Differential Impact of a Dutch Alcohol Prevention Program Targeting Adolescents and Parents Separately and Simultaneously: Low Self-Control and Lenient Parenting at Baseline Predict Effectiveness

To test whether baseline levels of the factors accountable for the impact of the Prevention of Alcohol use in Students (PAS) intervention (self-control, perceived rules about alcohol and parental attitudes about alcohol), moderate the effect of the intervention. A cluster randomized trial including 3,490 Dutch early adolescents (M age = 12.66, SD = 0.49) and their parents randomized over four conditions: 1) parent intervention, 2) student intervention, 3) combined intervention and 4) control group. Moderators at baseline were used to examine the differential effects of the interventions on onset of (heavy) weekly drinking at 34-month follow-up. The combined intervention was only effective in preventing weekly drinking among those adolescents who reported to have lower self-control and more lenient parents at baseline. No differential effect was found for the onset of heavy weekly drinking. No moderating roles of self-control and lenient parenting were found for the separate student and parent interventions regarding the onset of drinking. The combined intervention is more effective among adolescents with low-self control and lenient parents at baseline, both factors that were a specific target of the intervention. The relevance of targeting self-control in adolescents and restrictive parenting is underlined

Genetical genomics: spotlight on QTL hotspots

No abstract available

Comparative genomics of drug resistance in <i>Trypanosoma brucei rhodesiense</i>

Trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to Sub-Saharan Africa. Here we investigate two independent lines of T. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. We apply comparative genomics and transcriptomics to identify the underlying mutations. Only few mutations have become fixed during selection. Three genes were affected by mutations in both lines: the aminopurine transporter AT1, the aquaporin AQP2, and the RNA-binding protein UBP1. The melarsoprol-selected line carried a large deletion including the adenosine transporter gene AT1, whereas the pentamidine-selected line carried a heterozygous point mutation in AT1, G430R, which rendered the transporter non-functional. Both resistant lines had lost AQP2, and both lines carried the same point mutation, R131L, in the RNA-binding motif of UBP1. The finding that concomitant deletion of the known resistance genes AT1 and AQP2 in T. b. brucei failed to phenocopy the high levels of resistance of the T. b. rhodesiense mutants indicated a possible role of UBP1 in melarsoprol-pentamidine cross-resistance. However, homozygous in situ expression of UBP1-Leu(131) in T. b. brucei did not affect the sensitivity to melarsoprol or pentamidine

Detecting parent of origin and dominant QTL in a two-generation commercial poultry pedigree using variance component methodology

<p>Abstract</p> <p>Introduction</p> <p>Variance component QTL methodology was used to analyse three candidate regions on chicken chromosomes 1, 4 and 5 for dominant and parent-of-origin QTL effects. Data were available for bodyweight and conformation score measured at 40 days from a two-generation commercial broiler dam line. One hundred dams were nested in 46 sires with phenotypes and genotypes on 2708 offspring. Linear models were constructed to simultaneously estimate fixed, polygenic and QTL effects. Different genetic models were compared using likelihood ratio test statistics derived from the comparison of full with reduced or null models. Empirical thresholds were derived by permutation analysis.</p> <p>Results</p> <p>Dominant QTL were found for bodyweight on chicken chromosome 4 and for bodyweight and conformation score on chicken chromosome 5. Suggestive evidence for a maternally expressed QTL for bodyweight and conformation score was found on chromosome 1 in a region corresponding to orthologous imprinted regions in the human and mouse.</p> <p>Conclusion</p> <p>Initial results suggest that variance component analysis can be applied within commercial populations for the direct detection of segregating dominant and parent of origin effects.</p

Raising the profile of pilot and feasibility studies in relation to the development, evaluation and implementation of patient-reported outcome measures.

