bluuebunny/crossref_metadata_2025_split huggingface dataset:
The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis
Authors: Schreier Barbara , Wolf Anja , Hammer Stefanie , Pohl Sabine , Mildenberger Sigrid , Rabe Sindy , Gekle Michael , Zipprich Alexander 
Published: April 2018

Background and PurposeThe mineralocorticoid receptor (MR) contributes to fibrosis in various tissues, and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists in hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MRs and eplerenone in cirrhosis development.Experimental ApproachLiver fibrosis (5 weeks) and cirrhosis, without (8 weeks) and with ascites (12 weeks), were induced by CCl4 in rats and comprehensively analysed. The effect of eplerenone on the development of cirrhosis with ascites was assessed. MR expression, cellular and subcellular distribution and impact of hypoxia were investigated in vivo and ex vivo. Primary rat hepatocytes and cell lines were used to investigate MR trafficking and transcriptional activity mechanistically.Key ResultsIn cirrhosis with ascites, MR mRNA and protein expressions were reduced in hepatocytes of hypoxic areas. While in normoxic areas MRs were mainly cytosolic, the remaining MRs in hypoxic areas were mainly localized in the nuclei, indicating activation followed by translocation and degradation. Accordingly, eplerenone treatment prevented nuclear MR translocation and the worsening of cirrhosis. Exposing hepatocytes ex vivo to hypoxia induced nuclear MR translocation and enhanced transcriptional MR activity at response elements of the NF‐κB pathway.Conclusions and ImplicationsWe showed for the first time that hypoxia leads to a pathogenetic ligand‐independent activation of hepatic MRs during cirrhosis resulting in their nuclear translocation and transcriptional activation of the NF‐κB pathway. Treatment with eplerenone prevented the worsening of cirrhosis by blocking this ligand‐independent activation of the MR.
Phase 2a, randomized, double‐blind, placebo‐controlled, multicentre, parallel‐group study of an H4R‐antagonist (JNJ‐39758979) in adults with uncontrolled asthma
Authors: Kollmeier A. P. , Greenspan A. , Xu X. L. , Silkoff P. E. , Barnathan E. S. , Loza M. J. , Jiang J. , Zhou B. , Chen B. , Thurmond R. L. 
Published: April 2018

SummaryBackgroundThe effects of H4R antagonists in preclinical asthma models support the study of antagonists of the H4R in the treatment of asthma in humans. JNJ‐39758979 is a potent and highly selective oral H4R antagonist.ObjectiveWe sought to evaluate the safety and efficacy of the H4R‐antagonist JNJ‐39758979 in adult patients with uncontrolled asthma.MethodsOne hundred and fifteen eligible patients were randomly assigned to JNJ‐39758979 300 mg or placebo once daily for 12 weeks in this phase 2a, double‐blind, multicenter, placebo‐controlled study. Primary efficacy was assessed via week‐12 change from baseline in pre‐bronchodilator forced expiratory volume in 1 second (FEV1). Secondary efficacy assessments included patient‐reported outcome (PRO) asthma assessments (Asthma Daily Diary data [AM and PM peak expiratory flow rate, number of puffs of albuterol/salbutamol, the presence of nocturnal awakenings and asthma symptom score]).ResultsThe study did not meet the primary end‐point. However, nominally significant improvements in pre‐bronchodilator FEV1 were observed with JNJ‐39758979 versus placebo at week 12 in pre‐specified subgroups with elevated exhaled nitric oxide, sputum eosinophils or blood eosinophils at baseline. Nominally significant improvements across PRO assessments were consistently observed in the overall population, as well as in eosinophilic subgroups. Safety, such as adverse event rates, was comparable between JNJ‐39758979 and placebo. No serious adverse events were reported. No clinically relevant changes in laboratory values were observed.Conclusions and Clinical RelevanceThe findings suggest potential benefit of H4R antagonists on lung function and asthma control in eosinophilic asthma patients and warrant further evaluation of this mechanism in asthma with eosinophilic inflammation. NCT00946569.
Low incidence of heparin‐induced skin lesions in orthopedic surgery patients with low‐molecular‐weight heparins
Authors: Schindewolf M. , Paulik M. , Kroll H. , Kaufmann R. , Wolter M. , Boehncke W.‐H. , Lindhoff‐Last E. , Recke A. , Ludwig R. J. 
Published: April 2018

SummaryBackgroundHeparins are widely prescribed for prevention and therapy of arterial and venous thromboembolic diseases. Heparin‐induced skin lesions are the most frequent adverse effect of subcutaneous heparin treatment in non‐surgical patients (7.5%‐39.8%); no data exist on surgical patients. Commonly, they are due to a delayed‐type hypersensitivity reaction (DTH), but may also be a manifestation of life‐threatening heparin‐induced thrombocytopenia (HIT). Lesions of both entities resemble initially. The risk of HIT is highest among heparin‐anticoagulated orthopedic surgery patients.ObjectiveTo determine incidence and causes of heparin‐induced skin lesions in major orthopedic surgery patients.MethodsIn a prospective cohort study, consecutive patients with subcutaneous low‐molecular‐weight heparin (LMWH) treatment were examined for cutaneous adverse effects. Further diagnostics (skin biopsy, clinical/laboratory assessment for thrombosis, bleeding, HIT, cross‐allergies) were performed.ResultsSix of 316 enrolled patients (1.9%; 95% CI: 0.4%‐3.4%) developed heparin‐induced skin lesions. All were caused by a DTH reaction, and none was due to HIT or other rare heparin‐associated skin diseases. Therapeutic use (dosage) of LMWH was identified as only risk factor (odds ratio: 3.1, 95% CI: 1.4‐4.9; P = .00141). In addition to DTH, 5 thromboembolic, 4 major bleeding complications but no cases of HIT or cross‐allergies were observed.Conclusions and Clinical RelevanceOrthopedic surgery patients have—unlike non‐surgical patients—a low risk for heparin‐induced skin lesions during LMWH treatment; all lesions were due to a DTH reaction. The risk for DTH differs considerably between individual patient cohorts. No association with HIT was observed. These data help to tailor anticoagulatory treatment individually and to increase patient safety.
Mortality data from the European Adrenal Insufficiency Registry—Patient characterization and associations
Authors: Quinkler Marcus , Ekman Bertil , Zhang Pinggao , Isidori Andrea M. , Murray Robert D. ,   on behalf of the EU‐AIR Investigators
Published: April 2018

SummaryObjectiveMortality from primary and secondary adrenal insufficiency (AI; PAI and SAI, respectively) is 2‐3‐fold higher than in the general population. Mortality relates to cardiovascular disease, acute adrenal crisis (AC), cancer and infections; however, there has been little further characterization of patients who have died.Design/MethodsWe analysed real‐world data from 2034 patients (801 PAI, 1233 SAI) in the European Adrenal Insufficiency Registry (EU‐AIR; NCT01661387). Baseline clinical and biochemical data of patients who subsequently died were compared with those who remained alive.ResultsFrom August 2012 to June 2017, 26 deaths occurred (8 PAI, 18 SAI) from cardiovascular disease (n = 9), infection (n = 4), suicide (n = 2), drug‐induced hepatitis (n = 2), and renal failure, brain tumour, cachexia and AC (each n = 1); cause of death was unclear in 5 patients. Patients who died were significantly older at baseline than alive patients. Causes of AI were representative of patients with SAI; however, 3‐quarters of deceased patients with PAI had undergone bilateral adrenalectomy (3 with uncontrolled Cushing's disease, 3 with metastatic renal cell cancer). There were no significant differences in body mass index, blood pressure, low‐density lipoprotein cholesterol, total cholesterol or electrolytes between deceased and alive patients. Deceased patients with SAI were more frequently male individuals, were receiving higher daily doses of hydrocortisone (24.0 ± 7.6 vs 19.3 ± 5.7 mg, P = .0016) and experienced more frequent ACs (11.1 vs 2.49/100 patient‐years, P = .0389) than alive patients.ConclusionsThis is the first study to provide detailed characteristics of deceased patients with AI. Older, male patients with SAI and frequent AC had a high mortality risk.
Hypogonadism and male obesity: Focus on unresolved questions
Authors: Grossmann Mathis 
Published: April 2018

SummaryObesity, increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men and presents as one of the strongest predictors of receiving testosterone treatment. While low circulating total testosterone concentrations in modest obesity primarily reflect reduced concentrations of sex hormone binding globulin, more marked obesity can lead to genuine hypothalamic‐pituitary‐testicular axis (HPT) suppression. HPT axis suppression is likely mediated via pro‐inflammatory cytokine and dysregulated leptin signalling and aggravated by associated comorbidities. Whether oestradiol‐mediated negative hypothalamic‐pituitary feedback plays a pathogenic role requires further study. Although the obesity‐hypogonadism relationship is bidirectional, the effects of obesity on testosterone concentrations are more substantial than the effects of testosterone on adiposity. In markedly obese men submitted to bariatric surgery, substantial weight loss is very effective in reactivating the HPT axis. In contrast, lifestyle measures are less effective in reducing weight and generally only associated with modest increases in circulating testosterone. In randomized controlled clinical trials (RCTs), testosterone treatment does not reduce body weight, but modestly reduces fat mass and increases muscle mass. Short‐term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone. However, longer term, larger RCTs designed for patient‐important outcomes and potential risks are required. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity‐associated nonclassical hypogonadism. Lifestyle measures or where indicated bariatric surgery to achieve weight loss, and optimization of comorbidities remain first line.
Ghrelin as a potential molecular marker of adrenal carcinogenesis: In vivo and in vitro evidence
Authors: Komarowska Hanna , Rucinski Marcin , Tyczewska Marianna , Sawicka‐Gutaj Nadia , Szyszka Marta , Hernik Aleksandra , Klimont Anna , Milecka Paulina , Migasiuk Laura , Biczysko Mateusz , Idasiak‐Piechocka Ilona , Karczewski Marek , Ruchala Marek 
Published: April 2018

SummaryContextAdrenal tumours belong to one of the most prevalent neoplasms. It is a heterogeneous group with different aetiology, clinical manifestation and prognosis. Its histopathologic diagnosis is difficult and identification of differentiation markers for tumorigenesis is extremely valuable for diagnosis.DesignTo assess ghrelin expression and the relationship among ghrelin, IGF2 and the clinicopathological characteristics of adrenal tumours. To investigate the influence of ghrelin on ACC cell line proliferation.Materials and methodsExpression of ghrelin and IGF2 in a total of 84 adrenal tissue samples (30 adenoma, 12 hyperplasia, 8 myelolipoma, 20 pheochromocytoma, 7 carcinoma and 7 unchanged adrenal glands) were estimated. Every operated patient from whom samples were obtained underwent clinicopathological analysis. All the parameters were compared among the groups examined and correlations between these were estimated.H295R cell line was incubated with ghrelin to assess its effect on proliferation and migration rate.ResultsThe highest ghrelin expression was observed in carcinoma samples and the lowest in the control group. Ghrelin expression was 21 times higher in carcinoma (P = .017) and 2.4 times higher in adenoma (P = .029) compared with controls. There were no statistically significant differences between myelolipoma (P = .093) and pheochromocytoma (P = .204) relative to the control. Ghrelin level was significantly higher in carcinoma compared to adenoma (P = .049) samples. A positive correlation between ghrelin and IGF2 expression was observed only in myelolipoma (P = .001).Ghrelin at concentrations of 1 × 10−6 mol/L and 1 × 10−8 mol/L significantly stimulated proliferation and migration rate in the H295R cell line.ConclusionGhrelin appears to be an essential factor in driving adrenal tumours development.
Computer‐guided chin harvest: A novel approach for autogenous block harvest from the mandibular symphesis
Authors: Osman Ahmed H. , Atef Mohammed 
Published: April 2018

AbstractBackgroundThe introduction of CAD/CAM technology allowed clinicians to carry out complex procedures with a high level of precision and reproducibility and minimize the risk of injury during the procedure.PurposeThe aim of the present study is to evaluate the efficacy of the CAD/CAM surgical guide during chin harvesting procedures in reducing the risk of neurosensory damage and patient morbidity compared with the standard technique.Materials and MethodsAbout 20 cases of autogenous block chin harvest were randomly into two groups. The first group received computer‐guided chin block harvest while the second group received autogenous block chin harvest using the standard approach.ResultsIn the guided group, out of the 10 subjects, 2 subjects presented with wound dehiscence which resolved within 1 month. No teeth showed any negative pulp sensitivity results. The pointed‐Blunt test and 2 point discrimination tests showed a single case of neurodeficits at 1 week follow‐up appointment which resolved within 1 month. In the nonguided group, out of the 10 subjects, 1 case presented with wound dehiscence that resolved completely within 1 month. Pulp vitality test showed negative results in 29.4% of the involved teeth at 1 week which decreased to 9.8% and 3.9% at 1 and 6 months follow‐up, respectively. The pointed blunt test revealed 3 subjects with neurodeficits at 1 week, out of which 2 subjects showed persisting symptoms at 6 months follow‐up. The 2 point discrimination test showed 3 subjects with neurodeficits, out of which two subjects showed persistent symptoms with no resolution at the 6 months follow‐up.ConclusionWithin the limits of this study, computer‐guided chin harvest shows promising results in the reduction of neurosensory complications following harvesting procedures and presents as a safe alternative to the standard technique.
Morphology combined with ancillary techniques: An algorithm approach for thyroid nodules
Authors: Rossi E. D. , Martini M. , Capodimonti S. , Cenci T. , Bilotta M. , Pierconti F. , Pontecorvi A. , Lombardi C. P. , Fadda G. , Larocca L. M. 
Published: April 2018

IntroductionSeveral authors have underlined the limits of morphological analysis mostly in the diagnosis of follicular neoplasms (FN). The application of ancillary techniques, including immunocytochemistry (ICC) and molecular testing, contributes to a better definition of the risk of malignancy (ROM) and management of FN. According to literature, the application of models, including the evaluation of ICC, somatic mutations (ie, BRAFV600E), micro RNA analysis is proposed for FNs. This study discusses the validation of a diagnostic algorithm in FN with a special focus on the role of morphology then followed by ancillary techniques.MethodsFrom June 2014 to January 2016, we enrolled 37 FNs with histological follow‐up. In the same reference period, 20 benign nodules and 20 positive for malignancy were selected as control. ICC, BRAFV600E mutation and miR‐375 were carried out on LBC.ResultsThe 37 FNs included 14 atypia of undetermined significance/follicular lesion of undetermined significance and 23 FN. Specifically, atypia of undetermined significance/follicular lesion of undetermined significance resulted in three goitres, 10 follicular adenomas and one NIFTP whereas FN/suspicious for FN by seven follicular adenomas and 16 malignancies (nine non‐invasive follicular thyroid neoplasms with papillary‐like nuclear features, two invasive follicular variant of papillary thyroid carcinoma [PTC] and five PTC). The 20 positive for malignancy samples included two invasive follicular variant of PTC, 16 PTCs and two medullary carcinomas. The morphological features of BRAFV600E mutation (nuclear features of PTC and moderate/abundant eosinophilic cytoplasms) were associated with 100% ROM. In the wild type cases, ROM was 83.3% in presence of a concordant positive ICC panel whilst significantly lower (10.5%) in a negative concordant ICC. High expression values of MirR‐375 provided 100% ROM.ConclusionsThe adoption of an algorithm might represent the best choice for the correct diagnosis of FNs. The morphological detection of BRAFV600E represents the first step for the identification of malignant FNs. A significant reduction of unnecessary thyroidectomies is the goal of this application.
A retrospective 3‐year study of salivary gland FNAC with categorisation using the Milan reporting system
Authors: Thiryayi S. A. , Low Y. X. , Shelton D. , Narine N. , Slater D. , Rana D. N. 
Published: April 2018

IntroductionTo assess our practice using the recently developed standardised classification system designated The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and to ascertain the rates of malignancy for each category by means of a retrospective study.MethodsAll salivary gland FNAC samples received between 1 January 2013 and 31 December 2015 were retrospectively assigned a diagnostic category code from the MSRSGC. Cytology results were correlated with subsequent histology (where available), and clinical and radiological follow up.ResultsA total of 287 salivary gland FNA samples were received from 272 patients. The specimens were classified as non‐diagnostic (21.3%), non‐neoplastic (22%), atypia of undetermined significance (2.4%), neoplasm benign (36.9%), neoplasm of uncertain malignant potential (5.2%), suspicious for malignancy (1.7%) and malignant (10.5%; low grade 1.4% and high grade 9.1%). Histological and clinical/radiological follow up was available for 138 (48.1%) specimens, clinical/radiological follow up only for 145 (50.5%) and no follow up for the remaining four (1.4%) samples. The risk of malignancy for each category was non‐diagnostic (8.5%), non‐neoplastic (1.6%), atypia of undetermined significance (0%), neoplasm benign (1.9%), neoplasm of uncertain malignant potential (26.7%), suspicious for malignancy (100%) and malignant (100%).ConclusionsThe MSRSGC appears to be a useful tool to guide clinical management and provide an indication of possible risk of malignancy. We favour implementing use of these categories in our reporting practice with a future re‐evaluation to assess maintenance of service quality as well as the clinical utility of this reporting system.
Moving from representation to persistence: The capacity of Australia's National Reserve System to support viable populations of mammals
Authors: Clements Hayley S. , Kearney Stephen G. , Cook Carly N. 
Published: April 2018

