CTLA4CT60 gene polymorphism is not associated with differential susceptibility to pemphigus foliaceus

Pemphigus foliaceus is an organ-specific autoimmune disease characterized by autoantibodies against the extracellular region of desmoglein 1, a protein that mediates intercellular adhesion in desmosomes. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key negative regulator of the T cell immune response, playing an important role in T cell homeostasis and maintenance of peripheral tolerance. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases and the functional CT60 single nucleotide polymorphism (rs3087243, also named 6230G > A) has been proposed to be a casual variant in several of these diseases. The aim of this study was to ascertain whether this polymorphism is associated with inter-individual variation in susceptibility to pemphigus foliaceus. The population sample in this case-control association study comprised 248 patient and 367 controls. We did not found a significant association of pemphigus foliaceus with the CT60 variants. We conclude that the CTLA4CT60 polymorphism is not an important factor for pemphigus foliaceus pathogenesis in the population analyzed

Correction: Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy

An affiliation for the last author is missing. Vincent C. Emery is also affiliated with Department of Microbial and Cellular Sciences, University of Surrey, Guildford, Surrey, United Kingdom

Cytomegalovirus viral load parameters associated with earlier initiation of pre-emptive therapy after solid organ transplantation

BACKGROUND: Human cytomegalovirus (HCMV) can be managed by monitoring HCMV DNA in the blood and giving valganciclovir when viral load exceeds a defined value. We hypothesised that such pre-emptive therapy should occur earlier than the standard 3000 genomes/ml (2520 IU/ml) when a seropositive donor transmitted virus to a seronegative recipient (D+R-) following solid organ transplantation (SOT). METHODS: Our local protocol was changed so that D+R- SOT patients commenced valganciclovir once the viral load exceeded 200 genomes/ml; 168 IU/ml (new protocol). The decision point remained at 3000 genomes/ml (old protocol) for the other two patient subgroups (D+R+, D-R+). Virological outcomes were assessed three years later, when 74 D+R- patients treated under the old protocol could be compared with 67 treated afterwards. The primary outcomes were changes in peak viral load, duration of viraemia and duration of treatment in the D+R- group. The secondary outcome was the proportion of D+R- patients who developed subsequent viraemia episodes. FINDINGS: In the D+R- patients, the median values of peak viral load (30,774 to 11,135 genomes/ml, p<0.0215) were significantly reduced on the new protocol compared to the old, but the duration of viraemia and duration of treatment were not. Early treatment increased subsequent episodes of viraemia from 33/58 (57%) to 36/49 (73%) of patients (p< 0.0743) with a significant increase (p = 0.0072) in those episodes that required treatment (16/58; 27% versus 26/49; 53%). Median peak viral load increased significantly (2,103 to 3,934 genomes/ml, p<0.0249) in the D+R+ but not in the D-R+ patient subgroups. There was no change in duration of viraemia or duration of treatment for any patient subgroup. INTERPRETATION: Pre-emptive therapy initiated at the first sign of viraemia post-transplant significantly reduced the peak viral load but increased later episodes of viraemia, consistent with the hypothesis of reduced antigenic stimulation of the immune system

Homocitrullination of lysine residues mediated by myeloid derived suppressor cells in the tumour environment is a target for cancer immunotherapy

