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The progression of fibrosis in chronic liver disease is dependent upon hepatic stellate cells (HSCs) transdifferentiating to a myofibroblast-like phenotype. This pivotal process is controlled by enzymes that regulate histone methylation and chromatin structure, which may be targets for developing anti-fibrotics. There is limited pre-clinical experimental support for the potential to therapeutically manipulate epigenetic regulators in fibrosis. In order to learn if epigenetic treatment can halt the progression of pre-established liver fibrosis, we treated mice with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep) in a naked form or by selectively targeting HSC-derived myofibroblasts via an antibody-liposome-DZNep targeting vehicle. We discovered that DZNep treatment inhibited multiple histone methylation modifications, indicative of a broader specificity than previously reported. This broad epigenetic repression was associated with the suppression of fibrosis progression as assessed both histologically and biochemically. The anti-fibrotic effect of DZNep was reproduced when the drug was selectively targeted to HSC-derived myofibroblasts. Therefore, the in vivo modulation of HSC histone methylation is sufficient to halt progression of fibrosis in the context of continuous liver damage. This discovery and our novel HSC-targeting vehicle, which avoids the unwanted effects of epigenetic drugs on parenchymal liver cells, represents an important proof-of-concept for epigenetic treatment of liver fibrosis. Fibrosis results in progressive deposition of scar tissue leading to cirrhosis. The histone methyltransferase EZH2 regulates the activity of scar-forming myofibroblasts. By developing a liposome vehicle decorated with an antibody selective for myofibroblasts, we demonstrate that in vivo pharmacological targeting of myofibroblast EZH2 is sufficient to block fibrosis progression in chronic liver disease.

This phase 3 trial showed that persons with noninfectious uveitis who received adalimumab were more likely to have serious adverse events and less likely to have ophthalmic inflammation, uveitic flare, or visual impairment than were those who received placebo. Noninfectious uveitis is a group of vision-threatening diseases that are characterized by intraocular inflammation; it can occur as a syndrome isolated to the eye or in association with a systemic condition. Uveitis has an estimated incidence of 17 to 52 cases per 100,000 person-years 1 and is estimated to cause 10 to 15% of cases of blindness in Western countries. 2 , 3 Glucocorticoids remain the mainstay of therapy despite their well-known ocular and systemic adverse effects. 4 – 6 Thus, there is a large unmet medical need for and a great interest in identifying more effective, glucocorticoid-sparing therapies, ideally targeting specific mediators of the . . .

Immersion in tricaine methanesulfonate (i.e. TMS) has been used for euthanasia of Xenopus laevis (African Clawed frogs). However, the time for preparation and potential human health hazards may pose as a barrier for large group culls. Here, we aimed to investigate whether immersion in bupivacaine is an effective means to euthanize this species. In experiment one, frogs (n = 10/group) were randomly assigned to 1-h immersion in 1 of 3 treatment groups: 1) TMS-5 (MS-222, 5g/L); 2) TMS-10 (MS-222, 10 g/L); or 3) Bupi-1 . 5 (0.5% Bupivacaine, 1.5 g/L). Frogs were then removed from solutions, rinsed with system water, and placed into a recovery cage. Heart rate was evaluated audibly via doppler ultrasound flow over 1 min at immediate removal (T1h), at 2 (T2h), and 3 (T3h) h in the recovery cage. In experiment two, frogs (n = 7/group) underwent 5-h & 19-h immersion in either TMS-5 or Bupi-1 . 5 , with heart rate assessment at 5 and 19 hrs. Righting reflex and withdrawal reflex of the hindlimb were tested during the experiments. Experiment one— after the 1-h immersion, Bupi-1 . 5 treated animals had decreased heart rates compared to TMS-5 and TMS-10 treated animals by T2h. Neither TMS-5 , TMS-10 , nor Bupi-1 . 5 ceased heart rate after the 1-h immersion. Experiment two— after the 5-h immersion, Bupi-1 . 5 and TMS-5 treated animals were comparable in heart rates. 43% of TMS-5 animals and 14% of the Bupi-1 . 5 animals had completely ceased heart rates at T5h. At 19 h all remaining animals exhibited rigor mortis and had ceased heart rate. We recommend 19-h of immersion using either TMS-5 or Bupi-1.5 for cessation of heart rate in African Clawed frogs. These data are strong support for the use of secondary physical methods for euthanasia in African Clawed frogs when euthanasia by immersion is performed.

