Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non‐obese diabetic mice

Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of β cells and perforin deficiency effectively reduces diabetes in non‐obese diabetic (NOD) mice, it can be deduced that β cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non‐obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB–/– mice developed diabetes spontaneously with kinetics similar to those of wild‐type NOD (wt‐NOD) mice. Adoptive transfer study with regulatory T cell (Treg)‐depleted splenocytes (SPCs) into NOD‐SCID mice or in‐vivo Treg depletion by anti‐CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB–/– mice and wt‐NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre‐diabetic NOD.GzmB–/– mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide‐promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4+, CD8+ and CD4+CD25+ T cells in SPCs from NOD.GzmB–/– mice than those from wt‐NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for β cell destruction in NOD mice.
Treatment of substance use disorders with co-occurring severemental health disorders.

PURPOSE OF REVIEW To provide an update of treatment for substance use in patients with co-occurring substance use disorders (SUD) and mental health disorders (dual diagnosis) with a focus on both pharmacological and psychosocial interventions. RECENT FINDINGS A total of 1435 abstracts were identified, of which we selectively reviewed 43 for this narrative review. There is emerging evidence, both clinical and neurobiological, that clozapine is a more efficacious antipsychotic in treatment of individuals with schizophrenia and SUD. The use of depot atypical antipsychotic paliperidone palmitate in this population is also promising. Although valproate remains the treatment of choice in individuals with bipolar disorder and SUD, present evidence suggests that lithium and quetiapine may not be effective in this population. Naltrexone is the most effective anticraving agent in individuals with severe mental illness (SMI) and comorbid alcohol use disorders. The use of opioid substitution therapy in individuals with SMI and comorbid opioid use disorders is also associated with favorable outcomes. Varenicline shows promise in patients with SMI who smoke tobacco. Psychosocial interventions should be instituted early in the course of treatment. They should ideally be high intensity and based on established therapies used for SUD. SUMMARY The paucity of systematic studies in individuals with co-occurring mental health disorders and SUD remains a concern, given the enormous burden that they pose. However, there are a number of studies which have evaluated interventions, both psychosocial and pharmacological, which show promise and can guide clinical practice.
Quercetin reduced the formation of N‐acetyl‐p‐benzoquinoneimine, a toxic metabolite of paracetamol in rats and isolated rat hepatocytes

N‐acetyl‐p‐benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration–time curve (AUC0‐∞) and the peakplasma concentration (Cmax) of paracetamol were dose‐dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC0‐∞ and Cmax of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1‐mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.
Nivolumab in patients with advanced hepatocellular carcinoma and Child‐Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series

Nivolumab demonstrated durable responses and safety in patients with hepatocellular carcinoma (HCC) with Child‐Pugh class A cirrhosis in the CheckMate 040 trial, with rates of hepatotoxicity that were similar to those of non‐HCC populations. To the authors' knowledge, the safety and efficacy of nivolumab has not been established in patients with Child‐Pugh class B (CPB) cirrhosis, a population with limited therapeutic options and a poor prognosis.
A Third Lethal in the T (Brachy) Series in the House Mouse.

I Sonneborn, T. M. , Proc. Nat. Acad. Sci., 23, 378-385 (1937). 2 Sonneborn, T. M. , Genetics, 21, 503-514 (1936). 3 Woodruff, L. L. , and Erdmann, R. , Jour. Exptl. Zool. , 17, 425-518 (1914). 4 Sonneborn, T. M. , Biol. Bull., 72, 196-202 (1937). 6 Diller, W. F. , Jour. Morph. , 59, 11-67 (1936). 6 Erdmann, R. , Arch. f. Entwmech. , 46, 85-148 (1920). 7 Parker, R. C. , Jour. Exptl. Zool. , 49, 401-439 (1927). 8 Caldwell, L. , Jour. Exptl. Zool. , 66, 371-407 (1933). 9 Sonneborn, T. M. , and Lynch, R. S. , Genetics, 22, 284-296 (1937). 10 The author wishes to acknowledge his great indebtedness to Dr. T. M. Sonneborn for his constant interest and many valuable suggestions throughout the course of the work.
Adolescent Internalizing, Externalizing, and Social Problems Following Iron Deficiency at 12-18 Months: The Role of Maternal Responsiveness.

This study tested whether maternal responsiveness moderated or mediated pathways from iron deficiency (ID) at 12-18 months to adolescent behavior problems. Participants were part of a large Chilean cohort (N = 933). Iron status was assessed at 12 and 18 months. Maternal responsiveness was assessed at 9 months and 5 years. Parents reported their child's symptomology at 5 years, 10 years, and adolescence (11-17 years; M = 14.4). Structural equation modeling identified a previously unrecognized pathway by which child externalizing problems and negative maternal responsiveness at 5 years mediated associations between ID at 12-18 months and adolescent internalizing, externalizing, and social problems. Positive maternal responsiveness in infancy did not buffer those with ID anemia from developing 5-year internalizing problems.
Carotid artery stenosis, an underestimated cause of stroke recurrence in patients with ischaemic monocular visual loss.

INTRODUCTION Isolated monocular ischaemic events are thought to be low risk for stroke recurrence. In the presence of carotid stenosis however, the risks should not be treated similarly and surgical intervention should be considered at an early stage. The aim of this study was to determine the vascular risk profile and stroke recurrence in patients with ischaemic monocular visual loss. METHODS AND METHODS Consecutive records for all patients with monocular ischaemia were reviewed from January 2014 to October 2016. Stroke, transient ischaemic attack or monocular ischaemia recurrence within 90 days were recorded. Carotid stenosis was assessed with duplex ultrasound, computed tomography or magnetic resonance angiography. RESULTS In total, 400 patients presented with monocular ischaemia; 391 had carotid imaging (97.8%). Causality was symptomatic carotid stenosis ≥ 50% in 53 (13.6%), including carotid stenosis ≥ 70% in 31 (7.9%). Patients with permanent visual loss (n = 131) were more likely to have significant stenosis compared with patients with transient visual loss (n = 260), 19.8% compared with 10.4% (P = 0.012). Recurrent stroke, transient ischaemic attack or monocular ischaemia within 90 days after presentation occurred in three patients (5.7%) in the carotid stenosis group, compared to three (0.9%) who did not have stenosis (P = 0.035). Age, male sex and hypertension were associated with carotid stenosis but hypercholesterolaemia, diabetes and smoking were not. CONCLUSIONS Carotid stenosis ≥ 50% is present in patients with ocular ischaemia in approximately 20% of those with persistent visual loss and in 10% with transient visual loss. Those with carotid stenosis have a higher risk of stroke recurrence and should be considered urgent surgical intervention as other forms of stroke.
Cerebrospinal Fluid Concentrations of Extracellular Matrix Proteins in Alzheimer's Disease.

BACKGROUND Brevican, neurocan, tenascin-C, and tenascin-R are extracellular matrix (ECM) proteins that are mainly expressed in the brain. They play important roles in proliferation and migration of neurons and other cell types in the brain. These ECM proteins may also be involved in various pathologies, including reactive gliosis. OBJECTIVE The aim of the study was to investigate if ECM protein concentrations in cerebrospinal fluid (CSF) are linked to the neurodegenerative process in Alzheimer's disease (AD). METHODS Lumbar CSF samples from a non-AD control group (n = 50) and a clinically diagnosed AD group (n = 42), matched for age and gender, were analyzed using commercially available ELISAs detecting ECM proteins. Mann-Whitney U test was used to examine group differences, while Spearman's rho test was used for correlations. RESULTS Brevican, neurocan, tenascin-R, and tenascin-C concentrations in AD patients did not differ compared to healthy controls or when the groups were dichotomized based on the Aβ42/40 cut-off. CSF tenascin-C and tenascin-R concentrations were significantly higher in women than in men in the AD group (p = 0.02). CONCLUSION ECM proteins do not reflect AD-pathology in CSF. CSF tenascin-C and tenascin-R upregulation in women possibly reveal sexual dimorphism in the central nervous system immunity during AD.
Management of hyperglycaemia in persons with non-insulin-dependent type 2 diabetes mellitus who are started on systemic glucocorticoid therapy: a systematic review

Objectives What is the most effective pharmacological intervention for glycaemic control in known type 2 diabetes mellitus (DM) without prior insulin treatment and newly started on systemic glucocorticoid therapy? Design We conducted a systematic literature review. Data sources We searched MEDLINE, Embase and Cochrane Library databases and Google for articles from 2002 to July 2018. Eligibility criteria We combined search terms relating to DM (patients, >16 years of age), systemic glucocorticoids, glycaemic control, randomised controlled trials (RCTs) and observational studies. Data extraction and synthesis We screened and evaluated articles, extracted data and assessed risk of bias and quality of evidence according to Grading of Recommendations Assessment, Development and Evaluation guidelines. Results Eight of 2365 articles met full eligibility criteria. Basal-bolus insulin (BBI) strategy for patients under systemic glucocorticoid therapy was comparatively effective but provided insufficient glucose control, depending on time of day. BBI strategy with long-acting insulin and neutral protamin Hagedorn as basal insulin provided similar overall glycaemic control. Addition of various insulin strategies to standard BBI delivered mixed results. Intermediate-acting insulin (IMI) as additional insulin conferred no clear benefits, and glycaemic control with sliding scale insulin was inferior to BBI or IMI. No studies addressed whether anticipatory or compensatory insulin adjustments are better for glycaemic control. Conclusion The lack of suitably designed RCTs and observational studies, heterogeneity of interventions, target glucose levels and glucose monitoring, poor control of DM subgroups and low to moderate quality of evidence render identification of optimal pharmacological interventions for glycaemic control and insulin management difficult. Even findings on the widely recommended BBI regimen as intensive insulin therapy for patients with DM on glucocorticoids are inconclusive. High-quality evidence from studies with well-defined DM phenotypes, settings and treatment approaches is needed to determine optimal pharmacological intervention for glycaemic control. PROSPERO registration number CRD42015024739.
Genotype distribution of Panton-Valentine leukocidin (PVL) positive Staphylococcus aureus strains isolated from wound related infections: A three year multi-center study in Tehran, Iran.

The spread of PVL-carrying S. aureus strains in patients with wound infections in both the community and hospitals are increasing in some areas of Iran. In the present study, we determined the molecular characteristics and distribution of PVL-producing S. aureus strains isolated in wound infections. Genes encoding resistance, toxin, and staphylococcal enterotoxins were analyzed by polymerase chain reaction assays. Genotyping was performed by using multi-locus sequence typing. Aminoglycoside resistance genes including ant (4΄)-Ia gene (57.4%) and aac (6΄)-Ie/aph (2˝) (45.7%) were the most prevalent genes in isolates. Staphylococcal enterotoxin type A, as the most frequent type, was present in 20.2% of isolates. Strains belonged to seven clonal complexes. The most frequent clonal complex was CC30 (ST30) (29.8%); followed by CC22 (ST22) (21.3%), CC8 (ST8 and ST931) (17%), CC88 (ST88) (10.6%), CC59 (ST59 and ST338) (8.5%), CC1 (ST772 and ST1) (7.5%), and CC15 (ST15) (5.3%). Our findings indicated an increasing trend of CC30, carrying a wide range of resistance and toxin genes that could be a dilemma for treating the patients with wound infections indeed. Further studies are required to investigate the carriage of resistance, the antibiotic susceptibility pattern, and toxins encoding genes in different molecular types.
Borderline personality disorder and eating disorders: a trans-diagnostic approach to unravelling diagnostic complexity

Objectives: This opinion paper considers co-morbid borderline personality disorder (BPD) and eating disorders and proposes that a trans-diagnostic approach looking at presenting problems and treatment approaches may be of value. Conclusions: Trans-diagnostic elements can be identified across the two syndromes. Trans-diagnostic elements appear to include some shared aetiological factors as well as some shared syndromal components. The shared syndromal components include problems with affect, interpersonal problems, problems with self-concept and impulsivity. The pathoplastic effects of culture, attitudes to fatness and the neurobiology of starvation and/or restriction of intake are crucial to integrate into the understanding of co-morbidity of these two disorders. Trans-diagnostic approaches to treatment lead to trans-diagnostic improvements across the two disorders.
Internal Consistency and Convergent Validity of the Personality Assessment Inventory English and European-Spanish Version with English/Spanish Bilinguals

Abstract Practitioners have few personality inventory options when assessing Spanish-speakers, despite professional guidelines that encourage them to administer measures that are validated with their populations of interest. To build on research in this area, we examined the internal consistency and convergent validity of the Personality Assessment Inventory (PAI) and the Personality Assessment Inventory European-Spanish (PAIE-S) version among bilingual Latin American Spanish-speakers (final n = 53). For the PAI, 72.72% of scales and 35.48% of subscales had alphas above . 70. For the PAIE-S, 50.00% of scales and 25.81% of scales met this alpha. Participants tended to score lowest on the PAI Alcohol Problems scale (T = 47.19) and the PAIE-S Warmth scale (T = 45.49). On average, participants scored highest on the PAI’s Paranoia-Hypervigilance scale (T = 61.15) and the PAIE-S’s Paranoia scale (T = 57.64). We identified 10 scales and subscales on which participants were significantly more likely (p < .00094) to score higher on one measure than the other. Participants more often scored higher on the PAI than the PAIE-S. All parallel scales and subscales converged at p < . 00094 with the exception of the Antisocial Features-Egocentricity scale. Taken together, findings suggest taking caution when administering these measures to Latin American bilingual Spanish-speakers.
Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study

