Harnessing endogenous peptide compounds as potential therapeutics for severe influenza.

BACKGROUND: Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic, 16 amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter, linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides. A 6 amino acid linear peptide fragment of LAT8881, LAT9997, was investigated as a potential influenza therapy. METHODS: LAT9997 was evaluated for its potential to limit disease in a preclinical mouse model of severe influenza infection. RESULTS: Intranasal treatment of mice with either LAT8881 or LAT9997 from day 1 following influenza infection significantly improved survival outcomes. Initiating LAT9997 treatment at the onset of severe disease, also significantly improved disease severity. Greater disease resistance in LAT9997-treated mice correlated with reduced lung immunopathology, damage markers, vascular leak, and epithelial cell death. Treatment reduced viral loads, cytokines, and neutrophil infiltration in the airways, yet maintained protective alveolar macrophages in a dose-dependent manner. Sequential trimming of N- and C-terminal amino acids from LAT9997 revealed a structure-activity relationship. CONCLUSIONS: These findings provide preclinical evidence that therapeutic LAT9997 treatment limits viral burden and characteristic features of severe influenza, including hyperinflammation and lung damage.

Naturally derived cytokine peptides limit virus replication and severe disease during influenza A virus infection.

Objectives: Novel host-targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C-terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis. LAT8881 has been assessed in clinical trials for the treatment of obesity and neuropathy and has an excellent safety profile. We investigated the potential for LAT8881, its metabolite LAT9991F and LAT7771 derived from prolactin, a growth hormone structural homologue, to treat severe IAV infection. Methods: LAT8881, LAT9991F and LAT7771 were evaluated for their effects on cell viability and IAV replication in vitro, as well as their potential to limit disease in a preclinical mouse model of severe IAV infection. Results: In vitro LAT8881 treatment enhanced cell viability, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C-like proteins. Daily intranasal treatment of mice with LAT8881 or LAT9991F, but not LAT7771, from day 1 postinfection significantly improved influenza disease resistance, which was associated with reduced infectious viral loads, reduced pro-inflammatory cytokines and increased abundance of protective alveolar macrophages. LAT8881 treatment in combination with the antiviral oseltamivir phosphate led to more pronounced reduction in markers of disease severity than treatment with either compound alone. Conclusion: These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host-protective therapies that improve survival, limit viral replication, reduce local inflammation and curtail tissue damage during severe IAV infection. Evaluation of LAT8881 and LAT9991F in other infectious and inflammatory conditions of the airways is warranted.

The Families and Schools for Health Project: A Longitudinal Cluster Randomized Controlled Trial Targeting Children with Overweight and Obesity.

This cluster randomized controlled trial aimed at overweight and obese children compared three treatments. Two psychoeducation interventions for parents and children were conducted: Family Lifestyle (FL) focused on food and physical activity; Family Dynamics (FD) added parenting and healthy emotion management. A third Peer Group (PG) intervention taught social acceptance to children. Crossing interventions yielded four conditions: FL, FL + PG, FL + FD, and FL + FD + PG-compared with the control. Longitudinal BMI data were collected to determine if family- and peer-based psychosocial components enhanced the Family Lifestyle approach. Participants were 1st graders with BMI%ile >75 (n = 538: 278 boys, 260 girls). Schools were randomly assigned to condition after stratifying for community size and percent American Indian. Anthropometric data were collected pre- and post-intervention in 1st grade and annually through 4th grade. Using a two-level random intercept growth model, intervention status predicted differences in growth in BMI or BMI-M% over three years. Children with obesity who received the FL + FD + PG intervention had lower BMI gains compared to controls for both raw BMI (B = -0.05) and BMI-M% (B = -2.36). Interventions to simultaneously improve parent, child, and peer-group behaviors related to physical and socioemotional health offer promise for long-term positive impact on child obesity.

Transcriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression.

BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.

Too young to die? How aging affects cellular innate immune responses to influenza virus and disease severity.

Influenza is a respiratory viral infection that causes significant morbidity and mortality worldwide. The innate immune cell response elicited during influenza A virus (IAV) infection forms the critical first line of defense, which typically is impaired as we age. As such, elderly individuals more commonly succumb to influenza-associated complications, which is reflected in most aged animal models of IAV infection. Here, we review the important roles of several major innate immune cell populations in influenza pathogenesis, some of which being deleterious to the host, and the current knowledge of how age-associated numerical, phenotypic and functional cell changes impact disease development. Further investigation into age-related modulation of innate immune cell responses, using appropriate animal models, will help reveal how immunity to IAV may be compromised by aging and inform the development of novel therapies, tailored for use in this vulnerable group.

Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

The Social and Emotional Lives of Overweight, Obese, and Severely Obese Children.

This study examines inter- and intrapersonal problems associated with being overweight among one thousand one hundred sixty-four 6- to 7-year-olds (49% boys) in 29 rural schools. Socioemotional data include child self-reports, peer sociometrics, and teacher reports. Results support the hypothesis that children with weight problems struggle socially and emotionally, and extend current understanding of child obesity by demonstrating that problems appear early, are evident in a community sample, can be identified using standard sociometric methods, and are worse among children with severe obesity. Sociometric status difference between levels of obesity were also found. Although obese children were neglected by peers, severely obese children were rejected.

Child gender and weight status moderate the relation of maternal feeding practices to body esteem in 1st grade children.

Prevention of body dissatisfaction development is critical for minimizing adverse effects of poor body esteem on eating behaviors, self-esteem, and overall health. Research has examined body esteem and its correlates largely in pre-adolescents and adolescents; however, important questions remain about factors influencing body esteem of younger children. The main purpose of this study was to test moderation by children's gender and weight status of the relation of maternal controlling feeding practices to 1st graders' body esteem. The Body Esteem Scale (BES) and anthropometric measurements were completed during one-on-one child interviews at school. Mothers completed the Child Feeding Questionnaire (restriction, monitoring, concern, self-assessed maternal weight). A total of 410 mother/child dyads (202 girls) participated. Percent of children classified as overweight (BMI-for-age ≥85th) was: girls - 29%; boys - 27%. Gender moderated the relation between restriction and body esteem (ß = -.140, p = .05), with maternal restriction predicting body esteem in girls but not boys. The hypothesized three-way interaction among gender, child weight status, and monitoring was confirmed. Monitoring was significantly inversely related to body esteem only for overweight/obese girls (b = -1.630). The moderating influence of gender or gender and weight status on the link between maternal feeding practices and body esteem suggests the importance of body esteem interventions for girls as early as first grade.

CSF xanthochromia analysis takes longer following centralisation of the laboratories testing samples - how can we improve the time to result?

Lumbar puncture is an essential tool for excluding subarachnoid haemorrhage. In August 2012, the laboratory at which cerebrospinal fluid (CSF) is analysed for xanthochromia in Lanarkshire was centralised at Hairmyres (East Kilbride, UK). Prior to this, each of the three hospitals analysed their own specimens. We aim to assess whether or not the change in xanthochromia processing has resulted in diagnostic delay at Wishaw General Hospital in the assessment of CT negative possible subarachnoid haemorrhage. We subsequently assessed the impact of a strategy to minimise any delay, i.e. increasing laboratory processing hours. Patients undergoing CSF analysis for xanthochromia were identified directly from the laboratory database. Time of lumbar puncture, and time of xanthochromia results were obtained from the hospital's laboratory computer system. Data were analysed using a commercially available statistical software programme (Microsoft Excel). Audit was repeated after the change to a centralised laboratory, and again following the increased laboratory working hours. Mean time from lumbar puncture to availability of xanthochromia result was significantly longer following the laboratory change (20.8±3.5 hours post [n=35] vs. 12.5±3.0 pre, p=0.01 [n=17]). However, following a change in the laboratory's practice, there was no improvement (19.8±3.4 hours post practice change [n=35]), and this remained significantly longer when compared to the original laboratory set-up (p=0.025). The change in laboratory processing CSF samples for xanthochromia in Lanarkshire resulted in a significant delay in analysing the samples. Attempts by the laboratory to extend processing hours did not make any significant improvement, but having expanded our knowledge of the issues, further measures are now planned to minimise delays in the future. Centralisation of laboratory services for CSF analysis, whilst cheaper, may impact negatively on clinical care.

