GTT). Gestational diabetes was defined as two or more abnormal values on 3-hour GTT. Ultrasound evidence of hyperglycemia was defined as abdominal circumference >95th centile and/or polyhydramnios. Individuals with IGM were divided into those with ultrasound evidence of hyperglycemia (impaired glucose metabolism consistent with ultrasound findings [IGM-US]) and those without IGM. Maternal demographics, delivery outcomes (gestational age at delivery, delivery mode, shoulder dystocia, lacerations), postpartum hemorrhage, and neonatal outcome (birth weight centile [BW%], neonatal intensive care unit admission, hypoglycemia, and glucose) were recorded. Composite morbidity was tabulated. Delivery and neonatal outcome variables were compared in individuals with IGM-US, IGM, and gestational diabetes mellitus (GDM). Odds ratios were calculated and adjusted for maternal age, BMI, and gestational weight gain. RESULTS: A total of 637 individuals with an abnormal 1-hour GST were included (122 with IGM-US, 280 with IGM, and 235 with GDM). When compared to the IGM group, IGM-US had higher rates of cesarean delivery and BW% > 90th centile at delivery (adjusted odds ratio [aOR]: 1.7 [1.1-2.8] and aOR: 5.9 [2.7-13.0], respectively). Individuals with GDM also demonstrated similar rates with BW% > 90% but not cesarean section(aOR: 3.9 [1.8-8.5] and aOR: 1.4 [0.9-2.1], respectively). The remaining maternal and fetal outcomes were similar. CONCLUSION: Women with impaired glucose tolerance should have a third-trimester ultrasound to identify an increased risk of perinatal complications. KEY POINTS: · Women with elevated blood glucose screening should be evaluated with third-trimester ultrasound to identify risks for perinatal morbidity.. · The third-trimester ultrasound identifies individuals at risk for cesarean section.. · Counseling should be completed with individuals with polyhydramnios or accelerated growth..

Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration.

Nicotinamide riboside kinases (NRKs) control the conversion of dietary Nicotinamide Riboside (NR) to NAD+, but little is known about their contribution to endogenous NAD+ turnover and muscle plasticity during skeletal muscle growth and remodeling. Using NRK1/2 double KO (NRKdKO) mice, we investigated the influence of NRKs on NAD+ metabolism and muscle homeostasis, and on the response to neurogenic muscle atrophy and regeneration following muscle injury. Muscles from NRKdKO animals have altered nicotinamide (NAM) salvage and a decrease in mitochondrial content. In single myonuclei RNAseq of skeletal muscle, NRK2 mRNA expression is restricted to type IIx muscle fibers, and perturbed NAD+ turnover and mitochondrial metabolism shifts the fiber type composition of NRKdKO muscle to fast glycolytic IIB fibers. NRKdKO does not influence muscle atrophy during denervation but alters muscle repair after myofiber injury. During regeneration, muscle stem cells (MuSCs) from NRKdKO animals hyper-proliferate but fail to differentiate. NRKdKO also alters the recovery of NAD+ during muscle regeneration as well as mitochondrial adaptations and extracellular matrix remodeling required for tissue repair. These metabolic perturbations result in a transient delay of muscle regeneration which normalizes during myofiber maturation at late stages of regeneration via over-compensation of anabolic IGF1-Akt signaling. Altogether, we demonstrate that NAD+ synthesis controls mitochondrial metabolism and fiber type composition via NRK1/2 and is rate-limiting for myogenic commitment and mitochondrial maturation during skeletal muscle repair.

Treatment with Ginkgo biloba supplement modulates oxidative disturbances, inflammation and vascular functions in oxygen deprived hypothyroid mice: Involvement of endothelin-1/NO signaling pathways.

A double-hit biological alteration involving exposure to oxygen deprivation in hypothyroid condition may exacerbate cellular oxidative and inflammatory disturbances comparative to a one-hit biological exposure. This study investigated the therapeutic effect of Ginkgo biloba as cardioprotective against aortic oxido-inflammatory disturbances following oxygen deprivation in hypothyroid mice. Male Swiss mice were partitioned into 5 groups (n = 6) for hypothyroidism (Carbimazole 1.2 mg/kg) and hypoxia induction. Group 1 (normal control), group 2 (hypoxic stress control), group 3 (hypoxic and hypothyroid stress), group 4 (hypoxic and hypothyroid stress and Ginkgo biloba 20 mg/kg; p.o) and group 5 (hypoxic and hypothyroid stress and Levothyroxine 10 µg/kg; p.o) for 14 days. Thereafter, serum and aorta was collected for biochemical evaluation. GBS did not up-regulate the serum thyroid hormone imbalances (tri-iodothyronine (T3), thyroxin (T4)) but maintains the TSH levels. The blood glucose level was reduced with decrease oxidative stress and inflammatory mediators in the serum/aorta indicated by inhibited redox status following treatment with GBS. Moreover, endothelin-1/nitric oxide signaling pathways were markedly regulated in the aorta. Conclusively, GBS acts as a therapeutic agent and may be consider as a potential vasodilator candidate in the management and control of hypoxic stress in hypothyroid condition. PRACTICAL APPLICATIONS: Treatment with Gingko biloba supplement abated endothelial abnormalities via elevation of nitric oxide release and suppression of endothelin activity in hypothyroid mice exposed to hypoxic hypoxia. The activity of myeloperoxidase enzyme and redo-inflammatory status was downregulated following treatment with Gingko biloba supplement in hypothyroid mice exposed to hypoxic hypoxia. Treatment with Gingko biloba supplement modulates hypothalamic-pituitary-adrenal (HPA) axis by inhibiting corticosterone release in hypothyroid mice exposed to hypoxic hypoxia.