Genetic and Informatic Analyses Implicate Kif12 as a Candidate Gene within the Mpkd2 Locus That Modulates Renal Cystic Disease Severity in the Cys1cpk Mouse.

We have previously mapped the interval on Chromosome 4 for a major polycystic kidney disease modifier (Mpkd) of the B6(Cg)-Cys1cpk/J mouse model of recessive polycystic kidney disease (PKD). Informatic analyses predicted that this interval contains at least three individual renal cystic disease severity-modulating loci (Mpkd1-3). In the current study, we provide further validation of these predicted effects using a congenic mouse line carrying the entire CAST/EiJ (CAST)-derived Mpkd1-3 interval on the C57BL/6J background. We have also generated a derivative congenic line with a refined CAST-derived Mpkd1-2 interval and demonstrated its dominantly-acting disease-modulating effects (e.g., 4.2-fold increase in total cyst area;

Racial disparities in fifth-grade sun protection: Evidence from the Healthy Passages study

Background/Objectives: Despite rising skin cancer rates in children, multiple studies reveal inadequate youth sun-protective behavior (eg, sunscreen use). Using Healthy Passages data for fifth-graders, we set out to determine sunscreen adherence in these children and investigated factors related to sunscreen performance. Methods: Survey data were collected from 5119 fifth-graders and their primary caregivers. Logistic regression was used to assess associations between sunscreen adherence and performance of other preventive health behaviors (eg, flossing, helmet use) and examine predictors of sunscreen adherence. Analyses were repeated in non-Hispanic black, Hispanic, and non-Hispanic white subgroups. Results: Five thousand one hundred nineteen (23.4%) children almost always used sunscreen, 5.9% of non-Hispanic blacks (n = 1748), 23.7% of Hispanics (n = 1802), and 44.8% of non-Hispanic whites (n = 1249). Performing other preventive health behaviors was associated with higher odds of sunscreen adherence (all P \u3c.001), with the greatest association with flossing teeth (odds ratio = 2.41, 95% confidence interval = 1.86-3.13, P \u3c.001). Factors for lower odds of sunscreen adherence included being male and non-Hispanic black or Hispanic and having lower socioeconomic status. School-based sun-safety education and involvement in team sports were not significant factors. Conclusion: Our data confirm low use of sun protection among fifth-graders. Future research should explore how public health success in increasing prevalence of other preventive health behaviors may be applied to enhance sun protection messages. Identifying risk factors for poor adherence enables providers to target patients who need more education. Improving educational policies and content in schools may be an effective way to address sun safety

Peer-Assessed Outcomes in the Multimodal Treatment Study of Children With Attention Deficit Hyperactivity Disorder

Peer-assessed outcomes were examined at the end of treatment (14 months after study entry) for 285 children (226 boys, 59 girls) with attention deficit hyperactivity disorder (ADHD) who were rated by their classmates (2,232 classmates total) using peer sociometric procedures. All children with ADHD were participants in the Multimodal Treatment Study of Children with ADHD (MTA). Treatment groups were compared using the orthogonal treatment contrasts that accounted for the largest amount of variance in prior MTA outcome analyses: Medication Management + Combined Treatment versus Behavior Therapy + Community Care; Medication Management versus Combined Treatment; Behavior Therapy versus Community Care. There was little evidence of superiority of any of the treatments for the peer-assessed outcomes studied, although the limited evidence that emerged favored treatments involving medication management. Post hoc analyses were used to examine whether any of the four treatment groups yielded normalized peer relationships relative to randomly selected- classmates. Results indicated that children from all groups remained significantly impaired in their peer relationships

Venglustat, a novel glucosylceramide synthase inhibitor, in patients at risk of rapidly progressing ADPKD: primary results of a double-blind, placebo-controlled, phase 2/3 randomized clinical trial

RATIONALE AND OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STUDY DESIGN: STAGED-PKD was a two-stage, multicenter, double-blind, randomized, placebo-controlled Phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, selected based on Mayo Kidney Volume Class 1C-1E and an estimated glomerular filtration rate (eGFR) of 30-89.9 mL/min/1.73 m2. SETTING AND PARTICIPANTS: Enrollment included 236 and 242 patients in Stages 1 and 2, respectively. INTERVENTION(S): In Stage 1, patients were randomized 1:1:1 to venglustat 8 mg or 15 mg, or placebo. In Stage 2, patients were randomized 1:1 to venglustat 15 mg (highest dose identified as safe and well tolerated in Stage 1) or placebo. OUTCOMES: Primary endpoints were rate of change in TKV over 18 months in Stage 1 and eGFR slope over 24 months in Stage 2. Secondary endpoints were eGFR slope over 18 months (Stage 1), rate of change in TKV (Stage 2), and safety/tolerability, pain, and fatigue (Stages 1 and 2). RESULTS: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (Stage 1) and had a faster rate of decline in eGFR slope over 24 months (Stage 2). Due to this lack of efficacy, the study was terminated early. LIMITATIONS: The short follow-up after end-of-treatment and limited generalizability of findings. CONCLUSIONS: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8 mg or 15 mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in the STAGED-PKD trial despite a dose-dependent decrease in plasma glucosylceramide (GL-1) levels

Constructing meaning about the delinquency of young girls in public-housing neighbourhoods

UID/SOC/04647/2013 SFRH/BPD/116119/2016Rooted in the theoretical approaches of social ecology and in childhood studies, the Ph.D. research project on which this paper is based aimed to achieve a better understanding of children’s socialization processes in multi-problematic spaces, particularly concerning their involvement in violence and delinquency. A case study based on ethnographic research and child-centred methods was carried out in six public-housing neighbourhoods in Portugal, which were chosen because they had relatively high levels of social deprivation, violence and crime. The specificity of the social group under study—children aged from 6 to 12 years old—and their living conditions, led us to extend the data collected by trying to learn, from the girls, the reasoning and the meanings they assign to their own actions in daily social practices. The intention was to study the features of girls’ socialization in the field through their own accounts of their lives and to examine their perspectives on offending behaviours. The genderized process of social learning in delinquency identified in the girls’ conversation is an important variable, as familial and social experiences tend to facilitate their entry into delinquency. The transmission of delinquent values takes place essentially within the female family circle or via female peers, rather than from the influence of male individuals.authorsversionpublishe

Community Violence Exposure and Conduct Problems in Children and Adolescents with Conduct Disorder and Healthy Controls

Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self-report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD

Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase

The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure–activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation

Growing Up in Violent Contexts: Differential Effects of Community, Family, and School Violence on Child Adjustment

Although different than in war-torn areas, violence affects children even in the most economically developed countries. In this chapter we review the empirical evidence supporting the detrimental effects of early violence exposure on a wide range of developmental outcomes. We also provide an examination of mechanisms linking violence exposure to negative developmental outcomes, as well as the predisposing and precipitating factors that intervene in these complex relationships. We conclude that the problem of exposure to violence in children is often underestimated and discuss the implications for child welfare policy and preventive interventions