Emotion regulation is related to children's emotional and external eating.

OBJECTIVE: The objective of this study was to examine the associations between 2 types of emotion regulation (reactivity and inhibition) and 2 types of non-hunger-based eating (emotional eating and external eating). Although emotion regulation and eating regulation problems have both been linked to obesity in previous studies, there is little research examining the link between the two, particularly among children. METHODS: A total of 782 rural second graders (49% girls, 20% American Indian) were followed longitudinally through third grade. During both data collection points, children participated in face-to-face interviews at school using the Children's Emotion Management Scales and the revised Dutch Eating Behavior Questionnaire. RESULTS: Correlational analyses revealed that children's emotion regulation was significantly related to both external and emotional eating within and across grades, with reactivity appearing to be more consistently related to eating regulation than was inhibition. Regression analyses showed that second to third grade increases in external and emotional eating were predicted by increases in reactivity to anger and reactivity to worry. CONCLUSIONS: Given the established link in previous research between poor behavioral regulation and obesity in children, findings from this study linking child emotional reactivity and emotional and external eating (both forms of behavior dysregulation) are important in informing prevention and treatment programs. Based on these findings, targeting child emotion regulation in addition to behavior regulation skills as part of prevention and intervention programs may improve program effectiveness.

The TACI receptor regulates T-cell-independent marginal zone B cell responses through innate activation-induced cell death.

Activation-induced cell death (AICD) plays a critical role in immune homeostasis and tolerance. In T-cell-dependent humoral responses, AICD of B cells is initiated by Fas ligand (FasL) on T cells, stimulating the Fas receptor on B cells. In contrast, T-cell-independent B cell responses involve innate-type B lymphocytes, such as marginal zone (MZ) B cells, and little is known about the mechanisms that control AICD during innate B cell responses to Toll-like receptor (TLR) activation. Here, we show that MZ B cells undergo AICD in response to TLR4 activation in vivo. The transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor and TLR4 cooperate to upregulate expression of both FasL and Fas on MZ B cells and also to repress inhibitors of Fas-induced apoptosis signaling. These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses.

The CD19 signalling molecule is elevated in NOD mice and controls type 1 diabetes development.

AIMS/HYPOTHESIS: Type 1 diabetes is characterised by early peri-islet insulitis and insulin autoantibodies, followed by invasive insulitis and beta cell destruction. The immunological events that precipitate invasive insulitis are not well understood. We tested the hypothesis that B cells in diabetes-prone NOD mice drive invasive insulitis through elevated expression of CD19 and consequent enhanced uptake and presentation of beta cell membrane-bound antigens to islet invasive T cells. METHODS: CD19 expression and signalling pathways in B cells from NOD and control mice were compared. Expansion of CD8(+) T cells specific for insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were compared in CD19-deficient and wild-type NOD mice and this was correlated with insulitis severity. The therapeutic potential of anti-CD19 treatment during the period of T cell activation was assessed for its ability to block invasive insulitis. RESULTS: CD19 expression and signalling in B cells was increased in NOD mice. CD19 deficiency significantly diminished the expansion of CD8(+) T cells with specificity for the membrane-bound beta cell antigen, IGRP. Conversely the reduction in CD8(+) T cells with specificity for the soluble beta cell antigen, insulin, was relatively small and not significant. CONCLUSIONS/INTERPRETATION: Elevated CD19 on NOD B cells promotes presentation of the membrane-bound antigen, IGRP, mediating the expansion of autoreactive T cells specific for antigens integral to beta cells, which are critical for invasive insulitis and diabetes. Downregulating the CD19 signalling pathway in insulin autoantibody-positive individuals before the development of type 1 diabetes may prevent expansion of islet-invasive T cells and preserve beta cell mass.

Differences in body esteem by weight status, gender, and physical activity among young elementary school-aged children.

