bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammasomes in stroke: a triggering role for acid‐sensing ion channels
Authors: Vats Kanchan , Sarmah Deepaneeta , Kaur Harpreet , Wanve Madhuri , Kalia Kiran , Borah Anupom , Dave Kunjan R. , Yavagal Dileep R. , Bhattacharya Pallab 
Published: June 2018

AbstractStroke is devastating and a major cause of morbidity and mortality around the world. The innate immune response plays an important role in various brain injuries, including stroke, and targeting it for therapeutic interventions would likely prove beneficial. The panoply of inflammatory cells, which induce various cellular, hormonal, and biochemical alterations, mediates the rapid progression of injury in stroke. The inflammasome, a multiprotein oligomer and a key component of specific innate immune responses, contributes toward the worsening of stroke outcomes by activating inflammatory cytokines. Acidotoxicity, mediated by acid‐sensing ion channels (ASICs), also contributes toward exacerbating the condition. A role for ASICs in stroke, through the activation of the inflammasome, is emerging, which opens new avenues for understanding and intervening in stroke. In this review, we describe the various types of inflammasomes and their mechanisms of activation in stroke. Furthermore, therapeutic approaches targeting the inflammasome and that may be helpful in improving stroke outcome are discussed.
Saliva on the oral mucosa and whole saliva in women diagnosed with burning mouth syndrome
Authors: Acharya Shikha , Hägglin Catharina , Jontell Mats , Wenneberg Bengt , Ekström Jörgen , Carlén Anette 
Published: June 2018

AbstractObjectiveThe aim of the study was to examine mucosal saliva and unstimulated (UWS) and stimulated (SWS) whole saliva secretion rates and associated factors, in 56 female patients diagnosed with BMS and age‐matched control women.Material and MethodsMucosal saliva was assessed using the Periotron® method and blood flow using laser Doppler flowmetry. Diseases, drug usage and xerostomia were registered using questionnaires.ResultsThe patients with BMS displayed less lingual and whole saliva, and more hyposalivation, xerostomia diseases/disorders and drug usage, compared to the controls. Only a low SWS and xerostomia differed after adjusting for drugs and systemic diseases. Regression analyses suggested an importance of saliva affecting drugs for saliva on the tongue and for SWS, and the total number of drugs used for UWS. Lingual saliva and UWS were also associated with systemic diseases in the patients. Xerostomia was significantly associated with drug use and whole saliva for all subjects but not in separate analyses of the groups.ConclusionLess saliva in patients with BMS could be related to more systemic diseases and medication and not to the syndrome per se. Xerostomia in the patients was not related to any of these factors.
Increased susceptibility to oral Trichuris muris infection in the specific absence of CXCR5+CD11c+ cells
Authors: Bradford Barry M. , Donaldson David S. , Forman Ruth , Else Kathryn J. , Mabbott Neil A. 
Published: June 2018

SummaryTrichuris muris is a natural mouse helminth pathogen which establishes infection specifically in the caecum and proximal colon. The rapid expulsion of T. muris in resistant mouse strains is associated with the induction of a protective T helper cell type 2 (Th2)‐polarized immune response. Susceptible mouse strains, in contrast, mount an inappropriate Th1 response to T. muris infection. Expression of the chemokine CXCL13 by stromal follicular dendritic cells attracts CXCR5‐expressing cells towards the B‐cell follicles. Previous studies using a complex in vivo depletion model have suggested that CXCR5‐expressing conventional dendritic cells (cDC) help regulate the induction of Th2‐polarized responses. Here, transgenic mice with CXCR5 deficiency specifically restricted to CD11c+ cells were used to determine whether the specific absence CXCR5 on CD11c+ cells such as cDC would influence susceptibility to oral T. muris infection by affecting the Th1/Th2 balance. We show that in contrast to control mice, those which lacked CXCR5 expression on CD11c+ cells failed to clear T. muris infection and developed cytokine and antibody responses that suggested a disturbed Th1/Th2 balance with enhanced IFN‐γ expression. These data suggest an important role of CXCR5‐expressing CD11c+ cells such as cDC in immunity to oral T. muris infection.
Hospital readmission: Older married male patients’ experiences of life conditions and critical incidents affecting the course of care, a qualitative study
Authors: Pedersen Mona Kyndi , Mark Edith , Uhrenfeldt Lisbeth 
Published: June 2018

