Progression of Anterograde Trans-Synaptic Degeneration in the Human Retina Is Modulated by Axonal Convergence and Divergence.

In the visual pathway of patients with multiple sclerosis (MS), the inner nuclear layer (INL) of the retina is a tight barrier for retrograde trans-synaptic degeneration. In this observational, retrospective cross-sectional study, segmented macular spectral domain optical coherence tomography (OCT) volume scans were reviewed to investigate if this observation also holds true for anterograde trans-synaptic degeneration. Significant thinning was found in all retinal layers in patients with outer retinal diseases compared with the healthy controls, while there was no significant attenuation of the outer retina in patients with MS. In contrast to the tight barrier function observed with retrograde trans-synaptic degeneration, the INL appears to be more permissive for the propagation of anterograde trans-synaptic degeneration. We speculate that this may be due to the size of the area affected and be explained by convergence and divergence of axons within the retinal layers. These findings are likely relevant to future restorative stem cell treatment of the outer retinal layers, as time may matter

Adherence and virologic suppression during the first 24 weeks on antiretroviral therapy among women in Johannesburg, South Africa - a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Adherence is a necessary part of successful antiretroviral treatment (ART). We assessed risk factors for incomplete adherence among a cohort of HIV-infected women initiating ART and examined associations between adherence and virologic response to ART.</p> <p>Methods</p> <p>A secondary data analysis was conducted on a cohort of 154 women initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART at a single site in Johannesburg, South Africa. Ninety women had been enrolled in a prevention of mother-to-child transmission (pMTCT) program and were exposed to single-dose nevirapine (sdNVP) >18 months earlier. Women were interviewed pre-treatment and clinical, virologic and adherence data were collected during follow-up to 24 weeks. Incomplete adherence to ART was defined as returning >5% of medications, estimated by pill counts at scheduled visits. Multivariable logistic regression analysis and unadjusted odds ratio (95%CI) were performed, using STATA/SE (ver 10.1).</p> <p>Results</p> <p>About half of the women (53%) were <30 years of age, 63% had <11 years of schooling, 69% were unemployed and 37% lived in a shack. Seven percent of women had a viral load >400 copies/ml at 24 weeks and 37% had incomplete adherence at one or more visits. Incomplete adherence was associated with less education (p = 0.01) and lack of financial support from a partner (p = 0.02) after adjustment for confounders. Only when adherence levels dropped below 80% was there a significant association with viremia in the group overall (p = 0.02) although adherence <95% was associated with viremia in the sdNVP-exposed group (p = 0.03). The main reasons for incomplete adherence were being away from home, busy with other things and forgetting to take their medication.</p> <p>Conclusion</p> <p>Virologic response to NNRTI-treatment in the cohort was excellent. However, women who received sdNVP were at greater risk of virologic failure when adherence was <95%. Women exposed to sdNVP, and those with less education and less social support may benefit from additional adherence counseling to ensure the long-term success of ART. More than 80% adherence may be sufficient to maintain virologic suppression on NNRTI-based regimens in the short-term, however complete adherence should be encouraged.</p

Adherence to Drug-Refill Is a Useful Early Warning Indicator of Virologic and Immunologic Failure among HIV Patients on First-Line ART in South Africa

Affordable strategies to prevent treatment failure on first-line regimens among HIV patients are essential for the long-term success of antiretroviral therapy (ART) in sub-Saharan Africa. WHO recommends using routinely collected data such as adherence to drug-refill visits as early warning indicators. We examined the association between adherence to drug-refill visits and long-term virologic and immunologic failure among non-nucleoside reverse transcriptase inhibitor (NNRTI) recipients in South Africa.In 2008, 456 patients on NNRTI-based ART for a median of 44 months (range 12-99 months; 1,510 person-years) were enrolled in a retrospective cohort study in Soweto. Charts were reviewed for clinical characteristics before and during ART. Multivariable logistic regression and Kaplan-Meier survival analysis assessed associations with virologic (two repeated VL>50 copies/ml) and immunologic failure (as defined by WHO).After a median of 15 months on ART, 19% (n = 88) and 19% (n = 87) had failed virologically and immunologically respectively. A cumulative adherence of <95% to drug-refill visits was significantly associated with both virologic and immunologic failure (p<0.01). In the final multivariable model, risk factors for virologic failure were incomplete adherence (OR 2.8, 95%CI 1.2-6.7), and previous exposure to single-dose nevirapine or any other antiretrovirals (adj. OR 2.1, 95%CI 1.2-3.9), adjusted for age and sex. In Kaplan-Meier analysis, the virologic failure rate by month 48 was 19% vs. 37% among adherent and non-adherent patients respectively (logrank p value = 0.02).One in five failed virologically after a median of 15 months on ART. Adherence to drug-refill visits works as an early warning indicator for both virologic and immunologic failure

A Distinct Layer of the Medulla Integrates Sky Compass Signals in the Brain of an Insect

Mass migration of desert locusts is a common phenomenon in North Africa and the Middle East but how these insects navigate is still poorly understood. Laboratory studies suggest that locusts are able to exploit the sky polarization pattern as a navigational cue. Like other insects locusts detect polarized light through a specialized dorsal rim area (DRA) of the eye. Polarization signals are transmitted through the optic lobe to the anterior optic tubercle (AOTu) and, finally, to the central complex in the brain. Whereas neurons of the AOTu integrate sky polarization and chromatic cues in a daytime dependent manner, the central complex holds a topographic representation of azimuthal directions suggesting a role as an internal sky compass. To understand further the integration of sky compass cues we studied polarization-sensitive (POL) neurons in the medulla that may be intercalated between DRA photoreceptors and AOTu neurons. Five types of POL-neuron were characterized and four of these in multiple recordings. All neurons had wide arborizations in medulla layer 4 and most, additionally, in the dorsal rim area of the medulla and in the accessory medulla, the presumed circadian clock. The neurons showed type-specific orientational tuning to zenithal polarized light and azimuth tuning to unpolarized green and UV light spots. In contrast to neurons of the AOTu, we found no evidence for color opponency and daytime dependent adjustment of sky compass signals. Therefore, medulla layer 4 is a distinct stage in the integration of sky compass signals that precedes the time-compensated integration of celestial cues in the AOTu

