Miracle-dz/UniFAR-FTUs huggingface dataset:
Bioluminescence for Assessing Drug Potency against Nonreplicating Mycobacterium tuberculosis

ABSTRACT Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In this study, we generated a luminescent 18b strain, named 18b-Lux, by transforming the bacteria with a vector expressing the luxCDABE operon from Photorhabdus luminescens. Luciferase expression was demonstrated under replicating conditions, and, more importantly, luminescence levels significantly above background were detected following STR removal. The sensitivity of STR-starved 18b-Lux to approved and candidate antituberculosis therapeutic agents was evaluated by means of a luciferase assay in a 96-well format. Results mirrored the data obtained with the standard resazurin reduction microplate assay, and the luminescence readout allowed time course assessments of drug efficacy in vitro. Specifically, we proved that bedaquiline, the rifamycins, and sutezolid displayed time-dependent activity against dormant bacteria, while pyrazinamide and SQ109 showed bactericidal effects at the highest concentrations tested. Overall, we established the optimal conditions for an inexpensive, simple, and very sensitive assay with great potential for future applications.
Percutaneous implantation of the first repositionable aortic valve prosthesis in a patient with severe aortic stenosis

Percutaneous aortic valve replacement is a new less‐invasive alternative for high‐risk surgical candidates with aortic stenosis. However, the clinical experience is still limited, and the currently available ‘first‐generation devices’ revealed technical shortcomings, such as lack of repositionability and presence of paravalvular leakages. We report the first‐in‐man experience with the new self‐expanding Lotus™ Valve prosthesis composed of a nitinol frame with implemented bovine pericardial leaflets which is designed to address these issues, being repositionable and covered by a flexible membrane to seal paravalvular gaps. We implanted this prosthesis in a 93‐year old patient presenting with severe symptomatic aortic stenosis (valve area: 0.6 cm2). Surgical valve replacement had been declined due to comorbidities.
Differential effects of poststressor rumination and distraction on cortisol and C-reactive protein.

OBJECTIVE Stress-related physiological activation may last longer for those who ruminate, or dwell, on past stressors. Correlational and quasi-experimental research has linked rumination to immune activity and elevated cortisol. This study's aim was to experimentally test whether rumination (relative to distraction) can sustain stress-induced increases in inflammation and cortisol. Concentrations of poststressor cortisol and inflammatory markers were hypothesized to be greater for those who ruminated compared with those who were distracted. METHOD Thirty-four healthy young women completed a laboratory speech stressor and were then randomly assigned to either ruminate on the stressor or engage in distraction for 5 minutes. Salivary cortisol and circulating plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were assessed throughout the 2-hr visit. RESULTS As predicted, CRP and cortisol responses differed for the rumination and distraction groups. In the distraction group, participants' CRP concentrations increased poststressor and then returned to prestressor levels by the end of the visit. In contrast, participants in the rumination condition demonstrated increases in CRP that did not return to prestressor levels by the end of the visit. Similarly, poststressor cortisol was higher for those who ruminated compared with those who were distracted. Plasma IL-6 and TNF-α concentrations increased over the visit, but did not differ by experimental group. CONCLUSIONS RESULTS suggest that ruminating on stressors may sustain CRP and cortisol responses, whereas distraction may diminish them. Findings have implications for understanding potential risk and protective factors for stress-related activation.
Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo.

AIMS Although there is accumulating evidence that increased formation of reactive nitrogen species in cerebral vasculature contributes to the progression of ischemic damage, but the underlying molecular mechanisms remain elusive. Peroxiredoxin 1 (Prx1) can initiate the antioxidant response by scavenging free radicals. Therefore, we tested the hypothesis that Prx1 regulates the susceptibility to nitrosative stress damage during cerebral ischemia in vitro and in vivo. RESULTS Proteomic analysis in endothelial cells revealed that Prx1 was upregulated after stress-related oxygen-glucose deprivation (OGD). Although peroxynitrite upregulated Prx1 rapidly, this was followed by its polyubiquitination within 6 h after OGD mediated by the E3 ubiquitin ligase E6-associated protein (E6AP). OGD colocalized E6AP with nitrotyrosine in endothelial cells. To assess translational relevance in vivo, mice were studied after middle cerebral artery occlusion (MCAO). This was accompanied by Prx1 ubiquitination and degradation by the activation of E6AP. Furthermore, brain delivery of a lentiviral vector encoding Prx1 in mice inhibited blood-brain barrier leakage and neuronal damage significantly following MCAO. INNOVATION AND CONCLUSIONS Nitrosative stress during ischemic insult activates E6AP E3 ubiquitin ligase that ubiquitinates Prx1 and subsequently worsens cerebral damage. Thus, targeting the Prx1 antioxidant defense pathway may represent a novel treatment strategy for neurovascular protection in stroke.
Human Papillomavirus Positivity in Women Undergoing Intrauterine Insemination Has a Negative Effect on Pregnancy Rates

Background: Sexually transmitted infections are a major cause of infertility. Human papillomavirus (HPV) infection is one of the most common viral infections of the female genital tract. Only a limited number of studies have investigated the influence of HPV on fertility and its impact remains controversial. Objective: We investigated the relationship between cervical HPV infection and pregnancy outcome after intrauterine insemination (IUI). Since other sexually transmitted infections could also influence outcome, we also analyzed the influence of Trichomonas vaginalis (TV) and Chlamydia trachomatis (CT) on pregnancy outcome. Methods: We performed a retrospective analysis of 590 women who underwent 1,529 IUI cycles at AML between 2010 and 2014. Positivity of 18 different HPV types (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68) and TV was assessed by PCR in cervical cytology specimens. CT status was ascertained by detection of IgA/IgG antibodies on serum samples or by PCR on cervical swabs. Results: The HPV prevalence per IUI cycle was 11.0 and 6.9% for CT; none of the women tested positive for TV. HPV-positive women were six times less likely to become pregnant after IUI (1.87 vs. 11.36%; p = 0.0041). There was no significant difference in pregnancy rates between women with or without a history of CT (8.51 vs. 11.10%; p > 0.05). Conclusion: Detection of HPV is associated with a negative IUI outcome.
Rivaroxaban for Preventing Venous Thromboembolism in High-Risk Ambulatory Patients with Cancer: Rationale and Design of the CASSINI Trial

Abstract Venous thromboembolism (VTE) is a frequent complication of cancer associated with morbidity, mortality, increased hospitalizations and higher health care costs. Cancer patients at increased risk for VTE can be identified using a validated risk assessment score, and the incidence of VTE can be reduced in high-risk settings using anticoagulation. Rivaroxaban is a potent, oral, direct, factor Xa inhibitor approved for the prevention and treatment of thromboembolic events, including VTE. CASSINI is a double-blind, randomized, parallel-group, multicentre study comparing rivaroxaban with placebo in adult ambulatory patients with various cancers who are initiating systemic cancer therapy and are at high risk of VTE (Khorana score ≥ 2). Patients with primary brain tumours or those at risk for bleeding are excluded. Approximately 700 patients will be randomized 1:1 to rivaroxaban 10 mg daily or placebo for up to 6 months if there is no evidence of VTE from compression ultrasonography (CU) during screening or from routine care imaging within 30 days prior to randomization. Mandatory CU will also be performed at weeks 8 and 16 (±7 days), and at study end (±3 days). The primary efficacy hypothesis is that anticoagulation with rivaroxaban reduces the composite of objectively confirmed symptomatic or asymptomatic, lower-extremity, proximal deep-vein thrombosis (DVT); symptomatic, upper-extremity DVT; symptomatic or incidental pulmonary embolism; and VTE-related death compared with placebo. The primary safety objective is to assess major bleeding events (Clinical trial information: NCT02555878).
Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration

In diabetic retinopathy, endothelial cell apoptosis is paradoxically increased despite upregulation of the potent pro-survival factor VEGF. We tested the hypothesis that elevated glucose levels disrupt VEGF's pro-survival function via peroxynitrite-mediated alteration of the Akt-1/p38 MAP kinase signaling pathway by studies of retinal endothelial cells in vitro. High glucose or exogenous peroxynitrite caused significant increases in apoptosis in the presence or absence of VEGF. Treatment with a peroxynitrite decomposition catalyst blocked these effects, implying a causal role of peroxynitrite. Peroxynitrite or high glucose treatment also increased phosphorylation of p38 MAP kinase, whereas phosphorylation of Akt-1 was significantly decreased in basal or VEGF-stimulated conditions. High glucose- or peroxynitrite-treated cells also showed significant increases in tyrosine nitration on the p85 subunit of PI 3-kinase that blocked PI 3-kinase and Akt-1 kinase activity. Inhibiting peroxynitrite formation or blocking tyrosine nitration of p85 restored the activity of PI 3-kinase and Akt-1 kinase, blocked phosphorylation of p38 MAP kinase and normalized pro-survival function. Transfecting the cells with constitutively active Akt-1 or inhibiting activity of p38 MAP kinase completely masked the pro-apoptotic effects of high glucose and exogenous peroxynitrite, suggesting an interaction between the Akt-1 and p38 MAP kinase pathways. In conclusion, high glucose treatment blocks the pro-survival effect of VEGF and causes accelerated endothelial cell apoptosis via the action of peroxynitrite in causing tyrosine nitration of PI 3-kinase, inhibiting activity of Akt-1 kinase and increasing the activity of p38 MAP kinase.
The Arabidopsis SIAMESE-RELATED Cyclin-Dependent Kinase Inhibitors SMR5 and SMR7 Regulate the DNA Damage Checkpoint in Response to Reactive Oxygen Species[W]

Reactive oxygen species (ROS) cause DNA damage. In this work, two SIAMESE/SIAMESE-RELATED (SIM/SMR) genes that encode cyclin-dependent kinase inhibitors are described as being part of a signaling pathway that arrests cell proliferation in response to ROS, revealing a novel cell cycle checkpoint-signaling cascade. Whereas our knowledge about the diverse pathways aiding DNA repair upon genome damage is steadily increasing, little is known about the molecular players that adjust the plant cell cycle in response to DNA stress. By a meta-analysis of DNA stress microarray data sets, three family members of the SIAMESE/SIAMESE-RELATED (SIM/SMR) class of cyclin-dependent kinase inhibitors were discovered that react strongly to genotoxicity. Transcriptional reporter constructs corroborated specific and strong activation of the three SIM/SMR genes in the meristems upon DNA stress, whereas overexpression analysis confirmed their cell cycle inhibitory potential. In agreement with being checkpoint regulators, SMR5 and SMR7 knockout plants displayed an impaired checkpoint in leaf cells upon treatment with the replication inhibitory drug hydroxyurea (HU). Surprisingly, HU-induced SMR5/SMR7 expression depends on ATAXIA TELANGIECTASIA MUTATED (ATM) and SUPPRESSOR OF GAMMA RESPONSE1, rather than on the anticipated replication stress-activated ATM AND RAD3-RELATED kinase. This apparent discrepancy was explained by demonstrating that, in addition to its effect on replication, HU triggers the formation of reactive oxygen species (ROS). ROS-dependent transcriptional activation of the SMR genes was confirmed by different ROS-inducing conditions, including high-light treatment. We conclude that the identified SMR genes are part of a signaling cascade that induces a cell cycle checkpoint in response to ROS-induced DNA damage.
Influence of submission form characteristics on clinical information received in biopsy accession

Clinical information supplied to diagnostic laboratories through biopsy submission forms is crucial to accurate, timely diagnosis and to clinicopathologic correlation between microscopic findings and the clinical condition of the patient. The current study attempts to quantify the prevalence of deficient and inadequate submissions in veterinary biopsy service and to determine whether form characteristics, such as the open or closed nature of the form and the presence of specific prompts, influence reporting of essential case information. The hypotheses of this study are, first, that deficient and inadequate biopsy submissions do occur in veterinary medicine and, second, that open-type biopsy submission forms elicit quantitatively and qualitatively more complete case information overall, and in specific content areas, compared to closed-type biopsy submission forms. Three percent of submissions reviewed were information deficient, devoid of information beyond patient signalment, and more than 88% of forms supplied inadequate clinical information in at least 1 key content area. Both form type and specific prompts significantly influenced reporting of important clinical information. This study demonstrates the need and lays the foundation for informational completeness research in veterinary medicine.
[Effects of Angelica sinensis polysaccharides on hepatic drug metabolism enzymes activities in mice].

OBJECTIVE To study the effects of Angelica sinensis Polysaccharides (ASP) on the hepatic drug metabolism enzymes activities in normal mice and those prednisolone (PSL)-induced liver injury. METHOD The activities of phase II enzymes (GSH-related enzymes) and cytochrome P450 enzymes were measured by biochemical method. RESULT ASP increased the activities of glutathione S-transferase in liver microsomes and mitochondria. The cytochrome P450 content, NADPH-cytochrome c reductase, aminopyrine N-demethylase, and aniline hydroxylase activities in liver microsomes were also increased. PSL significantly increased serum ALT levels, and decreased the liver mitochondrial glutathione content. At the same time, other enzymes activities were all increased. When mice were treated with ASP 2.0 g.kg-1, the PSL-induced changes on cytochrome P450 enzymes, glutathione S-transferase, and GSH content were restored. CONCLUSION ASP can modulate the activities of drug metabolism enzymes.
IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES INDUCED BY HYDROXYUREA IN RETICULOCYTES FROM SICKLE CELL ANAEMIA PATIENTS

1 The major effect associated with hydroxyurea (HU) treatment of sickle cell anaemia (SCA) patients is an increase in fetal haemoglobin (HbF) synthesis, which inhibits the polymerization of haemoglobin S. 2 Hydroxyurea improves clinical symptoms by reducing the frequency of pain and vaso‐occlusive crises, acute chest syndrome, transfusion requirements and hospitalization. 3 The molecular mechanisms responsible for HU‐mediated induction of fetal globin transcription are not completely understood. Therefore, the aim of the present study was to identify differentially expressed genes participating in these mechanisms. 4 We established two suppression subtractive hybridization (SSH) libraries from reticulocytes obtained from SCA patients either not on or on HU treatment. The gene expression of some of the genes identified was subsequently evaluated by real‐time polymerase chain reaction (PCR). 5 Genes identified with altered expression included SUDS3, FZD5 and PHC3, which may be associated with the regulation of globin expression. 6 This is the first demonstration of an association between HU treatment and the expression of genes identified in erythroid cells.
2016 Update for the Rogers’ Textbook of Pediatric Intensive Care: Recognition and Initial Management of Shock

Objective: To review important articles in the field of pediatric shock and pediatric septic shock published subsequent to the Fifth Edition of the Rogers’ Textbook of Pediatric Intensive Care. Data Sources: The U.S. National Library of Medicine PubMed (www.ncbi.nlm.nih.gov/pubmed) was searched for combination of the term “pediatric” and the following terms: “sepsis, septic shock, shock, antibiotics, extracorporeal membrane oxygenation, and steroid. ” The abstract lists generated by these searches were screened for potential inclusion. The authors were also aware of a number of key recent articles in pediatric shock, and these were also screened. Study Selection and Data Extraction: Promising articles published subsequent to the fifth edition of the textbook were included based on the consensus of the authors and via the peer review process. Data Extraction: Articles were grouped by category. Each author was assigned categories and extracted data from articles in that category. All authors contributed to final review of extracted data. Data Synthesis: Articles in the following categories were included: epidemiology and recognition of shock; laboratory markers of shock; antimicrobial therapy; vasoactive therapy; extracorporeal therapies; mortality patterns, prediction, and risk stratification; bundled approaches to shock recognition and management; and corticosteroid use. Conclusion: Research efforts in pediatric shock have largely centered on pediatric septic shock, with significant progress in the understanding of sepsis epidemiology, the use of extracorporeal therapies in critically ill children with sepsis, the role of hyperlactatemia and risk stratification in pediatric septic shock, and the impact of bundled care for pediatric sepsis, including evaluation of individual bundle elements such as the optimal timing of antibiotic administration and vasoactive medication choice. A consistent theme in the literature is the beneficial role of a bundled approach to septic shock recognition and management to improve both care and outcomes.
Quality management for IT support services

