Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10-9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Isolation of epithelial stem cells from dermis by a three-dimensional culture system

Skin is a representative self-renewing tissue containing stem cells. Although many attempts have been made to define and isolate skin-derived stem cells, establishment of a simple and reliable isolation procedure remains a goal to be achieved. Here, we report the isolation of cells having stem cell properties from mouse embryonic skin using a simple selection method based on an assumption that stem cells may grow in an anchorage-independent manner. We inoculated single cell suspensions prepared from mouse embryonic dermis into a temperature-sensitive gel and propagated the resulting colonies in a monolayer culture. The cells named dermis-derived epithelial progenitor-1 (DEEP) showed epithelial morphology and grew rapidly to a more than 200 population doubling level over a period of 250 days. When the cells were kept confluent, they spontaneously formed spheroids and continuously grew even in spheroids. Immunostaining revealed that all of the clones were positive for the expression of cytokeratin-8, -18, -19, and E-cadherin and negative for the expression of cytokeratin-1, -5, -6, -14, -20, vimentin, nestin, a ckit. Furthermore, they expressed epithelial stem cell markers such as p63, integrin beta1, and S100A6. On exposure to TGFbeta in culture, some of DEEP-1 cells expressed alpha-smooth muscle actin. When the cells were transplanted into various organs of adult SCID mice, a part of the inoculated cell population acquired neural, hepatic, and renal cell properties. These results indicate that the cells we isolated were of epithelial stem cell origin and that our new approach is useful for isolation of multipotent stem cells from skin tissues.

Subarachnoid haemorrhage (SAH):long-term cognitive outcome in patients treated with surgical clipping or endovascular coiling

Purpose: To compare long-term cognitive outcomes of patients treated with surgical clipping or endovascular coiling after subarachnoid haemorrhage (SAH). Method: Retrospective matched cohort study assessed neuropsychological functioning at least 12 months after aneurysmal SAH treatment. Fourteen patients treated by endovascular coiling and nine patients treated by surgical clipping participated. After gaining written consent, a comprehensive neuropsychological battery was completed. Standardised tests were employed to assess pre-morbid and current intellectual functioning (IQ), attention, speed of information processing, memory and executive function as well as psychosocial functioning and affect. Results: Treatment groups were not significantly different in terms of age, pre-morbid IQ, time from injury to treatment or time since injury. A significant effect of treatment on full-scale IQ score (p = 0.025), performance IQ (p = 0.045) and verbal IQ score (p = 0.029), all favouring the coiled group was observed. A medium effect size between groups difference in immediate memory (p = 0.19, partial ?(2) = 0.08) was also observed. No significant between group differences on attention, executive functioning and speed of information processing measures or mood and psychosocial functioning were noted. Both groups reported increased anxiety and memory, attention and speed of information processing deficits relative to normative data. Conclusions: Study findings indicate fewer cognitive deficits following endovascular coiling. Cognitive deficits in the clipped group may be due in part to the invasive nature of neurosurgical clipping. Further prospective research with regard to long-term cognitive and emotional outcomes is warranted. [Box: see text].

First results on cell irradiation with laser-driven protons on the TARANIS system

The ultra short duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 10 Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live, cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source.

Viscosity Control for Extrusion Processes Using Recycled Polymers

The aim of this paper is to develop a new extruder control system for recycled materials which has ability to automatically maintain constant a polymer melt viscosity of mixed recycled polymers during extrusion, regardless of variations in the Melt Flow Index (MFI) of recycled mixed grade high density polyethylene (HDPE) feedstock. A closed-loop controller is developed to automatically regulate screw speed and barrel temperature profile to achieve constant viscosity and enable consistent processing of variable grade recycled HDPE materials. The experimental results of real time viscosity measurement and control using a 38mm single screw extruder with different recycled HDPEs with widely different MFIs are reported in this work

A survey of perceived training differences between ophthalmology residents in Hong Kong and China.

Background: To study the differences in ophthalmology resident training between China and the Hong Kong Special Administrative Region (HKSAR).Methods: Training programs were selected from among the largest and best-known teaching hospitals. Ophthalmology residents were sent an anonymous 48-item questionnaire by mail. Work satisfaction, time allocation between training activities and volume of surgery performed were determined.Results: 50/75 residents (66.7 %) from China and 20/26 (76.9 %) from HKSAR completed the survey. Age (28.9 ± 2.5 vs. 30.2 ± 2.9 years, p = 0.15) and number of years in training (3.4 ± 1.6 vs. 2.8 ± 1.5, p = 0.19) were comparable between groups. The number of cataract procedures performed by HKSAR trainees (extra-capsular, median 80.0, quartile range: 30.0, 100.0; phacoemulsification, median: 20.0, quartile range: 0.0, 100.0) exceeded that for Chinese residents (extra-capsular: median = 0, p < 0.0001; phacoemulsification: median = 0, p < 0.0001). Chinese trainees spent more time completing medical charts (>50 % of time on charts: 62.5 % versus 5.3 %, p < 0.0001) and received less supervision (≥90 % of training supervised: 4.4 % versus 65 %, p < 0.0001). Chinese residents were more likely to feel underpaid (96.0 % vs. 31.6 %, p < 0.0001) and hoped their children would not practice medicine (69.4 % vs. 5.0 %, p = 0.0001) compared HKSAR residents.Conclusions: In this study, ophthalmology residents in China report strikingly less surgical experience and supervision, and lower satisfaction than HKSAR residents. The HKSAR model of hands-on resident training might be useful in improving the low cataract surgical rate in China.

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.

Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.

Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.

Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.