Notes

[Interactions in between medications compliance, blood pressure levels goals, as well as despression symptoms within hypertensive individuals obtaining attention in the Family Wellness Strategy].
The results indicate a possible role of beta HPV in the pathogenesis of cutaneous SCC in photo-exposed areas. Further studies are needed to establish the role of HPV and voriconazole in the pathogenesis of the lesion. © 2020 The International Society of Dermatology.BACKGROUND AND PURPOSE Recruitment and involvement of bone/blood-derived circulating fibrocytes (CF) in the promotion of fibrotic tissue remodelling processes have shown by several reports. However, their direct contribution to pathological changes is not clear. The purpose of the present investigation is to delineate the causal role of circulating fibrocytes in the pathogenesis of pulmonary hypertension (PH). EXPERIMENTAL APPROACH For selective ablation of CF, we applied the suicidal gene strategy with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir. The transgenic mice were generated, having HSV-TK-GFP transgene under the collagen1 promoter. To selectively target CF, HSV-TK-GFP+ bone marrow from transgenic mice transplanted into irradiated wild type mice. These chimera mice subjected to hypoxia for PH induction and ganciclovir treatment for CF ablation. KEY RESULTS In vivo circulating fibrocytes ablation reduced right ventricular hypertrophy, vascular remodelling with reduced total collagen content. We quantified the CF recruited in the perivascular area and arterial wall of small pulmonary arteries. There was significant recruitment of circulating fibrocytes in the lung in response to hypoxia. The characterization of CF showed the expression of CD45, collagen1 (GFP) along with alpha-smooth muscle actin (αSMA). CONCLUSIONS AND IMPLICATIONS Our data demonstrate that circulating fibrocytes ablation has a potential impact on right ventricular hypertrophy and vascular remodelling in the setting of experimental PH induced by hypoxia. The beneficial effects may be related to the direct contribution of fibrocytes or its paracrine effect on other resident cell types. Thus, clinical manipulation of circulating fibrocytes may represent a novel therapeutic approach to ameliorate disease state in PH. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). We previously showed pancreas-specific dopamine D2 receptor (DRD2) signaling protects against AP severity. However, it is unclear to what extent myeloid-specific DRD2 mediates AP. In this study, we investigated the role of myeloid-specific DRD2 signaling in AP. EXPERIMENTAL APPROACH Using wild-type and LysM+/cre Drd2fl/fl mice, L-arginine-induced or caerulein and lipopolysaccharide-induced AP was built. Murine bone marrow-derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs) were isolated and cultured, then induced to M1 phenotype. AP severity was assessed by measurements of serum amylase and lipase and histologic grading. Macrophage phenotype was assessed by flow cytometry and qRT-PCR. Selleckchem U0126 NADPH oxidase-induced oxidative stress and NFκB and NLRP3 inflammasome signaling pathways were also evaluated. KEY RESULTS We found that dopaminergic system was activated and dopamine reduced inflammatory cytokine expression in M1-polarized macrophages from human PBMCs. Similarly, dopaminergic synthesis was activated but DRDs expression was down-regulated in M1-polarized macrophages from murine bone marrows. During AP, myeloid-specific DRD2 deletion worsened pancreatic injury and systemetic inflammation and promoted macrophages to M1 phenotype. Furthermore, M1 macrophages from LysM+/cre Drd2fl/fl mice exhibited increased NADPH oxidase-induced oxidative stress and consequently enhanced NF-κB and NLRP3 inflammasome activation. While DRD2 activation inhibited M1 macrophage polarization, oxidative stress-induced NF-κB and NLRP3 inflammasome activation. CONCLUSION AND IMPLICATIONS Our data for the first time showed that myeloid-specific DRD2 signaling controls pancreatic injury and systemic inflammation via inhibiting M1 macrophage, suggesting DRD2 might serve as a potential therapeutic target for AP. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Th17 cells play critical roles in chronic inflammation, including fibrosis. Histone acetyltransferase p300, a bromodomain-containing protein, acetylates RORγt and promotes Th17 cell development. The bromodomain inhibitor JQ1, was shown to alleviate Th17-mediated pathologies, but the underlying mechanism remains unclear. We hypothesized that JQ1 suppresses the response of Th17 cells by impairing p300-mediated acetylation of RORγt. EXPERIMENTAL APPROACH The effect of JQ1 on p300-mediated acetylation of RORγt was investigated in HEK293T (overexpressing Flag-p300 and Myc-RORγt) and human Th17 cells through immunoprecipitation and western blotting. To determine the regions of p300 responsible for JQ1-mediated suppression of HAT activity, we performed HAT assays on recombinant p300 fragments with/without the bromodomain, after exposure to JQ1. Additionally, the effect of JQ1 on p300-mediated acetylation of RORγt and Th17 cell function was verified in vivo, using murine Schistosoma-induced fibrosis models. Liver injury was assessed by histopathological examination and measurement of serum enzyme levels. Expression of Th17 effectors was detected by qRT-PCR, whereas IL-17- and RORγt-positive granuloma cells were detected by FACS. KEY RESULTS JQ1 impaired p300-mediated RORγt acetylation in human Th17 and HEK293T cells. JQ1 failed to suppress the acetyltransferase activity of p300 fragments lacking the bromodomain. JQ1 