Otteclemons8611

Purpose. Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a severe complication of malaria despite effective anti-malarial treatment. Currently, non-invasive imaging procedures such as chest X-rays are used to assess oedema in established MA-ARDS but earlier detection methods are needed to reduce morbidity and mortality. The early stages of MA-ARDS are characterized by the infiltration of leukocytes, in particular monocyte/macrophages, thus monitoring of immune infiltrates may provide a useful indicator of early pathology. Procedures. Plasmodium berghei ANKA-infected C57BL/6 mice, a rodent malaria model of MA-ARDS, were longitudinally imaged using the TSPO imaging agent [18F]FEPPA as a marker of macrophage accumulation during the development of pathology and response to combined artesunate and chloroquine diphosphate therapy (ART+CQ). [18F]FEPPA uptake was compared to blood parasitemia levels and pulmonary immune cell infiltrates using flow cytometry. Results. Infected animals showed rapid increases lung retention of [18F]FEPPA, correlating well with increases in blood parasitemia and pulmonary accumulation of interstitial inflammatory macrophages and MHC II+ alveolar macrophages. Treatment with ART+CQ therapy abrogated this increase in parasitemia and significantly reduced both lung uptake of [18F]FEPPA and macrophage infiltrates. Conclusions. Retention of [18F]FEPPA in the lungs is well correlated with changes in blood parasitemia and lung associated macrophages during disease progression and in response to ART+CQ therapy. With further development TSPO biomarkers may have the potential to be able to accurately assess early onset of MA-ARDS.The cell walls and capsules of Cryptococcus neoformans, a yeast-type fungal pathogen, are rich in polysaccharides. Dectin-2 is a C-type lectin receptor (CLR) that recognizes high-mannose polysaccharides. Tanespimycin chemical structure Previously, we demonstrated that Dectin-2 is involved in cytokine production by bone marrow-derived dendritic cells (BM-DCs) in response to stimulation with C. neoformans. In the present study, we analyzed the role of Dectin-2 in the phagocytosis of C. neoformans by BM-DCs. The engulfment of this fungus by BM-DCs was significantly decreased in mice lacking Dectin-2 (Dectin-2KO) or caspase recruitment domain-containing protein 9 (CARD9KO), a common adapter molecule that delivers signals triggered by CLRs, compared to wild-type (WT) mice. Phagocytosis was likewise inhibited, to a similar degree, by the inhibition of Syk, a signaling molecule involved in CLR-triggered activation. A PI3K inhibitor, in contrast, completely abrogated the phagocytosis of C. neoformans. Actin polymerization, i.e., conformational changes in cytoskeletons detected at sites of contact with C. neoformans, was also decreased in BM-DCs of Dectin-2KO and CARD9KO mice. Finally, the engulfment of C. neoformans by macrophages was significantly decreased in the lungs of Dectin-2KO mice compared to WT mice. These results suggest that Dectin-2 may play an important role in the actin polymerization and phagocytosis of C. neoformans by DCs, possibly through signaling via CARD9 and a signaling pathway mediated by Syk and PI3K.Recently, the roles of inflammation and insulin resistance in neurodegeneration have become better appreciated. NE3107, an oral small molecule, blood-brain permeable anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase, has been shown to selectively inhibit inflammation-driven ERK- and NFκB-stimulated inflammatory mediators, including TNFα, without inhibiting their homeostatic functions. We describe the rationale and design of NM101, the first randomized, multicenter Phase III clinical study to examine the safety and efficacy of 30 week treatment with NE3107 versus placebo in elderly adults with mild to moderate Alzheimer's disease. Patients (316) will be randomized in a 11 ratio. The co-primary end points measure cognitive function (ADAS Cog12), and functional and behavioral characteristics (ADCS CGIC). Trial registration number NCT04669028 (Clinicaltrials.gov).Low tidal volume ventilation protects the lung in mechanically ventilated patients. The impact of the accompanying permissive hypoxemia and hypercapnia on endothelial cell recovery from injury is poorly understood. Carbonic anhydrase IX (CA IX) is expressed in pulmonary microvascular endothelial cells (PMVECs), where it contributes to CO2 and pH homeostasis, bioenergetics and angiogenesis. We hypothesized that CA IX is important for PMVEC survival, and CA IX expression and release from PMVECs are increased during infection. While plasma CA IX was unchanged in human and rat pneumonia, there was a trend towards increasing CA IX in bronchoalveolar fluid of mechanically ventilated critically ill pneumonia patients and a significant increase in CA IX in lung tissue lysate of rat pneumonia. To investigate functional implications of the lung CA IX increase, we generated PMVEC cell lines harboring domain-specific CA IX mutations. Using these cells, we found that infection promotes intracellular expression, release and metalloproteinase-mediated extracellular cleavage of CA IX in PMVECs. Intracellular domain deletion uniquely impaired CA IX membrane localization. Loss of the CA IX intracellular domain promoted cell death following infection, suggesting the important role of intracellular domain in PMVEC survival. We also found that hypoxia improves survival, whereas hypercapnia reverses the protective effect of hypoxia, during infection. Thus, we report that (1) CA IX increases in rat pneumonia lung; and, (2) the CA IX intracellular domain and hypoxia promote PMVEC survival during infection.The current study was designed to identify new compounds as potential antiproliferative drug candidates. Synthesis of heteroaromatic bicyclic and monocyclic derivatives as purine bioisosters was employed. Their antiproliferative activity was studied against U937 cancer cells. The most effective compounds were evaluated for their selectivity against cancer cells, the possible mechanism of cell death, and their interference with DNA replication. Among the synthesized compounds, only three (4b, 4j and 4l) demonstrated a value of IC50 less than 20 μM. However, two of them (4b and 4l) were specific against cancer cells, with 4l presenting high selectivity. The presence of substituted pyrazolo[3,4-d]pyrimidine core is as essential for this activity as the presence of substituents at the thiol function in 6-position.Tunnel portal sections located in the soft-hard rock junction are vulnerable to the strong earthquake motions in seismically active regions. The main objective of this paper is to investigate the seismic response of tunnel portals located in the soft-hard rock junction. Taking the Baiyunding tunnel in northeast China as a background, a shaking table test with a geometric scaling ratio of 130 was built. Details of test setup and procedures are introduced first and then the test results are presented. The discussion of the results is based on the peak ground acceleration (PGA), the longitudinal, the contact stress, and the safety factor. The results show that the soft section of the soft-hard rock junction suffers remarkable damages under strong seismic motions, while the hard rock section is less affected by earthquakes. The increasing soft rock range causes a rise of the forced displacement of tunnel linings, which, together with the seismic inertia force, leads to the increase of the contact stress of the linings, and ultimately resulting in the deterioration of the tunnel seismic safety. To mitigate the seismic damage of tunnel portals in the soft-hard rock junction, rock grouting, bolt support, and other effective reinforced methods should be considered in the seismic design of the soft section.

