Miracle-dz/UniFAR-FTUs huggingface dataset:
TNF Receptor‐Associated Factor 6 Mediates TNFα‐Induced Skeletal Muscle Atrophy in Mice During Aging

During aging, muscle mass decreases, leading to sarcopenia, associated with low‐level chronic inflammation (inflammaging), which induces sarcopenia by promoting proteolysis of muscle fibers and inhibiting their regeneration. Patients with a variety of pathologic conditions associated with sarcopenia, including rheumatoid arthritis (RA), have systemically elevated TNFα serum levels, and transgenic mice with TNFα overexpression (TNF‐Tg mice, a model of RA) develop sarcopenia between adolescence and adulthood before they age. However, if and how TNFα contributes to the pathogenesis of sarcopenia during the normal aging process and in RA remains largely unknown. We report that TNFα levels are increased in skeletal muscles of aged WT mice, associated with muscle atrophy and decreased numbers of satellite cells and Type IIA myofibers, a phenotype that we also observed in adult TNF‐Tg mice. Aged WT mice also have increased numbers of myeloid lineage cells in their skeletal muscles, including macrophages and granulocytes. These cells have increased TNFα expression, which impairs myogenic cell differentiation. Expression levels of TNF receptor‐associated factor 6 (TRAF6), an E3 ubiquitin ligase, which mediates signaling by some TNF receptor (TNFR) family members, are elevated in skeletal muscles of both aged WT mice and adult TNF‐Tg mice. TRAF6 binds to TNFR2 in C2C12 myoblasts and mediates TNFα‐induced muscle atrophy through NF‐κB‐induced transcription of the muscle‐specific E3 ligases, Atrogen1 and Murf1, which promote myosin heavy‐chain degradation. Haplo‐deficiency of TRAF6 prevents muscle atrophy and the decrease in numbers of satellite cells, Type IIA myofibers, and myogenic regeneration in TRAF6+/−;TNF‐Tg mice. Our findings suggest that pharmacologic inhibition of TRAF6 signaling in skeletal muscles during aging could treat/prevent age‐ and RA‐related sarcopenia by preventing TNFα‐induced proteolysis and inhibition of muscle fiber regeneration. © 2020 American Society for Bone and Mineral Research.
The Frog Motor Nerve Terminal Has Very Brief Action Potentials and Three Electrical Regions Predicted to Differentially Control Transmitter Release

The action potential (AP) waveform controls the opening of voltage-gated calcium channels and contributes to the driving force for calcium ion flux that triggers neurotransmission at presynaptic nerve terminals. Although the frog neuromuscular junction (NMJ) has long been a model synapse for the study of neurotransmission, its presynaptic AP waveform has never been directly studied, and thus the AP waveform shape and propagation through this long presynaptic nerve terminal are unknown. Using a fast voltage-sensitive dye, we have imaged the AP waveform from the presynaptic terminal of male and female frog NMJs and shown that the AP is very brief in duration and actively propagated along the entire length of the terminal. Furthermore, based on measured AP waveforms at different regions along the length of the nerve terminal, we show that the terminal is divided into three distinct electrical regions: A beginning region immediately after the last node of Ranvier where the AP is broadest, a middle region with a relatively consistent AP duration, and an end region near the tip of nerve terminal branches where the AP is briefer. We hypothesize that these measured changes in the AP waveform along the length of the motor nerve terminal may explain the proximal-distal gradient in transmitter release previously reported at the frog NMJ. SIGNIFICANCE STATEMENT The AP waveform plays an essential role in determining the behavior of neurotransmission at the presynaptic terminal. Although the frog NMJ is a model synapse for the study of synaptic transmission, there are many unknowns centered around the shape and propagation of its presynaptic AP waveform. Here, we demonstrate that the presynaptic terminal of the frog NMJ has a very brief AP waveform and that the motor nerve terminal contains three distinct electrical regions. We propose that the changes in the AP waveform as it propagates along the terminal can explain the proximal-distal gradient in transmitter release seen in electrophysiological studies.
Hog1 activation delays mitotic exit via phosphorylation of Net1

