Aquaporin-4 distribution in control and stressed astrocytes in culture and in the cerebrospinal fluid of patients with traumatic brain injuries

Distribution of aquaporin-4 (AQP4) was studied by western analysis and immunofluorescence in rat astrocytes exposed to either hypothermic (30 °C) or hyperosmolar (0.45 M sucrose) stress, and in the cerebrospinal fluid (CSF) of patients who suffered traumatic brain injury (TBI). CSF was obtained from 5 healthy subjects and from 20 patients suffering from severe TBI. CSF samples were taken at admission and on days 3 and 5-7. Here we report that, in response to both hypothermia and hyperosmolar stress, AQP4 was markedly reduced in cultured astrocytes. We also found that AQP4 significantly increased in patients with severe brain injury in respect to healthy subjects (P < 0.002). AQP4 in CSF remained unchanged in patients with elevated intracranial pressure (ICP), whereas there was a clear tendency to further increase in those patients whose ICP could be controlled within the normal range. We conclude that AQP4 levels in CSF are elevated after TBI and it might serve as a useful biochemical marker to assess brain water metabolism in clinical settings

High response rate to PD-1 blockade in desmoplastic melanomas

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression

The Association Between Time Spent in Sedentary Behaviors and Blood Pressure: A Systematic Review and Meta-Analysis

Background and Objective: Sedentary behaviors, defined as waking behaviors with low energy expenditure while sitting, are positively associated with several adverse health outcomes. However, the association between sedentary behaviors and blood pressure (BP) is inconclusive. This study aimed to conduct a systematic review and meta-analysis on the association between time spent in sedentary behaviors and BP. Methods: We searched PubMed, MEDLINE, and Web of Science for papers published before August 2014 that assessed the association between time spent in sedentary behaviors and BP. Studies on both adults and children were included. Only good quality studies were included. The pooled estimates of systolic BP (SBP) and diastolic BP (DBP) increase per hour of time spent in sedentary behaviors a day were computed using a fixed-effects model and a random-effects model, respectively. Another pooled estimate of odds ratio per hour of time spent in sedentary behaviors a day on having high BP was computed using a fixed-effects model. A sub-group analysis was conducted for studies using self-reported and objectively assessed time spent in sedentary behaviors separately. Results: A total of 31 papers of good quality were included in the systematic review, 18 of which found no association between time spent in sedentary behaviors and BP (58.1?%). A total of 28 papers were included in the meta-analysis. Pooled effects showed that an additional hour of time spent in sedentary behaviors per dSchool of Nursin