Background: Homocitrullination is the post translational modification of lysine that is recognized by T cells. Methods: This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and Bip and used HLA transgenic mice to assess immunogenicity by ELISpot assay. Vaccine efficacy was assessed in tumour therapy studies using HLA matched B16 melanoma expressing constitutive or IFNγ inducible MHC-II as represented by most human tumours. To determine the mechanism behind the therapy, immune cell infiltrates were analysed using flow cytometry and therapy studies in the presence of MPO inhibitor and T cell depletion performed. We assessed the T cell repertoire to homocitrullinated peptides in cancer patients and healthy donors using flow cytometry. Results: Homocitrulline peptide vaccination stimulated strong CD4 T cell responses and induced significant anti-tumour therapy in an established tumour model. The anti-tumour response was dependent upon CD4 T-cells and the effect was driven mainly via direct tumour recognition, as responses were only observed if the tumours were induced to express MHC-II. In vitro proliferation assays show that healthy donors and cancer patients have an oligoclonal CD4 T-cell repertoire recognizing homocitrullinated peptides. Inhibition of cyanate generation, which mediates homocitrullination, by myeloperoxidase (MPO) inhibition reduced tumour therapy by the vaccine induced T cells (P=0.0018). Analysis of the tumour microenvironment (TME) suggested that myeloid-derived suppressor cells (MDSCs) were a potential source of MPO. The selected B16 melanoma model showed MDSC infiltration. and was appropriate to see if the homocitrulline vaccine could overcome the immunosuppression associated with MDSCs. The vaccine was very effective (90% survival) as the induced CD4 T cells directly targeted the homocitrullinated tumour and likely reversed the immunosuppressive environment. Conclusion: We propose that MPO, potentially produced by MDSCs, catalyses the build-up of cyanate in the TME which diffuses into tumour cells causing homocitrullination of cytoplasmic proteins which are degraded and, in the presence of IFNγ, presented by MHC-II for direct CD4 T-cell recognition. Homocitrullinated proteins are a new target for cancer vaccines and may be particularly effective against tumours containing high levels of MPO expressing MDSCs

Hypoglycaemia in severe malaria, clinical associations and relationship to quinine dosage

<p>Abstract</p> <p>Background</p> <p>Hypoglycaemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine. In 2006 our hospital changed quinine treatment policy from 15 mg/kg loading (plus 10 mg/kg 12-hourly) to 20 mg/kg loading (plus 10 mg/kg 8-hourly) to comply with new WHO guidelines. This presented us with the opportunity to examine whether there was any dose relationship of quinine and hypoglycaemia occurrence.</p> <p>Methods</p> <p>Retrospective case notes review of all children admitted to hospital with severe falciparum malaria between April 2002 - July 2009, before and after the introduction of the new WHO quinine regimen. Four-hourly bedside glucose levels were measured until intravenous quinine was discontinued. Clinical events immediately preceding or concurrent with each episode of hypoglycaemia (glucose < = 3.0 mmol/l) were recorded.</p> <p>Results</p> <p>954 children received the old quinine regime and 283 received the new regime. We found no evidence of an increased prevalence of hypoglycaemia (< = 3.0 mmol/L) on the new regime compared to former (15% vs. 15%); similar findings were noted for profound hypoglycaemia (< 2.2 mmols/L) 8% v 5%, P = 0.07. Episodes were co-incident with disease severity markers: coma (57%), circulatory failure (38%) and respiratory distress (21%) but less commonly with seizures (10%). Disruption of maintenance fluids and/or blood transfusion concurred with 42% of the hypoglycaemia episodes. Post admission hypoglycaemia increased odds of fatal outcome (24%) compared to euglycaemic counterparts (8%), odds ratio = 3.45 (95% confidence interval = 2.30-5.16) P < 0.01.</p> <p>Conclusion</p> <p>There was no evidence to indicate a dose relationship between quinine and occurrence of hypoglycaemia. Hypoglycaemia concurred with severity features, disruption of glucose infusion and transfusion. Careful glucose monitoring should be targeted to these complications where resources are limited.</p

The effects on performance, combustion and emission characteristics of DICI engine fuelled with TiO2 nanoparticles addition in diesel/biodiesel/n-butanol blends

