Molecular mechanism of SHP2 activation by PD-1 stimulation.

In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.

Altered gray matter organization in children and adolescents with ADHD: a structural covariance connectome study.

Although multiple studies have reported structural deficits in multiple brain regions in attention-deficit hyperactivity disorder (ADHD), we do not yet know if these deficits reflect a more systematic disruption to the anatomical organization of large-scale brain networks. Here we used a graph theoretical approach to quantify anatomical organization in children and adolescents with ADHD. We generated anatomical networks based on covariance of gray matter volumes from 92 regions across the brain in children and adolescents with ADHD (n=34) and age- and sex-matched healthy controls (n=28). Using graph theory, we computed metrics that characterize both the global organization of anatomical networks (interconnectivity (clustering), integration (path length) and balance of global integration and localized segregation (small-worldness)) and their local nodal measures (participation (degree) and interaction (betweenness) within a network). Relative to Controls, ADHD participants exhibited altered global organization reflected in more clustering or network segregation. Locally, nodal degree and betweenness were increased in the subcortical amygdalae in ADHD, but reduced in cortical nodes in the anterior cingulate, posterior cingulate, mid temporal pole and rolandic operculum. In ADHD, anatomical networks were disrupted and reflected an emphasis on subcortical local connections centered around the amygdala, at the expense of cortical organization. Brains of children and adolescents with ADHD may be anatomically configured to respond impulsively to the automatic significance of stimulus input without having the neural organization to regulate and inhibit these responses. These findings provide a novel addition to our current understanding of the ADHD connectome.

A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents.

BACKGROUND: Anorexia nervosa (AN) is a serious disorder incurring high costs due to hospitalization. International treatments vary, with prolonged hospitalizations in Europe and shorter hospitalizations in the USA. Uncontrolled studies suggest that longer initial hospitalizations that normalize weight produce better outcomes and fewer admissions than shorter hospitalizations with lower discharge weights. This study aimed to compare the effectiveness of hospitalization for weight restoration (WR) to medical stabilization (MS) in adolescent AN. METHOD: We performed a randomized controlled trial (RCT) with 82 adolescents, aged 12-18 years, with a DSM-IV diagnosis of AN and medical instability, admitted to two pediatric units in Australia. Participants were randomized to shorter hospitalization for MS or longer hospitalization for WR to 90% expected body weight (EBW) for gender, age and height, both followed by 20 sessions of out-patient, manualized family-based treatment (FBT). RESULTS: The primary outcome was the number of hospital days, following initial admission, at the 12-month follow-up. Secondary outcomes were the total number of hospital days used up to 12 months and full remission, defined as healthy weight (>95% EBW) and a global Eating Disorder Examination (EDE) score within 1 standard deviation (s.d.) of published means. There was no significant difference between groups in hospital days following initial admission. There were significantly more total hospital days used and post-protocol FBT sessions in the WR group. There were no moderators of primary outcome but participants with higher eating psychopathology and compulsive features reported better clinical outcomes in the MS group. CONCLUSIONS: Outcomes are similar with hospitalizations for MS or WR when combined with FBT. Cost savings would result from combining shorter hospitalization with FBT.

Mitochondrial DNA sequence and phylogenetic evaluation of geographically disparate Sus scrofa breeds.

Next generation sequencing of mitochondrial DNA (mtDNA) facilitates studies into the metabolic characteristics of production animals and their relation to production traits. Sequence analysis of mtDNA from pure-bred swine with highly disparate production characteristics (Mangalica Blonde, Mangalica Swallow-bellied, Meishan, Turopolje, and Yorkshire) was initiated to evaluate the influence of mtDNA polymorphisms on mitochondrial function. Herein, we report the complete mtDNA sequences of five Sus scrofa breeds and evaluate their position within the phylogeny of domestic swine. Phenotypic traits of Yorkshire, Mangalica Blonde, and Swallow-belly swine are presented to demonstrate their metabolic characteristics. Our data support the division of European and Asian breeds noted previously and confirm European ancestry of Mangalica and Turopolje breeds. Furthermore, mtDNA differences between breeds suggest function-altering changes in proteins involved in oxidative phosphorylation such as ATP synthase 6 (MT-ATP6), cytochrome oxidase I (MT-CO1), cytochrome oxidase III (MT-CO3), and cytochrome b (MT-CYB), supporting the hypothesis that mtDNA polymorphisms contribute to differences in metabolic traits between swine breeds. Our sequence data form the basis for future research into the roles of mtDNA in determining production traits in domestic animals. Additionally, such studies should provide insight into how mtDNA haplotype influences the extreme adiposity observed in Mangalica breeds.

IBM's Health Analytics and Clinical Decision Support.

OBJECTIVES: This survey explores the role of big data and health analytics developed by IBM in supporting the transformation of healthcare by augmenting evidence-based decision-making. METHODS: Some problems in healthcare and strategies for change are described. It is argued that change requires better decisions, which, in turn, require better use of the many kinds of healthcare information. Analytic resources that address each of the information challenges are described. Examples of the role of each of the resources are given. RESULTS: There are powerful analytic tools that utilize the various kinds of big data in healthcare to help clinicians make more personalized, evidenced-based decisions. Such resources can extract relevant information and provide insights that clinicians can use to make evidence-supported decisions. There are early suggestions that these resources have clinical value. As with all analytic tools, they are limited by the amount and quality of data. CONCLUSION: Big data is an inevitable part of the future of healthcare. There is a compelling need to manage and use big data to make better decisions to support the transformation of healthcare to the personalized, evidence-supported model of the future. Cognitive computing resources are necessary to manage the challenges in employing big data in healthcare. Such tools have been and are being developed. The analytic resources, themselves, do not drive, but support healthcare transformation.

Food insecurity, food assistance and weight status in US youth: new evidence from NHANES 2007-08.

OBJECTIVE: To investigate food assistance participation as a risk factor for overweight and obesity in youth, and food insecurity as an effect modifier. METHODS: The sample included youth ages 4-17, in families ≤200% of the federal poverty line in the 2007-2008 National Health and Nutrition Examination Survey (n = 1321). Food insecurity was measured with the US Department of Agriculture survey module. Food assistance participation was assessed for Supplemental Nutrition Assistance Program, Special Supplemental Nutrition Program for Women, Infants and Children and school meals. Body size was classified by age- and sex-specific body mass index (BMI) percentile, BMI z-score and waist circumference percentile. Regression models with direct covariate adjustment and programme-specific propensity scores, stratified by food insecurity, estimated associations between food assistance participation and body size. RESULTS: Food assistance participation was not associated with increased body size among food-insecure youth in models with direct covariate adjustment or propensity scores. Compared with low-income, food-secure youth not participating in food assistance, BMI z-scores were higher among participants in models with direct covariate adjustment (0.27-0.38 SD and 0.41-0.47 SD, for boys and girls, respectively). Using propensity scores, results were similar for boys, but less so for girls. CONCLUSIONS: Food assistance programme participation is associated with increased body size in food-secure youth, but not food-insecure youth. Using both direct covariate adjustment and a propensity score approach, self-selection bias may explain some, but not all, of the associations. Providing healthy food assistance that improves diet quality without contributing to excessive intake remains an important public health goal.

Two-year outcomes of an adjunctive telephone coaching and electronic contact intervention for adolescent weight-loss maintenance: the Loozit randomized controlled trial.

This paper reports the final 24-month outcomes of a randomized controlled trial evaluating the effect of additional therapeutic contact (ATC) as an adjunct to a community-based weight-management program for overweight and obese 13-16-year-olds. ATC involved telephone coaching or short-message-service and/or email communication once per fortnight. Adolescents were randomized to receive the Loozit group program-a two-phase behavioral lifestyle intervention with (n=73), or without (n=78), ATC in Phase 2. Adolescents/parents separately attended seven weekly group sessions (Phase 1), followed by quarterly adolescent sessions (Phase 2). Assessor-blinded, 24-month changes in anthropometry and metabolic health included primary outcomes body mass index (BMI) z-score and waist:height ratio (WHtR). Secondary outcomes were self-reported psychosocial and lifestyle changes. By 24 months, 17 adolescents had formally withdrawn. Relative to the Loozit program alone, ATC largely had no impact on outcomes. Secondary pre-post assessment of the Loozit group program showed mean (95% CI) reductions in BMI z-score (-0.13 (-0.20, -0.06)) and WHtR (-0.02 (-0.03, -0.01)) in both arms, with several metabolic and psychosocial improvements. Adjunctive ATC did not provide further benefits to the Loozit group program. We recommend that further work is needed to optimize technological support for adolescents in weight-loss maintenance. Australian New Zealand Clinical Trials Registry Number ACTRNO12606000175572.

