Miracle-dz/UniFAR-FTUs huggingface dataset:
The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).
Whole-transcriptome RNA-seq, gene set enrichment pathway analysis, and exon coverage analysis of two plastid RNA editing mutants

ABSTRACT In land plants, plastid and mitochondrial RNAs are subject to post-transcriptional C-to-U RNA editing. T-DNA insertions in the ORGANELLE RNA RECOGNITION MOTIF PROTEIN6 gene resulted in reduced photosystem II (PSII) activity and smaller plant and leaf sizes. Exon coverage analysis of the ORRM6 gene showed that orrm6–1 and orrm6–2 are loss-of-function mutants. Compared to other ORRM proteins, ORRM6 affects a relative small number of RNA editing sites. Sanger sequencing of reverse transcription-PCR products of plastid transcripts revealed 2 plastid RNA editing sites that are substantially affected in the orrm6 mutants: psbF-C77 and accD-C794. The psbF gene encodes the β subunit of cytochrome b559, an essential component of PSII. The accD gene encodes the β subunit of acetyl-CoA carboxylase, a protein required in plastid fatty acid biosynthesis. Whole-transcriptome RNA-seq demonstrated that editing at psbF-C77 is nearly absent and the editing extent at accD-C794 was significantly reduced. Gene set enrichment pathway analysis showed that expression of multiple gene sets involved in photosynthesis, especially photosynthetic electron transport, is significantly upregulated in both orrm6 mutants. The upregulation could be a mechanism to compensate for the reduced PSII electron transport rate in the orrm6 mutants. These results further demonstrated that Organelle RNA Recognition Motif protein ORRM6 is required in editing of specific RNAs in the Arabidopsis (Arabidopsis thaliana) plastid.
Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity

Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanisms remain to be fully elucidated. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide–dependent deacetylase located primarily inside mitochondria. In this study, we demonstrated that an SFA‐rich high‐fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated HFD rich in fatty acids. Unexpectedly, SIRT3 expression and activity were significantly elevated in the livers of mice exposed to the SFA‐rich HFD. Using cultured HepG2 and AML‐12 hepatocytes, we demonstrated that unlike monounsaturated fatty acids, SFAs up‐regulate SIRT3 expression and activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate‐induced cell death, which can be alleviated by SIRT3 small interfering RNA (siRNA) transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, thereby enhancing the susceptibility of hepatocytes to SFA‐induced cytotoxicity. Mechanistic investigations revealed that SIRT3 overexpression causes manganese superoxide dismutase deacetylation and activation, which depleted intracellular superoxide contents, leading to adenosine monophosphate–activated protein kinase (AMPK) inhibition and mammalian target of rapamycin C1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhanced autophagy flux. A similar result was observed in the liver tissue of SIRT3 knockout mice. Conclusion: Our data indicate that SIRT3 is a negative regulator of autophagy whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. (Hepatology 2017;66:936–952).
Regulatory interplay between LEAFY, APETALA1/CAULIFLOWER and TERMINAL FLOWER1: New insights into an old relationship

ABSTRACT The gene regulatory network comprised of LEAFY (LFY), APETALA1 (AP1), the AP1 paralog CAULIFLOWER (CAL), and TERMINAL FLOWER1 (TFL1) is a major determinant of the flowering process in Arabidopsis thaliana. TFL1 activity in the shoot apical meristem provides inflorescence identity while the transcription factors LFY and AP1/CAL confer floral identity to emerging floral primordia. It has been thought that LFY and AP1/CAL control the onset of flowering in part by repressing TFL1 expression in flowers. However, in the June issue of Plant Physiology, we reported that LFY and AP1 act antagonistically in the regulation of several key flowering regulators, including TFL1. Specifically, TFL1 transcription was suppressed by AP1 but promoted by LFY. Here, we present additional evidence for the role of LFY as an activator of TFL1 and propose that this regulatory activity is pivotal for the indeterminate growth of the SAM during the reproductive phase of development.
Plasmapheresis and Intravenous Immunoglobulin in Early Antibody‐Mediated Rejection of the Renal Allograft: A Single‐Center Experience

Antibody‐mediated rejection (AMR) is a rare complication which often results in the loss of the kidney graft. The objective of this retrospective single center study was to evaluate two different approaches to AMR. We retrospectively evaluated data files from 936 patients who had undergone renal transplantation in 2002–2006. In 2002–2003, patients with AMR were treated with five plasmapheresis sessions (PP group, N = 13), and in 2004–2006 they received five plasmapheresis session along with intravenous immunoglobulin 0.5 g/kg (PP+IVIg group, N = 11). Twelve months of follow‐up data was analyzed. First year graft survival was significantly higher in the PP+IVIg group than in the PP group (90.9% vs. 46.2%; P = 0.044); similarly, patient survival was higher in the PP+IVIg group (100% vs. 76.9%; P = 0.056). The incidence of infectious complications was similar in both groups. In re‐biopsies, patients in the PP group often suffered from cellular rejection. The deposition of C4d complement was similar in re‐biopsies in both groups. In this large single center study we proved the superiority of plasmapheresis with intravenous immunoglobulin administration in the treatment of early AMR of renal allografts.
A Case Report of Amitriptyline Poisoning Successfully Treated With the Application of Plasma Exchange

Amitriptyline is a very frequently prescribed antidepressant agent and is very often involved in attempted suicides. Amitriptyline intoxication necessitates primary therapeutic approaches that include gastric irrigation and recurrent administration of activated charcoal. In the case of pronounced anticholinergic findings, physostigmine is of proven benefit and hypertonic sodium bicarbonate can be used to shorten the QRS duration and AV interval. In cases of a comatosed state, hemoperfusion and plasma exchange can be used. In this case report we present a case of severe amitriptyline poisoning that we successfully managed with plasma exchange. We confirmed a 59.5% reduction in the amitriptyline plasma level in our patient after a single plasma exchange session. She was discharged by the third day of admission without any complications. According to current literature, our patient is the fifth patient treated with plasma exchange to be the subject of a publication.
Planning a Social Activity to Improve Psychological Well‐being and Quality of Life of Hemodialysis Patients: A Pilot Study

We aimed to investigate the impact of social activity on anxiety‐depression, self‐esteem and quality of life in hemodialysis patients. Ninety‐one patients were recruited to the current study. Of these, 31 patients wanted to take part in a theater play, while 60 patients (group C) did not. Thirty‐one patients were randomly assigned to two groups: Group A (N = 15) started activities immediately and group B (N = 16) was assigned to a waiting list to be included in the activity of theater acting four months later. Beck Depression Inventory, Beck Anxiety Inventory, Rosenberg Self‐esteem Scale and World Health Organization Quality of Life Scale short form (WHOQOL‐BREF) were used to compare psychological parameters and quality of life of the groups before and after the social activity. The patients who were younger, more literate, and wealthier, had longer disease duration, and who were feeling physically and psychologically well, were willing to participate in social activity. The impact of social activity was evaluated between group A and C. After the social activity, there were significant differences in terms of depression (P = 0.008), self‐esteem (P = 0.003), and physical (P = 0.04) and psychological (P = 0.05) sub‐dimensions of quality of life between the groups. The depression score of the patients in group A decreased while their self‐esteem increased, but the increase in the physical and psychological sub‐dimension scores of quality of life scale did not reach statistical significance. This pilot study showed that social activity primarily improved depression and self‐esteem in hemodialysis patients.
AUXIN RESPONSE FACTOR3 plays distinct role during early flower development

ABSTRACT AUXIN RESPONSE FACTOR3 (ARF3), one of the auxin response factors family of transcription factors, is well characterized by its functions in polarity identification and organ patterning. We recently demonstrated that ARF3 plays important roles in floral meristem (FM) maintenance and termination by regulating cytokinin biosynthesis and signaling. However, the relationship of its multiple roles in differently developmental stage is still unclear. Here, we present data that ARF3 plays distinct roles during early flower development that are different from its roles in organ polarity determination and pattering. Thus, our findings shed light on the functional diversity of one specific transcription factor in plant development.
The Glenn A. Fry Award Lecture 2013: Blurred Vision, Spectacle Correction, and Falls in Older Adults

ABSTRACT This article reviews the literature on how blurred vision contributes to falls, gait, and postural control and discusses how these are influenced by spectacle correction. Falls are common and represent a very serious health risk for older people. They are not random events as studies have shown that falls are linked to a range of intrinsic and extrinsic risk factors. Vision provides a significant input to postural control in addition to providing information about the size and position of hazards and obstacles in the travel pathway and allows us to safely negotiate steps and stairs. Many studies have shown that reduced vision is a significant risk factor for falls. However, randomized controlled trials of optometric interventions and cataract surgery have not shown the expected reduction in falls rate, which may be due to magnification changes (and thus vestibulo-ocular reflex gain) in those participants who have large changes in refractive correction. Epidemiological studies have also shown that progressive addition lens and bifocal wearers are twice as likely to fall as non–multifocal wearers, laboratory-based studies have shown safer adaptive gait with single-vision glasses than progressive addition lenses or bifocals, and a randomized controlled trial has shown that an additional pair of distance vision single-vision glasses for outdoor use can reduce falls rate. Clinical recommendations to help optometrists prevent their frail, older patients from falling are suggested.
Infections as complications of neuroleptic malignant syndrome

