Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4(+) T cells

Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33(+)S100A9(+) cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17–producing CD4(+) T cells. This chemokine was released by activated IMCs. Elimination of CD4(+) T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4(+) T cells

Household, community, sub-national and country-level predictors of primary cooking fuel switching in nine countries from the PURE study

Introduction. Switchingfrom polluting (e.g. wood, crop waste, coal)to clean (e.g. gas, electricity) cooking fuels can reduce household air pollution exposures and climate-forcing emissions.While studies have evaluated specific interventions and assessed fuel-switching in repeated cross-sectional surveys, the role of different multilevel factors in household fuel switching, outside of interventions and across diverse community settings, is not well understood. Methods.We examined longitudinal survey data from 24 172 households in 177 rural communities across nine countries within the Prospective Urban and Rural Epidemiology study.We assessed household-level primary cooking fuel switching during a median of 10 years offollow up (∼2005–2015).We used hierarchical logistic regression models to examine the relative importance of household, community, sub-national and national-level factors contributing to primary fuel switching. Results. One-half of study households(12 369)reported changing their primary cookingfuels between baseline andfollow up surveys. Of these, 61% (7582) switchedfrom polluting (wood, dung, agricultural waste, charcoal, coal, kerosene)to clean (gas, electricity)fuels, 26% (3109)switched between different polluting fuels, 10% (1164)switched from clean to polluting fuels and 3% (522)switched between different clean fuels

Single nucleotide polymorphisms of ADRB2 gene and their association with susceptibility for Plasmodium falciparum malaria and asthma in an Indian population

The essential route to blood parasitaemia in malaria, erythrocyte invasion is facilitated by activation of the G-protein coupled receptor signaling pathway mediated by the ß2-adrenoreceptor as one of the proteins on the surface of red blood cells. The effectiveness of bronchodilators and inhaled corticosteroids in the clinical treatment for asthma patients also depend on polymorphisms in the ß2-adrenoreceptor gene (ADRB2). In a case control study, individuals affected by Plasmodium falciparum malaria, asthma and controls were tested for association of six ADRB2 single nucleotide polymorphisms (SNPs) viz. rs1042711, rs1801704, rs1042713, rs1042714, rs1042717 and rs1042718, by direct DNA sequencing. The rs1801704 locus was significantly associated with malaria when compared against controls. The rs1042713 polymorphism was associated with forced expiratory flow between 25% and 75% of the FVC in asthma patients, pre (p = 0.048) and post (p = 0.038) treatment measurements. Predicted haplotype of the six SNPs computed from genotype data showed T-T-A-C-G-C conferred significant risk of malaria (p = 0.02) whereas T-T-A-C-G-A was associated with risk of asthma (p = 0.02). The haplotype T-T-G-C-G-C was protective against both malaria (p = 0.02) as well as asthma (p = 0.026) and C-C-G-G-G-C was protective uniquely for asthma (p = 0.04). A significant outcome was that all variant alleles at the SNP loci were part of the haplotype conferring resistance to malaria disease and asthma, except rs1042713 and rs1042718 which showed very high frequency in asthma. The pairwise linkage disequilibrium (LD) estimates showed a distinct LD block of all SNP loci (D' = 1 or >0.8) in malaria patients. This characteristic haplotype block was disrupted in the controls due to non-significant pairwise LD of the SNP loci; and a more extensive disruption of the block was noted in asthma patients. The study provides evidence for the proposed role of ß2-adrenoreceptor mediated molecular mechanisms in etiology of malaria, as well as asthma disease and drug response, for further clinical and therapeutic application studies

Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data

Background: Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. Methods: We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level. Findings: The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle-income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2·23, 95% CI 1·59–3·12); p<0·0001), combination therapy (1·53, 1·13–2·07; p=0·054), and have their blood pressure controlled (2·06, 1·69–2·50; p<0·0001) than were those in communities where blood pressure-lowering medicines were not available. Participants with known hypertension from households able to afford four blood pressure-lowering drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted OR 1·42, 95% CI 1·25–1·62; p<0·0001), combination therapy (1·26, 1·08–1·47; p=0·0038), and have their blood pressure controlled (1·13, 1·00–1·28; p=0·0562) than were those unable to afford the medicines. Interpretation: A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure-lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries. Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries