Hobbsnedergaard3252

IPN in a Chinese high-stroke-risk population. Further prospective studies should be conducted to better understand how much finding IPN adds to current stroke prediction tools.Background 2-Indolinone-based hydrazinecarbothioamides carrying a 3-phenylsulfonamide moiety (7-9) were designed by replacement of donepezil's pharmacophore group indanone with a 2-indolinone ring. Method Compounds 7-9 were synthesized by reaction of N-(3-sulfamoylphenyl)hydrazinecarbothioamide (6) with 1H-indolin-2,3-diones (1-3). Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects of compounds 7-9 were assayed. Molecular modeling studies of 5-chloro-1,7-dimethyl-substituted compound 8e were carried out to determine the possible binding interactions at the active site of AChE. Results Compound 8e showed the strongest inhibition against AChE (Ki = 0.52 ± 0.11 μM) as well as the highest selectivity (SI = 37.69). The selectivity for AChE over BuChE of compound 8e was approximately 17-times higher than donepezil and 26-times higher than galantamine. MK-8719 Conclusion Further development of compounds 7-9 may present new promising agents for Alzheimer's treatment.

Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the enteric nervous system (ENS) and digestive dysfunction remains largely unexplored. This study examined allosteric modulation of the delta opioid receptor (DOR) in the ENS and assessed the suitability of DOR AMs for the treatment of irritable bowel syndrome (IBS) symptoms using mouse models.

The effects of the positive allosteric modulator (PAM) of DOR, BMS-986187, on neurogenic contractions of the mouse colon and on DOR internalization in enteric neurons were quantified. The ability of BMS-986187 to influence colonic motility was assessed both in vitro and in vivo.

BMS-986187 displayed DOR selective PAM-agonist activity and orthosteric agonist probe-dependence in the mouse colon. BMS-986187 augmented the inhibitory effects of DOR agonists on neurogenic contractions and enhanced reflex-evoked DOR internalization in myenteric neurons. BMS-986187 significantly increased DOR endocytosis in myenteric neurons in response to the weakly internalizing agonist ARM390. BMS-986187 reduced the generation of complex motor patterns in the isolated intact colon. BMS-986187 reduced fecal output and diarrhea onset in the novel environment stress and castor oil models of IBS symptoms, respectively.

DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for treatment of gastrointestinal motility disorders.

DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for treatment of gastrointestinal motility disorders.Background Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are increasing in prevalence. link2 The independent association between NAFLD and downstream risk of HF and HF subtypes (HF with preserved ejection fraction and HF with reduced ejection fraction) is not well established. Methods and Results This was a retrospective, cohort study among Medicare beneficiaries. We selected Medicare beneficiaries without known prior diagnosis of HF. NAFLD was defined using presence of 1 inpatient or 2 outpatient claims using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), claims codes. Incident HF was defined using at least 1 inpatient or at least 2 outpatient HF claims during the follow-up period (October 2015-December 2016). Among 870 535 Medicare patients, 3.2% (N=27 919) had a clinical diagnosis of NAFLD. Patients with NAFLD were more commonly women, were less commonly Black patients, and had a higher burden of comorbidities, such as diabetes, obesity, and kidney disease. Over a mean 14.3 months of follow-up, patients with (versus without) baseline NAFLD had a significantly higher risk of new-onset HF in unadjusted (6.4% versus 5.0%; P less then 0.001) and adjusted (adjusted hazard ratio [HR] [95% CI], 1.23 [1.18-1.29]) analyses. link3 Among HF subtypes, the association of NAFLD with downstream risk of HF was stronger for HF with preserved ejection fraction (adjusted HR [95% CI], 1.24 [1.14-1.34]) compared with HF with reduced ejection fraction (adjusted HR [95% CI], 1.09 [0.98-1.2]). Conclusions Patients with NAFLD are at an increased risk of incident HF, with a higher risk of developing HF with preserved ejection fraction versus HF with reduced ejection fraction. The persistence of an increased risk after adjustment for clinical and demographic factors suggests an epidemiological link between NAFLD and HF beyond the basis of shared risk factors that requires further investigation.Background Available evidence supports an association between atrial high-rate episode (AHRE) burden and thromboembolic risk, but the necessary extent and duration of AHREs to increase the thromboembolic risk remain to be defined. The aim of this systematic review and meta-analysis was to identify the thromboembolic risk associated with various AHRE thresholds. Methods and Results We searched PubMed and Scopus until January 9, 2020, for literature reporting AHRE duration and thromboembolic risk in patients with implantable electronic devices. The outcome assessed was stroke or systemic embolism. Risk estimates were reported as hazard ratio (HR) or relative risk alongside 95% CIs. We used the Paule-Mandel estimator, and heterogeneity was calculated with I2 index. Among 27 studies including 61 919 patients, 23 studies reported rates according to the duration of the longest AHRE and 4 studies reported rates according to the cumulative day-level AHRE duration. In patients with cardiac implantable devices, AHREs lasting ≥30 seconds significantly increased the risk of stroke or systemic embolism (HR, 4.41; 95% CI, 2.32-8.39; I2, 5.5%), which remained consistent for the thresholds of 5 minutes and 6 and 24 hours. Patients with previous stroke or transient ischemic attack and AHREs lasting ≥2 minutes had a marginally increased risk of recurrent stroke or transient ischemic attack. The risk of stroke or systemic embolism was higher in patients with cumulative AHRE ≥24 hours compared with those of shorter duration or no AHRE (HR, 1.25; 95% CI, 1.04-1.52; I2, 0%). Conclusions This systematic review and meta-analysis suggests that single AHRE episodes ≥30 seconds and cumulative AHRE duration ≥24 hours are associated with increased risk of stroke or systemic embolism.Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-gamma (IFN-g) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal Transducer and Activator of Transcription 1 (STAT1) activation by IFN-g is a key signaling pathway in Th1 inflammation, however its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In the present study, we challenged wild type (WT) and Stat1-/- mice with mixed allergens (MA) augmented with c-di-GMP, an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared to WT mice, Stat1-/- had reduced neutrophils, Th1 and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroid significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1-/- mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1-/- mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.Background Cerebral amyloid angiopathy (CAA) causes cognitive decline, but it is not known whether it is associated with neuropsychiatric symptoms (NPS). Methods and Results Participants with CAA, mild cognitive impairment, mild dementia due to Alzheimer's disease, and normal cognition were recruited from stroke and dementia clinics and community advertising. NPS were captured using the Neuropsychiatric Inventory Questionnaire short form. The number and total severity (number multiplied by severity of each symptom [mild, moderate, or severe]) of NPS were analyzed using generalized linear regression with a negative binomial link and multiple linear regression, adjusting for age, sex, and education. A total of 109 participants (43 with CAA, 15 with Alzheimer's disease, 28 with mild cognitive impairment, and 23 with normal cognition) (mean age 71.1 [SD=7.6]; 53.2% male) were included. The most frequent NPS in CAA were depression/dysphoria (48.8%), irritability/lability (37.2%), agitation/aggression (37.2%), apathy/indifference (34.9%), and anxiety (32.6%). In adjusted models, patients with CAA had 3.2 times (95% CI, 1.7-6.0) more NPS symptoms and 3.1 units (95% CI, 1.0-5.1) higher expected severity score. The number of NPS was similar to patients with mild cognitive impairment (3.2 times higher than controls) but less than in patients with Alzheimer's disease dementia (4.1 times higher than controls). Within patients with CAA, there were 1.20 times (95% CI, 1.01-1.32) more NPS per 1% increase in white matter hyperintensity as a percentage of intracranial volume. Conclusions NPS are common in CAA, with a similar prevalence as in mild cognitive impairment. The association of the total number of NPS with higher white matter hyperintensity volume suggests that white matter damage may underlie some of these symptoms.Acute ozone (O3) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across individuals in human populations and inbred mouse strains. However, molecular determinants of response, including susceptibility biomarkers that distinguish who will develop severe injury and inflammation, are not well characterized. We and others have demonstrated that airway macrophages (AMs) are an important resident immune cell type that are functionally and transcriptionally responsive to O3 inhalation. Here, we sought to explore influences of strain, exposure, and strain-by-O3 exposure interactions on AM gene expression and identify transcriptional correlates of O3-inducedinflammation and injury across 6 mouse strains, including 5 Collaborative Cross (CC) strains. We exposed adult mice of both sexes to filtered air (FA) or 2 ppm O3 for 3 hours, and measured inflammatory and injury parameters 21 hours later. Mice exposed to O3 developed airway neutrophilia and lung injury with strain-dependent severity.