Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis-associated Pulmonary Arterial Hypertension

Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the vascular and tissue damage of several chronic diseases, including systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I and T280M genetic polymorphisms influence CX3CR1 expression and function. We investigated whether these polymorphisms are associated with PAH secondary to SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography. Homozygosity for 249II as well as the combined presence of 249II and 280MM were significantly more frequent in patients with SSc compared to controls (17 vs 6%, p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75, p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion, the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of patients with SSc-associated PAH suggest a role for the fractalkine system in the pathogenesis of this condition. Further, the 249I allele might be associated with susceptibility to SSc

Protocol for a randomised controlled trial of risk screening and early intervention comparing child- and family-focused cognitive-behavioural therapy for PTSD in children following accidental injury

Background: Accidental injury represents the most common type of traumatic event to which a child or adolescent may be exposed, with a significant number of these children going on to experience posttraumatic stress disorder (PTSD). However, very little research has examined potential interventions for the treatment of PTSD in these children. The present trial aims to evaluate and compare child- and family-focused versions of a cognitive-behavioural early intervention for PTSD following accidental injury.Methods/Design: The principal clinical question under investigation is the efficacy of an early, trauma-focused cognitive-behavioural intervention for the treatment of PTSD in children following accidental injury. Specifically, we compare the efficacy of two active treatments (child-focused and family-focused CBT) and a waitlist control (no therapy) to determine which is associated with greater reductions in psychological and health-related outcome measures over time. The primary outcome will be a reduction in trauma symptoms on a diagnostic interview in the active treatments compared to the waitlist control and greater reductions in the family-compared to the child-focused condition. In doing so, this project will also trial a method of stepped screening and assessment to determine those children requiring early intervention for PTSD following accidental injury.Discussion: The present trial will be one of the first controlled trials to examine a trauma-focused CBT, early intervention for children experiencing PTSD following accidental injury (as opposed to other types of traumatic events) and the first within a stepped care approach. In addition, it will provide the first evidence comparing the efficacy of child and family-focused interventions for this target group. Given the significant number of children and adolescents exposed to accidental injury, the successful implementation of this protocol has considerable implications. If efficacious, this early intervention will assist in reducing symptoms of traumatic stress as well as preventing chronic disorder and disability in children experiencing acute PTSD following accidental injury

Patient-reported-outcomes in subjects with painful lumbar or cervical radiculopathy treated with pregabalin: evidence from medical practice in primary care settings

The objective of this study was to evaluate the effect of pregabalin in painful cervical or lumbosacral radiculopathy treated in Primary Care settings under routine clinical practice. An observational, prospective 12-week secondary analysis was carried-out. Male and female above 18 years, naïve to PGB, with refractory chronic pain secondary to cervical/lumbosacral radiculopathy were enrolled. SF-MPQ, Sheehan Disability Inventory, MOS Sleep Scale, Hospital Anxiety and Depression Scale and the EQ-5D were administered. A total of 490 (34%) patients were prescribed PGB-monotherapy, 702 (48%) received PGB add-on, and 159 (11%) were administered non-PGB drugs. After 12 weeks, significant improvements in pain, associated symptoms of anxiety, depression and sleep disturbances, general health; and level of disability were observed in the three groups, being significantly greater in PGB groups. In routine medical practice, monotherapy or add-on pregabalin is associated with substantial pain alleviation and associated symptoms improvements in painful cervical or lumbosacral radiculopathy

An exploratory study of the relationship between parental attitudes and behaviour and young people's consumption of alcohol

Background Concern is growing regarding frequent and excessive misuse of alcohol by young people. The average age at which young people in Europe start to drink is twelve and a half, and during the last decade, the quantity of alcohol consumed by younger adolescents in the UK has increased. Families are known to play an important role in shaping young people's alcohol misuse, although family risk and protective factors associated with misuse in a UK context are in need of further investigation. Methods The study used a cross-sectional design, involving secondary analyses of self-completion questionnaire responses from 6,628 secondary school children (i.e. aged 11-16 years), from 12 schools within an urban location in Wales. Items relating to family functioning and perceived parental attitudes were first subjected to factor analysis. Associations of family closeness and conflict, parental monitoring and attitudes and family history of substance misuse with children's self reported alcohol consumption were examined using logistic regression analyses. Results Approximately three quarters of respondents reported having tried alcohol, most of whom had first tried alcohol aged 12 or under. Parental monitoring and family closeness were positively correlated with one another and were both associated with significantly lower levels of drinking behaviours. Family violence and conflict, more liberal parental attitudes towards substance use and towards alcohol and petty crime, and family history of substance misuse were positively correlated with one another and with higher levels of drinking behaviours. Parental monitoring was identified as the family functioning factor most consistently associated with drinking behaviour in multivariate analyses. Conclusions Significant relationships were found between young people's drinking behaviours and perceptions of risk and protective factors in the family environment. Parental monitoring was strongly associated with family closeness and appeared to form one part of a parenting style of more general communication and regulation of children's behaviour. Findings support the need for alcohol misuse prevention interventions which address risk and protective factors within the family setting. Timing of such prevention work should be related both to the development of family relationships and the age at which young people begin drinking alcohol

The utility of the Historical Clinical Risk -20 Scale as a predictor of outcomes in decisions to transfer patients from high to lower levels of security-A UK perspective

<p>Abstract</p> <p>Background</p> <p>Structured Professional Judgment (SPJ) approaches to violence risk assessment are increasingly being adopted into clinical practice in international forensic settings. The aim of this study was to examine the predictive validity of the Historical Clinical Risk -20 (HCR-20) violence risk assessment scale for outcome following transfers from high to medium security in a United Kingdom setting.</p> <p>Methods</p> <p>The sample was predominately male and mentally ill and the majority of cases were detained under the criminal section of the Mental Health Act (1986). The HCR-20 was rated based on detailed case file information on 72 cases transferred from high to medium security. Outcomes were examined, independent of risk score, and cases were classed as "success or failure" based on established criteria.</p> <p>Results</p> <p>The mean length of follow up was 6 years. The total HCR-20 score was a robust predictor of failure at lower levels of security and return to high security. The Clinical and Risk management items contributed most to predictive accuracy.</p> <p>Conclusions</p> <p>Although the HCR-20 was designed as a violence risk prediction tool our findings suggest it has potential utility in decisions to transfer patients from high to lower levels of security.</p

Genetic Variation in the Familial Mediterranean Fever Gene (MEFV) and Risk for Crohn's Disease and Ulcerative Colitis

BACKGROUND AND AIMS: The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene. METHODOLOGY AND RESULTS: MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5' haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian-Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele. CONCLUSION: The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths

Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(-)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with "immunological chaos" evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody-mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe