Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Isoform prefiltering improves performance of count-based methods for analysis of differential transcript usage.

BACKGROUND: RNA-seq has been a boon to the quantitative analysis of transcriptomes. A notable application is the detection of changes in transcript usage between experimental conditions. For example, discovery of pathological alternative splicing may allow the development of new treatments or better management of patients. From an analysis perspective, there are several ways to approach RNA-seq data to unravel differential transcript usage, such as annotation-based exon-level counting, differential analysis of the percentage spliced in, or quantitative analysis of assembled transcripts. The goal of this research is to compare and contrast current state-of-the-art methods, and to suggest improvements to commonly used work flows. RESULTS: We assess the performance of representative work flows using synthetic data and explore the effect of using non-standard counting bin definitions as input to DEXSeq, a state-of-the-art inference engine. Although the canonical counting provided the best results overall, several non-canonical approaches were as good or better in specific aspects and most counting approaches outperformed the evaluated event- and assembly-based methods. We show that an incomplete annotation catalog can have a detrimental effect on the ability to detect differential transcript usage in transcriptomes with few isoforms per gene and that isoform-level prefiltering can considerably improve false discovery rate control. CONCLUSION: Count-based methods generally perform well in the detection of differential transcript usage. Controlling the false discovery rate at the imposed threshold is difficult, particularly in complex organisms, but can be improved by prefiltering the annotation catalog

Health and lifespan of Swiss men born in an alpine region in 1905–1907

This is the final version. Available on open access from Routledge via the DOI in this recordBody height and body mass index (BMI) are associated with later life outcomes in present and historical populations. We examine the case study of the Swiss Alpine canton of Glarus, which was highly industrialised at the beginning of the 20th century. Our study links conscription registers to genealogical registers at the individual level in Switzerland for the first time. We analyse whether body height, BMI, socioeconomic position (HISCLASS), region of residence, fitness to serve (as a proxy for health status in a military context), and goitre status (as a proxy for iodine deficiency) in young adulthood are associated with lifespan. We transcribed conscription records of 1073 men born between 1905 and 1907 and recruited between 1925 and 1927 (coverage birth cohorts 96%). Of the 827 young men residing within the canton, we were able to identify 635 (76.8%) in the cantonal genealogical register. Using body height, chest circumference, and upper arm circumference, we estimated BMI. We find socioeconomic differences for height and estimated BMI at conscription age. Young men with a recorded goitre were taller. We also present a positive association between body height and lifespan, with small men being particularly disadvantaged. In a small subsample of two municipalities, we estimated the heritability of height to be 65%.Mäxi Foundation ZürichSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschun

Verkaufen, kaufen und konsumieren – Eine Synthesestudie zu den Ernährungsunterschieden in den verschiedenen Gross- und Sprachregionen der Schweiz.

Bisherige Untersuchungen zu regionalen Ernährungsunterschieden in der Schweiz haben einzelne Datensätze ausgewertet, die vor allem die Konsum-Perspektive beispielsweise nach Sprachregionen berücksichtigt haben. Hingegen wurden bis anhin Daten über Lebensmittelverkäufe und Haushaltseinkäufe in den Analysen nicht berücksichtigt. Im vorliegenden Projekt wurden verschiedene schweizweite Datensätze zur Ernährung auf der Ebene der 7 administrativen Grossregionen (Mittelland, Genferseeregion, Nordwestschweiz, Ostschweiz, Tessin, Zentralschweiz und Zürich) verglichen. Zusätzlich wurden Datensätze zum Verkauf und Einkauf miteinbezogen. Wir analysierten 8 verschiedene Datensätze (6 Konsum, 1 Einkauf, 1 Verkauf). Die regionalen Unterschiede decken sich gut bei einigen Lebensmittelgruppen, besonders für Fisch und Milchprodukte. Es wird deutlich, dass in der Genferseeregion, der französischsprechenden Region des Mittellandes und im Tessin mehr Fisch gekauft, verkauft und konsumiert wird als in den Regionen der Deutschschweiz, wohingegen in der Deutschschweiz mehr Milchprodukte verkauft, eingekauft und konsumiert werden. Unterschiede zwischen Verkauf, Einkauf und Konsum sind für Früchte/Nüsse, Gemüse und Fleisch ersichtlich. Ebenso konnte gezeigt werden, dass die Sprachregionen und somit die kulturellen Unterschiede den grösseren Einfluss auf die Ernährung haben als die Grossregionen. Besonders gut ersichtlich ist dies beim Mittelland, wo wir die deutsch- und die französischsprechende Region separat ausgewertet haben und erhebliche Unterschiede zeigen konnten