Smidtjosephsen5562

Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.

Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 (



) display accelerated bone growth.

We examined vulnerability of



mice to OA following surgical induction of disease (destabilization of the medial meniscus (DMM)), and with ageing, by histology and micro-CT.

We observed a significant increase in mean number (wild-type (WT) DMM 532 (SD 56); WT sham 495 (SD 45); knockout (KO) DMM 169 (SD 49); KO sham 187 (SD 56); p < 0.001) and density (WT DMM 2.2 (SD 0.9); WT sham 1.2 (SD 0.5); KO DMM 13.0 (SD 0.5); KO sham 14.4 (SD 0.7)) of growth plate bridges in



in comparison with WT. Histological examination of WT and



knees revealed articular cartilage damage with DMM in comparison to sham. Articular cartilage lesion severity scores (mean and maximum) were similar in WT and



mice with either DMM, or with ageing. Micro-CT analysis revealed significant decreases in SCB thickness, epiphyseal trabecular number, and thickness in the medial compartment of



, in comparison with WT (p < 0.001). DMM had no effect on the SCB thickness in comparison with sham in either genotype.

Together, these data suggest that enhanced GH signalling through SOCS2 deletion accelerates growth plate fusion, however this has no effect on OA vulnerability in this model. Cite this article

2022;11(3)162-170.

Together, these data suggest that enhanced GH signalling through SOCS2 deletion accelerates growth plate fusion, however this has no effect on OA vulnerability in this model. Cite this article Bone Joint Res 2022;11(3)162-170.Circadian amplitude enhancement has the potential to be organ protective but has not been studied in acute lung injury (ALI). Consistent light and dark cycles are crucial for the amplitude regulation of the circadian rhythm protein Period2 (PER2). Housing mice under intense instead of ambient light for 1 wk (light dark cycle14h10h), we demonstrated a robust increase of pulmonary PER2 trough and peak levels, which is consistent with circadian amplitude enhancement. A search for the affected lung cell type suggested alveolar type 2 (ATII) cells as strong candidates for light induction of PER2. A head-to-head comparison of mice with cell-type-specific deletion of Per2 in ATII, endothelial, or myeloid cells uncovered a dramatic phenotype in mice with an ATII-specific deletion of Per2. During Pseudomonas aeruginosa-induced ALI, mice with Per2 deletion in ATII cells showed 0% survival, whereas 85% of control mice survived. Subsequent studies demonstrated that intense light therapy dampened lung inflammation or improved the alveolar barrier function during P. aeruginosa-induced ALI, which was abolished in mice with an ATII-specific deletion of Per2. A genome-wide mRNA array uncovered bactericidal/permeability-increasing fold-containing family B member 1 (BPIFB1) as a downstream target of intense light-elicited ATII-PER2 mediated lung protection. Using the flavonoid and PER2 amplitude enhancer nobiletin, we recapitulated the lung-protective and anti-inflammatory effects of light and BPIFB1, respectively. Together, our studies demonstrate that light-elicited amplitude enhancement of ATII-specific PER2 is a critical control point of inflammatory pathways during bacterial ALI.Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. click here With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab.

Worsened stroke outcomes with hypertension comorbidity are insensitive to blood pressure-lowering therapies. In an experimental stroke model with comorbid hypertension, we investigated causal roles of ang II (angiotensin II)-mediated stimulation of the brain WNK (with no lysine [K] kinases)-SPAK (STE20/SPS1-related proline/alanine-rich kinase)-NKCC1 (Na-K-Cl cotransporter) complex in worsened outcomes.

Saline- or ang II-infused C57BL/6J male mice underwent stroke induced by permanent occlusion of the distal branches of the middle cerebral artery. Mice were randomly assigned to receive either vehicle dimethyl sulfoxide/PBS (2 mL/kg body weight/day, IP), a novel SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (ZT-1a' 5 mg/kg per day, IP) or a NF-κB (nuclear factor-κB) inhibitor TAT-NBD (transactivator of transcription-NEMO-binding domain' 20 mg/kg per day, IP). Activation of brain NF-κB and WNK-SPAK-NKCC1 cascade as well as ischemic stroke outcomes wic target for stroke with comorbid hypertension.

The ang II-induced stimulation of NF-κB transcriptional activity upregulates brain WNK-SPAK-NKCC1 cascade and contributes to worsened ischemic stroke outcomes, illustrating the brain WNK-SPAK-NKCC1 complex as a therapeutic target for stroke with comorbid hypertension.

Evidence regarding the utilization and outcomes of endovascular thrombectomy (EVT) for pediatric ischemic stroke is limited, and justification for its use is largely based on extrapolation from clinical benefits observed in adults.

Weighted discharge data from the National Inpatient Sample were queried to identify pediatric patients with ischemic stroke (<18 years old) during the period of 2010 to 2019. Complex samples statistical methods were used to characterize the profiles and clinical outcomes of EVT-treated patients. Propensity adjustment was performed to address confounding by indication for EVT based on disparities in baseline characteristics between EVT-treated patients and those medically managed.

Among 7365 pediatric patients with ischemic stroke identified, 190 (2.6%) were treated with EVT. Utilization significantly increased in the post-EVT clinical trial era (2016-2019; 1.7% versus 4.0%;

<0.001), while the use of decompressive hemicraniectomy decreased (2.8% versus 0.7%;

<0.00 versus 49.5%;

=0.060).

This cross-sectional evaluation of the clinical course and short-term outcomes of pediatric patients with ischemic stroke treated with EVT demonstrates that EVT is likely a safe modality which confers high rates of favorable functional outcomes.

This cross-sectional evaluation of the clinical course and short-term outcomes of pediatric patients with ischemic stroke treated with EVT demonstrates that EVT is likely a safe modality which confers high rates of favorable functional outcomes.Background The hemoglobin-to-red cell distribution width ratio (HRR) has emerged as a novel integrative biomarker predictive of overall and disease-free survival in cancer patients. This study aimed to investigate the prognostic significance of HRR in the cancer population. Methods A literature search was performed in PubMed/MEDLINE from inception to 1 July 2021, to collect studies assessing the prognostic value of HRR in cancer patients. The primary and secondary end points were all-cause mortality and occurrence of disease progression or relapse, respectively. A meta-analytic approach was employed to estimate the pooled hazard ratio with 95% CI by fitting random-effects models. Results A total of 11 retrospective cohort studies representing 2985 cancer patients were included. Compared with patients with high HRR, patients with low HRR had a twofold risk of all-cause mortality (hazard ratio 2.29; 95% CI 1.76-2.98; p less then 0.0001). There was substantial heterogeneity in the association of HRR with mortality across the studies (I2 66.8%; 95% CI 35.3-82.9%; p = 0.0014). Similarly, low HRR was associated with a twofold risk of disease progression or relapse (hazard ratio 2.19; 95% CI 1.74-2.76; p less then 0.0001). No significant heterogeneity was observed (I2 16.8%; 95% CI 0.0-60.7%; p = 0.30). Conclusion Low HRR was associated with mortality and disease progression or relapse in patients with cancer. Further studies are required to standardize the HRR cutoff value and investigate whether HRR can be incorporated into risk assessment models for predicting adverse prognosis in cancer patients.Finding an easily accessible and reliable tool to diagnose the diseases collectively defined as 'synucleinopathies' is an urgent, unmet priority. The synucleinopathies include Parkinson's disease, multiple system atrophy, pure autonomic failure and dementia with Lewy bodies. There are millions of people who have a diagnosis of a synucleinopathy, with more diagnosed every year. With accessibility, ease of implementation, consistently high sensitivity (>80%) and specificity approaching 100%, skin biopsy has great potential as the clinical test of choice for the diagnosis of synucleinopathies. The large, multi-center Synuclein-One study will determine the sensitivity, specificity, accuracy and precision of α-synuclein detection within punch skin biopsies in patients with clinically established synucleinopathies using standardized, robust methods suitable for large-scale analysis. Clinical Trial Registration NCT04700722 (ClinicalTrials.gov).