Microstructural Visual Pathway White Matter Alterations in Primary Open-Angle Glaucoma:A Neurite Orientation Dispersion and Density Imaging Study

BACKGROUND AND PURPOSE: DTI studies of patients with primary open-angle glaucoma have demonstrated that glaucomatous degeneration is not confined to the retina but involves the entire visual pathway. Due to the lack of direct biologic interpretation of DTI parameters, the structural nature of this degeneration is still poorly understood. We used neurite orientation dispersion and density imaging (NODDI) to characterize the microstructural changes in the pregeniculate optic tracts and the postgeniculate optic radiations of patients with primary open-angle glaucoma, to better understand the mechanisms underlying these changes.& nbsp;MATERIALS AND METHODS: T1- and multishell diffusion-weighted scans were obtained from 23 patients with primary open-angle glaucoma and 29 controls. NODDI parametric maps were produced from the diffusion-weighted scans, and probabilistic tractography was used to track the optic tracts and optic radiations. NODDI parameters were computed for the tracked pathways, and the measures were compared between both groups. The retinal nerve fiber layer thickness and visual field loss were assessed for the patients with glaucoma.& nbsp;RESULTS: The optic tracts of the patients with glaucoma showed a higher orientation dispersion index and a lower neurite density index compared with the controls (

Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age

Background: Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation (VAS) for children aged 6 to 59 months. The last version of this review was published in 2017, and this is an updated version of that review. Objectives: To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years. Search methods: We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers up to March 2021. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies. Selection criteria: Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation. Data collection and analysis: For this update, two review authors independently assessed studies for inclusion resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence. Main results: The updated search identified no new RCTs. We identified 47 studies, involving approximately 1,223,856 children. Studies were set in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most studies included equal numbers of girls and boys and lasted about one year. The mean age of the children was about 33 months. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for VAS compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-certainty evidence). Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 children; high-certainty evidence). There was no evidence of a difference for VAS on mortality due to measles (RR 0.88, 95% CI 0.69 to 1.11; 6 studies, 1,088,261 children; low-certainty evidence), respiratory disease (RR 0.98, 95% CI 0.86 to 1.12; 9 studies, 1,098,538 children; low-certainty evidence), and meningitis. VAS reduced the incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies, 77,946 children; low-certainty evidence), measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies, 19,566 children; moderate-certainty evidence), Bitot's spots (RR 0.42, 95% CI 0.33 to 0.53; 5 studies, 1,063,278 children; moderate-certainty evidence), night blindness (RR 0.32, 95% CI 0.21 to 0.50; 2 studies, 22,972 children; moderate-certainty evidence), and VAD (RR 0.71, 95% CI 0.65 to 0.78; 4 studies, 2262 children, moderate-certainty evidence). However, there was no evidence of a difference on incidence of respiratory disease (RR 0.99, 95% CI 0.92 to 1.06; 11 studies, 27,540 children; low-certainty evidence) or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies, 10,541 children; moderate-certainty evidence). Authors' conclusions: This update identified no new eligible studies and the conclusions remain the same. VAS is associated with a clinically meaningful reduction in morbidity and mortality in children. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented VAD, it would be unethical to conduct placebo-controlled trials

Micro-Environmental Mechanical Stress Controls Tumor Spheroid Size and Morphology by Suppressing Proliferation and Inducing Apoptosis in Cancer Cells

Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved.We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway.Our results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation

An Autonomic Link Between Inhaled Diesel Exhaust and Impaired Cardiac Performance: Insight From Treadmill and Dobutamine Challenges in Heart Failure–Prone Rats

Cardiac disease exacerbation is associated with short-term exposure to vehicular emissions. Diesel exhaust (DE) might impair cardiac performance in part through perturbing efferent sympathetic and parasympathetic autonomic nervous system (ANS) input to the heart. We hypothesized that acute changes in ANS balance mediate decreased cardiac performance upon DE inhalation. Young adult heart failure–prone rats were implanted with radiotelemeters to measure heart rate (HR), HR variability (HRV), blood pressure (BP), core body temperature, and pre-ejection period (PEP, a contractility index). Animals pretreated with sympathetic antagonist (atenolol), parasympathetic antagonist (atropine), or saline were exposed to DE (500 µg/m3 fine particulate matter, 4h) or filtered air and then treadmill exercise challenged. At 1 day postexposure, separate rats were catheterized for left ventricular pressure (LVP), contractility, and lusitropy and assessed for autonomic influence using the sympathoagonist dobutamine and surgical vagotomy. During DE exposure, atenolol inhibited increases in HR, BP, and contractility, but not body temperature, suggesting a role for sympathetic dominance. During treadmill recovery at 4h post-DE exposure, HR and HRV indicated parasympathetic dominance in saline- and atenolol-pretreated groups that atropine inhibited. Conversely, at treadmill recovery 21h post-DE exposure, HRV and PEP indicated sympathetic dominance and subsequently diminished contractility that only atenolol inhibited. LVP at 1 day postexposure indicated that DE impaired contractility and lusitropy while abolishing parasympathetic-regulated cardiac responses to dobutamine. This is the first evidence that air pollutant inhalation both causes time-dependent oscillations between sympathetic and parasympathetic dominance and decreases cardiac performance via aberrant sympathetic dominance