Anorexia nervosa: towards an integrative neuroscience model.

We reviewed the evidence for emotion-related disturbances in anorexia nervosa (AN) from behavioural, cognitive, biological and genetic domains of study. These domains were brought together within the framework of an integrative neuroscience model that emphasizes the role of emotion and feeling and their regulation, in brain organization. PsychInfo and Medline searches were performed to identify published peer-reviewed papers on AN within each domain. This review revealed evidence for 'Emotion', 'Thinking and Feeling' and 'Self-regulation' disturbances in AN that span non-conscious to conscious processes. An integrative neuroscience framework was then applied to develop a model of AN, from which hypotheses for empirical investigation are generated. We propose that AN reflects a core disturbance in emotion at the earliest time stage of information processing with subsequent effects on the later stages of thinking, feeling and self-regulation.

Ascites improves upon [corrected] serum sodium plus [corrected] model for end-stage liver disease (MELD) for predicting mortality in patients with advanced liver disease.

BACKGROUND: The clinical impact of ascites has historically been well recognized; however, its value is unclear in the context of current prognostic models. AIM: To determine whether ascites can improve risk discrimination beyond model for end-stage liver disease (MELD) and serum sodium (MELDNa). METHODS: Consecutive cirrhotic patients were evaluated for ascites on the basis of an outpatient CT along with concurrent MELD and Na values. Cox models were used to determine the added value of ascites for predicting 1-year mortality. Increases in the C-index, integrated discrimination improvement (IDI) and the net reclassification index (NRI) were used to assess improvements in discrimination after the addition of ascites. RESULTS: A total of 1003 patients had Na and MELD scores available within 30 days of the CT scan. A total of 60 deaths occurred within 1 year, with mortality higher in patients with ascites (21.4% vs. 4.0%, HR 6.08, 95% CI 3.62-10.19, P < 0.0005). In the presence of ascites, the MELD and MELDNa scores underestimated mortality risk when the scores were less than 21. The addition of ascites to the MELDNa model substantially improved discrimination by the C-index (0.804 vs. 0.770, increase of 3.4%, 95% CI 0.2-9.9%), IDI (1.8%, P = 0.016) and NRI (15.8%, P = 0.0006). CONCLUSION: The incorporation of radiographic ascites significantly improves upon MELDNa for predicting 1-year mortality. The presence of ascites may help identify patients at increased risk for mortality, not otherwise captured by either MELD or MELDNa.

Determining genetic background in captive stocks of cynomolgus macaques (Macaca fascicularis).

BACKGROUND: As in other model organisms, genetic background in the non-human primates Macaca mulatta and Macaca fascicularis is an experimental variable that affects the response of other study variables. Genetic background in model organisms is manipulated by breeding schemes but is generally pre-determined by the source population used to found captive stocks. In M. fascicularis three such sources have been distinguished, however, these are not routinely taken into consideration when designing research. METHODS: We exemplify a mitochondrial DNA (mtDNA)-based strategy to trace the maternal geographic origins of M. fascicularis animals of unspecified origins. RESULTS: Macaca fascicularis of unspecified origins kept at primate research centers carry mtDNA haplotypes representing all three major genetic subdivisions. CONCLUSIONS: We suggest that the genetic background of study animals could be better specified in the future using an mtDNA-based approach, which would enable informed selection of study animals and help reduce variation within and among studies.

Recruitment of old genes to new functions: evidences obtained by comparing the orthologues of human XLMR genes in mouse and chicken.

Gene mapping data indicate that the human X chromosome is enriched in genes that affect both, higher cognitive efficiency and reproductive success. This raises the question whether these functions are ancient, or whether conserved X-linked genes were recruited to new functions. We have studied three X-linked mental retardation (XLMR) genes by RNA in situ hybridization in mouse and in chicken, in which these genes are autosomal: Rho guanine nucleotide exchange factor 6 (ARHGEF6), oligophrenin (OPHN1), and p21 activated kinase 3 (PAK3). In the mouse these genes are specifically expressed in telencephalic regions. Their orthologues in the chicken gave patterns of similar specificity in ancient parts of the brain, i.e. cerebellum and mesencephalon, but were not expressed in the telencephalon. Also in the testes, specific expression was only found in mouse, not in chicken. These data are interpreted such that certain genes on the X chromosome gained novel functions during evolution.

