A genome scan for eye color in 502 twin families: Most variation is due to a QTL on chromosome 15q

We have rated eye color on a 3-point scale (1=blue/grey, 2=hazel/green, 3=brown) in 502 twin families and carried out a 5-10 cM genome scan (400-757 markers). We analyzed eye color as a threshold trait and performed multipoint sib pair linkage analysis using variance components analysis in Mx. A lod of 19.2 was found at the marker D15S1002, less than 1 cM from OCA2, which has been previously implicated in eye color variation. We estimate that 74% of variance in eye color liability is due to this QTL and a further 18% due to polygenic effects. However, a large shoulder on this peak suggests that other loci affecting eye color may be telomeric of OCA2 and inflating the QTL estimate. No other peaks reached genome-wide significance, although lods >2 were seen on 5p and 14q and lods >1 were additionally seen on chromosomes 2, 3, 6, 7, 8, 9, 17 and 18. Most of these secondary peaks were reduced or eliminated when we repeated the scan as a two locus analysis with the 15q linkage included, although this does not necessarily exclude them as false positives. We also estimated the interaction between the 15q QTL and the other marker locus but there was only minor evidence for additive x additive epistasis. Elaborating the analysis to the full two-locus model including non-additive main effects and interactions did not strengthen the evidence for epistasis. We conclude that most variation in eye color in Europeans is due to polymorphism in OCA2 but that there may be modifiers at several other loci.

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

Background Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. Methods 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. Findings Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.101 and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. Interpretation Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamouscell tumours.

TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors

The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated the NR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of the NR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220.

Cost-effectiveness analysis of a kidney and cardiovascular disease treatment program in an Australian aboriginal population

The objective of the study was to assess, from a health service perspective, whether a systematic program to modify kidney and cardiovascular disease reduced the costs of treating end-stage kidney failure. The participants in the study were 1,800 aboriginal adults with hypertension, diabetes with microalbuminuria or overt albuminuria, and overt albuminuria, living on two islands in the Northern Territory of Australia during 1995 to 2000. Perindopril was the primary treatment agent, and other medications were also used to control blood pressure. Control of glucose and lipid levels were attempted, and health education was offered. Evaluation of program resource use and costs for follow-up periods was done at 3 and 4.7 years. On an intention-to-treat basis, the number of dialysis starts and dialysis-years avoided were estimated by comparing the fate of the treatment group with that of historical control subjects, matched for disease severity, who were followed in the before the treatment program began. For the first three years, an estimated 11.6 person-years of dialysis were avoided, and over 4.7 years, 27.7 person-years of dialysis were avoided. The net cost of the program was $1,210 more per person per year than status quo care, and dialyses avoided gave net savings of $1.0 million at 3 years and $3.4 million at 4.6 years. The treatment program provided significant health benefit and impressive cost savings in dialysis avoided. (C) 2005 by the National Kidney Foundation, Inc.

A Comparison of Paediatric Occupational Therapy University Program Curricula in New Zealand, Australia, and Canada

Comparisons were made of the paediatric content of professional entry-level occupational therapy university program curricula in Australia, New Zealand, and Canada using an ex post facto surveymethodology. The findings indicated that in Australia/New Zealand, paediatrics made up 20% of the total curriculum, but only 13% in Canada. Canadian reference materials were utilized less often in Canadian universities than in Australia/New Zealand. Theories taught most often in Australia/New Zealand were: Sensory Integration, Neurodevelopmental Therapy, Client-Centered Practice, Playfulness, and the Model of Human Occupation. In Canada, the most frequent theories were: Piaget’s Stages ofCognitive/Intellectual Development, Neurodevelopmental Therapy, Erikson’s Eight Stages of Psychosocial Development and Sensory Integration. The most frequently taught paediatric assessment tools in both regions were the Bruininks-Oseretsky Test of Motor Proficiency and Miller Assessment for Preschoolers. Paediatric interventionmethods taught to students in all three countries focused on activities of daily living/self-care, motor skills, perceptual and visual motor integration, and infant and child development. [Article copies available for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail address: Website: ©2006 by The Haworth Press, Inc. All rights reserved.]

Multiparametric evaluation of dysphonic severity

In recent years, the multiparametric approach for evaluating perceptual rating of voice quality has been advocated. This study evaluates the accuracy of predicting perceived overall severity of voice quality with a minimal set of aerodynamic, voice range profile (phonetogram), and acoustic perturbation measures. One hundred and twelve dysphonic persons (93 women and 19 men) with laryngeal pathologies and 41 normal controls (35 women and six men) with normal voices participated in this study. Perceptual severity judgement was carried out by four listeners rating the G (overall grade) parameter of the GRBAS scale.(1) The minimal set of instrumental measures was selected based on the ability of the measure to discriminate between dysphonic and normal voices, and to attain at least a moderate correlation with perceived overall severity. Results indicated that perceived overall severity was best described by maximum phonation time of sustained /a/, peak intraoral pressure of the consonant-vowel /pi/ strings production, voice range profile area, and acoustic jitter. Direct-entry discriminant function analysis revealed that these four voice measures in combination correctly predicted 67.3% of perceived overall severity levels.

An analysis of the images attached to referral messages in an e-mail based telemedicine system for developing countries

Little is known about the quality of the images transmitted in email telemedicine systems. The present study was designed to survey the quality of images transmitted in the Swinfen Charitable Trust email referral system. Telemedicine cases were examined for a 3 month period in 2002 and a 3 month period in 2006. The number of cases with images attached increased from 8 (38%) to 37 (53%). There were four types of images (clinical photographs, microscope pictures, notes and X-ray images) and the proportion of radiology images increased from 27 to 48%. The cases in 2002 came from four different hospitals and were associated with seven different clinical specialties. In 2006, the cases came from 19 different hospitals and 20 different specialties. The 46 cases (from both study periods) had a total of 159 attached images. The quality of the images was assessed by awarding each image a score in four categories: focus, anatomical perspective, composition and lighting. The images were scored on a five-point scale (1 = very poor to 5 =very good) by a qualified medical photographer. In comparing image quality between the two study periods, there was some evidence that the quality had reduced, although the average size of the attached images had increased. The median score for all images in 2002 was 16 (interquartile range 14-19) and the median score in 2006 was 15 (13-16). The difference was significant (P < 0.001, Mann-Whitney test).