Differential binding patterns of anti-sulfatide antibodies to glial membranes

Sulfatide is a major glycosphingolipid in myelin and a target for autoantibodies in autoimmune neuropathies. However neuropathy disease models have not been widely established, in part because currently available monoclonal antibodies to sulfatide may not represent the diversity of anti-sulfatide antibody binding patterns found in neuropathy patients. We sought to address this issue by generating and characterising a panel of new anti-sulfatide monoclonal antibodies. These antibodies have sulfatide reactivity distinct from existing antibodies in assays and in binding to peripheral nerve tissues and can be used to provide insights into the pathophysiological roles of anti-sulfatide antibodies in demyelinating neuropathies

Survival of, and competition between, oligodendrocytes expressing different alleles of the Plp gene

Mutations in the X-linked Plp gene lead to dysmyelinating phenotypes and oligodendrocyte cell death. Here, we exploit the X inactivation phenomenon to show that a hierarchy exists in the influence of different mutant Plp alleles on oligodendrocyte survival. We used compound heterozygote mice to study the long-term fate of oligodendrocytes expressing either the jimpy or rumpshaker allele against a background of cells expressing a Plp-null allele. Although mutant and null oligodendrocytes were generated in equal numbers, the proportion expressing the mutant allele subsequently declined, but whereas those expressing the rumpshaker allele formed a reduced but stable population, the number of jimpy cells fell progressively. The age of decline in the jimpy cells in different regions of the CNS correlated with the temporal sequence of myelination. In compound heterozygotes expressing rumpshaker and jimpy alleles, oligodendrocytes expressing the former predominated and were more abundant than when the rumpshaker and null alleles were in competition. Thus, oligodendrocyte survival is not determined solely by cell intrinsic factors, such as the conformation of the misfolded PLP, but is influenced by neighboring cells, possibly competing for cell survival factors

Patient and provider perceptions of a peer-delivered intervention ('Khanya') to improve anti-retroviral adherence and substance use in South Africa: a mixed methods analysis

BACKGROUND: Despite a high prevalence of problematic substance use among people living with HIV in South Africa, there remains limited access to substance use services within the HIV care system. To address this gap, our team previously developed and adapted a six-session, peer-delivered problem-solving and behavioral activation-based intervention (Khanya) to improve HIV medication adherence and reduce substance use in Cape Town. This study evaluated patient and provider perspectives on the intervention to inform implementation and future adaptation. METHODS: Following intervention completion, we conducted semi-structured individual interviews with patients (n = 23) and providers (n = 9) to understand perspectives on the feasibility, acceptability, and appropriateness of Khanya and its implementation by a peer. Patients also quantitatively ranked the usefulness of individual intervention components (problem solving for medication adherence 'Life-Steps', behavioral activation, mindfulness training, and relapse prevention) at post-treatment and six months follow-up, which we triangulated with qualitative feedback to examine convergence and divergence across methods. RESULTS: Patients and providers reported high overall acceptability, feasibility, and appropriateness of Khanya, although there were several feasibility challenges. Mindfulness and Life-Steps were identified as particularly acceptable, feasible, and appropriate components by patients across methods, whereas relapse prevention strategies were less salient. Behavioral activation results were less consistent across methods. CONCLUSIONS: Findings underscore the importance of examining patients' perspectives on specific intervention components within intervention packages. While mindfulness training and peer delivery models were positively perceived by consumers, they are rarely used within task-shared behavioral interventions in low- and middle-income countries

The flux of anthropogenic trace metals into the arctic from the mid-latitudes in 1979/80

The flux of trace metals into the Arctic atmosphere between 0 and 3.5 km altitude for the period July 1979-June 1980 was determined using a chemical transport modeling approach used previously for sulfur. The total annual flux of antimony, arsenic, cadmium, lead, zinc and vanadium into the Arctic from Eurasia was 4, 285, 47, 2400, 1350 and 474 tonnes, respectively. This represents 3.4, 6.0, 4.2, 3.0, 3.1 and 1.7% of the source emissions, respectively. In contrast, the corresponding flux of sulfur was 2.2 million tonnes or 6.7% of the total emissions. The following percentage contributions to the total flux, of all six metals, by the source regions were calculated: western Europe (7-34%), eastern Europe (42-54%) and the Soviet Union (21/2/2-39%). The model also showed that in addition to a late winter (February, March) maximum input to the Arctic, a peak was also observed in October. This peak was shown to have resulted from an unusual set of synoptic conditions, which produced a strong northerly flow into the Arctic around 0 longitude in October 1979. Comparison of the model-predicted trace metal concentrations with a set of limited observations at existing sampling stations close to the Arctic Circle (namely Ny Alesund in Spitsbergen, Jergul, Skrova and Jan Mayen) showed agreement within a factor of 2-3.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31953/1/0000906.pd

Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer

INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P 7.5 × 10(9)/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings

Source apportionment of circum-Arctic atmospheric black carbon from isotopes and modeling

Black carbon (BC) contributes to Arctic climate warming, yet source attributions are inaccurate due to lacking observational constraints and uncertainties in emission inventories. Year-round, isotope-constrained observations reveal strong seasonal variations in BC sources with a consistent and synchronous pattern at all Arctic sites. These sources were dominated by emissions from fossil fuel combustion in the winter and by biomass burning in the summer. The annual mean source of BC to the circum-Arctic was 39 ± 10% from biomass burning. Comparison of transport-model predictions with the observations showed good agreement for BC concentrations, with larger discrepancies for (fossil/biomass burning) sources. The accuracy of simulated BC concentration, but not of origin, points to misallocations of emissions in the emission inventories. The consistency in seasonal source contributions of BC throughout the Arctic provides strong justification for targeted emission reductions to limit the impact of BC on climate warming in the Arctic and beyond