AbstractAimSpecies require sufficiently large and connected areas of suitable habitat to support populations that can persist through change. With extensive alteration of unprotected natural habitat, there is increasing risk that protected areas (PAs) will be too small and isolated to support viable populations in the long term. Consequently, this study addresses the urgent need to assess the capacity of PA estates to facilitate species persistence.LocationAustralia.MethodsWe undertake the first assessment of the capacity of the Australian National Reserve System (NRS) to protect 90 mammal species in the long term, given the size and distribution of individual PAs across the landscape relative to species’ habitat and minimum viable area (MVA) requirements and dispersal capabilities.ResultsWhile all mammal ranges are represented within the NRS, the conservation capacity declined notably when we refined measures of representation within PAs to include species’ habitat and area requirements. The NRS could not support any viable populations for between three and seven species, depending on the MVA threshold used, and could support less than 10 viable populations for up to a third of the species. Planning and managing PAs for persistence emerged as most important for species with large MVA requirements and limited dispersal capabilities.Main conclusionsThe key species characteristics we identify can help managers recognize species at risk within the current PA estate and guide the types of strategies that would best reduce this risk. We reveal that current representation‐based assessments of PA progress are likely to overestimate the long‐term success of PA estates, obscuring vulnerabilities for many species. It is important that conservation planners and managers are realistic and explicit regarding the role played by different sizes and distributions of PAs, and careful in assuming that the representation of a species within a PA equates to its long‐term conservation.
Neutrophils as effectors of vascular inflammation
Authors: Gómez‐Moreno Diego , Adrover José María , Hidalgo Andrés 
Published: April 2018

AbstractVascular inflammation underlies most forms of cardiovascular disease, which remains a prevalent cause of death among the global population. Advances in the biology of neutrophils, as well as insights into their dynamics in tissues, have revealed that these cells are prominent drivers of vascular inflammation though derailed activation within blood vessels. The development of powerful imaging techniques, as well as identification of cells and molecules that regulate their activation within vessels, including platelets and catecholamines, has been instrumental to better understand the mechanisms through which neutrophils protect or damage the organism. Other advances in our understanding of how these leucocytes exert detrimental functions on neighbouring cells, including the formation of DNA‐based extracellular traps, constitute milestones in defining neutrophil‐driven inflammation. Here, we review emerging mechanisms that regulate intravascular activation and effector functions of neutrophils, and discuss specific pathologies in which these processes are relevant. We argue that identification of pathways and mechanisms specifically engaged within the vasculature may provide effective therapies to treat this prevalent group of pathologies.
Upper body fat predicts metabolic syndrome similarly in men and women
Authors: Grundy Scott M. , Williams Corbin , Vega Gloria L. 
Published: April 2018

AbstractBackgroundThe metabolic syndrome is a constellation of risk factors including dyslipidemia, dysglycemia, hypertension, a pro‐inflammatory state, and a prothrombotic state. All of these factors are accentuated by obesity. However, obesity can be defined by body mass index (BMI), percent body fat, or by body fat distribution. The latter consists of upper body fat (subcutaneous and visceral fat) and lower body fat (gluteofemoral fat). Waist circumference is a common surrogate marker for upper body fat.MethodsData from the National Health and Nutrition Examination Survey (NHANES) for the years 1999‐2006 was examined for associations of metabolic risk factors with percent body fat, waist circumference, and BMI.ResultsAssociations between absolute measures of waist circumference and risk factors were similiar for men and women. The similarities of associations between waist circumference and risk factors suggests that greater visceral fat in men does not accentuate the influence of upper body fat on risk factors.ConclusionsDifferent waist concumference values should not be used to define abdominal obesity in men and women.