Significance Proper chromosome segregation is critical for the maintenance of genomic information in every cell division, which is required for cell survival. Cells have orchestrated a myriad of control mechanisms to guarantee proper chromosome segregation. Upon stress, cells induce a number of adaptive responses to maximize survival that range from regulation of gene expression to control of cell-cycle progression. We have found here that in response to osmostress, cells also regulate mitosis to ensure proper telomeric and rDNA segregation during adaptation. Osmostress induces a Hog1-dependent delay of cell-cycle progression in early mitosis by phosphorylating Net1, thereby impairing timely nucleolar release and activation of Cdc14, core elements of mitosis regulation. Thus, Hog1 activation prevents segregation defects to maximize survival. Adaptation to environmental changes is crucial for cell fitness. In Saccharomyces cerevisiae, variations in external osmolarity trigger the activation of the stress-activated protein kinase Hog1 (high-osmolarity glycerol 1), which regulates gene expression, metabolism, and cell-cycle progression. The activation of this kinase leads to the regulation of G1, S, and G2 phases of the cell cycle to prevent genome instability and promote cell survival. Here we show that Hog1 delays mitotic exit when cells are stressed during metaphase. Hog1 phosphorylates the nucleolar protein Net1, altering its affinity for the phosphatase Cdc14, whose activity is essential for mitotic exit and completion of the cell cycle. The untimely release of Cdc14 from the nucleolus upon activation of Hog1 is linked to a defect in ribosomal DNA (rDNA) and telomere segregation, and it ultimately delays cell division. A mutant of Net1 that cannot be phosphorylated by Hog1 displays reduced viability upon osmostress. Thus, Hog1 contributes to maximizing cell survival upon stress by regulating mitotic exit.
Therapeutic apheresis in ABO‐incompatible kidney and liver transplantation: A single‐center experience of 50 patients

ABO antigens play an important role in solid organ transplantation. Desensitization for ABO incompatibility offers patients awaiting transplant a larger donor pool. The aim of this study was to assess outcome of desensitization using the institutional preconditioning protocol in ABO‐incompatible solid organ transplants. A retrospective analysis of ABO‐incompatible solid organ transplants between October 2015 and June 2018, at a tertiary healthcare center was performed. The preconditioning regimen consisted of immunosuppression and therapeutic apheresis (TA). Pre‐ and post‐TA titers were performed, until a target titer of 8 or below was achieved, at which transplant was performed. Follow‐up data till 1 year was analyzed. A total of 50 ABO‐incompatible solid organ transplantations, including 14 liver transplants and 36 renal transplants were analyzed. The median baseline anti‐A and anti‐B titers were 192 and 256, respectively. A total of 150 therapeutic plasma exchange (TPE) procedures were performed for renal transplant recipients; 19 TPE and eight immunoadsorption procedures (five preoperative and three intraoperative) were performed for liver transplant recipients. Five (10%) patients experienced minor adverse events. Biopsy revealed antibody‐mediated rejection was observed in three cases in the immediate posttransplant phase and in three (6.67%) cases over 1 year. There was one death due to transplant‐associated thrombotic microangiopathy. Graft survival for renal transplant was 100% and death‐censored graft survival for liver transplant was 100%. Despite difficulties, ABO‐incompatible transplants can be performed without antibody‐mediated rejection with the use of an appropriate protocol.
Impact of a district mental health care plan on suicidality among patients with depression and alcohol use disorder in Nepal