In this study, waste cooking oil biodiesel was mixed with titanium dioxide (TiO2), a metal-based nano particle, and n-butanol (C4H9OH) along with euro diesel to examine their effects on diesel engines. Various ratio of fuel blends were prepared with TiO2 nano particles-diesel-biodiesel and n-butanol. The tests fuels were euro diesel (D100), biodiesel (B100), B20, B20 + TiO2, B20But10 and B20But10 + TiO2, respectively. Thermo-physical properties such as density, pour point, cloud point, cold filter clogging point, flash point and kinematic viscosity of all test fuels were determined followed by investigating engine performance parameters such as torque, power, fuel consumption and etc. Combustion analysis was also investigated. In addition, the effects on emissions such as CO, CO2, HC, NO and smoke opacity were also carried out. The addition of n-butanol to the fuel blends substantially affected density, kinematic viscosity and cold flow properties, while the addition of TiO2 has not much effect on these properties. For all tested fuels, the maximum brake engine torque and power were recorded at approximately 1400 rpm and 2800 rpm, respectively. The addition of TiO2 increased the brake engine torque and power 10.20% and 9.74% and decreased the brake specific fuel consumption 27.73% and 28.37%, respectively compared to blends without TiO2 additive. TiO2 additive increases the maximum cylinder pressure and heat release rate, as a result improved the engine performance and combustion. The addition of n-butanol in the fuel blend increased the maximum cylinder pressure and heat release rate values in comparison to euro diesel. The results of exhaust emission showed a decrease in CO, HC and smoke opacity emissions, whereas increased CO2 and NO emission, except the use of n-butanol reduced the values of NO emission, in comparison to euro diesel and without TiO2 additive. The results show that biodiesel produced from waste cooking oil, n-butanol and TiO2 additive can be used in diesel engines at certain proportion and that the additive materials improve the combustion characteristics, engine performance and exhaust gas emission. © 2018 Elsevier Lt

Prediction and performance optimisation of a DI CI engine fuelled diesel–Bael biodiesel blends with DMC additive using RSM and ANN: Energy and exergy analysis

Synthesis of biofuel from bioresources represents one of the greatest propitious options for achieving a cleaner production of energy and the global circular bio-economy. The superior cetane rating of biodiesel makes it a fitting fuel for CI diesel engines. The present study aims to valorise Bael seeds for biodiesel production. Bael is a species of tree indigenous to India. The diesel–Bael biodiesel was blended with dimethyl carbonate (DMC) as an ignition enhancer and investigated in a selected diesel engine. This work reports that the Bael biodiesel blend gets a tolerable level of BTE against neat fossil diesel. An utmost BTE of 30.68% was achieved with B15DMC5 which is very close to diesel (31.8%) at peak load. Certainly, BSFC was suppressed and emissions lessened by DMC inclusion. For instance, the CO and HC emissions substantially reduced to a minimum of 0.19% and 179 ppm with the B17.5DMC2.5 blend at peak load. NOx emission is directly proportional to Bael biodiesel concentration, Notably, NOx emission is well controlled at 50% and 75% load even though with the increasing biodiesel concentration in the blend. Though, control of emissions at peak load is still a crucial issue. Nevertheless, the DMC additives controlled the NOx emission at peak load. B15DMC5 blend exhibits progress in combustion through the optimized value of HRR, CGP, and CGT against B20. The presence of NOx and smoke opacity without additives is suppressed up to 7% and 10% with additives. Availability (exergy) and exergy efficiency at different loads of both neat diesel and blended fuels, mainly shaft, cooling water, and exhaust availability were calculated. The results of the study illustrated that the input availability increased at peak loads, as well as gross work output, was maximum at peak load due to higher fuel exergy present in the combustion chamber. A maximum exergy efficiency of 68% was recorded by B15DMC5 at peak load. Finally, the process optimization by RSM has been validated by experimental results and further authenticated with ANN. The results of the RSM model promote it as statistically significant. Generate the regression equation for all output responses. The optimized operating parameters of engine load of 50%, 10% of biodiesel blend, and additive concentration of 3.59% achieved the most optimum output response. The results of the predicted optimized condition of BTE, BSFC, CO, HC, NOx, and Smoke opacity showed 24.051%, 0.441861 kg/kW hr, 0.2028%, 113.607 ppm, 316.099 ppm, and 14.4286% respectively. The R2 values from RSM and ANN DoE models were 0.992834 and 0.99984. This study concludes that a superior precision certainty from both RSM and ANN models is beneficial for engine overall performance estimation. This phenomenon provides a good sign to implement the ANN to forecast engine operational behavior in the future. The novel approach of process optimization by RSM and ANN for Bael biodiesel with DMC blended fuel operate DI CI engine supports the SDGs of the UN such as Good health and Well-being (SDG: 3), Affordable and Clean Energy (SDG: 7), Responsible Consumption and Production (SDG: 12), Climate Action (SDG: 13) and Life on Land (15)