IT services are a necessary support for most business processes; therefore the quality of IT support services is a topic of high importance. The aim of this study was to analyse how an IT helpdesk service can be improved in order to align with the organisation’s expectations. The study was conducted as a case study of an IT helpdesk service during spring 2013. The data collection combined a quantitative analysis of event logs data for a two-year period, with a qualitative approach conducting observations and ten interviews. The result showed that the quality issues arose from two main areas; resolution time of requests and professionalism of IT staff. The quality issues are, according to both the quantitative and qualitative analysis, caused by high workload for one of the IT department’s teams and high expectations of the organisation. Furthermore, this study emphasises that alignment between IT department and organisation is an issue of both sides, as alignment concerns mutual understanding and communication. To solve the service quality issues this study recommends starting to work with measurability and continuous improvements, for example Lean Six Sigma. The IT department can strive to increase the interdepartmental communication, share work tasks, educate internally, document competences and clarify responsibilities to decrease the workload.
Training listeners for multi-channel audio quality evaluation in MUSHRA with a special focus on loop setting

Audio quality evaluation for audio material of intermediate and high quality requires expert listeners. In comparison to non-experts, these are not only more critical in their ratings, but also employ different strategies in their evaluation. In particular they concentrate on shorter sections of the audio signal and compare more to the reference than inexperienced listeners. We created a listener training for detecting coding artifacts in multi-channel audio quality evaluation. Our training is targeted at listeners without technical background. For this training, expert listeners commented on smaller sections of an audio signal they focused on in the listening test and provided a description of the artifacts they perceived. The non-expert listeners participating in the training were provided with general advice for helpful strategies in MUSHRA tests (Multi Stimulus Tests with Hidden Reference and Anchor), with the comments on specific sections of the stimulus by the experts, and with feedback after rating. Listener's performance improved in the course of the training session. Afterwards they performed the same test without the training material and a further test with different items. Performance did not decrease in these tests, showing that they could transfer what they had learned to other stimuli. After the training they also set more loops and compared more to the reference.
Phase I and preliminary phase II evaluation of adriamycin (NSC 123127).

Summary Adriamycin is a new antibiotic isolated from cultures of Streptomyces peucetius caesius with antitumor activity in man. Its structural formula is very similar to that of daunorubicin. Preclinical studies in experimental animal tumors have shown that adriamycin has a higher therapeutic index (1.25) than daunorubicin (0.67). Of 155 patients (34 children and 121 adults) with different forms of leukemia and solid tumors studied for Phase I and II evaluation, 146 were evaluable. Adriamycin has been administered in 147 cases through rapid single i.v. injections with three different dosages (0.4, 0.65, and 0.8 mg/kg) and with three different schedules (loading, alternate, and intermittent). In 5 patients, the drug was given through an intraarterial infusion and in 3 cases it was given intrapleurally. Children tolerated higher doses than adults, while patients pretreated with other anticancer agents were usually rapidly intoxicated after few doses. Toxicity consisted primarily of stomatitis, bone marrow depression, and alopecia. Irreversible marrow aplasia was observed in 11 cases. Nausea, vomiting, diarrhea, and fever were of minor importance. No conclusive evidence of cardiac toxicity was found, although some EKG changes were seen after drug administration in 48 patients. No significant abnormalities in liver chemistries and renal function tests were observed. Adriamycin produced consistent regressions in ten histologically different types of neoplastic disease, but mostly in acute lymphoblastic and chronic (myeloid and lymphocytic) leukemias, as well as in all types of malignant lymphomas, neuroblastoma, Ewing sarcoma, soft-tissue sarcomas, and chorioepithelioma of the uterus. The drug appears to be a potent growth-inhibiting compound and seems more useful in inducing tumor regression rather than as maintenance therapy. In comparison to daunorubicin, adriamycin seems to be therapeutically active at lower doses and on a larger variety of neoplastic diseases.