Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product.

Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of the gene encoding insulin-like growth factor II (IGF-II) is often elevated in these tumors. Since many of the actions of IGF-II are mediated through activation of the IGF-I receptor (IGF-IR), we have measured the levels of IGF-IR mRNA in normal kidney and in Wilms tumor samples using solution hybridization/RNase protection assays. IGF-IR mRNA levels in the tumors were 5.8-fold higher than in adjacent normal kidney tissue. Among the tumors themselves, the levels of IGF-IR mRNA in those containing heterologous stromal elements were 2-fold higher (P < 0.01) than in tumors without these elements. IGF-IR gene (designated IGF1R) expression in the tumors was inversely correlated with the expression of the Wilms tumor suppressor gene WT1, whose inactivation appears to be a key step in the etiology of Wilms tumor. Cotransfection of Chinese hamster ovary cells with rat and human IGF-IR gene promoter constructs driving luciferase reporter genes and with WT1 expression vectors showed that the active WT1 gene product represses IGF-IR promoter activity in a dose-dependent manner. These results suggest that underexpression, deletion, or mutation of WT1 may result in increased expression of the IGF-IR, whose activation by IGF-II may be an important aspect of the biology of Wilms tumor.     

A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the « molar tooth sign ». JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice‐site mutation in PDE6D, encoding a prenyl‐binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild‐type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl‐dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP‐bound ARL3, which acts as a cargo‐release factor for PDE6D‐bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl‐binding‐dependent trafficking in ciliopathies.     

The Effectiveness of Electronic Screening and Brief Intervention for Reducing Levels of Alcohol Consumption: A Systematic Review and Meta-Analysis

Background

Electronic screening and brief intervention (eSBI) has been shown to reduce alcohol consumption, but its effectiveness over time has not been subject to meta-analysis.

Objective

The current study aims to conduct a systematic review and meta-analysis of the available literature to determine the effectiveness of eSBI over time in nontreatment-seeking hazardous/harmful drinkers.

Methods

A systematic review and meta-analysis of relevant studies identified through searching the electronic databases PsychINFO, Medline, and EMBASE in May 2013. Two members of the study team independently screened studies for inclusion criteria and extracted data. Studies reporting data that could be transformed into grams of ethanol per week were included in the meta-analysis. The mean difference in grams of ethanol per week between eSBI and control groups was weighted using the random-effects method based on the inverse-variance approach to control for differences in sample size between studies.

Results

There was a statistically significant mean difference in grams of ethanol consumed per week between those receiving an eSBI versus controls at up to 3 months (mean difference –32.74, 95% CI –56.80 to –8.68, z=2.67, P=.01), 3 to less than 6 months (mean difference –17.33, 95% CI –31.82 to –2.84, z=2.34, P=.02), and from 6 months to less than 12 months follow-up (mean difference –14.91, 95% CI –25.56 to –4.26, z=2.74, P=.01). No statistically significant difference was found at a follow-up period of 12 months or greater (mean difference –7.46, 95% CI –25.34 to 10.43, z=0.82, P=.41).

Conclusions

A significant reduction in weekly alcohol consumption between intervention and control conditions was demonstrated between 3 months and less than 12 months follow-up indicating eSBI is an effective intervention.     

Nanoindentation of dental composites

The intent of this project was to evaluate the elastic modulus and hardness of four composites with different fillers, a microfill, a hybrid, a dental resin cement, and a fiber filler, using nanoindentation. An indentation load of 0.001 N was used and 100 indents per specimen were taken. The elastic modulus measured for the Choice composite was 30.2-30.3 GPa, 15.9-16.0 GPa for Micronew, 24.6-27.1 GPa for Renew, and 36.4-47.1 GPa for Restolux. The statistical analysis indicated a significant difference in the elastic modulus for all four composites. Micronew had the lowest hardness (1.2-1.3 GPa) followed by Renew (1.6-1.8 GPa), Choice (2.6-2.8 GPa), and Restolux (2.7-4.0 GPa). The statistical analysis indicated a significant difference between Choice and Restolux from Micronew and Renew, with Renew and Micronew not being significantly different from each other. Nanoindentation of dental composites, using a 10 x 10 matrix of indentations, resulted in a wide range of measured values for the elastic modulus and hardness because of the size of the filler particle, the location of the indenter within the filler particle, the composition of the filler particles, and the location of the indenter within the filler/resin matrix.     

Species-dependent serum interference in a sandwich ELISA for Apo2L/TRAIL

To support pre-clinical studies of Apo2L/TRAIL in rodents and non-human primates, a sandwich ELISA was developed using two mouse monoclonal anti-Apo2L/TRAIL antibodies. Mouse, rat, cynomolgus monkey, and chimpanzee serum at concentrations of > or =1% were found to interfere with accurate quantitation of Apo2L/TRAIL. Moreover, the characteristics of the serum interference for each species were different. In order to resolve the observed serum effect, studies were performed in which salts, detergents, and blocking proteins were added to the sample diluent, and optimized sample diluents that eliminated serum interference were developed for mouse, cynomolgus monkey, and chimpanzee serum. These buffers consisted of a base assay diluent (PBS/0.5% BSA/0.05% Tween-20/10 ppm ProClin 300) supplemented with: NaCl (mouse serum); NaCl, EDTA, CHAPS, bovine gamma globulin (BGG), and human IgG (cynomolgus monkey serum); and NaCl and EDTA (chimpanzee serum). Full characterization studies were performed for the "buffer" ELISA run in base assay diluent (intended for non-serum samples) as well as the assays optimized for mouse serum and cynomolgus monkey serum. Precision, accuracy, linearity, and specificity were found to be satisfactory. With the availability of a rabbit polyclonal antibody against Apo2L/TRAIL, a new pAb/mAb ELISA was developed. This assay was not only more sensitive by > or =6-fold, but it was also much less subject to serum interference.     