BackgroundDespite the frequency of hospital readmissions, there is still a relatively incomplete understanding of the broader array of factors pertaining to readmission in older persons. Few studies have explored how older persons experience readmission and their perceptions of circumstances affecting the course of care. Research indicates that males experience poorer health outcomes and are at higher risk of readmission compared to women.AimTo explore life conditions and critical incidents pertained to hospital readmission from the perspective of older males.MethodsThe study used a qualitative explorative design using the Critical Incident Technique. A purposive sample of four males aged 65–75 were recruited from two internal medical wards. Data were collected through narrative double interviews. The study was registered by the North Denmark Region's joint notification of health research (ID 2008‐58‐0028).FindingsThe analysis revealed four themes of life conditions: ‘Ambiguity of ageing’, ‘Living with the burden of illness’, ‘Realisation of dependency’ and ‘Growing sense of vulnerability and mortality’. Critical incidents comprised four areas: ‘Balancing demands and resources in everyday life’, ‘Back home again – a period of recovery’, ‘Care interaction’ and ‘Navigating within and between healthcare system(s)’.ConclusionThis study illustrated the interconnectedness, dynamics and complexity of life conditions and critical incidents that over time and across diverse healthcare sectors affected the course of care in older persons. Hospital readmissions seem related to a complex web of interacting life conditions and critical incidents rather than growing age or specific illnesses.
The epidemiology of tuberculosis in the rural Balimo region of Papua New Guinea
Authors: Diefenbach‐Elstob Tanya , Graves Patricia , Dowi Robert , Gula Bisato , Plummer David , McBryde Emma , Pelowa Daniel , Siba Peter , Pomat William , Warner Jeffrey 
Published: June 2018

AbstractObjectivePapua New Guinea (PNG) has an emerging tuberculosis (TB) epidemic which has become a national public health priority. In Western Province, there are few data about TB outside Daru and the South Fly District. This study describes the epidemiology of TB diagnosed at Balimo District Hospital (BDH) in the Middle Fly District of Western Province, PNG.MethodsAll patients (n = 1614) diagnosed with TB at BDH from April 2013 to February 2017 were recorded. Incidence of reported new cases was calculated for the combined Balimo Urban and Gogodala Rural local level government areas. Analyses investigated patient demographic and clinical information, differences between pulmonary and extrapulmonary TB patients, and predictors of treatment failure.ResultsThe average case notification rate (2014–2016) was 727 TB cases per 100 000 people per year. One‐quarter of TB cases were in children, and 77.1% of all cases had an extrapulmonary TB diagnosis. There was a 1:1.1 ratio of female to male TB cases. When comparing pulmonary and extrapulmonary TB patients, extrapulmonary TB was more likely in those aged up to 14 years and over 54 years. Extrapulmonary TB was more likely in new patients, and pulmonary TB more likely in previously treated patients. Residence in rural regions was associated with treatment failure.ConclusionThere is a high burden of TB in the Balimo region, including a very high proportion of extrapulmonary TB. These factors emphasise the importance of BDH as the primary hospital for TB cases in the Balimo region and the Middle Fly District, and the need for resources and staff to manage both drug‐susceptible and drug‐resistant TB cases.
The impact of loading, unloading, ageing and injury on the human tendon
Authors: Magnusson S. Peter , Kjaer Michael 
Published: June 2018

AbstractA tendon transfers force from the contracting muscle to the skeletal system to produce movement and is therefore a crucial component of the entire muscle‐tendon complex and its function. However, tendon research has for some time focused on mechanical properties without any major appreciation of potential cellular and molecular changes. At the same time, methodological developments have permitted determination of the mechanical properties of human tendonsin vivo, which was previously not possible. Here we review the current understanding of how tendons respond to loading, unloading, ageing and injury from cellular, molecular and mechanical points of view. A mechanistic understanding of tendon tissue adaptation will be vital for development of adequate guidelines in physical training and rehabilitation, as well as for optimal injury treatment.image
Sex‐specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles
Authors: Chen Mu , Yin Dechun , Guo Shuai , Xu Dong‐Zhu , Wang Zhuo , Chen Zhenhui , Rubart‐von der Lohe Michael , Lin Shien‐Fong , Everett, IV Thomas H. , Weiss James N. , Chen Peng‐Sheng 
Published: June 2018

Key Points
It is unknown if a sex difference exists in cardiac apamin‐sensitive small conductance Ca2+‐activated K+ (SK) current (IKAS).
There is no sex difference in IKAS in the basal condition. However, there is larger IKAS in female rabbit ventricles than in male during isoproterenol infusion.
IKAS activation by isoproterenol leads to action potential triangulation in females, indicating its abundant activation at early phases of repolarization.
IKAS activation in females induces negative Ca2+–voltage coupling and promotes electromechanically discordant phase 2 repolarization alternans.
IKAS is important in the mechanisms of ventricular fibrillation in females during sympathetic stimulation.
AbstractSex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin‐sensitive small conductance Ca2+‐activated K+ (SK) current (IKAS) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. IKAS blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD25) more prominently than APD at the level of 80% repolarization (APD80), consequently reversing isoproterenol‐induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. IKAS in males did not respond to the L‐type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7‐tetrabromobenzotriazole. In addition, whole‐cell outward IKAS densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. IKAS activation in females induced negative intracellular Ca2+–voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca2+–voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that β‐adrenergic stimulation activates ventricular IKAS in females to a much greater extent than in males. IKAS activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation.
Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension
Authors: Hu Cheng‐Jun , Zhang Hui , Laux Aya , Pullamsetti Soni S. , Stenmark Kurt R. 
Published: June 2018

AbstractChronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation and extracellular matrix (ECM) remodelling. Current therapies for PH, focusing on vasodilatation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development. Although these approaches have produced a large number of compelling PH treatment targets, many promising human drugs have failed in PH clinical trials. Herein, we propose that one contributing factor to these failures is that processes important in PH development may not be good treatment targets in the established phase of chronic PH. We hypothesize that this is due to alterations of chromatin structure in PH cells, resulting in functional differences between the same factor or pathway in normal or early PH cells versus cells in chronic PH. We propose that the high expression of genes involved in the persistently activated phenotype of PH vascular cells is perpetuated by an open chromatin structure and multiple transcription factors (TFs) via the recruitment of high levels of epigenetic regulators including the histone acetylases P300/CBP, histone acetylation readers including BRDs, the Mediator complex and the positive transcription elongation factor (Abstract figure). Thus, determining how gene expression is controlled by examining chromatin structure, TFs and epigenetic regulators associated with aberrantly expressed genes in pulmonary vascular cells in chronic PH, may uncover new PH therapeutic targets.
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PHD2 inactivation in Type I cells drives HIF‐2α‐dependent multilineage hyperplasia and the formation of paraganglioma‐like carotid bodies
Authors: Fielding James W. , Hodson Emma J. , Cheng Xiaotong , Ferguson David J. P. , Eckardt Luise , Adam Julie , Lip Philomena , Maton‐Howarth Matthew , Ratnayaka Indrika , Pugh Christopher W. , Buckler Keith J. , Ratcliffe Peter J. , Bishop Tammie 
Published: June 2018

Key points
The carotid body is a peripheral arterial chemoreceptor that regulates ventilation in response to both acute and sustained hypoxia.
Type I cells in this organ respond to low oxygen both acutely by depolarization and dense core vesicle secretion and, over the longer term, via cellular proliferation and enhanced ventilatory responses.
Using lineage analysis, the present study shows that the Type I cell lineage itself proliferates and expands in response to sustained hypoxia.
Inactivation of HIF‐2α in Type I cells impairs the ventilatory, proliferative and cell intrinsic (dense core vesicle) responses to hypoxia.
Inactivation of PHD2 in Type I cells induces multilineage hyperplasia and ultrastructural changes in dense core vesicles to form paraganglioma‐like carotid bodies.
These changes, similar to those observed in hypoxia, are dependent on HIF‐2α.
Taken together, these findings demonstrate a key role for the PHD2–HIF‐2α couple in Type I cells with respect to the oxygen sensing functions of the carotid body.
AbstractThe carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests a rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlying these processes is of interest both to specialized chemoreceptive functions of that organ and, potentially, to the general physiology and pathophysiology of cellular hypoxia. We have combined cell lineage tracing technology and conditionally inactivated alleles in recombinant mice to examine the role of components of the HIF hydroxylase pathway in specific cell types within the carotid body. We show that exposure to sustained hypoxia (10% oxygen) drives rapid expansion of the Type I, tyrosine hydroxylase expressing cell lineage, with little transdifferentiation to (or from) that lineage. Inactivation of a specific HIF isoform, HIF‐2α, in the Type I cells was associated with a greatly reduced proliferation of Type I cells and hypoxic ventilatory responses, with ultrastructural evidence of an abnormality in the action of hypoxia on dense core secretory vesicles. We also show that inactivation of the principal HIF prolyl hydroxylase PHD2 within the Type I cell lineage is sufficient to cause multilineage expansion of the carotid body, with characteristics resembling paragangliomas. These morphological changes were dependent on the integrity of HIF‐2α. These findings implicate specific components of the HIF hydroxylase pathway (PHD2 and HIF‐2α) within Type I cells of the carotid body with respect to the oxygen sensing and adaptive functions of that organ.
Modulation of ClC‐3 gating and proton/anion exchange by internal and external protons and the anion selectivity filter
Authors: Rohrbough Jeffrey , Nguyen Hong‐Ngan , Lamb Fred S. 
Published: June 2018

