Antiviral immunity and T-regulatory cell function are retained after selective alloreactive T-cell depletion in both the HLA-identical and HLA-mismatched settings

AbstractNonselective T-cell depletion reduces the incidence of severe graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, but the cost is delayed and disordered antigen-specific immune reconstitution and increased infection. We use a method of selective depletion of alloreactive T cells expressing the activation marker CD69 after coculture with stimulator cells in a modified or standard mixed lymphocyte reaction. The technique has been shown to reduce alloreactivity while retaining third-party responses in vitro and, in a mismatched murine model, led to donor T-cell engraftment with a virtual absence of graft-versus-host disease and increased survival. We show in a human HLA-mismatched and unrelated HLA-identical setting that this technique retains >80% of specific cellular antiviral activity by cytomegalovirus-tetramer analysis and cytomegalovirus/Epstein-Barr virus peptide-stimulated interferon-γ ELISpot assay. Furthermore, CD4+ CD25+ T-regulatory cells are not removed by this method of selective allodepletion and retain their function in suppressing allogeneic proliferative responses. Preservation of antiviral cytotoxic T lymphocytes in selectively allodepleted stem cell grafts would lead to improved antiviral immunity after transplantation. The retention of immunosuppressive CD4+ CD25+ T-regulatory cells could lead to more ordered immune reconstitution and further suppress alloreactive responses after transplantation

Bayes linear kinematics in the analysis of failure rates and failure time distributions

Collections of related Poisson or binomial counts arise, for example, from a number of different failures in similar machines or neighbouring time periods. A conventional Bayesian analysis requires a rather indirect prior specification and intensive numerical methods for posterior evaluations. An alternative approach using Bayes linear kinematics in which simple conjugate specifications for individual counts are linked through a Bayes linear belief structure is presented. Intensive numerical methods are not required. The use of transformations of the binomial and Poisson parameters is proposed. The approach is illustrated in two examples, one involving a Poisson count of failures, the other involving a binomial count in an analysis of failure times

Black Hole and Neutron Star Transients in Quiescence

We consider the X-ray luminosity difference between neutron star and black hole soft X-ray transients (NS and BH SXTs) in quiescence. The current observational data suggest that BH SXTs are significantly fainter than NS SXTs. The luminosities of quiescent BH SXTs are consistent with the predictions of binary evolution models for the mass transfer rate if (1) accretion occurs via an ADAF in these systems and (2) the accreting compact objects have event horizons. The luminosities of quiescent NS SXTs are not consistent with the predictions of ADAF models when combined with binary evolution models, unless most of the mass accreted in the ADAF is prevented from reaching the neutron star surface. We consider the possibility that mass accretion is reduced in quiescent NS SXTs because of an efficient propeller and develop a model of the propeller effect that accounts for the observed luminosities. We argue that modest winds from ADAFs are consistent with the observations while strong winds are probably not.Comment: LateX, 37 pages, 7 figures; Accepted for publication in The Astrophysical Journa

Nonlinear Instability in a Semiclassical Problem

We consider a nonlinear evolution problem with an asymptotic parameter and construct examples in which the linearized operator has spectrum uniformly bounded away from Re z >= 0 (that is, the problem is spectrally stable), yet the nonlinear evolution blows up in short times for arbitrarily small initial data. We interpret the results in terms of semiclassical pseudospectrum of the linearized operator: despite having the spectrum in Re z < -c < 0, the resolvent of the linearized operator grows very quickly in parts of the region Re z > 0. We also illustrate the results numerically

Irrigation and women’s diet in Ethiopia: A longitudinal study

Some agricultural practices, such as irrigation, have the potential to buffer seasonal dietary gaps and thus improve diets, particularly for subsistence farmers but also for rural and urban households that purchase irrigated produce from local markets. While the seasonality of households and children’s diets is well documented, little is known about the seasonality of women’s diets and the influence of irrigation. Using longitudinal data from Ethiopia, this study characterized women’s diet over time and evaluated the potential implications of seasonality and irrigation on women’s diet. Women’s dietary diversity was low (3-4 out of 10 food groups) and exhibited high seasonal variability (P<0.05). Diets were predominantly plant-based, with little consumption of nutrientdense foods, such as fruits and animal source foods. High seasonal variability in energy, protein, vitamin C, calcium, iron, and zinc intakes were observed (P<0.01). Irrigators were more likely to meet the minimum dietary diversity for women (MDDW), had higher energy and calcium intake, and lower prevalence of anemia, than women from non-irrigating households (P< 0.05). No cases of malaria were reported from the three rounds of screening. Our preliminary findings suggest that there is high seasonal variation in women’s diet, but this can be partly offset by irrigation practices

Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity

Glycosylated diazeniumdiolates of structure R2NN(O)dNO-R ′ (R ′ ) a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)dNO- ion. Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.4, and 3.8-4.6 as background for further developing both the protecting group application and the ability to target NO pharmacologically to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)dNO-GlcNAc (where R2N) diethylamino or pyrrolidin-l-yl and GlcNAc) N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity

Adiponectin levels in people with Latent Autoimmune Diabetes-a case control study

<p>Abstract</p> <p>Background</p> <p>To examine adiponectin levels in people with Latent Autoimmune Diabetes in Adults using a matched pair case control study.</p> <p>Findings</p> <p>Patients with LADA (n = 64), were matched for sex with type 2 diabetic and non-diabetic controls. A matched paired T-test was used to examine average adiponectin levels in the LADA patients' versus controls. The average adiponectin level for the LADA patients was 9.96 μg/ml compared to 6.4 μg/ml for Type 2 matched controls and 9.6 μg/ml for non-diabetic controls. Mean difference for the LADA-type 2 comparison was calculated after data was log transformed and showed a difference of 1.58 μg/ml (95%CI: 1.28-1.95, p = 0.0001). There was no significant difference between LADA and non-diabetic controls (p = 0.54).</p> <p>Conclusions</p> <p>Adiponectin levels are higher among people with LADA compared to those with type 2 diabetes and are equivalent to levels seen in non-diabetic controls. This suggests that risk of complications in LADA, as with type 1 diabetes may be related more to glycaemic control rather than to factors of the metabolic syndrome.</p

Calorie restriction activates new adult born olfactory‐bulb neurones in a ghrelin‐dependent manner but acyl‐ghrelin does not enhance subventricular zone neurogenesis

The ageing and degenerating brain show deficits in neural stem/progenitor cell (NSPC) plasticity that are accompanied by impairments in olfactory discrimination. Emerging evidence suggests that the gut hormone ghrelin plays an important role in protecting neurones, promoting synaptic plasticity and increasing hippocampal neurogenesis in the adult brain. In the present study, we investigated the role of ghrelin with respect to modulating adult subventricular zone (SVZ) NSPCs that give rise to new olfactory bulb (OB) neurones. We characterised the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHSR), using an immunohistochemical approach in GHSR‐eGFP reporter mice to show that GHSR is expressed in several regions, including the OB but not in the SVZ of the lateral ventricle. These data suggest that acyl‐ghrelin does not mediate a direct effect on NSPC in the SVZ. Consistent with these findings, treatment with acyl‐ghrelin or genetic silencing of GHSR did not alter NSPC proliferation within the SVZ. Similarly, using a bromodeoxyuridine pulse‐chase approach, we show that peripheral treatment of adult rats with acyl‐ghrelin did not increase the number of new adult‐born neurones in the granule cell layer of the OB. These data demonstrate that acyl‐ghrelin does not increase adult OB neurogenesis. Finally, we investigated whether elevating ghrelin indirectly, via calorie restriction (CR), regulated the activity of new adult‐born cells in the OB. Overnight CR induced c‐Fos expression in new adult‐born OB cells but not in developmentally born cells, whereas neuronal activity was absent following re‐feeding. These effects were not present in ghrelin−/− mice, suggesting that adult‐born cells are uniquely sensitive to changes in ghrelin mediated by fasting and re‐feeding. In summary, ghrelin does not promote neurogenesis in the SVZ and OB; however, new adult‐born OB cells are activated by CR in a ghrelin‐dependent manner

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival in Patients With Head and Neck Cancer

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen. METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 were included. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were calculated. Kaplan-Meier and multivariate analyses adjusting for age, sex, TNM staging, comorbidities, and treatment modalities were performed to assess the effect of BBs on survival outcomes. RESULTS: In patients with HNSCC (n = 682), BB use was associated with worse OS and DFS (OS: adjusted hazard ratio [aHR], 1.67; 95% CI, 1.06 to 2.62; CONCLUSION: The effect of BBs on cancer survival outcomes is heterogeneous and varies according to cancer type and immunotherapy status. In this study, BB intake was associated with worse DSS and DFS in patients with head and neck cancer not treated with immunotherapy, but not in patients with NSCLC or skin cancer

Revisiting the agro-climatic zones of Ghana: a re-classification in conformity with climate change and variability

The Ghana Meteorological Agency delineated Ghana’s geographical space into four agro-climatic zones namely the north, transition, forest and coastal zones. Since the demarcation in the 1960s, previous studies have rarely provided a more dis-aggregated agro-climatic zone map in tandem with contemporary climate change and variability. The continued use of this age-old classified zones is a disservice to the public. In this study, therefore, we evaluated the existing agro-climatic zone map of Ghana and reconstructed it to a more appropriate and dis-aggregated map that reflect current climate change and variability impact. This was achieved by quantifying the contrast in rainfall and temperature amount over a 30 year period for different climate windows and mapped out areas with similar rainfall and temperature regimes. Our findings revealed significant changes in the existing agro-climatic zones especially in terms of number, the boundary size and geographical orientation of the zones. The newly proposed map consist of five distinctive climate zones namely: the Sudan Savannah, Guinea Savannah, Transition, Forest and Coastal zones. The Sudan and Guinea Savannah zones showed a southerly expansion. The transition zone shriveled in size as the Guinea Savannah zone took over most of it, notably in the southeast. The forest zone shrank in size with a northwest shift while the coastal belt grew to encompass the whole coast of Ghana. These changes are strong evidence of climate change and possible food production changes. These findings are useful to agriculture sector in planning their activities, the health sector in predicting specific diseases caused by changes in weather and climate, Ghana Meteorological Agency for weather forecasting purposes, and the National Disaster Management in identifying disaster prone zones