PURPOSE Pembrolizumab monotherapy has demonstrated durable antitumor activity in advanced programmed death ligand 1 (PD-L1)–expressing non‒small-cell lung cancer (NSCLC). We report 5-year outcomes from the phase Ib KEYNOTE-001 study. These data provide the longest efficacy and safety follow-up for patients with NSCLC treated with pembrolizumab monotherapy. PATIENTS AND METHODS Eligible patients had confirmed locally advanced/metastatic NSCLC and provided a contemporaneous tumor sample for PD-L1 evaluation by immunohistochemistry using the 22C3 antibody. Patients received intravenous pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Investigators assessed response per immune-related response criteria. The primary efficacy end point was objective response rate. Overall survival (OS) and duration of response were secondary end points. RESULTS We enrolled 101 treatment-naive and 449 previously treated patients. Median follow-up was 60.6 months (range, 51.8 to 77.9 months). At data cutoff—November 5, 2018—450 patients (82%) had died. Median OS was 22.3 months (95% CI, 17.1 to 32.3 months) in treatment-naive patients and 10.5 months (95% CI, 8.6 to 13.2 months) in previously treated patients. Estimated 5-year OS was 23.2% for treatment-naive patients and 15.5% for previously treated patients. In patients with a PD-L1 tumor proportion score of 50% or greater, 5-year OS was 29.6% and 25.0% in treatment-naive and previously treated patients, respectively. Compared with analysis at 3 years, only three new-onset treatment-related grade 3 adverse events occurred (hypertension, glucose intolerance, and hypersensitivity reaction, all resolved). No late-onset grade 4 or 5 treatment-related adverse events occurred. CONCLUSION Pembrolizumab monotherapy provided durable antitumor activity and high 5-year OS rates in patients with treatment-naive or previously treated advanced NSCLC. Of note, the 5-year OS rate exceeded 25% among patients with a PD-L1 tumor proportion score of 50% or greater. Pembrolizumab had a tolerable long-term safety profile with little evidence of late-onset or new toxicity.
Gastroesophageal Reflux: Pathogenesis, Diagnosis, and Therapy

: In recent years, considerable new information has become available on the pathogenesis, diagnosis and therapy of gastroesophageal reflux. Gastric contents, mucosal resistance, esophageal acid clearance, and gastric emptying are now recognized, along with incompetency of the lower esophageal sphincter, as contributing factors to gastroesophageal reflux disease. The potential tests for reflux are reviewed and the diagnostic accuracy of each is evaluated. A diagnostic approach to the patient with reflux symptoms is outlined that considers the sensitivity and specificity of these various tests as well as their availability to the generalist and gastrointestinal specialist. Finally, an overview of the current therapy for reflux disease summarizes the controlled studies in the medical literature.
A metabolic profile of polyamines in parkinson disease: A promising biomarker

Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age‐related, diagnostic, and severity‐associated PD biomarker.
Shared control–based bimanual robot manipulation

A bimanual shared-control method enables novice users to control a robot in real time to complete complex manipulation tasks. Human-centered environments provide affordances for and require the use of two-handed, or bimanual, manipulations. Robots designed to function in, and physically interact with, these environments have not been able to meet these requirements because standard bimanual control approaches have not accommodated the diverse, dynamic, and intricate coordinations between two arms to complete bimanual tasks. In this work, we enabled robots to more effectively perform bimanual tasks by introducing a bimanual shared-control method. The control method moves the robot’s arms to mimic the operator’s arm movements but provides on-the-fly assistance to help the user complete tasks more easily. Our method used a bimanual action vocabulary, constructed by analyzing how people perform two-hand manipulations, as the core abstraction level for reasoning about how to assist in bimanual shared autonomy. The method inferred which individual action from the bimanual action vocabulary was occurring using a sequence-to-sequence recurrent neural network architecture and turned on a corresponding assistance mode, signals introduced into the shared-control loop designed to make the performance of a particular bimanual action easier or more efficient. We demonstrate the effectiveness of our method through two user studies that show that novice users could control a robot to complete a range of complex manipulation tasks more successfully using our method compared to alternative approaches. We discuss the implications of our findings for real-world robot control scenarios.
Simultaneous assessment of DNA ploidy and biomarker expression in paraffin‐embedded tissue sections

Fleskens S J H M, Takes R P, Otte‐Höller I, van Doesburg L, Smeets A, Speel E‐J M, Slootweg P J & van der Laak J A W M (2010) Histopathology 57, 14–26 Simultaneous assessment of DNA ploidy and biomarker expression in paraffin‐embedded tissue sections
The Ocular and Otic Pathology of Bovine Beta-Mannosidosis

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