Background Aging is a dynamic and heterogeneous process that may better be captured by trajectories of aging biomarkers. Biological age has been advocated as a better biomarker of aging than chronological age, and plant-based dietary patterns have been found to be linked to aging. However, the associations of biological age trajectories with mortality and plant-based dietary patterns remained unclear. Methods Using group-based trajectory modeling approach, we identified distinctive aging trajectory groups among 12,784 participants based on a recently developed biological aging measure acquired at four-time points within an 8-year period. We then examined associations between aging trajectories and quintiles of plant-based dietary patterns assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) among 10,191 participants who had complete data on dietary intake, using multivariable multinomial logistics regression adjusting for sociodemographic and lifestyles factors. Cox proportional hazards regression models were applied to investigate the association between aging trajectories and all-cause mortality. Results We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (OR = 0.75, 95% CI: 0.65, 0.86 for PDI; OR = 0.73, 95% CI: 0.62, 0.85 for hPDI) or high-degree (OR = 0.63, 95% CI: 0.46, 0.86 for PDI; OR = 0.62, 95% CI: 0.44, 0.88 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (OR = 1.72, 95% CI: 1.48, 1.99) or high-degree (OR = 1.70, 95% CI: 1.21, 2.38) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (HR = 1.56, 95% CI: 1.29, 1.89) or high-degree (HR = 3.72, 95% CI: 2.73, 5.08) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory. Conclusions We identified three distinctive aging trajectories in a large Asian cohort and found that adopting a plant-based dietary pattern, especially when rich in healthful plant foods, was associated with substantially lowered pace of aging.

Gastrointestinal perforation is a serious adverse event associated with bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) widely used in current cancer treatment. The association is highlighted by a black-box warning issued by the US Food and Drug Administration, recommending that bevacizumab be permanently discontinued in patients with gastrointestinal perforation. However, no significant association has yet been established between bevacizumab and gastrointestinal perforation in randomised controlled trials. We did a systematic review and meta-analysis of published randomised controlled trials to assess the overall risk of gastrointestinal perforation associated with bevacizumab treatment. We searched PubMed and Web of Science for articles published between January, 1966, and July, 2008. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2008, were searched to identify relevant clinical trials. Eligible studies included prospective randomised controlled trials in which bevacizumab was compared with controls in combination with standard anti-neoplastic therapy. Summary incidence rates, relative risks, and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. 12 294 patients with a variety of solid tumours from 17 randomised controlled trials were included in our analysis. The incidence of gastrointestinal perforation was 0·9% (95% CI 0·7–1·2) among patients receiving bevacizumab, with a mortality of 21·7% (11·5–37·0). Patients treated with bevacizumab had a significantly increased risk of gastrointestinal perforation compared with patients treated with control medication, with a relative risk of 2·14 (95% CI 1·19–3·85; p=0·011). Risk varied with bevacizumab dose and tumour type. Relative risks for patients receiving bevacizumab at 5 and 2·5 mg/kg per week were 2·67 (95% CI 1·14–6·26) and 1·61 (0·76–3·38), respectively. Higher risks were observed in patients with colorectal carcinoma (relative risk 3·10, 95% CI 1·26–7·63) and renal cell cancer (relative risk 5·67, 0·66–48·42). The addition of bevacizumab to cancer therapy significantly increased the risk of gastrointestinal perforation compared with controls. The risk may vary with bevacizumab dose and tumour type. Further studies are recommended to investigate the use of bevacizumab in selected patients who have recovered from gastrointestinal perforation. Stony Brook University Research Foundation.

Background. Randomized trials support use of procalcitonin (PCT)-based algorithms to decrease duration of antibiotics for critically ill patients with sepsis. However, current use of PCT and associated outcomes in real-world clinical settings is unclear. We sought to determine PCT use in critically ill patients with sepsis in the United States and to examine associations between PCT use and clinical outcomes. Methods. This was a retrospective cohort study of approximately 20% of patients with sepsis hospitalized in US intensive care units. Hierarchical regression models were used to determine associations of PCT use with outcomes (antibiotic-days, incidence of Clostridium difficile infection, and in-hospital mortality). Sensitivity analyses were conducted to assess robustness of findings to different methods used to address unmeasured confounding (eg, instrumental variable, difference-in-differences analyses). Results. Among 20 750 critically ill patients with sepsis in 107 hospitals with PCT available, 3769 (18%) patients had PCT levels checked; 1119 (29.7%) had serial PCT measurements. PCT use was associated with increased antibiotic-days (adjusted relative risk, 1.1; 95% confidence interval [CI], 1.15–1.18) and incidence of C. difficile (adjusted odds ratio, 1.42; 95% CI, 1.09–1.85) without a change in mortality (adjusted hazard ratio, 1.05; 95% CI, 0.93–1.19). Analysis of PCT use by instrumental variable and difference-in-difference analyses showed similar lack of antibiotic or outcome improvements associated with PCT use. Conclusions. PCT use was not associated with improved antibiotic use or other clinical outcomes in real-world settings. Programs to improve implementation of PCT-based strategies are warranted prior to widespread adoption.