Neuroleptic malignant syndrome is an uncommon but potentially fatal side effect of antipsychotic drug treatment. Several serious complications have been associated with neuroleptic malignant syndrome, such as acute renal failure, deep venous thrombosis, pulmonary embolism and aspiration pneumonia. Reports on infections other than aspiration pneumonia appear, from the literature, to be uncommon. Four cases of infection (three cases of upper respiratory tract infection and one case of urinary tract infection) which developed during the course of neuroleptic malignant syndrome are reported and pathophysiological mechanisms underlying their presentation are suggested.
Towards Cost‐effective Strategies for Treatment of Chronic Kidney Disease‐Mineral and Bone Disorder in Japan

There is a growing interest worldwide in making a more effective and efficient use of limited health care resources. Dialysis treatment in Japan and other countries is being confronted with increasing expenditure due to an aging population, coverage of new medical technologies, and an increase in the dialysis population. Chronic kidney disease–mineral and bone disorder (CKD‐MBD) is an important issue related to the increased expenditure among dialysis patients because it is one of the main causes of morbidity and mortality, and results in a high economic burden. In recent years, several economic analyses on the treatment of CKD‐MBD have been reported from Western countries. Given the longer dialysis vintage of Japanese patients, it is very important to conduct economic evaluation from a long‐term viewpoint using clinical data on Japanese patients. This article reviews the recent literature on economic evaluation of CKD‐MBD treatments and discusses the road ahead for cost‐effectiveness analysis in Japanese dialysis patients with CKD‐MBD.
Survey of referrals to electroconvulsive therapy in Hungary

Background. The diagnostic distribution of patients treated with electroconvulsive therapy (ECT) in Hungary is significantly different from that in Western Europe or the USA. In Hungary most of the treated patients are diagnosed with schizophrenia. Aim. To analyze the practice of referring patients for ECT in Hungary. Methods. Questionnaires containing socio-demographic data were mailed to all Hungarian psychiatric units where ECT was used (n=34), and all of the psychiatrists working there were invited to participate. Respondents were asked to rate how often they considered ECT for various symptoms/syndromes on a five-point Likert Scale. Results. A total of 78 questionnaires were returned. Altogether, 89% of the respondents have referred patients to ECT, and 54.8% had done so in the last year. The respondents had most frequently recommended ECT for antipsychotic and antidepressant-resistant patients, catatonic symptoms, or patients with previous good treatment response to ECT. Conclusion. Considering the very high Hungarian suicide rate, the low referral rate in cases of severe suicidal intent and threat is surprising. The respondents also rarely considered ECT for NMS or severe depression. The discrepancy between current referral practices and standard recommendations could be decreased with more ECT training courses.
Change in aerobic fitness of patients with multiple sclerosis during a 6‐month training program

Twenty‐three individuals with multiple sclerosis (MS) participated in a 6‐month exercise training program; 11 ambulatory (AMB) and 8 semi‐ambulatory (SEMI). Four persons with MS served as non‐exercising controls (C). A test of maximal aerobic power (VO2max) was administered at baseline to all subjects. AMB and SEMI subjects exercised on alternating days for 30 minutes, at 55‐60% VO2max using either a commercially available recumbent or upright combination leg/arm bicycle ergometer. At the end of 12 and 24 weeks, exercising subjects were re‐evaluated. The C group was only re‐evaluated at 24 weeks. The results show that the AMB and SEMI groups experienced a +20% and +5% improvement in VO2max, respectively. The C group averaged a 12% decline in VO2max during the 6 months. These data demonstrate the possibility that although exercise improves cardiovascular fitness of some persons with less severe MS, this beneficial response may not apply to the more severely impaired patient. Nevertheless, improved cardiova.
Hepatitis B cure: From discovery to regulatory approval

The majority of persons currently treated for chronic hepatitis B require long‐term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof‐of‐concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).
Biological markers for anxiety disorders, OCD and PTSD – a consensus statement. Part I: Neuroimaging and genetics

Abstract Objectives: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. Results: The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition. Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition

Abstract Objective: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. Results: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.