Mejiabishop3014

The metazoan Hsp70 disaggregase protects neurons from proteotoxicity that arises from the accumulation of misfolded protein aggregates. Hsp70 and its co-chaperones disassemble and extract polypeptides from protein aggregates for refolding or degradation. The effectiveness of the chaperone system decreases with age and leads to accumulation rather than removal of neurotoxic protein aggregates. Therapeutic enhancement of the Hsp70 protein disassembly machinery is proposed to counter late-onset protein misfolding neurodegenerative disease that may arise. In the context of prion disease, it is not known whether stimulation of protein aggregate disassembly paradoxically leads to enhanced formation of seeding competent species of disease-specific proteins and acceleration of neurodegenerative disease. Here we have tested the hypothesis that modulation of Hsp70 disaggregase activity perturbs mammalian prion-induced neurotoxicity and prion seeding activity. To do so we used prion protein (PrP) transgenic Drosophila that authentically replicate mammalian prions. RNASeq identified that Hsp70, DnaJ-1 and Hsp110 gene expression was downregulated in prion-exposed PrP Drosophila. We demonstrated that RNAi knockdown of Hsp110 or DnaJ-1 gene expression in variant Creutzfeldt-Jakob disease prion-exposed human PrP Drosophila enhanced neurotoxicity, whereas overexpression mitigated toxicity. Strikingly, prion seeding activity in variant Creutzfeldt-Jakob disease prion-exposed human PrP Drosophila was ablated or reduced by Hsp110 or DnaJ-1 overexpression, respectively. Similar effects were seen in scrapie prion-exposed ovine PrP Drosophila with modified Hsp110 or DnaJ-1 gene expression. These unique observations show that the metazoan Hsp70 disaggregase facilitates the clearance of mammalian prions and that its enhanced activity is a potential therapeutic strategy for human prion disease.

To investigate and characterize the influence of sex, age, muscle strength, and cardiovascular fitness on manual lifting patterns using exposure variation analysis (EVA) during a full working day among blue-collar workers.

Muscular activity (surface electromyography [sEMG]) of the thigh, low-back, and shoulder was measured throughout the working day in 173 employees with manual lifting tasks from 14 workplaces. Relative sEMG loading was expressed as % of maximal voluntary contraction (MVC). As an additional and more practically oriented analysis, calibration of load from standardized box lifts (5, 10, 20, and 30 kg) identified corresponding sEMG values in kg. Using an EVA 'lifting periods' of [1 to 5, >5 to 10, >10 to 20, >20 to 30, and >30] kg in time intervals [0 to 0.5, >0.5 to 1, >1 to 2, >2 to 5, >5 to 10, and >10] s were identified. Arm elevation and back inclination were measured using accelerometers.

Females and older workers (≥50 years) primarily used the thighs for lifting and were exposed to more frequent thigh muscle 'lifting periods' of varying duration and load and performed more thigh lifts >30 kg and >60% of MVC compared with males and younger workers (P < 0.05). Females had less brief shoulder lifting periods and more work with bent back >30° than the males (P < 0.05), whereas stronger workers performed more work with elevated arm >60° and >90° than workers with low muscle strength (P < 0.05). However, besides a single difference where workers with lower cardiovascular fitness were exposed to more light (1-5 kg) and moderate duration (5-10 s) trapezius loading, the number of lifting periods was not affected by muscle strength nor cardiovascular fitness (P > 0.05).

This EVA demonstrated sex- and age-related differences in exposure to lifting periods involving shoulder and thigh muscles.

