The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity.

Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.This work was supported by the Medical Research Council (U105192732 and U105178805), the European Research Council (309756), the Lister Institute for Preventive Medicine, and the EMBO Young Investigator Program (to D.K.); a Marie-Sklodowska Curie Individual Fellowship from the European Commission (MC-IF-654019) and a Research Fellowship from Corpus Christi College Cambridge (to R.B.D.); and Wellcome Trust (to N.V.M., E.R.M., and A.N.J.M [100963/Z/13/Z]), WellChild (to N.V.M. and E.R.M.), and UCB (to H.L.T., D.M. and E.R.M.).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2016.07.01

Impact of oral administration of single strain Lactococcus lactis spp. cremoris on immune responses to keyhole limpet hemocyanin immunization and gut microbiota: A randomized placebo-controlled trial in healthy volunteers

IntroductionLactococcus lactis spp. cremoris has been associated with promising immunomodulatory results in preclinical trials. The aim of this study was to investigate the pharmacodynamic (PD) effects of three monoclonal microbial formulations of L. lactis spp. cremoris (EDP1066) on the immune response to keyhole limpet hemocyanin (KLH). Potential effects on the gut microbiota were also investigated.MethodsThe trial was registered on Netherlands Trial Register (trial ID NL7519, https://trialsearch.who.int). Eighty-one healthy subjects (median 28, range 18–59 years) were randomized to 28 days of enteric-coated capsules at five doses (n = 13) (1.5 * 1012 total cells daily), freeze-dried powder at one dose (n = 12) (3.0 * 1011 total cells daily) or five doses (n = 12), minitablets at one dose (n = 12) or five doses (n = 12), or placebo (n = 20) prior to KLH immunization. Antibody responses and circulating regulatory T cells (Tregs) were measured after KLH immunization, and skin responses were evaluated after a KLH rechallenge by laser speckle contrast imaging and multispectral imaging. Ex vivo lymphocyte (phytohemagglutinin) and monocyte (lipopolysaccharide (LPS)) cytokine release assays were explored in the minitablet-treated groups only. The prevalence of L. lactis spp. cremoris in the gastrointestinal tract and the impact on the fecal microbiota were assessed by qPCR and 16S rRNA sequencing, respectively.ResultsRepeated-measures analysis of covariances revealed no significant treatment effects on the antibody responses to KLH, number of Tregs, or KLH skin rechallenge outcomes. Ex vivo LPS-driven cytokine responses in whole blood were lower in the low dose minitablet group compared to placebo: tumor necrosis factor (estimated difference (ED) from placebo: −44.2%, 95% confidence interval (CI) −65.3% to −10.3%), interleukin (IL)-1β (ED −41.4%, 95% CI −63.5% to −5.8%), and IL-6 (ED −39.2%, 95% CI −56.8% to −14.5%). The fecal presence of L. lactis spp. cremoris increased during treatment by all EDP1066 formulations and normalized 5 days after the last dose. Microbiome α-diversity did not change by the treatments compared to placebo.DiscussionThe EDP1066 formulations did not affect the immune response to KLH immunization in healthy individuals. However, exposure to L. lactis spp. cremoris in minitablet formulation impacted ex vivo whole blood LPS cytokine response. The clinical impact of these effects awaits further investigations.Netherlands Trial Registertrialsearch.who.int, trial ID NL7519

Fine motor skills predict maths ability better than they predict reading ability in the early primary school years

Fine motor skills have long been recognised as an important foundation for development in other domains. However, more precise insights into the role of fine motor skills, and their relationships to other skills in mediating early educational achievements, are needed to support the development of optimal educational interventions. We explored concurrent relationships between two components of fine motor skills, Fine Motor Precision and Fine Motor Integration, and early reading and maths development in two studies with primary school children of low-to-mid socio-economic status in the U.K. Two key findings were revealed. First, despite being in the first two years of primary school education, significantly better performance was found in reading compared to maths across both studies. This may reflect the protective effects of recent national-level interventions to promote early literacy skills in young children in the U.K. that have not been similarly promoted for maths. Second, fine motor skills were a better predictor of early maths ability than they were of early reading ability. Hierarchical multiple regression revealed that fine motor skills did not significantly predict reading ability when verbal short-term memory was taken into account. In contrast, Fine Motor Integration remained a significant predictor of maths ability, even after the influence of nonverbal IQ had been accounted for. These results suggest that fine motor skills should have a pivotal role in educational interventions designed to support the development of early mathematical skills