Background Large scale efforts to expand access to mental healthcare in low- and middle-income countries have focused on integrating mental health services into primary care settings using a task sharing approach delivered by non-specialist health workers. Given the link between mental disorders and risk of suicide mortality, treating common mental disorders using this approach may be a key strategy to reducing suicidality. Methods and findings The Programme for Improving Mental Health Care (PRIME) evaluated mental health services for common mental disorders delivered by non-specialist health workers at ten primary care facilities in Chitwan, Nepal from 2014 to 2016. In this paper, we present the indirect impact of treatment on suicidality, as measured by suicidal ideation, among treatment and comparison cohorts for depression and AUD using multilevel logistic regression. Patients in the treatment cohort for depression had a greater reduction in ideation relative to those in the comparison cohort from baseline to three months (OR = 0.16, 95% CI: 0.05–0.59; p = 0.01) and twelve months (OR = 0.31, 95% CI: 0.08–1.12; p = 0.07), with a significant effect of treatment over time (p = 0.02). Among the AUD cohorts, there were no significant differences between treatment and comparison cohorts in the change in ideation from baseline to three months (OR = 0.64, 95% CI: 0.07–6.26; p = 0.70) or twelve months (OR = 0.46, 95% CI: 0.06–3.27; p = 0.44), and there was no effect of treatment over time (p = 0.72). Conclusion The results provide evidence integrated mental health services for depression benefit patients by accelerating the rate at which suicidal ideation naturally abates over time. Integrated services do not appear to impact ideation among people with AUD, though baseline levels of ideation were much lower than for those with depression and may have led to floor effects. The findings highlight the importance of addressing suicidality as a specific target–rather than an indirect effect–of treatment in community-based mental healthcare programs.
Altered calcium-handling produces reentry-promoting action potential alternans in atrial fibrillation-remodeled hearts.

Atrial fibrillation (AF) alters atrial-cardiomyocyte (ACM) Ca2+-handling, promoting ectopic-beat formation. Here, we examined the effects of AF-associated remodeling on Ca2+-related action-potential (AP) dynamics and consequences for AF-susceptibility. AF was maintained electrically (x1 week) in dogs by right-atrial (RA) tachypacing. ACMs isolated from AF-dogs showed increased Ca2+-release refractoriness, spontaneous Ca2+-spark frequency and cycle-length (CL) threshold for Ca2+ and APD alternans versus controls. Similarly, AF increased the in-situ CL-threshold for Ca2+/APD-alternans and spatial dispersion in Ca2+-release recovery kinetics, leading to spatially-discordant alternans associated with reentrant rotor formation and susceptibility to AF induction/maintenance. The clinically-available agent dantrolene reduced Ca2+-leak and CL-threshold for Ca2+/APD-alternans in both ACMs and AF-dog RA, while suppressing AF-susceptibility; caffeine increased Ca2+-leak, CL-threshold for Ca2+/APD-alternans in control-dog ACMs and RA-tissues. In vivo, the atrial repolarization alternans CL-threshold was increased in AF vs control, as was AF-vulnerability. Intravenous dantrolene restored repolarization alternans-threshold and reduced AF-vulnerability. Immunoblots showed significantly reduced expression of total and phosphorylated ryanodine-receptors and calsequestrin in AF, along with unchanged phospholamban/SERCA expression. Thus, in addition to promoting spontaneous ectopy, AF-induced Ca2+-handling abnormalities favor AF-occurrence by enhancing vulnerability to repolarization-alternans, thereby promoting the initiation and maintenance of reentrant activity; the clinically-available compound dantrolene provides a lead-molecule to target this mechanism.
Study on dietary constituents, hs-CRP serum levels and investigation of correlation between them in excess weight adolescents.