Zebrafish are an established and widely used animal model, yet there is limited understanding of their welfare needs. Despite an increasing number of studies on zebrafish enrichment, in-tank environmental enrichment remains unpopular among researchers. This is due to perceived concerns over health/hygiene when it comes to introducing enrichment into the tank, although actual evidence for this is sparse. To accommodate this belief, regardless of veracity, we tested the potential benefits of enrichments presented outside the tank. Thus, we investigated the preferences and physiological stress of zebrafish with pictures of pebbles placed underneath the tank. We hypothesized that zebrafish would show a preference for enriched environments and have lower stress levels than barren housed zebrafish. In our first experiment, we housed zebrafish in a standard rack system and recorded their preference for visual access to a pebble picture, with two positive controls: visual access to conspecifics, and group housing. Using a crossover repeated-measures factorial design, we tested if the preference for visual access to pebbles was as strong as the preference for social contact. Zebrafish showed a strong preference for visual access to pebbles, equivalent to that for conspecifics. Then, in a second experiment, tank water cortisol was measured to assess chronic stress levels of zebrafish housed with or without a pebble picture under their tank, with group housing as a positive control. Cortisol levels were significantly reduced in zebrafish housed with pebble pictures, as were cortisol levels in group housed zebrafish. In fact, single housed zebrafish with pebble pictures showed the same cortisol levels as group housed zebrafish without pebble pictures. Thus, the use of an under-tank pebble picture was as beneficial as being group housed, effectively compensating for the stress of single housing. Pebble picture enrichment had an additive effect with group housing, where group housed zebrafish with pebble pictures had the lowest cortisol levels of any treatment group.

Background Bovine leukemia virus (BLV) infection is widespread in cattle globally and is present in marketed beef and dairy products. Human infection with BLV has been reported in breast and lung cancer tissues and was significantly associated with breast cancer in 3 case-control studies. The purpose of this current research was to determine if BLV is present in human blood cells and if antibodies to BLV are related to blood cell infection. Methods Standard liquid PCR and Sanger DNA sequencing were used to test for BLV in buffy coat cells (leukocytes and platelets) of blood specimens from 95 self-selected female subjects. Enzyme-linked immunosorbent assay (ELISA) for IgG, IgM, and IgA was used to detect antibodies to BLV in the plasma of the corresponding blood samples. Results BLV DNA was detected in the buffy coat cells of blood in 33/95 (38%) of the subjects by PCR and DNA sequencing. IgG antibodies were detected in 30/95(32%), IgM in 55/95(58%), and IgA in 30/95(32%) of the subjects. There was no significant correlation between presence of the antibodies and presence of BLV DNA. Conclusions This first report of BLV in human blood raises the question of whether infection of leukocytes could conceivably lead to leukemia as it does in infected cattle. Also, system wide circulation of infected blood cells could facilitate BLV transit to various internal tissues/organs with potential for their infection and subsequent development of cancer. The most likely route of BLV transmission to humans would be zoonotic, as a foodborne infection. Although eradicated from cattle in some countries, BLV still has a high rate of infection in the Americas, the Middle East, and parts of Europe and Asia. This report of BLV in the blood layer containing human leukocytes/platelets adds important information which could be useful to elucidate possible routes of transmission of BLV to humans and to prevent further human infection.

A bstract We analyse finite-size scaling behaviour of a four-dimensional Higgs-Yukawa model near the Gaussian infrared fixed point. Through improving the mean-field scaling laws by solving one-loop renormalisation group equations, the triviality property of this model can be manifested in the volume-dependence of moments of the scalar-field zero mode. The scaling formulae for the moments are derived in this work with the inclusion of the leading-logarithmic corrections. To test these formulae, we confront them with data from lattice simulations in a simpler model, namely the O(4) pure scalar theory, and find numerical evidence of good agreement. Our results of the finite-size scaling can in principle be employed to establish triviality of Higgs-Yukawa models, or to search for alternative scenarios in studying their fixed-point structure, if sufficiently large lattices can be reached.

Catheter-related (CR) thrombosis is a significant complication of midline catheters (MCs) and peripherally inserted central catheters (PICCs). Limited existing data for MCs suggest a favorable complication profile for MCs. To compare incidence of CR thrombosis between MCs and PICCs and to evaluate the impact of quantity of lumens and catheter diameter on CR thrombosis. This was a retrospective comparison spanning 13 months of MCs and PICCs for symptomatic CR thrombosis at an 1100 bed tertiary care academic medical center. Adult patients who had an MC or a PICC placed by the were included. Data were collected using the electronic medical record. Statistical analysis was performed using SAS software. A total of 2577 catheters were included in the analysis with 1094 MCs and 1483 PICCs. One hundred thirty (11.88%) MCs developed CR thrombosis (deep vein thrombosis [DVT] or superficial venous thrombophlebitis [SVT]) as compared to 112 (6.88%) PICCs (odds ratio [OR]: 1.82; P < .0001). Midline catheters had a 53% greater odds of developing CR DVT than PICCs (7.04% MCs and 4.72% PICCs; OR: 1.53; P = .0126). For CR SVT, MCs have a 2.29-fold greater odds of developing CR SVT than PICCs (4.84% MCs and 2.16% PICCs; OR: 2.29; P = .0002). For MCs and PICCs, the incidence of CR thrombosis was 13.50% for double lumen/5F lines and was 6.92% for single lumen/4F lines (OR: 2.10; P = <.0001). Symptomatic CR thrombosis is a serious, life-threatening complication that occurs more frequently in MCs compared to PICCs. Inserters should consider placement of single lumen catheters with the smallest diameter to reduce this risk when a midline is used.