Notes

Radiologically singled out symptoms: Any single-center, retrospective cohort review.
Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remains unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone, a synthetic glucocorticoid. Treating wild type (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue and gastrocnemius muscle. This DEX effect was diminished in gastrocnemius muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in gastrocnemius muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced gastrocnemius myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.We have shown that nitric oxide limits ataxia-telangiectasia mutated (ATM) signaling by inhibiting mitochondrial oxidative metabolism in a β-cell selective manner. In this study, we examined the actions of nitric oxide on a second DNA damage response (DDR) transducer kinase, ataxia-telangiectasia and Rad3-related protein (ATR). In β-cells and non-β-cells, nitric oxide activates ATR signaling by inhibiting ribonucleotide reductase (RNR); however, when produced at iNOS-derived (low μM) levels, nitric oxide impairs ATR signaling in a β-cell selective manner. The inhibitory actions of nitric oxide are associated with impaired mitochondrial oxidative metabolism and lack of glycolytic compensation that results in a decrease in β-cell ATP. Like nitric oxide, inhibitors of mitochondrial respiration reduce ATP levels and limit ATR signaling in a β-cell selective manner. When non-β-cells are forced to utilize mitochondrial oxidative metabolism for ATP generation their response is more like β-cells, as nitric oxide and inhibitors of mitochondrial respiration attenuate ATR signaling. These studies support a dual role for nitric oxide in regulating ATR signaling. Nitric oxide activates ATR in all cell types examined by inhibiting RNR, and in a β-cell selective manner, iNOS-derived levels of nitric oxide limit ATR signaling by attenuating mitochondrial oxidative metabolism and depleting ATP.Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. During lethal cryptococcal meningitis in the brain, C. neoformans senses a Cu deficient environment and is highly dependent upon its ability to scavenge trace levels of Cu from its host and adapt to Cu scarcity to successfully colonize this niche. In this study we demonstrate for this critical adaptation, the Cu-sensing transcription factor Cuf1 differentially regulates the expression of the SOD1 and SOD2 superoxide dismutases in novel ways. Genetic and transcriptional analysis reveals Cuf1 specifies 5'-truncations of the SOD1 and SOD2 mRNAs through specific binding to copper responsive elements (CuREs) within their respective promoter regions. This results in Cuf1-dependent repression of the highly abundant SOD1 and simultaneously induces expression of two isoforms of SOD2 from a single alternative transcript produced specifically under Cu limitation; the canonical mitochondrial targeted isoform and a novel alternative cytosolic isoform. The generation of cytosolic Sod2 during Cu limitation is required to maintain cellular antioxidant defense against superoxide stress both in vitro and in vivo. Further, decoupling Cuf1 regulation of Sod2 localization compromises the ability of C. neoformans to colonize organs in murine models of cryptococcosis. Our results provide a link between transcription factor-mediated alteration of protein localization and cell proliferation under stress, which could impact tissue colonization by a fungal pathogen.Acinetobacter baumannii, a leading cause of nosocomial infections, is a serious health threat. Limited therapeutic options due to multi-drug resistance and tolerance due to persister cells have urged the scientific community to develop new strategies to combat infections caused by this pathogen effectively. Since combination antibiotic therapy is an attractive strategy, the effect of combinations of antibiotics, belonging to four classes, was investigated on eradication of persister cells in A. baumannii. Among the antibiotics included in the study, tobramycin-based combinations were found to be the most effective. Tobramycin, in combination with colistin or ciprofloxacin, eradicated persister cells in A. selleck chemicals llc baumannii in late exponential and stationary phases of growth. Mechanistically, colistin facilitated the entry of tobramycin into cells by increasing membrane permeability and inducing hyperpolarization of the inner membrane accompanied by increase in ROS production. Expression of the genes encoding universal stress protein and efflux pumps was down-regulated in response to tobramycin and colistin, suggesting increased lethality of their combination that might be responsible for eradication of persister cells. Thus, a combination of tobramycin and colistin could be explored as a promising option for preventing the relapse of A. baumannii infections due to persister cells.
To investigate the short-term effects of dry needling (DN) on physical function, pain, and hip muscle strength in patients with hip osteoarthritis (OA).

A double-blind, placebo-control, randomized controlled trial.

Private practice physiotherapy clinic.

Patients with unilateral hip OA (N=45) were randomly allocated to a DN group, sham DN group, or control group.

Patients in the DN and sham groups received 3 treatment sessions. Three active myofascial trigger points (MTrPs) were treated in each session with DN or a sham needle procedure. The treatment was applied in active MTrPs of the iliopsoas, rectus femoris, tensor fasciae latae, and gluteus minimus muscles.

Physical function was assessed with the Western Ontario and McMaster Universities (WOMAC) physical function subscale, the timed Up and Go test, and the 40-meter self-paced walk test. Intensity of hip pain related to physical function was evaluated using the visual analog scale and WOMAC pain subscale. The maximal isometric force of hip muscles was recorded with a handheld dynamometer.

Significant group by time interactions were shown for physical function, pain, and hip muscle force variables. Post hoc tests revealed a significant reduction in hip pain and significant improvements in physical function and hip muscle strength in the DN group compared with the sham and control groups. The DN group showed within- and between-groups large effect sizes (d>0.8).

DN therapy in active MTrPs of the hip muscles reduced pain and improved hip muscle strength and physical function in patients with hip OA. DN in active MTrPs of the hip muscles should be considered for the management of hip OA.
DN therapy in active MTrPs of the hip muscles reduced pain and improved hip muscle strength and physical function in patients with hip OA. DN in active MTrPs of the hip muscles should be considered for the management of hip OA.
To evaluate the benefits of aerobic training (AT) programs on cardiorespiratory fitness, functional capacity, balance, and fatigue in individuals with multiple sclerosis (MS) and to identify the optimal dosage of AT programs for individuals with MS via a systematic review with meta-analysis.

Two electronic databases were searched until March 2020 (PubMed-Medline and Web of Science).

Studies examining the effect of AT program on cardiorespiratory fitness, functional capacity, balance, and fatigue were included.

After applying the inclusion and exclusion criteria, we included 43 studies. A total sample of 1070 individuals with MS (AT group, n=680; control group, n=390) were analyzed.

The AT group demonstrated a significant increase in cardiorespiratory fitness (standardized mean difference [SMD], 0.29; P=.002), functional capacity (timed Up and Go Test SMD, -1.14; P<.001; gait speed SMD, -1.19; P<.001; walking endurance SMD, 0.46; P<.001), and balance (SMD, 3.49; P<.001) after training. Faous and walking methods could optimize gait speed.
Aerobic training improves gait speed, walking endurance, and balance. Cardiorespiratory fitness and fatigue perception also improved after AT, but we found no differences with the control group. In addition, subgroup analysis suggested that training using continuous and walking methods could optimize gait speed.
Few studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. A retrospective observational cohort study was undertaken in neonates to determine this target and dosing recommendations (chictr.org.cn, ChiCTR1900027919).

A Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes, including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo simulations based on the optimised exposure target.

Pop-PK modelling included 182 neonates with 411 observations. On covariate analysis, neonatal physiological maturation, renal function and concomitant use of vasoactive agents (VAS) significantly affected vancomycin PK. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0-24 hours (AUC
) ≥ 485 mg•h/L was an independent risk factor for AKI after adjusting for VAS co-administration. The clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC
to minimum inhibitory concentration (AUC
/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. Monte Carlo simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were unsuitable for all neonates.

An AUC
of 240-480 (assuming MIC=1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.
An AUC0-24 of 240-480 (assuming MIC = 1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.
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