Monitoring changes of paramagnetically-shifted 31P signals in phospholipid vesicles

Phospholipid vesicles are commonly used as biomimetics in the investigation of the interaction of various species with cell membranes. In this paper we present a 31P NMR investigation of a simple vesicle system using a paramagnetic shift reagent to probe the inner and outer layers of the lipid bilayer. Time-dependent changes in the 31P NMR signal are observed, which differ whether the paramagnetic species is inside or outside the vesicle, and on the choice of buffer solution used. An interpretation of these results is given in terms of the interaction of the paramagnetic shift reagent with the lipids

Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

The morphology of human rod ERGs obtained by silent substitution stimulation

YesPurpose To record transient ERGs from the lightadapted human retina using silent substitution stimuli which selectively reflect the activity of rod photoreceptors. We aim to describe the morphology of these waveforms and examine how they are affected by the use of less selective stimuli and by retinal pathology. Methods Rod-isolating stimuli with square-wave temporal profiles (250/250 ms onset/offset) were presented using a 4 primary LED ganzfeld stimulator. Experiment 1: ERGs were recorded using a rodisolating stimulus (63 ph Td, rod contrast, Crod = 0.25) from a group (n = 20) of normal trichromatic observers. Experiment 2: Rod ERGs were recorded from a group (n = 5) using a rodisolating stimulus (Crod = 0.25) which varied in retinal illuminance from 40 to 10,000 ph Td. Experiment 3: ERGs were elicited using 2 kinds of nonisolating stimuli; (1) broadband and (2) rod-isolating stimuli which contained varying degrees of L- and M-cone excitation. Experiment 4: Rod ERGs were recorded from two patient groups with rod monochromacy (n = 3) and CSNB (type 1; n = 2). Results The rod-isolated ERGs elicited from normal subjects had a waveform with a positive onset component followed by a negative offset. Response amplitude was maximal at retinal illuminances\100 ph Td and was virtually abolished at 400 ph Td. The use of non-selective stimuli altered the ERG waveform eliciting more photopic-like ERG responses. Rod ERGs recorded from rod monochromats had similar features to those recorded from normal trichromats, in contrast to those recorded from participants with CSNB which had an electronegative appearance. Conclusions Our results demonstrate that ERGs elicited by silent substitution stimuli can selectively reflect the operation of rod photoreceptors in the normal, light-adapted human retina.Deutsche Forschungsgemeinschaft (DFG) (KR1317/13-1) and Bundesministerium für Bildung und Forschung (BMBF) (01DN14009) provided financial support for JK

Life expectancy and disease burden in the Nordic countries : results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017

Background The Nordic countries have commonalities in gender equality, economy, welfare, and health care, but differ in culture and lifestyle, which might create country-wise health differences. This study compared life expectancy, disease burden, and risk factors in the Nordic region. Methods Life expectancy in years and age-standardised rates of overall, cause-specific, and risk factor-specific estimates of disability-adjusted life-years (DALYs) were analysed in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Data were extracted for Denmark, Finland, Iceland, Norway, and Sweden (ie, the Nordic countries), and Greenland, an autonomous area of Denmark. Estimates were compared with global, high-income region, and Nordic regional estimates, including Greenland. Findings All Nordic countries exceeded the global life expectancy; in 2017, the highest life expectancy was in Iceland among females (85.9 years [95% uncertainty interval [UI] 85.5-86.4] vs 75.6 years [75.3-75.9] globally) and Sweden among males (80.8 years [80.2-81.4] vs 70.5 years [70.1-70.8] globally). Females (82.7 years [81.9-83.4]) and males (78.8 years [78.1-79.5]) in Denmark and males in Finland (78.6 years [77.8-79.2]) had lower life expectancy than in the other Nordic countries. The lowest life expectancy in the Nordic region was in Greenland (females 77.2 years [76.2-78.0], males 70.8 years [70.3-71.4]). Overall disease burden was lower in the Nordic countries than globally, with the lowest age-standardised DALY rates among Swedish males (18 555.7 DALYs [95% UI 15 968.6-21 426.8] per 100 000 population vs 35 834.3 DALYs [33 218.2-38 740.7] globally) and Icelandic females (16 074.1 DALYs [13 216.4-19 240.8] vs 29 934.6 DALYs [26 981.9-33 211.2] globally). Greenland had substantially higher DALY rates (26 666.6 DALYs [23 478.4-30 218.8] among females, 33 101.3 DALYs [30 182.3-36 218.6] among males) than the Nordic countries. Country variation was primarily due to differences in causes that largely contributed to DALYs through mortality, such as ischaemic heart disease. These causes dominated male disease burden, whereas non-fatal causes such as low back pain were important for female disease burden. Smoking and metabolic risk factors were high-ranking risk factors across all countries. DALYs attributable to alcohol use and smoking were particularly high among the Danes, as was alcohol use among Finnish males. Interpretation Risk factor differences might drive differences in life expectancy and disease burden that merit attention also in high-income settings such as the Nordic countries. Special attention should be given to the high disease burden in Greenland. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.Peer reviewe