This EVA demonstrated sex- and age-related differences in exposure to lifting periods involving shoulder and thigh muscles.Placental insufficiency (PI) lowers fetal oxygen and glucose concentrations, which disrupts glucose-insulin homeostasis and promotes fetal growth restriction (FGR). To date, prenatal treatments for FGR have not attempted to correct the oxygen and glucose supply simultaneously. Therefore, we investigated whether a five-day correction of oxygen and glucose concentrations in PI-FGR fetuses would normalize insulin secretion and glucose metabolism. Experiments were performed in near-term FGR fetal sheep with maternal hyperthermia-induced PI. Fetal arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction and glucose was infused into FGR fetuses (FGR-OG). FGR-OG fetuses were compared to maternal air insufflated, saline-infused fetuses (FGR-AS) and control fetuses. Prior to treatment, FGR fetuses were hypoxemic and hypoglycemic and had reduced glucose-stimulated insulin secretion (GSIS). During treatment, oxygen, glucose, and insulin concentrations increased, and norepinephrine concentrations decreased in FGR-OG fetuses, whereas FGR-AS fetuses were unaffected. On treatment day 4, glucose fluxes were measured with euglycemic and hyperinsulinemic-euglycemic clamps. During both clamps, rates of glucose utilization and production were greater in FGR-AS than FGR-OG fetuses, while glucose fluxes in FGR-OG fetuses were not different than control rates. After five-days of treatment, GSIS increased in FGR-OG fetuses to control levels and their ex vivo islet GSIS was greater than FGR-AS islets. Despite normalization in fetal characteristics, GSIS, and glucose fluxes, FGR-OG and FGR-AS fetuses weighed less than controls. These findings show that sustained, simultaneous correction of oxygen and glucose normalized GSIS and whole-body glucose fluxes in PI-FGR fetuses after the onset of FGR.Numerous reversed-phase high-pressure liquid chromatography (RP-HPLC) and high-performance thin-layer chromatography (HPTLC) techniques have been published for the estimation of fixed-dose combinations (FDCs) of telmisartan (TEL). No published literature has been reported to date which described the synchronous estimation of FDCs of TEL using a single chromatography condition. Hence, the RP-HPLC method has been developed and validated for synchronous analysis of FDCs of TEL using an enhanced analytical quality by design (AQbD) approach to save time, cost and solvent for analysis. The implementation of AQbD was initiated with the identification of failure modes (FMs) using the Ishikawa diagram, and their critical effect analysis was carried out by risk priority number ranking and filtering method. The identified critical FMs were optimized by design of experiments-based response surface modeling using the Box-Behnken design. The method operable design region was navigated and control strategy was framed to mitigate the risk of critical FM. The RP-HPLC method was developed using Shim-Pack octadecyl silane C18 column and acetonitrile 1.0%v/v triethylamine (pH 6.5 adjusted using perchloric acid; 4258, %v/v). The developed method was found to be validated as per the International Council For Harmonization Q2 (R1) guideline. The method was applied for the synchronous assay of seven different FDCs of TEL and assay results were found in good compliance with the respective labeled claim.The earliest cortical neural signals following consciously perceived visual stimuli in humans are poorly understood. Using intracranial electroencephalography, we investigated neural activity changes associated with the earliest stages of stimulus detection during visual conscious perception. Participants (N = 10; 1,693 electrode contacts) completed a continuous performance task where subjects were asked to press a button when they saw a target letter among a series of nontargets. Broadband gamma power (40-115 Hz) was analyzed as marker of cortical population neural activity. Regardless of target or nontarget letter type, we observed early gamma power changes within 30-180 ms from stimulus onset in a network including increases in bilateral occipital, fusiform, frontal (including frontal eye fields), and medial temporal cortex; increases in left lateral parietal-temporal cortex; and decreases in the right anterior medial occipital cortex. No significant differences were observed between target and nontarget stimuli until >180 ms post-stimulus, when we saw greater gamma power increases in left motor and premotor areas, suggesting a possible role in perceptual decision-making and/or motor responses with the right hand. The early gamma power findings support a broadly distributed cortical visual detection network that is engaged at early times tens of milliseconds after signal transduction from the retina.We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin and cyclosporin A with (n=49) or without (n=49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR+IST and IST groups was similar (65% vs. 53%, p=0.218); however, the complete response (CR) rate was significantly higher in ELTR+IST group (31% vs. 12%, p=0.027). In severity subgroups, the ORR was 89% vs. 57% (p=0.028) in favor of IST+ELTR in SAA, but it did not differ in patients with vSAA (52% vs. 50%, p=0.902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared to 17% of initial ELTR(+) patients (p=0.016). No significant difference in ELTR+IST and IST groups was observed in the 3-year OS (89% vs. 91%, p=0.673) or the 3-year EFS (53% vs. 41%, p=0.326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA, but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. Clinicaltrials.gov #NCT03413306.Metastasis around dental implant are extremely rare. They usually represent a secondary localization of a multi-organ metastatic neoplasm but also, exceptionally, recognized as first clinical manifestation of a still unknown cancer of whatever organ. Metastases usually manifest as rapidly growing lesions of hard and soft tissues, and always represent a true diagnostic/therapeutic dilemma both for clinicians, in choosing the more appropriate treatment, and for pathologists to recognize the primary tumor when still un-diagnosed. We report two distinct cases of metastasis both occurring around dental implants in the maxilla and mimicking perimplantitis at the onset; more precisely, in one case lesion involved exclusively the alveolar bone where implant were previously inserted, while in the other case neoplasm caused bone destruction around the fixture with an impressive and rapid exophytic growth. In both cases, maxillary lesions were the first metastatic manifestation of an unknown adenocarcinoma of the lung.