A latent growth curve model to estimate electronic screen use patterns amongst adolescents aged 10 to 17 years

Background: High quality, longitudinal data describing young people's screen use across a number of distinct forms of screen activity is missing from the literature. This study tracked multiple screen use activities (passive screen use, gaming, social networking, web searching) amongst 10- to 17-year-old adolescents across 24 months. Methods: This study tracked the screen use of 1948 Australian students in Grade 5 (n = 636), Grade 7 (n = 672), and Grade 9 (n = 640) for 24 months. At approximately six-month intervals, students reported their total screen time as well as time spent on social networking, passive screen use, gaming, and web use. Patterns of screen use were determined using latent growth curve modelling. Results: In the Grades 7 and 9 cohorts, girls generally reported more screen use than boys (by approximately one hour a day), though all cohorts of boys reported more gaming. The different forms of screen use were remarkably stable, though specific cohorts showed change for certain forms of screen activity. Conclusion: These results highlight the diverse nature of adolescent screen use and emphasise the need to consider both grade and sex in future research and policy

The Prevalence and Psychopathological Correlates of Sibling Bullying in Children with and without Autism Spectrum Disorder

Using data from a prospective population based study, the prevalence and psychopathological correlates of sibling bullying in children with and without autism spectrum disorder (ASD) were estimated. There were 475 children with ASD and 13,702 children without ASD aged 11 years. Children with ASD were more likely to be bullied by their siblings compared to those without ASD. They were also more likely than those without ASD to both bully and be bullied by their siblings, which was associated with lower prosocial skills as well as more internalizing and externalizing problems compared to those not involved in any sibling bullying. Interventions to improve social and emotional outcomes in children with ASD should focus on both the affected and the unaffected sibling

Mindful Parenting in Mental Health Care

Mindfulness is a form of meditation based on the Buddhist tradition, which has been used over the last two decades to successfully treat a multitude of mental health problems. Bringing mindfulness into parenting (“mindful parenting”) is one of the applications of mindfulness. Mindful parenting interventions are increasingly being used to help prevent and treat mental disorders in children, parenting problems, and prevent intergenerational transmission of mental disorders from parents to children. However, to date, few studies have examined the hypothesized mechanisms of change brought about by mindful parenting. We discuss six possible mechanisms through which mindful parenting may bring about change in parent–child interactions in the context of child and parent mental health problems. These mechanisms are hypothesized to be mediated by the effects of mindfulness on parental attention by: (1) reducing parental stress and resulting parental reactivity; (2) reducing parental preoccupation resulting from parental and/or child psychopathology; (3) improving parental executive functioning in impulsive parents; (4) breaking the cycle of intergenerational transmission of dysfunctional parenting schemas and habits; (5) increasing self-nourishing attention; and (6) improving marital functioning and co-parenting. We review research that has applied mindful parenting in mental health settings, with a focus on evidence for these six mechanisms. Finally, we discuss directions for future research into mindful parenting and the crucial questions that this research should strive to answer

Advice about Life Plans from Mothers, Fathers, and Siblings in Always-Married and Divorced Families during Late Adolescence

The frequency of advice about life plans that older adolescents in always-married and divorced families received from mothers, fathers, and siblings was examined. Also, a pattern-analytic approach that grouped adolescents according to the amount of advice about life plans received from each parent and a sibling was employed to explore the connections between patterns of advice and adolescents' future occupational, educational, and family plans. The sample included 544 and 95 older adolescents in always-married and divorced families, respectively. Findings suggested that while adolescents relied on mothers for advice in both always-married and divorced families, adolescents in divorced families depended on fathers and siblings for advice less often than did adolescents in always-married families. Although there was some evidence of family context differences in the connections between patterns of advice and life plans, overall, adolescents in both family contexts who received more advice from a parent and, in some cases, a sibling compared to other adolescents were the most positive about their future life plans.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45291/1/10964_2004_Article_345952.pd

Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions

Background: A typical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman. Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management. This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer. Objectives Main objective: To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+). Secondary objective: To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done. Search methods: We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer. More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review. Selection criteria: Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification. Data collection and analysis: The review authors independently extracted data from the selected studies, and obtained additional data from report authors. Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests. Main results: The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001). Authors' conclusions: HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account