Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections.

BACKGROUND: Monitoring resistance phenotypes for Plasmodium falciparum, using in vitro growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins. METHODS: Plasmodium falciparum isolates cultured from 28 returning travellers diagnosed with malaria were assessed for sensitivity to artemisinin, artemether, dihydroartemisinin and artesunate and findings related to mutations in pfatp6 and pfmdr1. RESULTS: Resistance to artemether in vitro was significantly associated with a pfatp6 haplotype encoding two amino acid substitutions (pfatp6 A623E and S769N; (mean IC50 (95% CI) values of 8.2 (5.7 - 10.7) for A623/S769 versus 623E/769 N 13.5 (9.8 - 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of pfmdr1 was not itself associated with increased IC50 values for artemether, but when interactions between the pfatp6 haplotype and increased copy number of pfmdr1 were examined together, a highly significant association was noted with IC50 values for artemether (mean IC50 (95% CI) values of 8.7 (5.9 - 11.6) versus 16.3 (10.7 - 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in pfmdr1 are also associated with differences in sensitivity to some artemisinins. CONCLUSIONS: These findings were further explored in molecular modelling experiments that suggest mutations in pfatp6 are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in pfmdr1. Implications for a hypothesis that artemisinin resistance may be exacerbated by interactions between PfATP6 and PfMDR1 and for epidemiological studies to monitor emerging resistance are discussed

Loess in Cornwall

RESP-864

Tobacco smoking, alcohol drinking and Hodgkin's lymphoma: a European multi-centre case–control study (EPILYMPH)

We analysed the effects of tobacco and alcohol in the aetiology of Hodgkin's lymphoma (HL), based on 340 cases and 2465 controls enrolled in Spain, France, Italy, Germany, Ireland and Czech Republic, between 1998 and 2004. Current smokers showed a significantly increased odds ratio (OR) of HL of 1.39 (95% confidence interval (CI)=1.04–1.87). Analyses were also conducted separately for subjects younger than 35 years (179 cases) and for older subjects (161 cases). For subjects below age 35, no association was observed between tobacco and HL, whereas for older subjects, ever-smokers experienced a doubled risk of HL as compared to never smokers and the OR of HL for current smoking was 2.35 (95% CI=1.52–3.61), with suggestion of a dose–response relationship. A protective effect of alcohol was observed in both age groups. The OR for ever-regular drinking was 0.58 (95% CI=0.38–0.89) for younger subjects and 0.50 (95% CI=0.34–0.74) for older subjects. There was no evidence of interaction between tobacco and alcohol. Our results are consistent with previous studies, suggesting a protective effect of alcohol on HL. An effect of tobacco was suggested for HL occurring in middle and late age, although this finding might have occurred by chance

Child Health Care in Ireland

The Irish health care system is based on a complex and costly mix of private, statutory, and voluntary provisions. The majority of health care expenditure comes from the state, with a significant proportion of acute hospital care funded from private insurance, but there are relatively high out-of-pocket costs for most service users. There is free access to acute hospital care, but not for primary care, for all children. About 40% of the population have free access to primary care. Universal preventive public health services, including vaccination and immunization, newborn blood spot screening, and universal neonatal hearing screening are free. Major health challenges include poverty, obesity, drug and alcohol use, and mental health. The health care system has been dominated for the last 5 years by the impact of the current recession, which has led to very sharp cuts in health care expenditure. It is unclear if the necessary substantial reform of the system will happen. Government policy calls for a move toward a patient-centered, primary care-led system, but without very substantial transfers of resources and investment in Information and Communication Technology, this is unlikely to occur

Occupational exposure to ionizing radiation and risk of lymphoma subtypes: Results of the Epilymph European case-control study

Background: Evidence linking risk of lymphoma and B-cell lymphoma subtypes to ionizing radiation is inconclusive, particularly at low exposure levels. Methods: We investigated risk of lymphoma (all subtypes), B-cell lymphomas, and its major subtypes, associated with low-level occupational exposure to ionizing radiation, in 2346 lymphoma cases and 2463 controls, who participated in the multicenter EpiLymph case-control study. We developed a job-exposure matrix to estimate exposure to ionizing radiation, distinguishing between internal and external radiation, and we applied it to the lifetime occupational history of study subjects, We calculated the Odds Ratio (OR) and its 95% confidence interval (95% CI) for lymphoma (all subtypes combined), B-cell lymphoma, and its major subtypes using unconditional, polytomous logistic regression adjusting for age, gender, and education. Results: We did not observe an association between exposure metrics of external and internal radiation and risk of lymphoma (all subtypes), nor with B-cell lymphoma, or its major subtypes, at the levels regularly experienced in occupational settings. An elevated risk of diffuse large B cell lymphoma was observed among the most likely exposed study subjects with relatively higher exposure intensity, which would be worth further investigation. Conclusions: Further investigation is warranted on risk of B cell lymphoma subtypes associated with low-level occupational exposure to external ionizing radiation, and to clarify whether lymphoma should be included among the cancer outcomes related to ionizing radiation

All-electronic frequency stabilization of a DFB laser diode

A laser diode’s junction voltage is a sensitive measure of its temperature and can be used in a thermal control feedback loop. To compensate for the temperature dependence of the laser’s internal resistance, we have measured the dynamic resistance, ∂V/∂I, by modulating the injection current and measuring the demodulated voltage. The junction voltage was thus controlled while operating at fixed DC injection current. Over an external temperature range of 15°C to 35°C, this stabilised the centre frequency (wavelength) of a 1651 nm DFB laser diode with a residual mean frequency shift of 60 MHz (0.5pm), less than the uncertainty on the centre frequency of 80 MHz (0.7 pm). Under the same conditions, conventional thermistor control gave a systematic wavelength shift of −8.4 GHz (−76 pm), and control of the uncompensated forward voltage gave a shift of 9.9 GHz (90 pm)

Gramene 2013: comparative plant genomics resources

Gramene (http://www.gramene.org) is a curated online resource for comparative functional genomics in crops and model plant species, currently hosting 27 fully and 10 partially sequenced reference genomes in its build number 38. Its strength derives from the application of a phylogenetic framework for genome comparison and the use of ontologies to integrate structural and functional annotation data. Whole-genome alignments complemented by phylogenetic gene family trees help infer syntenic and orthologous relationships. Genetic variation data, sequences and genome mappings available for 10 species, including Arabidopsis, rice and maize, help infer putative variant effects on genes and transcripts. The pathways section also hosts 10 species-specific metabolic pathways databases developed in-house or by our collaborators using Pathway Tools software, which facilitates searches for pathway, reaction and metabolite annotations, and allows analyses of user-defined expression datasets. Recently, we released a Plant Reactome portal featuring 133 curated rice pathways. This portal will be expanded for Arabidopsis, maize and other plant species. We continue to provide genetic and QTL maps and marker datasets developed by crop researchers. The project provides a unique community platform to support scientific research in plant genomics including studies in evolution, genetics, plant breeding, molecular biology, biochemistry and systems biology

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways