Pittmanrodriguez1562

Tau aggregates consisting of hyperphosphorylated tau fibrils are associated with many neurodegenerative diseases, including Alzheimer's disease, Pick's disease, frontotemporal dementia, and progressive supranuclear palsy. Tau may contribute to the pathogenesis of these diseases, collectively referred to as tauopathies. In human genetic prion diseases, tau aggregates are detected in association with amyloid plaques consisting of prion protein (PrP). However, the role of abnormal tau aggregates in PrP amyloid disease remains unclear. Previously we inoculated scrapie prions into transgenic mice expressing human tau, mouse tau, glycophosphatidylinositol (GPI) anchored PrP, and anchorless PrP. These mice developed both spongiform vacuolar pathology and PrP amyloid pathology, and human tau was detected near PrP amyloid plaques. However, the presence of human tau did not alter the disease tempo or prion-induced neuropathology. In the present study, we tested mice which more closely modeled familial human prion disease. These mice expressed human tau but lacked both mouse tau and GPI-anchored PrP. However, they did produce anchorless PrP, resulting in perivascular PrP amyloid plaques, i.e. cerebral amyloid angiopathy (CAA), without spongiform degeneration. Typical of PrP amyloid disease, the clinical course was very slow in this model. Nevertheless, the accumulation of aggregated, phosphorylated human tau and its association with PrP amyloid plaques failed to alter the timing or course of the clinical disease observed. These data suggest that human tau does not contribute to the pathogenesis of mouse PrP amyloid brain disease and raise the possibility that tau may also not be pathogenic in human PrP amyloid disease.A GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Compelling evidence suggests that gain of toxicity from the bidirectionally transcribed repeat expanded RNAs plays a central role in disease pathogenesis. Two potential mechanisms have been proposed including RNA-mediated toxicity and/or the production of toxic dipeptide repeat proteins. In this review, we focus on the role of RNA mediated toxicity in ALS/FTD caused by the C9orf72 mutation and discuss arguments for and against this mechanism. In addition, we summarize how G4C2 repeat RNAs can elicit toxicity and potential therapeutic strategies to mitigate RNA-mediated toxicity.

This study evaluated the potential safety, efficacy, and durability advantages of investigational triamcinolone acetonide suspension (CLS-TA; Clearside Biomedical, Alpharetta, GA) administered suprachoroidally in conjunction with intravitreal aflibercept compared with aflibercept monotherapy for treatment of diabetic macular edema (DME).

TYBEE was a prospective, controlled, double-masked study. Patients were randomized 11 to CLS-TA and aflibercept (active) or aflibercept monotherapy (control), and assessed over 24 weeks.

Treatment-naive DME patients with best-corrected visual acuity (BCVA) of 20 to 70 letters and central subfield retinal thickness (CST) of more than 300 μm.

Patients in the active group (n= 36) received CLS-TA and aflibercept at baseline and week 12. buy SJ6986 Patients in the control group (n= 35) received aflibercept at baseline, week 4, week 8, and week 12. To mask both groups, sham suprachoroidal and intravitreal injections were utilized. All patients were eligible to receive aflibercept as n the active group.

CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provides simliar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, is well tolerated and shows modest anatomic benefit with potential to reduce treatment burden.

CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provides simliar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, is well tolerated and shows modest anatomic benefit with potential to reduce treatment burden.Tripartite motif (TRIM) proteins are a highly versatile family of host-cell factors that play an integral role in the mammalian defense against pathogens. TRIM proteins regulate either transcription-dependent antiviral responses such as pro-inflammatory cytokine induction, or they modulate other important cell-intrinsic defense pathways like autophagy. Additionally, TRIM proteins exert direct antiviral activity whereby they antagonize specific viral components through diverse mechanisms. Here, we summarize the latest discoveries on the molecular mechanisms of antiviral TRIM proteins and also discuss current and future trends in this fast-evolving field.The immune system has evolved multiple mechanisms to restrict microbial infections and regulate inflammatory responses. Without appropriate regulation, infection-induced inflammatory pathology can be deadly. The innate immune system recognizes the microbial molecules conserved in many pathogens and engages a rapid response by producing inflammatory mediators and activating programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis. Activation of pattern recognition receptors, in combination with inflammatory cytokine-induced signaling through death domain-containing receptors, initiates a highly interconnected cell death process called PANoptosis (pyroptosis, apoptosis, necroptosis). Broadly speaking, PANoptosis is critical for restricting a wide range of pathogens (including bacteria, viruses, fungi, and parasites), which we describe in this review. We propose that re-examining the role of cell death and inflammatory cytokines through the lens of PANoptosis will advance our understanding of host-pathogen evolution and may reveal new treatment strategies for controlling a wide range of infectious diseases.

The optimal surgical strategy for treating internal carotid artery (ICA) blood blister-like aneurysms (BBAs) has remained unclear. Although some have preferred bypass surgery, others have favored less-demanding surgical methods. The aim of the present meta-analysis was to assess the efficacy, safety, and outcomes of bypass and non-bypass surgical methods when intended as primary treatment of ICA BBAs.

Studies reporting data on the outcomes of interest for surgically treated patients with ICA BBAs were searched for in the PubMed/MEDLINE, Evidence-Based Medicine Reviews, Cochrane Central, ProQuest, and Scopus databases. The data were analyzed using random effects modeling.

Seven observational studies involving 140 patients met the inclusion criteria. The patients treated with bypass surgery, compared with those treated with non-bypass techniques, had lower odds of poor outcomes (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.28-2.02; P= 0.57; I

= 0%), postoperative vasospasm (OR, 1.73; 95% CI, 0.