The effects of executive and behavioral dysfunction on the course of ALS.

OBJECTIVE: To determine whether patients with ALS-frontotemporal lobar dementia (FTLD) have a shorter survival and are less compliant with recommended treatments than those with ALS who have normal executive and behavioral function (classic ALS). METHODS: Survival analysis from ALS symptom onset to death included 81 of 100 consecutive patients who could be classified definitely as ALS with abnormal executive or behavioral function or as classic ALS. Criteria were defined for compliance with noninvasive positive-pressure ventilation (NPPV) and percutaneous endoscopic gastrostomy (PEG). RESULTS: Median survival was 2 years 4 months for the 28 patients with FTLD and 3 years 3 months for the 53 patients with classic ALS (relative hazard for death 1.93, CI 1.09 to 3.43; p = 0.024). However, the relative hazard associated with FTLD (1.49) in the multivariate model was diminished by the association of FTLD with bulbar onset and older age and was not significant in this sample size. With bulbar onset, median survival was 2 years 0 months for the 14 with ALS-FTLD and 2 years 10 months for the 10 with classic ALS (relative hazard for death 2.78, CI 1.02 to 7.55; p = 0.045), and older age was not a significant risk. Noncompliance with NPPV and PEG were 75% and 72% in ALS-FTLD, respectively, vs 38% and 31% in classic ALS (relative risks 2.00 and 2.34; p = 0.013 and 0.022). CONCLUSIONS: Survival is significantly shorter among patients with ALS-FTLD than with classic ALS. Furthermore, patients with ALS-FTLD are twice as likely to be noncompliant.

Attention deficit disorder: not just for children.

Abstract Attention deficit/hyperactivity disorder (ADHD) has long been described in children who demonstrate developmentally inappropriate symptoms of inattention, impulsivity and motor restlessness. In adults, symptoms are known to persist and the validity of adult ADHD as an entity is now recognized. There is an associated high proportion of other serious psychiatric comorbidities, especially substance abuse, mood and anxiety disorders. Advances have been made into the aetiology and management of ADHD. Many of these focus on the dopamine and noradrenaline pathways.

Localization of human X chromosomal mental retardation (MRX) genes in chicken and comparison with the chicken genome sequence data.

In an ongoing study human X chromosomal mental retardation genes (MRX) were mapped in the chicken genome. Up to now the homologs of 13 genes were localized by FISH techniques. Four genes from HSAXp (TM4SF2, RSK2/RPS6KA3, NLGN4, ARX) map to GGA1q13-->q31, and seven genes from HSAXq (OPHN1, AGTR2, ARHGEF6, PAK3, FACL4/ACS4, FMR2, ATRX) to GGA4p. The gene-rich region of HSAXq28 proved to be much less conserved. GDI1 localized to GGA1pter and SLC6A8 to a mid-sized microchromosome. The order of the genes was determined from the newly available genome sequence data from chicken, which reveals exact colinearity between the genes in HSAXp and GGA1q13-->q31, but completely scrambled gene order between the genes with common synteny from HSAXq and GGA4p. This result supports the hypothesis that the human X chromosome is a real ancient autosomal linkage group.

High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene.

