Acute Pancreatitis Complicated with Choledochal Duct Rupture

Recurrent acute pancreatitis is a rare clinical entity in childhood with unknown incidence (Rosendahl et al., 2007) and often occurring in a familial context. Genetic factors such as PRSS1 mutations (cationic trypsinogen gene) can be found in some patients. However, many remain idiopathic. The natural history remains poorly documented and the most frequent complications reported are pain, exocrine pancreatic insufficiency, diabetes mellitus, and pancreatic adenocarcinoma after long-standing hereditary pancreatitis. We describe a patient with hereditary pancreatitis in whom a mild pancreatitis episode was complicated by a perforation of the ductus choledochus

Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5

Vomocytosis, or non-lytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date the host signaling events that underpin expulsion remain entirely unknown. Here we use a targeted inhibitor screen to identify the MAP-kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages whilst stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies

Ferric carboxymaltose versus ferrous fumarate in anemic children with inflammatory bowel disease:the POPEYE randomized controlled clinical trial

OBJECTIVE: To determine whether intravenous (IV) or oral iron suppletion is superior in improving physical fitness in anemic children with inflammatory bowel disease (IBD).STUDY DESIGN: We conducted a clinical trial at 11 centers. Children aged 8 to 18 with IBD and anemia (defined as hemoglobin (Hb) z-score &lt; -2) were randomly assigned to a single IV dose of ferric carboxymaltose or 12 weeks of oral ferrous fumarate. Primary endpoint was the change in 6-minute walking distance (6MWD) from baseline, expressed as z-score. Secondary outcome was a change in Hb z-score from baseline.RESULTS: We randomized 64 patients (33 IV iron; 31 oral iron) and followed them for 6 months. One month after the start of iron therapy, the 6MWD z-score of patients in the IV group had increased by 0.71 compared with -0.11 in the oral group (P=0.01). At 3- and 6-months follow-up, no significant differences in 6MWD z-scores were observed. Hb z-scores gradually increased in both groups and the rate of increase was not different between groups at 1, 3 and 6 months after initiation of iron therapy (overall P=0.97).CONCLUSION: In this trial involving anemic children with IBD, a single dose of IV ferric carboxymaltose was superior to oral ferrous fumarate with respect to quick improvement of physical fitness. At 3 and 6 months after initiation of therapy, no differences were discovered between oral or IV therapy. The increase of Hb over time was comparable in both treatment groups.TRIAL REGISTRATION: NTR4487 [Netherlands Trial Registry].</p

Misfolded SOD1 Associated with Motor Neuron Mitochondria Alters Mitochondrial Shape and Distribution Prior to Clinical Onset

Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS

Novel insights into host-fungal pathogen interactions derived from live-cell imaging

Acknowledgments The authors acknowledge funding from the Wellcome Trust (080088, 086827, 075470 and 099215) including a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377 and FP7-2007–2013 grant agreement HEALTH-F2-2010-260338–ALLFUN to NARG.Peer reviewedPublisher PD

Reconciling nature, people and policy in the mangrove social-ecological system through the adaptive cycle heuristic

© 2021 The Authors. While mangroves are increasingly described as social-ecological systems (SESs), performing SES research is so much more than merely documenting local resource utilisation patterns in case studies. The aim of this paper is to review and show how ecological, human and institutional resilience could be understood and fostered in an era of uncertainty, through the adaptive cycle (AC) heuristic. Uncertainties come in many forms and shapes: climate change, social and economic dynamics, natural disasters, political and institutional disruption and ever-increasing public demands for participation. Social-ecological studies form windows of experimentation that can provide insights beyond their case-specific context. In order to synthesise and structure the cumulative knowledge base arising from existing and future studies, the need for a suitable overarching framework arose. Here, the AC heuristic represents the connectedness between variables of the mangrove SES versus the mangrove's accumulated capital (natural, built, human and social). We posit that the AC heuristic can be used to interpret spatial and temporal changes (ecological, social, economic, political) in mangrove SESs and we exemplify it by using the 2004 Indian Ocean tsunami as well as a century-long silviculture case. The AC, combined with the SES scheme, allows integration of the spato-temporal dynamics and the multi-dimensional character of mangrove SESs. We also reviewed the ecosystem functions, services and disservices of mangrove SESs, linking each of them to SES capital and variable (fast or slow) attributes, which in turn are closely linked to the different axes and phases of the AC. We call upon mangrove scientists from the natural, applied, social and human sciences to join forces in fitting diversified empirical data from multiple case studies around the world to the AC heuristic. The aim is to reflect on and understand such complex dynamic systems with stakeholders having various (mutual) relationships at risk of breaking down, and to prepare for interactive adaptive planning for mangrove forests.Belgian Science Policy Office ‘EVAMAB – Economic valuation of ecosystem services in Man & Biosphere Reserves' - BELSPO (BL/58/UN32); Erasmus Mundus Masters Course in Tropical Biodiversity and Ecosystems (TROPIMUNDO); VLIR-UOS-funded GREENDYKE Project (ZEIN2008PR347); BELSPO-funded MAMAFOREST-Project (SR/00/323); ZMT Academy travel grant; Singapore National Parks Board (NParks); TUYF Charitable Trust; HKU Seed Fund for Research; International Coral Reef Initiative (ICRI); UNEP/GEF Blue Forest Project; Pew Charitable Trust; Department of Science and Technology, India INSPIRE Faculty scheme (IFA18-LSPA111)

Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies

Mutant Huntingtin induces activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3)

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive neuronal death in the basal ganglia and cortex. Although increasing evidence supports a pivotal role of mitochondrial dysfunction in the death of patients' neurons, the molecular bases for mitochondrial impairment have not been elucidated. We provide the first evidence of an abnormal activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNip3) in cells expressing mutant Huntingtin. In this study, we show an abnormal accumulation and dimerization of BNip3 in the mitochondria extracted from human HD muscle cells, HD model cell cultures and brain tissues from HD model mice. Importantly, we have shown that blocking BNip3 expression and dimerization restores normal mitochondrial potential in human HD muscle cells. Our data shed light on the molecular mechanisms underlying mitochondrial dysfunction in HD and point to BNip3 as a new potential target for neuroprotective therapy in HD