BACKGROUND The prevalence of childhood obesity has increased in Greece as well as worldwide. Mediterranean diet is considered the world's most popular healthy eating pattern. C-reactive protein (CRP) has been shown to play an important pathophysiological role between inflammation and cardiovascular diseases and has been linked to obesity. Our study aimed to investigate the adolescents' diet, their high-sensitivity CRP (hs-CRP) serum levels, and whether low-grade inflammation, present in obesity, is related to adolescents' diet. METHODS The sample of the study consisted of 142 adolescents age- and gender- matched 13.4 ± 1.46 years, divided into two groups: the study group and the controls. The study group of 71 excess body weight adolescents was further divided into two subgroups of 28 overweight and 43 obese respectively; 71 normal weight age- and gender-matched served as controls. Dietary constituents (food weight, energy intake, protein, carbohydrate and fat consumption, fiber, and sugars) were analyzed. Adherence to the Mediterranean diet was investigated, and hs-CRP serum levels were determined. The findings were compared between/among groups. Furthermore, the correlation of hs-CRP serum levels and food constituents between/among groups was investigated. RESULTS We documented differences in several parameters among the groups: waist to hip ratio (p =0.001), food weight (p =0.040), energy intake (p =0.024), protein intake (p =0.001), total fibre (p =0.017), sugars (p =0.001), and the Mediterranean Diet Quality Index for children and adolescents (KIDMED; p =0.008). No statistically significant difference was found for hs-CRP serum levels among the three groups. No correlation was found between hs-CRP serum levels and any of the dietary constituents. CONCLUSIONS Comparing the three groups (obese, overweight, and controls), we found statistically significant differences for food constituents but not for hs-CRP serum levels. In our study, inflammation was not found to be correlated with any of the dietary constituents. Further studies in a larger sample are required to consolidate these findings. HIPPOKRATIA 2019, 23(1): 3-8.
Free prostate-specific antigen outperforms total prostate-specific antigen as a predictor of prostate volume in patients without prostate cancer.

OBJECTIVE In the management of benign prostatic hyperplasia (BPH), urology guide- lines recommend medical or surgical treatments according to different prostate volumes (PV). The aim of this study was to analyze the relationships between PV and age, total and free prostate specific antigen (tPSA, fPSA) and fPSA/tPSA ratio in patients without histologically proven prostate cancer. MATERIALS AND METHODS A retrospective analysis was made of the data of 1334 patients who underwent transrectal ultra- sound (TRUS)-guided prostate biopsy between January 2016 and October 2018. A total of 438 patients with available data for age, tPSA and fPSA levels and PV calculated by TRUS were enrolled in the study. Patients with chronic prostatitis pathology in addition to BPH were also noted and evaluated as a separate group. RESULTS There were significant correlations between PV and age, tPSA, fPSA, fPSA/tPSA ratio (r = 0.210, r = 0.338, r = 0.548, r = 0.363 respectively). In multivariate linear regression analysis, fPSA was found to be the only predictor for PV (p < 0.001) when compared to age (p = 0.097), tPSA (p = 0.979) and fPSA/tPSA ratio (p = 0.425). In patients with chronic prostatitis pathology there were significant correla- tions between PV and age, tPSA, fPSA, fPSA/tPSA ratio (r = 0.279, r = 0.379, r = 0.592, r = 0.359, respectively). The multivariate linear regression analysis showed a signifi- cant correlation only between PV and tPSA and fPSA/tPSA ratio but not with fPSA and age (p = 0.008, p = 0.015, p = 0.430, p = 0.484, respectively). In men with only BPH pathology there were significant correlations between PV and age, tPSA, fPSA, fPSA/tPSA ratio (r = 0.223, r = 0.385, r = 0.520, r = 0.287, respectively) In multivariate linear regression model the significant correlation was shown only between PV and fPSA (p < 0.001). CONCLUSIONS Although tPSA was significantly correlated with PV in patients without prostate cancer, the correlation between fPSA and PV was much stronger. However, it should be kept in mind that the efficacy of fPSA may be limited in patients with clinically unknown prostatic inflammation.
Determinants of hand hygiene compliance among nurses in US hospitals: A formative research study

Hand hygiene is the simplest and most effective measure for preventing healthcare-associated infections. Despite the simplicity of this procedure and advances made in infection control, hospital health care workers’ compliance to hand hygiene recommendations is generally low. Nurses have the most frequent patient care interactions, and thus more opportunities to practice hand hygiene. As such, it is important to identify and understand determinants of nurses’ reported compliance. Formative research was undertaken to assess the potential impact of several unexamined factors that could influence HH among nurses: professional role and status, social affiliation, social norms, and physical modifications to the work environment (as well as institutional factors like safety climate). A survey questionnaire was developed primarily to inform the creation of a behaviour change intervention. The survey looked at how these factors influence HH among nurses and sought to identify barriers and levers to reported hand hygiene. It was administered to a survey panel of acute care nurses, working in US hospitals, with a year or more of experience. Multivariate regression modelling suggested that reported hand hygiene compliance was most likely to be a function of a hospital management’s communication openness, perceived performance by peers, increased interactions with patients and other staff members, and the reduction in stress, busyness, and cognitive load associated with role performance. A powerful, effective intervention on HH among nurses therefore could be directed at improving communication openness, consider the impact of perceived performance by peers, increase interactions with patients and staff, and determine how to reduce the stress and cognitive load associated with role performance.
The art of obtaining a high yield of cell-free DNA from urine

Although liquid biopsies offer many advantages over tissue biopsies, they are not yet standard practice. An important reason for the lack of implementation is the unavailability of well standardized techniques and guidelines, especially for pre-analytical conditions which are an important factor causing the current sensitivity issues. To overcome these limitations, we investigated the effect of several pre-analytical conditions on the concentration of cell-free DNA (cfDNA) and cellular genomic DNA (gDNA) contamination. Urine samples from healthy volunteers (HVs) and cancer patients were collected and processed according to specific pre-analytical conditions. Our results show that in samples with a relatively small volume more than 50% of the cfDNA can be found in the first 50 mL of the urine sample. The total DNA concentration increased again when samples were collected more than 3.5 hours apart. Adding preservative to urine samples is recommended to obtain high concentrations of cfDNA. To remove the cellular content, high speed centrifugation protocols as 4,000g 10min or 3,000g 15min are ideal for urine collected in cfDNA Urine Preserve (Streck). Although this study was a pilot study and needs to be confirmed in a larger study population, clear trends in the effect of several pre-analytical conditions were observed.
Urine Calcium-Creatinine Ratio and Microalbuminuria in Prediction of Preeclampsia

INTRODUCTION : Hypertensive disorders of pregnancy have been a challenge to obstetricians worldwide. Preeclampsia and its complications are frequent causes for maternal and perinatal morbidity and mortality, particularly in developing countries. AIM : To determine whether low urinary calcium to creatinine ratio and microalbuminuria in asymptomatic pregnant women, can predict the later development of preeclampsia. OBJECTIVE : To do urine calcium and creatinine estimation and microalbuminuria in spot urine sample between 20 to 24 weeks of gestation. To follow these patients until delivery for development of pre eclampsia and To see if there is any correlation. MATERIALS AND METHOD : Specimen: Spot urine sample collected in calcium free vials. Methods : a) Estimation of urinary calcium by Ortho-Cresolphthalein complexone method. b) Estimation of urinary creatinine by Jaffe’s reaction . c) Estimtion of microalbuminuria by Turbidimetric Immunoassay. Statistical method : Chi square test / Fisher Exact test to find the association of preeclampsia with UCCR and microalbuminuria. p value ≤0.01 strongly significant, 0.01-0.05 moderately significant and 0.05-0.1 suggestively significant. Inclusion Criteria : 1. Normotensive asymptomatic pregnant women between 20-24 weeks of gestation attending antenatal OPD. 2. Urine albumin nil by dipstick method 3. Women with previous and family history of preeclampsia/ GHT are included in the study. Exclusion criteria : 1. Patients with history of chronic hypertension / use of any anti-hypertensive drugs. 2. Patients with diabetes, renal diseases / or on diuretics. 3. Proteinuria or BP >140/90mmHg at booking visit. 4. Other chronic medical illness. CONCLUSION UCCR and microalbuminuria are excellent tests for prediction of preclampsia. Primi along with low UCCR are the one who are at higher risk of developing preeclampsia. The sensitivity, specificity, PPV and NPV are very good for both the tests, but when compared with microalbuminuria UCCR scores more. Both these tests are ideal because: They were simple and easy to perform, Inexpensive and less time consuming, Non invasive and comfortable for the patient. Microalbuminuria alone can be a good predictor of pre eclampsia but UCCR is a better test for prediction. Thus UCCR and microalbuminuria can be used as routine screening tests in early second trimester for predicting preeclampsia at a much early stage in order to reduce the numerous adverse outcomes and to improve the standards of antenatal care. Its use can be better accomplished in developing countries where incidence of pre eclampsia is high.