This editorial introduces a new special series on the pilot and feasibility testing of patient-reported outcome measures (PROMs) in the on-line open access journal Pilot and Feasibility Studies. Pilot and feasibility studies are typically implemented to address issues of uncertainty before undertaking a larger definitive study such as a randomised controlled trial or large scale survey. This editorial considers the role that such pilot and feasibility testing plays in relation to the development, evaluation and implementation of PROMs. This is often an essential element of PROM research but is typically overlooked-especially within current methodological guidance, reporting space and also debate. This editorial aims to open up a dialogue about the role of pilot and feasibility testing in relation to PROMs. It highlights some of the areas in PROMs research where these types of studies have been carried out and discusses the ways in which the PROM community may be better supported and encouraged to integrate this element of the research process into their PROM-based work

Amino acid synthesis deficiencies

In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the "classical" inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. This makes the biochemical diagnosis of this relatively new group of metabolic diseases challenging. Defects in the synthesis pathways of serine metabolism, glutamine, proline and, recently, asparagine have all been reported. Although these amino acid synthesis defects are in unrelated metabolic pathways, they do share many clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early onset seizures and varying degrees of mental disability. The brain abnormalities are accompanied by skin disorders such as cutis laxa in defects of proline synthesis, collodion-like skin and ichthyosis in serine deficiency, and necrolytic erythema in glutamine deficiency. Hypomyelination with accompanying loss of brain volume and gyration defects can be observed on brain MRI in all synthesis disorders. In adults with defects in serine or proline synthesis, spastic paraplegia and several forms of polyneuropathy with or without intellectual disability appear to be the major symptoms in these late-presenting forms of amino acid disorders. This review provides a comprehensive overview of the disorders in amino acid synthesis

Anxiety and depression after prostate cancer diagnosis and treatment: 5-year follow-up

To document anxiety and depression from pretreatment till 5-year follow-up in 299 men with localized prostate cancer. To assess, if baseline scores were predictive for anxiety and depression at 1-year follow-up. Respondents completed four assessments (pretreatment, at 6 and 12 months, and at 5-year follow-up) on anxiety, depression and mental health. Respondents were subdivided according to therapy (prostatectomy or radiotherapy) and high vs low-anxiety. Pretreatment 28% of all patients were classified as ‘high-anxiety'; their average anxiety scores decreased significantly post-treatment, that is towards less anxiety. At all assessments, high-anxiety men treated by prostatectomy reported less depression than high-anxiety men treated by radiotherapy. Of men treated by radiotherapy, 27% reported clinical significant levels of depression while 20% is expected in a general population. The improvement in mental health at 6-months follow-up was statistically significant and clinically meaningful in all respondent groups. Sensitivity of anxiety at baseline as a screening tool was 71% for anxiety and 60% for symptoms of depression. We recommend clinicians to attempt early detection of patients at risk of high levels of anxiety and depression after prostate cancer diagnosis since prevalence is high. STAI-State can be a useful screening tool but needs further development

Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen

Background: Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.Methods: Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).Results: If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.Conclusions: Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening

Microarray Analyses of Inflammation Response of Human Dermal Fibroblasts to Different Strains of Borrelia burgdorferi Sensu Stricto

In Lyme borreliosis, the skin is the key site of bacterial inoculation by the infected tick, and of cutaneous manifestations, erythema migrans and acrodermatitis chronica atrophicans. We explored the role of fibroblasts, the resident cells of the dermis, in the development of the disease. Using microarray experiments, we compared the inflammation of fibroblasts induced by three strains of Borrelia burgdorferi sensu stricto isolated from different environments and stages of Lyme disease: N40 (tick), Pbre (erythema migrans) and 1408 (acrodermatitis chronica atrophicans). The three strains exhibited a similar profile of inflammation with strong induction of chemokines (CXCL1 and IL-8) and IL-6 cytokine mainly involved in the chemoattraction of immune cells. Molecules such as TNF-alpha and NF-κB factors, metalloproteinases (MMP-1, -3 and -12) and superoxide dismutase (SOD2), also described in inflammatory and cellular events, were up-regulated. In addition, we showed that tick salivary gland extracts induce a cytotoxic effect on fibroblasts and that OspC, essential in the transmission of Borrelia to the vertebrate host, was not responsible for the secretion of inflammatory molecules by fibroblasts. Tick saliva components could facilitate the early transmission of the disease to the site of injury creating a feeding pit. Later in the development of the disease, Borrelia would intensively multiply in the skin and further disseminate to distant organs