Key points
The ClC‐3 2Cl−/1H+ exchanger modulates endosome pH and Cl− concentration. We investigated the relationships between ClC‐3‐mediated ion transport (steady‐state transport current, ISS), gating charge (Q) and cytoplasmic alkalization.
ClC‐3 transport is functionally unidirectional. ClC‐5 and ClC‐3 display indistinguishable exchange ratios, but ClC‐3 cycling is less “efficient”, as reflected by a large Q/ISS. An M531A mutation predicted to increase water‐wire stability and cytoplasmic proton supply improves efficiency.
Protonation (pH 5.0) of the outer glutamate gate (Gluext; E224) reduces Q, inhibits transport, and weakens coupling.
Removal of the central tyrosine anion gate (Y572S) greatly increases uncoupled anion current. Tyrosine –OH removal (Y572F) alters anion selectivity and impairs coupling.
E224 and Y572 act as anion barriers, and contribute to gating. The Y572 side chain and –OH regulate Q movement kinetics and voltage dependence. E224 and Y572 interact to create a “closed” inner gate conformation that maintains coupling during cycling.
AbstractWe utilized plasma membrane‐localized ClC‐3 to investigate relationships between steady‐state transport current (ISS), gating charge (Q) movement, and cytoplasmic alkalization rate. ClC‐3 exhibited lower transport efficiency than ClC‐5, as reflected by a larger Q/ISS ratio, but an indistinguishable Cl−/H+ coupling ratio. External SCN− reduced H+ transport rate and uncoupled anion/H+ exchange by 80–90%. Removal of the external gating glutamate (“Gluext”) (E224A mutation) reduced Q and abolished H+ transport. We hypothesized that Methionine 531 (M531) impedes “water wire” H+ transfer from the cytoplasm to E224. Accordingly, an M531A mutation decreased the Q/ISS ratio by 50% and enhanced H+ transport. External protons (pH 5.0) inhibited ISS and markedly reduced Q while shifting the Q–voltage (V) relationship positively. The Cl−/H+ coupling ratio at pH 5.0 was significantly increased, consistent with externally protonated Gluext adopting an outward/open position. Internal “anion gate” removal (Y572S) dramatically increased ISS and impaired coupling, without slowing H+ transport rate. Loss of both gates (Y572S/E224A) resulted in a large “open pore” conductance. Y572F (removing only the phenolic hydroxide) and Y572S shortened Q duration similarly, resulting in faster Q kinetics at all voltages. These data reveal a complex relationship between Q and ion transport. Q/ISS must be assessed together with coupling ratio to properly interpret efficiency. Coupling and transport rate are influenced by the anion, internal proton supply and external protons. Y572 regulates H+ coupling as well as anion selectivity, and interacts directly with E224. Disruption of this “closed gate” conformation by internal protons may represent a critical step in the ClC‐3 transport cycle.
Diagnosis, treatment and prevention of ankle sprains: update of an evidence-based clinical guideline
Authors: Vuurberg Gwendolyn , Hoorntje Alexander , Wink Lauren M , van der Doelen Brent F W , van den Bekerom Michel P , Dekker Rienk , van Dijk C Niek , Krips Rover , Loogman Masja C M , Ridderikhof Milan L , Smithuis Frank F , Stufkens Sjoerd A S , Verhagen Evert A L M , de Bie Rob A , Kerkhoffs Gino M M J 
Published: June 2018

This guideline aimed to advance current understandings regarding the diagnosis, prevention and therapeutic interventions for ankle sprains by updating the existing guideline and incorporate new research. A secondary objective was to provide an update related to the cost-effectiveness of diagnostic procedures, therapeutic interventions and prevention strategies. It was posited that subsequent interaction of clinicians with this guideline could help reduce health impairments and patient burden associated with this prevalent musculoskeletal injury. The previous guideline provided evidence that the severity of ligament damage can be assessed most reliably by delayed physical examination (4–5 days post trauma). After correct diagnosis, it can be stated that even though a short time of immobilisation may be helpful in relieving pain and swelling, the patient with an acute lateral ankle ligament rupture benefits most from use of tape or a brace in combination with an exercise programme.New in this update:Participation in certain sports is associated with a heightened risk of sustaining a lateral ankle sprain. Care should be taken with non-steroidal anti-inflammatory drugs (NSAIDs) usage after an ankle sprain. They may be used to reduce pain and swelling, but usage is not without complications and NSAIDs may suppress the natural healing process. Concerning treatment, supervised exercise-based programmes preferred over passive modalities as it stimulates the recovery of functional joint stability. Surgery should be reserved for cases that do not respond to thorough and comprehensive exercise-based treatment. For the prevention of recurrent lateral ankle sprains, ankle braces should be considered as an efficacious option.