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Pulmonary hypertension (PH) is associated with decreased survival in patients with pulmonary fibrosis and combined pulmonary fibrosis and emphysema. Main pulmonary artery (PA) diameter and PA diameter/ascending aortic diameter (PA/AA) ratio, as measured on CT, have recently emerged as specific markers for PH. Our single-center retrospective study found that PA/AA ratio > 1 is associated with decreased survival in individuals with pulmonary fibrosis, with or without emphysema. Our study also describes markers of cardiac remodeling, and the echocardiographic diagnosis of PH in this patient population., Author(s): F. Zeba [sup.1], W. Yanning [sup.2], J. Melek [sup.3], F. Duan [sup.2], M. K. Atalay [sup.4], M. Jankowich [sup.5], S. Rounds [sup.5] Author Affiliations: (1) grid.413480.a, 0000 0004 0440 [...]

Introduction: Noroviruses are most frequent agents causing gastroenteritis worldwide. They are high infective non-capsulated RNA viruses classified in the Caliciviridae family spreading out by the fecal-oral route and by aerosol. Clinical manifestation in the newborns is not known very well. Methods: The clinical observation study was performed at the Neonatal Intensive Care Unit (NICU) of University Hospital in Hradec Kralove. The diagnostics employed antigenic tests based on immunochromatography using the Immunocard Stat Norovirus (Meridian, Bioscience Europe, Milano, Italy and RIDAQUICK Norovirus test (R-Biopharm, AG, Darmstadt, Germany). The results were confirmed at the National Reference Laboratory for Electron Microscopy, National Institute of Public Health, Prague. At the same time all patients underwent the test demonstrating the rotavirus and adenovirus antigens in stools by the cassette immunochromatographic Rota-Adeno-Card test (Vidia, Certest, Spain). The cultivation examination of stools was executed by means of standard microbiological procedures. Necrotizing enterocolitis (NEC) was defined as a disease in the maximum stage IIa according to Bell criteria modified by Walsh and Kliegman at least. Results: Noroviral antigen was demonstrated in the stools of 21 patients, electron microscopy was positive in another patient despite negative antigen test. Immunochromatographic tests were confirmed by electron microscopy in 17 cases, agreement was in 75%. The age median in developed clinical symptoms or first positivity was on day 17.5 with variance of 5 to 38 days, the median of gestation weeks and birth weight was 29 gestation weeks (24--28) resp. 1073 g (530--3260). Six patients lacked clinical symptoms. Enterorrhagia was the most frequent symptom of the disease in nine patients (56%). Desaturations and apnea were also very frequent -- 8 (50%) or 5 (31%) patients; six patients (38%) required mechanical ventilation. Clinical and radiological signs of necrotizing enterocolitis were observed in 7 patients (44%). Conclusions: The symptoms of noroviral infections in newborns are different from those encountered in adults and older children. The most frequent include abdominal distension, enterorrhagia, respiration instability with increased demand for oxygen therapy, and apneas, which take place in different time order. Necrotizing enterocolitis requiring surgical treatment is not an exceptional solution of noroviral infection. The diagnostics of noroviral infection is complicated and the authors recommend confirmation of antigenic tests by RT-PCR or electron microscopy. A complete cohort arrangement of the patients and personnel and strict adherence to hygienic-epidemiological measures is a prerequisite for controlling the infection in the NICU. [ABSTRACT FROM AUTHOR]

Case reports of two children with the case history of diarrhea disease followed by suddenly developed neurological symptomatology at the age of 15 and 17 months are described. The clinical, manifestations and examinations performed made it possible to establish the diagnosis of benign seizures associated with noroviral gastroenteritis. Benign infantile seizures associated with noroviral gastroenteritis represent a relatively new unit described mainly in Asia. Noroviruses belong to the most frequent provoking agents. The disease affects so far healthy individuals at the age of 15--21 months. The main clinical manifestations include several although not many says lasting afebrile gastroenteritis, followed by seizure attacks, most often generalized tonic clonic seizures. The seizures tend to be rather recurrent in the first 24 hours and are rather resistant to anticonvulsant therapy. Noroviruses are often demonstrated in the stools. The basic biochemical parameters of serum, examination of liquor and imaging examination of the brain are often normal. Interictal EEG record may be normal or detecting abnormities which adjust in time. The prognosis despite apparently serious condition is usually excellent. The children further develop in a normal way and do not need anticonvulsant therapy. [ABSTRACT FROM AUTHOR]