This study investigated the 1-year clinical outcomes of directional atherectomy combined with drug-coated balloon (DA + DCB) in femoropopliteal artery disease (FPAD) from real-world experience.

A retrospective study was conducted of patients treated between July 2016 and June 2019 using DA + DCB for FPAD. Patients' demographics, comorbidities, clinical characteristics and outcomes, and angiography and duplex ultrasound findings were analyzed. The 6-month and 1-year primary patency, primary assisted patency, secondary patency, and freedom from clinically-driven target lesion revascularization (CD-TLR) were evaluated. Univariate and multivariate analyses were performed to identify risk factors of primary patency loss or CD-TLR.

Seventy-nine consecutive patients (83 lesions, mean age 70.9 years, 52 men) were included. Twenty-seven limbs had lifestyle-limiting claudication and 56 limbs had critical limb ischemia. There were 73 and 10 limbs with de novo lesion and in-stent restenosis, respectively. The mean lesion length of all the patients was 22.1 cm. The mean length of chronic total occlusions (CTOs) was 8.3 cm. Severe calcification was found in 32.5% cases. The 1-year primary patency rate was 80.8% and freedom from CD-TLR was 92.2%. The bailout stenting rate was 2.4%. Patients with CTO >10 cm had significantly lower 1-year primary patency rate and freedom from CD-TLR than did patients with CTO ≤10 cm. Total length of CTO (stratified as ≤5 cm, 5-10 cm, >10 cm) was identified as an independent risk factor of 1-year primary patency loss and CD-TLR.

DA + DCB appears to be a safe and effective endovascular therapy to treat FPAD in real-world clinical practice, with a promising 1-year patency rate with a low rate of bailout stenting.

DA + DCB appears to be a safe and effective endovascular therapy to treat FPAD in real-world clinical practice, with a promising 1-year patency rate with a low rate of bailout stenting.To date research on intimate partner violence (IPV) has focused on the experience of females. The limited studies on male IPV survivors have shown that they are less likely to disclose their IPV experiences. Systemic biases may marginalize and silence male IPV survivors.The current study sought to explore the discourse around perceived systemic biases that may be present for male IPV survivors.A widely used social networking site (http//www.reddit.com/) was scraped for submissions relating to male IPV. Search was carried out using three keywords resulting in 917 submissions, out of which 82 met inclusion criteria. Submissions were included in final analysis if they consisted of more than half a page of data pertaining to male IPV. Thematic content analysis was utilized to analyze the data.Responses reflect common experiences with participants identifying multiple sources of perceived systemic biases (1) social norms, (2) legal system, (3) social services, (4) media, and (5) government.The sources of potential support for male IPV survivors exhibit substantial pervasive biases against males as victims of IPV. Findings from current study can inform policies across multiple systems.

We aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF).

We conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients.

Patients' mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m

increase odds ratio 2.45, 95% confidence interval 1.