treatment attenuated Schistosoma-induced fibrosis in mice, by inhibiting RORγt acetylation and IL-17 expression. CONCLUSIONS AND IMPLICATIONS JQ1 impairs p300-mediated RORγt acetylation, thus reducing the expression of RORγt target genes, including Th17-specific cytokines. JQ1-mediated inhibition of p300 acetylase activity requires the p300 bromodomain. Strategies targeting p300 may provide new therapeutic approaches for controlling Th17-related diseases. This article is protected by copyright. All rights reserved.Efficient therapies are available for the treatment of osteoporosis. Anti-resorptive therapies, including bisphosphonates and denosumab increase bone mineral density (BMD) and reduce the risk of fractures by 20-70%. Bone-forming or dual-action treatments stimulate bone formation and increase BMD more than the anti-resorptive therapies. Two studies have demonstrated that these treatments are superior to anti-resorptives in preventing fractures in patients with severe osteoporosis. Bone-forming or dual-action treatments should be followed by anti-resorptive treatment to maintain the fracture risk reduction. The BMD gains seen with bone-forming and dual-action treatments are greater in treatment naïve patients compared to patients pretreated with anti-resorptive treatments, however, the antifracture efficacy seems to be preserved. Treatment failure will often lead to switch of treatment from orally to parentally administrated anti-resorptives treatment or from anti-resorptive to bone-forming or dual-action treatment. Osteoporosis is a chronic condition and therefore needs a long-term management plan with a personalized approach to treatment. This article is protected by copyright. All rights reserved.In physiology, homeostasis refers to the condition where a system exhibits an optimum functional level. In contrast, any variation from this optimum is considered as a dysfunctional or pathological state. In this review, we address the proposal that a critical cholesterol level in the plasma membrane is required for the proper functioning of transmembrane proteins. Thus, membrane cholesterol depletion or enrichment produces a loss or gain of direct cholesterol-protein interaction and/or changes in the physical properties of the plasma membrane which affect the basal or optimum activity of transmembrane proteins. Whether or not this functional switching is a generalized mechanism exhibited for all transmembrane proteins, or if it works just for an exclusive group of them is an open question and an attractive subject to explore at basic, pharmacological and clinical level. This article is protected by copyright. All rights reserved.Pancreatic cancer has the highest mortality rate (5-year survival ~9%) among major types of malignant tumors. Pancreatic adenocarcinoma (PAAD) is the most common (>80%) and most lethal type of pancreatic cancer. A strong need thus exists for new approaches to treat PAAD. G protein-coupled receptors (GPCRs), the largest family of cell-surface receptors and drug targets, account for ~35% of approved drugs. Recent studies have revealed roles for GPCRs in PAAD cells and cells in the tumor microenvironment. This review assesses current information regarding GPCRs in PAAD by first summarizing omics data for GPCRs expression in PAAD. The PAAD "GPCRome" includes GPCRs with approved agents, thereby offering potential for their repurposing/repositioning. In addition, we review the evidence for functional roles of specific GPCRs in PAAD. We also highlight gaps in understanding the contribution of GPCRs to PAAD biology and identify several GPCRs that may be novel therapeutic targets so as to help guide future work in search of GPCR-targeted drugs to treat PAAD tumors. This article is protected by copyright. All rights reserved.BACKGROUND Percutaneous dilatational tracheostomy have been performed increasingly since its introduction in 1985, and is today one of the most commonly performed operative procedures in intensive care units. The aim of this study was to document patient-reported outcomes from percutaneous dilatational tracheostomy after hospital discharge. METHODS This study is based on retrospective extraction of data from the databases in the ICU at Haukeland University Hospital from 2004 to 2016. Patients alive by April 2018 and with a code for dilatation tracheostomy were sent a questionnaire about their experiences with having a tracheostomy performed. The occurrence of problems and their relations were registered. RESULTS Of 5769 admitted patients, 900 patients ≥ 15 years (15.7%) had a percutaneous dilatation tracheostomy performed. The median time from admission to follow-up was 6.1 years, and the 30 days mortality in those who received a tracheostomy was 315/900 (35%). Of the 441 survivors contacted, 181 answered the questionnaire and a total of 293 problems were reported. The majority of these problems were reported as no or moderate in 115 patients (78.3%). The presence of any problem was significantly associated with occurrence for other problems; however, there were no significant differences related to the elapsed time since the ICU stay. Pain and difficulties with breathing were the two single factors most often related to occurrence of other problems. CONCLUSION Although self-reported problems after percutaneous tracheostomy occurring after hospital discharge were often reported, most (78.3%) were considered by the patients to be moderate. © 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin-releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells.
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