Self-Directed Behavioral Family Intervention for Parents of Oppositional Children in Rural and Remote Areas

Twenty-four parents of oppositional preschoolers were randomly assigned to either a self-directed behavioral family intervention condition (SD) or to a waitlist control group (WL). The self-directed parent training program based on self-regulation principles, consisted of a written information package and weekly telephone consultations for 10 weeks. At posttest, in comparison to the WL group, children in the SD group had lower levels of behavior problems on parent report measures of child behavior. At posttreatment, parents in the SD condition reported increased levels of parenting competence and lower levels of dysfunctional parenting practices as compared to parents in the WL condition. In addition, mothers reported lower levels of anxiety, depression, and stress as compared to mothers in the WL condition at posttreatment. Using mother's reports, gains in child behavior and parenting practices achieved at posttreatment were maintained at 4-month follow-up.

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development(1,2). Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations(3), is necessary for normal esophageal squamous development(4), promotes differentiation and proliferation of basal tracheal cells(5) and cooperates in induction of pluripotent stem cells(6-8). SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.

Comparative epidemiology of chronic fatigue syndrome in Brazilian and British primary care: prevalence and recognition

Background Although fatigue is a ubiquitous symptom across countries, clinical descriptions of chronic fatigue syndrome have arisen from a limited number of high-income countries. This might reflect differences in true prevalence or clinical recognition influenced by sociocultural factors. Aims To compare the prevalence, physician recognition and diagnosis of chronic fatigue syndrome in London and Sao Paulo. Method Primary care patients in London (n=2459) and Sao Paulo n=3914) were surveyed for the prevalence of chronic fatigue syndrome. Medical records were reviewed for the physician recognition and diagnosis. Results The prevalence of chronic fatigue syndrome according to Centers for Disease Control 1994 criteria was comparable in Britain and Brazil, 2.1% v. 1.6% (P=0.20). Medical records review identified 11 diagnosed cases of chronic fatigue syndrome in Britain, but none in Brazil (P<0.001). Conclusions The primary care prevalence of chronic fatigue syndrome was similar in two Culturally and economically distinct nations. However, doctors are unlikely to recognise and label chronic fatigue syndrome as a discrete disorder in Brazil. The recognition of this illness rather than the illness itself may be culturally induced.

IRF8 Mutations and Human Dendritic-Cell Immunodeficiency

BACKGROUND The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guerin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.)

Twelve-Month Prevalence of and Risk Factors for Suicide Attempts in the World Health Organization World Mental Health Surveys

Objective: Although suicide is a leading cause of death worldwide, clinicians and researchers lack a data-driven method to assess the risk of suicide attempts. This study reports the results of an analysis of a large cross-national epidemiologic survey database that estimates the 12-month prevalence of suicidal behaviors, identifies risk factors for suicide attempts, and combines these factors to create a risk index for 12-month suicide attempts separately for developed and developing countries. Method: Data come from the World Health Organization (WHO) World Mental Health (WMH) Surveys (conducted 2001-2007), in which 108,705 adults from 21 countries were interviewed using the WHO Composite International Diagnostic Interview. The survey assessed suicidal behaviors and potential risk factors across multiple domains, including socio-demographic characteristics, parent psychopathology, childhood adversities, DSM-IV disorders, and history of suicidal behavior. Results: Twelve-month prevalence estimates of suicide ideation, plans, and attempts are 2.0%, 0.6%, and 0.3%, respectively, for developed countries and 2.1%, 0.7%, and 0.4%, respectively, for developing countries. Risk factors for suicidal behaviors in both developed and developing countries include female sex, younger age, lower education and income, unmarried status, unemployment, parent psychopathology, childhood adversities, and presence of diverse 12-month DSM-IV mental disorders. Combining risk factors from multiple domains produced risk indices that accurately predicted 12-month suicide attempts in both developed and developing countries (area under the receiver operating characteristic curve = 0.74-0.80). Conclusions: Suicidal behaviors occur at similar rates in both developed and developing countries. Risk indices assessing multiple domains can predict suicide attempts with fairly good accuracy and may be useful in aiding clinicians in the prediction of these behaviors. J Clin Psychiatry 2010;71(12):1617-1628 (C) Copyright 2010 Physicians Postgraduate Press, Inc.

Associations of serious mental illness with earnings: results from the WHO World Mental Health surveys

Background Burden-of-illness data, which are often used in setting healthcare policy-spending priorities, are unavailable for mental disorders in most countries. Aims To examine one central aspect of illness burden, the association of serious mental illness with earnings, in the World Health Organization (WHO) World Mental Health (WMH) Surveys. Method The WMH Surveys were carried out in 10 high-income and 9 low- and middle-income countries. The associations of personal earnings with serious mental illness were estimated. Results Respondents with serious mental illness earned on average a third less than median earnings, with no significant between-country differences (chi(2)(9)=5.5-8.1, P=0.5-0.79). These losses are equivalent to 0.3-0.8% of total national earnings. Reduced earnings among those with earnings and the increased probability of not earning are both important components of these associations: Conclusions These results add to a growing body of evidence that mental disorders have high societal costs. Decisions about healthcare resource allocation should take these costs into consideration.

Childhood adversities as risk factors for onset and persistence of suicidal behaviour

Background Suicide is a leading cause of death worldwide, but the precise effect of childhood adversities as risk factors for the onset and persistence of suicidal behaviour (suicide ideation, plans and attempts) are not well understood. Aims To examine the associations between childhood adversities as risk factors for the onset and persistence of suicidal behaviour across 21 countries worldwide. Method Respondents from nationally representative samples (n = 55 299) were interviewed regarding childhood adversities that occurred before the age of 18 years and lifetime suicidal behaviour. Results Childhood adversities were associated with an increased risk of suicide attempt and ideation in both bivariate and multivariate models (odds ratio range 1.2-5.7). The risk increased with the number of adversities experienced, but at a decreasing rate. Sexual and physical abuse were consistently the strongest risk factors for both the onset and persistence of suicidal behaviour, especially during adolescence. Associations remained similar after additional adjustment for respondents` lifetime mental disorder status. Conclusions Childhood adversities (especially intrusive or aggressive adversities) are powerful predictors of the onset and persistence of suicidal behaviours.

alpha-Melanocyte Stimulating Hormone Analogue AP214 Protects Against Ischemia Induced Acute Kidney Injury in a Porcine Surgical Model

Purpose: alpha-Melanocyte stimulating hormone protects kidneys against ischemia and sepsis induced acute kidney injury in rodents. We examined the efficacy of a-melanocyte stimulating hormone analogue AP214 to protect against acute kidney injury in higher vertebrates. Materials and Methods: We performed a prospective, blinded, randomized, placebo controlled study in 26 pigs. Laparoscopic technique was used for left nephrectomy and to induce complete warm ischemia in the right kidney for 120 minutes. AP214 (200 mu g/kg intravenously) was administered daily on the day of surgery and for 5 days thereafter. Kidney function was measured for 9 days. We measured changes in serum creatinine, estimated glomerular filtration rate, serum C-reactive protein and urine interleukin-18. Results: In the placebo control and AP214 groups mean peak serum creatinine was 10.2 vs 3.92 mg/dl and the estimated glomerular filtration rate nadir was 22.9 vs 62.6 ml per minute per kg (each p = 0.001). Functional nadir occurred at 72 vs 24 hours in the control vs AP214 groups. Estimated glomerular filtration rate outcome on postoperative day 9 was 118 vs 156 ml per minute per kg in the control vs AP214 groups (p = 0.04). Conclusions: We noted a robust renoprotective effect of AP214. A similar AP214 effect may be observed in humans. Future research includes mechanistic studies in pigs and a phase II human clinical trial of AP214 in kidney transplant and partial nephrectomy populations.

Combination of Multiple Molecular Markers Can Improve Prognostication in Patients With Locally Advanced and Lymph Node Positive Bladder Cancer

Purpose: We tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker. Materials and Methods: The study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy. Results: Individual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly 1 higher predictive accuracy than any single biomarker (p < 0.001.). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p < 0.001) and cancer specific mortality (4.3%, p < 0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p < 0.001). Conclusions: While the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.

Right adolescent idiopathic thoracic curve (Lenke 1 A and B): does cost of instrumentation and implant density improve radiographic and cosmetic parameters?

In adolescent idiopathic scoliosis (AIS) there has been a shift towards increasing the number of implants and pedicle screws, which has not been proven to improve cosmetic correction. To evaluate if increasing cost of instrumentation correlates with cosmetic correction using clinical photographs. 58 Lenke 1A and B cases from a multicenter AIS database with at least 3 months follow-up of clinical photographs were used for analysis. Cosmetic parameters on PA and forward bending photographs included angular measurements of trunk shift, shoulder balance, rib hump, and ratio measurements of waist line asymmetry. Pre-op and follow-up X-rays were measured for coronal and sagittal deformity parameters. Cost density was calculated by dividing the total cost of instrumentation by the number of vertebrae being fused. Linear regression and spearman`s correlation were used to correlate cost density to X-ray and photo outcomes. Three independent observers verified radiographic and cosmetic parameters for inter/interobserver variability analysis. Average pre-op Cobb angle and instrumented correction were 54A degrees (SD 12.5) and 59% (SD 25) respectively. The average number of vertebrae fused was 10 (SD 1.9). The total cost of spinal instrumentation ranged from $6,769 to $21,274 (Mean $12,662, SD $3,858). There was a weak positive and statistically significant correlation between Cobb angle correction and cost density (r = 0.33, p = 0.01), and no correlation between Cobb angle correction of the uninstrumented lumbar spine and cost density (r = 0.15, p = 0.26). There was no significant correlation between all sagittal X-ray measurements or any of the photo parameters and cost density. There was good to excellent inter/intraobserver variability of all photographic parameters based on the intraclass correlation coefficient (ICC 0.74-0.98). Our method used to measure cosmesis had good to excellent inter/intraobserver variability, and may be an effective tool to objectively assess cosmesis from photographs. Since increasing cost density only improves mildly the Cobb angle correction of the main thoracic curve and not the correction of the uninstrumented spine or any of the cosmetic parameters, one should consider the cost of increasing implant density in Lenke 1A and B curves. In the area of rationalization of health care expenses, this study demonstrates that increasing the number of implants does not improve any relevant cosmetic or radiographic outcomes.

The genome of the blood fluke Schistosoma mansoni

Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

Aicardi-Goutieres syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

The Genome Sequence of Taurine Cattle: A Window to Ruminant Biology and Evolution

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.