Taking a Broad Approach to Public Health Program Adaptation: Adapting a Family-Based Diabetes Education Program

Diabetes health disparities among Hispanic populations have been countered with federally funded health promotion and disease prevention programs. Dissemination has focused on program adaptation to local cultural contexts for greater acceptability and sustainability. Taking a broader approach and drawing on our experience in Mexican American communities at the U.S.–Mexico Border, we demonstrate how interventions are adapted at the intersection of multiple cultural contexts: the populations targeted, the community- and university-based entities designing and implementing interventions, and the field team delivering the materials. Program adaptation involves negotiations between representatives of all contexts and is imperative in promoting local ownership and program sustainability.     

Comparison of brief interventions in primary care on smoking and excessive alcohol consumption: a population survey in England

Background

Brief interventions have a modest but meaningful effect on promoting smoking cessation and reducing excessive alcohol consumption. Guidelines recommend offering such advice opportunistically and regularly but incentives vary between the two behaviours.

Aim

To use representative data from the perspective of patients to compare the prevalence and characteristics of people who smoke or drink excessively and who receive a brief intervention.

Design and setting

Data was from a representative sample of 15 252 adults from household surveys in England.

Method

Recall of brief interventions on smoking and alcohol use, sociodemographic information, and smoking and alcohol consumption patterns were assessed among smokers and those who drink excessively (AUDIT score of ≥8), who visited their GP surgery in the previous year.

Results

Of 1775 smokers, 50.4% recalled receiving brief advice on smoking in the previous year. Smokers receiving advice compared with those who did not were more likely to be older (odds ratio [OR] 17-year increments 1.19, 95% confidence interval [CI] =1.06 to 1.34), female (OR 1.35, 95% CI =1.10 to 1.65), have a disability (OR 1.44, 95% CI = 1.11 to 1.88), have made more quit attempts in the previous year (compared with no attempts: one attempt, OR 1.65, 95% CI = 1.32 to 2.08; ≥2 attempts, OR 2.02, 95% CI =1.49 to 2.74), and have greater nicotine dependence (OR 1.17, 95% CI =1.05 to 1.31) but were less likely to have no post-16 qualifications (OR 0.81, 95% CI = 0.66 to 1.00). Of 1110 people drinking excessively, 6.5% recalled receiving advice in their GP surgery on their alcohol consumption in the previous year. Those receiving advice compared with those who did not had higher AUDIT scores (OR 1.17, 95% CI =1.12 to 1.23) and were less likely to be female (OR 0.44, 95% CI = 0.23 to 0.87).

Conclusion

Whereas approximately half of smokers in England visiting their GP in the past year report having received advice on cessation, <10% of those who drink excessively report having received advice on their alcohol consumption.     

Rules for the classification of younger children with nonverbal learning disabilities and basic phonological processing disabilities.

Rules for the classification of Nonverbal Learning Disabilities (NLD) and Basic Phonological Processing Disabilities (BPPD) that had been generated and tested on older children (ages 9-15) were applied to younger children (ages 7-8). The goal was to evaluate the applicability of these classification rules for a younger population with NLD and BPPD, and to make revisions if necessary. These rules were used to differentiate these two subtypes of learning disabilities using levels and patterns of performance on motor/psychomotor, tactile/perceptual, visual-spatial, auditory-perceptual, problem solving, and language measures. An experienced child-clinical neuropsychologist classified each child. Only those children who received a classification of NLD or BPPD by the neuropsychologist and those who met criteria for definite or probable NLD and BPPD as defined by the rules were used in this study. Revisions were made to these rules for younger children. Revised rules allow for their use as a source of information to assist a clinician in deciding whether a comprehensive neuropsychological evaluation would be valuable. They may also be useful for research purposes.     

The neural basis of the psychomotor vigilance task

STUDY OBJECTIVE: To identify brain regions underlying the fastest and slowest reaction times on the Psychomotor Vigilance task (PVT) under well-rested conditions, as well as brain regions related to particularly poor performance after sleep deprivation. DESIGN: Subjects took the PVT twice while undergoing functional magnetic resonance imaging: once 12 hours after waking from a normal night of sleep and once after 36 hours of total sleep deprivation (TSD). Session order was counterbalanced. SETTING: UCSD J. Christian Gillin Laboratory for Sleep and Chronobiology (the sleep core of the General Clinical Research Center) and UCSD Magnetic Resonance Institute. PATIENTS OR PARTICIPANTS: Twenty right-handed healthy adults (8 women; age = 27.4 +/- 6.7 years; education = 15.6 +/- 1.5 years). MEASUREMENTS AND RESULTS: After a normal night of sleep, optimal performance was related to greater cerebral responses within a cortical sustained attention network and the cortical and subcortical motor systems. Slow reaction times, particularly after TSD, were associated with greater activity in the "default mode network" consisting of frontal and posterior midline regions. CONCLUSIONS: Optimal performance on the PVT appears to rely on activation both within the sustained attention system and within the motor system. Poor performance following TSD may result from a disengagement from the task and related inattention, and brain regions responsible for this localize within midline structures shown to be involved in the brain's "default mode." Finally, particularly poor performance after TSD may elicit a subsequent attentional recovery that manifests as greater activation within the same regions normally responsible for fast reaction times.