Detailed analyses of 20 patients with sporadic neurofibromatosis type 1 (NF1) microdeletions revealed an unexpected high frequency of somatic mosaicism (8/20 [40%]). This proportion of mosaic deletions is much higher than previously anticipated. Of these deletions, 16 were identified by a screen of unselected patients with NF1. None of the eight patients with mosaic deletions exhibited the mental retardation and facial dysmorphism usually associated with NF1 microdeletions. Our study demonstrates the importance of a general screening for NF1 deletions, regardless of a special phenotype, because of a high estimated number of otherwise undetected mosaic NF1 microdeletions. In patients with mosaicism, the proportion of cells with the deletion was 91%-100% in peripheral leukocytes but was much lower (51%-80%) in buccal smears or peripheral skin fibroblasts. Therefore, the analysis of other tissues than blood is recommended, to exclude mosaicism with normal cells in patients with NF1 microdeletions. Furthermore, our study reveals breakpoint heterogeneity. The classic 1.4-Mb deletion was found in 13 patients. These type I deletions encompass 14 genes and have breakpoints in the NF1 low-copy repeats. However, we identified a second major type of NF1 microdeletion, which spans 1.2 Mb and affects 13 genes. This type II deletion was found in 8 (38%) of 21 patients and is mediated by recombination between the JJAZ1 gene and its pseudogene. The JJAZ1 gene, which is completely deleted in patients with type I NF1 microdeletions and is disrupted in deletions of type II, is highly expressed in brain structures associated with learning and memory. Thus, its haploinsufficiency might contribute to mental impairment in patients with constitutional NF1 microdeletions. Conspicuously, seven of the eight mosaic deletions are of type II, whereas only one was a classic type I deletion. Therefore, the JJAZ1 gene is a preferred target of strand exchange during mitotic nonallelic homologous recombination. Although type I NF1 microdeletions occur by interchromosomal recombination during meiosis, our findings imply that type II deletions are mediated by intrachromosomal recombination during mitosis. Thus, NF1 microdeletions acquired during mitotic cell divisions differ from those occurring in meiosis and are caused by different mechanisms.

Iron status and haematological changes in adolescent female inpatients with anorexia nervosa.

OBJECTIVES: (i) To investigate the incidence of iron deficiency (both latent iron deficiency and iron deficiency anaemia) in post menarchal female adolescent patients hospitalized with anorexia nervosa. (ii) To observe changes in iron status during refeeding. METHODS: During the study period all post menarchal female patients admitted to the adolescent unit with anorexia nervosa were invited to participate. Ferritin, serum iron, transferrin and transferrin saturation were measured on admission and discharge. Haemoglobin, haematocrit, weight, and body mass index were monitored weekly. RESULTS: All 12 eligible patients participated in the study. Four patients had elevated ferritin levels on admission. Ten of the 12 showed a statistically significant fall in serum ferritin at time of discharge compared with admission (P = 0.004). One of 12 patients had a low serum iron at presentation. All 12 had normal serum iron levels at discharge. Nine of the 12 subjects had a higher serum iron at discharge which was statistically significant (P = 0.046). There was no significant change in haemoglobin levels when comparing admission and discharge levels. Nine of the 12 patients however, transiently developed anaemia, at some stage during treatment. CONCLUSIONS: Iron deficiency is uncommon at both presentation and after nutritional rehabilitation in post menarchal adolescent females with anorexia nervosa. This is most likely due to increased iron storage secondary to the contraction of the circulating blood volume and reduced iron losses from (secondary) amenorrhoea. The fall in ferritin observed during treatment is due to haemopoiesis necessary to fill the increased blood volume associated with weight gain. This also results in normalization of the haemoglobin and haematocrit.

Biochemical origins of the non-monotonic receptor-mediated dose-response.

A mathematical model was created to examine how xenobiotic ligands that bind to nuclear receptor proteins may affect transcriptional activation of hormone-regulated genes. The model included binding of the natural ligand (e.g. hormone) and xenobiotic ligands to the receptor, binding of the liganded receptor to receptor-specific DNA response sequences, binding of co-activator or co-repressor proteins (Rp) to the resulting complex, and the consequent transcriptional rate relative to that in the absence of the xenobiotic agent. The model predicted that the xenobiotic could act as a pure agonist, a pure antagonist, or a mixed agonist whose dose-response curve exhibits a local maximum. The response to the agent depends on the affinity of the liganded receptor-DNA complex for binding additional transcription factors (e.g. co-activator proteins). An inverted U-shaped dose-response occurred when basal levels of the natural ligand did not saturate receptor binding sites and the affinity for co-activator is weaker when the xenobiotic ligand is bound to the receptor than when the endogenous ligand is bound. The dose-response curve shape was not dependent on the affinity of the receptor for the xenobiotic agent; alteration of this value merely shifted the curve along the concentration axis. The amount of receptor, the density of DNA response sequences, and the affinity of the DNA-bound receptor for Rp determine the amplitude of the computed response with little overall change in curve shape. This model indicates that a non-monotonic dose-response is a plausible outcome for xenobiotic agents that activate nuclear receptors in the same manner as natural ligands.