A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Aspects of the biology of the Lake Tanganyika sardine, Limnothrissa miodon (Boulenger), in Lake Kariba

Juveniles of limnothrissa miodon (Boulenger) were introduced into the man-made Lake Kariba in 1967-1968. Thirty months of night-fishing for this species from Sinazongwe, near the centre of the Kariba North bank, from 1971 to 1974 are described. Biological studies were carried out on samples of the catch during most of these months. Limnological studies were carried out over a period of four months in 1973. Limnothrissa is breeding successfully and its number have greatly increased. It has reached an equilibrium level of population size at a lower density than that of Lake Tanganyika sardines, but nevertheless is an important factor in the ecology of Lake Kariba. The growth rate, size at maturity and maximum size are all less than those of Lake Tanganyika Limnothrissa. A marked disruption in the orderly progression of length frequency modes occurs in September, for which the present body of evidence cannot supply an explanation.

A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone

Purpose: We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of 186Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC).

Methods: Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of 186Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life.

Results: Thirty-eight patients with a median age of 67 years (range 50–77) and a median PSA of 57 ng/ml (range 4–3,628) received a median activity of 4,978 MBq 186Re-HEDP (range 4,770–5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18–24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66–90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15–49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months.

Conclusion: We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.

Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours

Background: Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure.

Asymmetries in Business Cycles

Esta disertación busca estudiar los mecanismos de transmisión que vinculan el comportamiento de agentes y firmas con las asimetrías presentes en los ciclos económicos. Para lograr esto, se construyeron tres modelos DSGE. El en primer capítulo, el supuesto de función cuadrática simétrica de ajuste de la inversión fue removido, y el modelo canónico RBC fue reformulado suponiendo que des-invertir es más costoso que invertir una unidad de capital físico. En el segundo capítulo, la contribución más importante de esta disertación es presentada: la construcción de una función de utilidad general que anida aversión a la pérdida, aversión al riesgo y formación de hábitos, por medio de una función de transición suave. La razón para hacerlo así es el hecho de que los individuos son aversos a la pérdidad en recesiones, y son aversos al riesgo en auges. En el tercer capítulo, las asimetrías en los ciclos económicos son analizadas junto con ajuste asimétrico en precios y salarios en un contexto neokeynesiano, con el fin de encontrar una explicación teórica de la bien documentada asimetría presente en la Curva de Phillips.

Glaciodynamics of the central sector of the last British–Irish ice sheet in Northern England

The central sector of the last British–Irish Ice Sheet (BIIS) was characterised by considerable complexity, both in terms of its glacial stratigraphy and geomorphological signature. This complexity is reflected by the large number and long history of papers that have attempted to decipher the glaciodynamic history of the region. Despite significant advances in our understanding, reconstructions remain hotly debated and relatively local, thereby hindering attempts to piece together BIIS dynamics. This paper seeks to address these issues by reviewing geomorphological mapping evidence of palimpsest flow signatures and providing an up-to-date stratigraphy of the region. Reconciling geomorphological and sedimentological evidence with relative and absolute dating constraints has allowed us to develop a new six-stage glacial model of ice-flow history and behaviour in the central sector of the last BIIS, with three major phases of glacial advance. This includes: I. Eastwards ice flow through prominent topographic corridors of the north Pennines; II. Cessation of the Stainmore ice flow pathway and northwards migration of the North Irish Sea Basin ice divide; III. Stagnation and retreat of the Tyne Gap Ice Stream; IV. Blackhall Wood–Gosforth Oscillation; V. Deglaciation of the Solway Lowlands; and VI. Scottish Re-advance and subsequent final retreat of ice out of the central sector of the last BIIS. The ice sheet was characterised by considerable dynamism, with flow switches, initiation (and termination) of ice streams, draw-down of ice into marine ice streams, repeated ice-marginal fluctuations and the production of large volumes of meltwater, locally impounded to form ice-dammed glacial lakes. Significantly, we tie this reconstruction to work carried out and models developed for the entire ice sheet. This therefore situates research in the central sector within contemporary understanding of how the last BIIS evolved over time.

Comparison of two scoring systems for evaluation of treatment outcome in patients with complete bilateral cleft lip and palate

Objective : To compare two scoring systems: the Huddart/Bodenham system (HB system) and the Bauru-BCLP yardstick (BCLP yardstick), which classify treatment outcome in terms of dental arch relationships in patients with complete bilateral cleft lip and palate (CBCLP). The predictive value of these scoring systems for treatment outcome was also evaluated. Design : Retrospective longitudinal study. Patients : Dental arch relationships of 43 CBCLP patients were evaluated at 6, 9, and 12 years. Setting : Treatment outcome in BCLP patients using two scoring systems. Main Outcome Measures : For each age group, the HB scores were correlated with the BCLP yardstick scores using Spearman's correlation coefficient. The predictive value of the two scoring systems was evaluated by backward regression analysis. Results : Intraobserver Kappa values for the BCLP yardstick scoring for the two observers were .506 and .627, respectively, and the interobserver reliability ranged from .427 and .581. The intraobserver reliability for the HB system ranged from .92 to .97 and the interobserver reliability from .88 to .96. The BCLP yardstick scores of 6 and 9 years together were predictors for the outcome at 12 years (explained variance 41.3%). Adding the incisor and lateral HB scores in the regression model increased the explained variance to 67%. Conclusions : The BCLP yardstick and the HB system are reliable scoring systems for evaluation of dental arch relationships of CBCLP patients. The HB system categorizes treatment outcome into similar categories as the BCLP yardstick. In case a more sensitive measure of treatment outcome is needed, selectively both scoring systems should be used.