Various strategies have been employed to improve the reliability of 2D, 3D, and co-culture in vitro models of nonalcoholic fatty liver disease, including using extracellular matrix proteins such as collagen I to promote cell adhesion. While studies have demonstrated the significant benefits of culturing cells on collagen I, its effects on the HepG2 cell line after exposure to palmitate (PA) have not been investigated. Therefore, this study aimed to assess the effects of PA-induced lipotoxicity in HepG2 cultured in the absence or presence of collagen I. HepG2 cultured in the absence or presence of collagen I was exposed to PA, followed by analyses that assessed cell proliferation, viability, adhesion, cell death, mitochondrial respiration, reactive oxygen species production, gene and protein expression, and triacylglycerol accumulation. Culturing HepG2 on collagen I was associated with increased cell proliferation, adhesion, and expression of integrin receptors, and improved cellular spreading compared to culturing them in the absence of collagen I. However, PA-induced lipotoxicity was greater in collagen I-cultured HepG2 than in those cultured in the absence of collagen I and was associated with increased α2β1 receptors. In summary, the present study demonstrated for the first time that collagen I-cultured HepG2 exhibited exacerbated cell death following exposure to PA through integrin-mediated death. The findings from this study may serve as a caution to those using 2D models or 3D scaffold-based models of HepG2 in the presence of collagen I.

Background: Mucosal healing (MH) has become a perspective treatment target in patients with Crohn's disease (CD). Data about the impact of MH on long-term outcome in pediatric patients are still scarce., Methods: Seventy-six pediatric patients with CD were evaluated retrospectively (2000-2015) in a tertiary care center. Based on MH achievement, they were divided into two groups (MH, N.=17; and No MH, N.=59). The primary endpoint was to assess the association of MH and the need for CD-related hospitalizations or surgery in pediatric patients with CD., Results: The number of hospitalized patients was 24% in the MH group and 42% in the No MH group (P=0.26). The total number of CD-related hospitalizations was not significant between the MH group and the No MH group (5 vs. 41, P=0.15). The time to the first hospitalization was 24 months in MH and 21 months in No MH (P>0.99). About 24% of the patients in the MH group and 39% patients in the No MH group underwent CD-related operation (P=0.39). Time to the first operation was 43 months for MH and 19 months for the No MH group (P=0.13). The follow-up period was 91 months in the MH group and 80 months in the No MH group (P=0.74). The use of infliximab was positively associated with MH (P=0.002)., Conclusions: MH was not associated with fewer CD-related hospitalizations or operations in pediatric patients with CD during seven years of follow-up.

Although some clinical studies have reported increased mitochondrial respiration in patients with fatty liver and early non‑alcoholic steatohepatitis (NASH), there is a lack of in vitro models of non‑alcoholic fatty liver disease (NAFLD) with similar findings. Despite being the most commonly used immortalized cell line for in vitro models of NAFLD, HepG2 cells exposed to free fatty acids (FFAs) exhibit a decreased mitochondrial respiration. On the other hand, the use of HepaRG cells to study mitochondrial respiratory changes following exposure to FFAs has not yet been fully explored. Therefore, the present study aimed to assess cellular energy metabolism, particularly mitochondrial respiration, and lipotoxicity in FFA‑treated HepaRG and HepG2 cells. HepaRG and HepG2 cells were exposed to FFAs, followed by comparative analyses that examained cellular metabolism, mitochondrial respiratory enzyme activities, mitochondrial morphology, lipotoxicity, the mRNA expression of selected genes and triacylglycerol (TAG) accumulation. FFAs stimulated mitochondrial respiration and glycolysis in HepaRG cells, but not in HepG2 cells. Stimulated complex I, II‑driven respiration and β‑oxidation were linked to increased complex I and II activities in FFA‑treated HepaRG cells, but not in FFA‑treated HepG2 cells. Exposure to FFAs disrupted mitochondrial morphology in both HepaRG and HepG2 cells. Lipotoxicity was induced to a greater extent in FFA‑treated HepaRG cells than in FFA‑treated HepG2 cells. TAG accumulation was less prominent in HepaRG cells than in HepG2 cells. On the whole, the present study demonstrates that stimulated mitochondrial respiration is associated with lipotoxicity in FFA‑treated HepaRG cells, but not in FFA‑treated HepG2 cells. These findings suggest that HepaRG cells are more suitable for assessing mitochondrial respiratory adaptations in the developed in vitro model of early‑stage NASH.

Background: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy., Methods: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse., Results: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031)., Conclusions: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision., Impact: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC VCAM-1 in murine NASH. Moreover, LSEC VCAM-1 expression was significantly increased in human NASH. LSEC VCAM-1 expression was upregulated by palmitate treatment in vitro and reduced with inhibition of the mitogen-activated protein 3 kinase (MAP3K) mixed lineage kinase 3 (MLK3). Likewise, LSEC VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing Ab or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH and might serve as a potential therapeutic strategy for human NASH.

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.

Objectives: Over the past few years, mucosal healing (MH) has emerged as a promising goal in the treatment of pediatric patients with Crohn's disease (CD). We aimed to assess whether combination therapy with infliximab (IFX) + azathioprine (AZA) was more effective than AZA therapy alone in achieving mucosal healing in pediatric patients with CD., Methods: Newly diagnosed pediatric patients with CD at the Department of Pediatrics in University Hospital in Hradec Králové were retrospectively recruited (2000-2014). The patients were divided into two groups according to the therapy: (a) IFX + AZA ± corticosteroids ± 5-aminosalicylic acid (5-ASA) (n = 16); and (b) AZA ± corticosteroids ± 5-ASA (n = 40). The patients were also divided into two groups: "MH" and "no MH," according to their MH status. MH was defined as the complete endoscopic disappearance of all mucosal ulcerations (including aphthous ulcerations) and the absence of any sign of mucosal inflammation in the terminal ileum and the large bowel., Results: Of 56 patients, MH was observed in 56% (9/16) treated with combined therapy in comparison with 15% (6/40) of patients in the AZA group (P = 0.006). The median dose of AZA in both groups was 2.1 mg/kg per day. We observed eight adverse events in seven patients from the IFX + AZA group. Adverse effects were less common in the AZA group (P = 0.002)., Conclusion: Combined therapy (IFX + AZA) was more effective in achieving MH in pediatric CD than treatment with AZA alone., (© 2020 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

A two-year-old girl with two weeks of abdominal pain, vomiting, and food refusal, ten months after percutaneous endoscopic gastrostomy insertion because of inadequate peroral intake, was admitted to a tertiary centre hospital. On admission, the extracorporeal part of the gastrostomy was much shortened. X-ray examination revealed migration of the end of the gastrostomy tube with a left-shifted course of the tube through the duodenum. Gastroscopy and subsequently laparotomy were performed. A longitudinal pressure necrosis was identified under the tube, with two perforations in the duodenojejunal region. Ten centimeters of that duodenojejunal region were resected, and end-to-end anastomosis was made. The migration of the gastrostomy was probably caused by insufficient care by the parents. Pathophysiologically, the tube caused the pressure necrosis in the duodenojejunal area; this was supported by histology. This is a hitherto undescribed complication of a percutaneous endoscopic gastrostomy, showing that migration of the gastrostomy to the deeper part of the small bowel can lead to pressure necrosis, a potentially life-threatening condition in children which cannot be treated without invasive procedures.

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment., Methods: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally., Results: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES., Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD., (© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Goals: In order to provide a comparative evaluation of available pharmacologic treatments for eosinophilic esophagitis (EoE), we conducted a network meta-analysis., Background: A variety of pharmacologic treatments for EoE have been reported, however there exists a paucity of direct comparisons., Study: We searched randomized controlled trials using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials database through December 2014. Studies were analyzed using a random-effects network meta-analysis to identify the most effective therapy. Subgroup analysis was performed among studies that excluded gastroesophageal reflux disease or proton-pump inhibitor responsive esophageal eosinophilia, and also among pediatric and adult populations. The ranking probability for the efficacy of each treatment was analyzed. Consistency of the included randomized controlled trials was checked by applying inconsistency and node-splitting models., Results: Eleven studies of a total of 456 patients were identified. Six pharmacologic treatments (budesonide suspension and viscous, fluticasone, prednisone, esomeprazole, and mepolizumab) and placebo were included in our analysis. Meta-analysis showed superiority of budesonide viscous, budesonide suspension, and fluticasone over placebo. Network meta-analysis demonstrated the rank order of efficacy as budesonide viscous, esomeprazole, prednisone, budesonide suspension, fluticasone, mepolizumab, and placebo. The results were consistent from the inconsistency model analysis and node-splitting analysis. Subgroup analysis demonstrated prednisone, budesonide suspension, and esomeprazole were the most effective when network meta-analyses were performed among studies that excluded gastroesophageal reflux disease or proton-pump inhibitor responsive esophageal eosinophilia, and among pediatric and adult populations, respectively., Conclusions: On the basis of this network meta-analysis, viscous budesonide was shown to be the most effective pharmacologic therapy for EoE among the reported pharmacologic treatments.

Background: Treatment quality and outcomes of paediatric home parenteral nutrition (HPN) program during its development in the Czech Republic., Methods: A retrospective study of patients receiving HPN from May 1995 till June 2011., Results: Sixty-six patients were treated in 8 centres. In 48 patients, long-term PN began in the first year of life and in 35 of them in the first month. Sixty children had gastrointestinal and 6 had non-gastrointestinal disease. In a majority of the patients, the Broviac catheter was used. Thirty-two (48.5%) patients were weaned from PN after 1-117 months, 21 (32.8%) continued on HPN after 7-183 months, and 13 (19.7%) patients died, all on PN. The mortality in patients with primary gastrointestinal disease was significantly lower than in patients with non-gastrointestinal disease. Thirty-one paediatric patients were receiving HPN for 14,480 catheter days in 2009-2010. Fourteen patients had 23 Catheter Related Blood Stream Infections (CRBSI) episodes. The incidence of CRBSI in 2009-2010 was 1.58/1,000 catheter days., Conclusion: Submitted data showed that even in the absence of expert centres, patient care may achieve results comparable to countries with well-developed HPN program. A majority of Czech HPN patients are at present treated in specialized centres, following the most desirable pattern of care., (© 2017 S. Karger AG, Basel.)

Background & Aims: Patients with inflammatory bowel disease (IBD) are at risk for osteoporosis and fracture. However, the efficacy of medical treatments for osteoporosis in increasing bone mineral density (BMD) in patients with IBD has not been well characterized., Methods: We conducted a meta-analysis and systematic review of controlled trials to evaluate the efficacy and safety of medical therapies used for low BMD in patients with IBD (Crohn's disease, ulcerative colitis, or indeterminate colitis). We searched MEDLINE, EMBASE, Google scholar, the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, and Cochrane Central Register of Controlled Trials for studies that assessed the efficacy of medical treatment for low BMD in patients with IBD. We also manually searched abstracts from scientific meetings and bibliographies of identified articles for additional references. The primary outcome assessed was changes in BMD at the lumbar spine. We also collected data on hip BMD, numbers of new fractures, and adverse effects. Data were pooled by using random-effects models and by mixed-effects analysis for primary aims, when subgroup analysis by individual drug was possible., Results: We analyzed data from 19 randomized controlled studies; 2 used calcium and vitamin D as therapies, 13 used bisphosphonates, 4 used fluoride, 1 used calcitonin, and 1 used low-impact exercise. The pooled effect of bisphosphonates was greater than that of controls in increasing BMD at the lumbar spine (standard difference in means, 0.51; 95% confidence interval, 0.29-0.72) and hip (standard difference in means, 0.26; 95% confidence interval, 0.04-0.49) with comparable tolerability, and the risk of vertebral fractures was reduced. Fluoride increased lumbar spine BMD, but its ability to reduce risk of fracture was unclear. There was no evidence that the other interventions increased BMD., Conclusions: On the basis of a meta-analysis, bisphosphonate is effective and well tolerated for the treatment of low BMD in patients with IBD and reduces the risk of vertebral fractures. There are insufficient data to support the efficacy of calcium and vitamin D, fluoride, calcitonin, or low-impact exercise. However, the small number of randomized controlled trials limited our meta-analysis., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Natalizumab is an efficacious agent for the induction and maintenance of remission in patients with Crohn's disease (CD) who have failed anti-tumor necrosis factor (TNF) agents. We aimed to assess the efficacy and safety of natalizumab outside of clinical trial at a US tertiary center., Methods: Retrospective case review of patients with CD receiving natalizumab., Results: Forty-nine patients with CD (28 women; median age, 33 years) receiving natalizumab from April 2008 to November 2011 were identified. Median duration of disease was 180 months (range, 36-576 months); 40 patients had ileocolonic disease, 1 had ileal disease, and 8 had colonic disease. Twenty-one patients had penetrating disease, and 28 had a history of CD-related surgical treatment. Forty-seven patients previously failed treatment with at least 1 anti-TNF agent. Median duration of natalizumab treatment was 7 months (interquartile range, 3-21.5 months). Twenty-four patients (49%) were continuing natalizumab at the time of this review, and 25 discontinued treatment because of the lack of response, side effects, or positive JC virus antibody. Seventeen patients (35%) successfully continued treatment with natalizumab for longer than 12 months, and nonpenetrating disease phenotype was identified as a predictor of longer response (compared with penetrating phenotype; P = 0.013). Nine patients (18.4%) experienced adverse effects, 5 of which were serious, but no case of progressive multifocal leukoencephalopathy occurred., Conclusions: This is the largest series of natalizumab-treated patients with CD. Our results show that natalizumab is an efficacious and safe treatment agent for patients refractory to anti-TNF agents and that nonpenetrating disease phenotype has more durable response over time.