Body satisfaction is important for the prevention of disordered eating and body image disturbances. Yet, little is known about body esteem and what influences it among younger children. The purpose of this study was to evaluate body esteem and the relationships between body esteem, weight, gender, and physical activity in elementary school children. A total of 214 third graders in a U.S. Midwestern state participated in this correlational study. The Body Mass Index-for-age, the Body Esteem Scale (BES), BE-Weight, BE-Appearance, and a Physical Activity Checklist were used to examine the relationships between the variables using bivariate correlations and analysis of variance. While children's body esteem did not differ by physical activity, important interactions were identified between weight status and gender in global body esteem and BE-Appearance. It is critical to examine attitudes about weight and appearance and the relationship between body esteem and self-esteem further among middle childhood-aged children.

The relationship of maternal and child illness uncertainty to child depressive symptomotology: a mediational model.

OBJECTIVE: To examine the relationship of parent and child ratings of illness uncertainty to depressive symptomotology in children with a chronic illness using a mediational model framework. METHOD: Mother-child dyads (N = 103 pairs) each completed measures of perceived illness uncertainty, while youth also completed a measure of depressive symptomotology. RESULTS: Maternal uncertainty was directly related to child depressive symptoms; however, this relationship was mediated by child uncertainty. CONCLUSION: It would appear that a key mechanism by which parent-related uncertainty influences child depressive symptoms is through child uncertainty, underscoring the importance of examining cognitive appraisal variables and means of transmission in parent-child interactions.

Weight status, physical activity, and fitness among third-grade rural children.

BACKGROUND: Rural children are at a particular high risk for obesity. Given the importance of exercise in obesity and chronic disease prevention, this study evaluated the level and relationship between physical activity and fitness in a sample of rural third graders. The second purpose of the study was to determine potential differences in physical activity and fitness level by weight status in this sample. METHODS: Twelve schools participating in a multidisciplinary research project were randomly selected for the study. Body mass index-for-age percentile, the modified Self-administered Physical Activity Checklist, and the FITNESSGRAM battery tests were utilized to determine children's weight status, physical activity, and fitness level, respectively. RESULTS: Thirty-eight percent of the 237 participating children (9.2 ± 0.4 years) were overweight or obese. Nearly 15% were extremely obese. Children spent 91.8 ± 83.8 and 32.2 ± 47.7 minutes in moderate- and vigorous-intensity activities. Obese children spent less time in moderate-intensity activity (p < .01) and combined moderate- and vigorous-intensity activity more than other children (p < .05). Forty-three percent of all children failed to meet the fitness standard for muscular strength and 36% failed to meet it for flexibility. CONCLUSIONS: Rural children in this sample had higher rates of obesity compared to the national average; they had poor fitness and 30% failed to meet the minimum physical activity recommendations on the previous day. Future interventions should focus on increasing physical activity, especially of moderate-intensity, and improving physical fitness in order to reduce obesity and decrease the risk of future chronic diseases in this high-risk population.

Parenting styles, parental response to child emotion, and family emotional responsiveness are related to child emotional eating.

The aim of the present study was to examine the relations of parenting style, parent response to negative child emotion, and family emotional expressiveness and support to child emotional eating. Mothers (N=450) completed questionnaires and their 6-8-year-old children (N=450) were interviewed. Results showed that emotional eating was negatively predicted by authoritative parenting style and family open expression of affection and emotion, and positively predicted by parent minimizing response to child negative emotion. Results suggest the need for early prevention/intervention efforts directed to these parenting and family variables.

Maternal depression and socio-economic status moderate the parenting style/child obesity association.

OBJECTIVE: The purpose of the study was to test the moderating influence of two risk factors, maternal depression and socio-economic status (SES), on the association between authoritarian and permissive parenting styles and child obesity. DESIGN: Correlational, cross-sectional study. Parenting style was measured with the Parenting Styles and Dimensions Questionnaire (PSDQ). Maternal depression was measured using the Center for Epidemiologic Studies Depression Scale (CES-D). BMI-for-age percentile was used to categorize children by weight status (children with BMI-for-age > or = 95th percentile were classified as obese). SES was computed from parent education and occupational status using the four-factor Hollingshead index. SETTING: Rural public schools in a mid-western state in the USA. SUBJECTS: One hundred and seventy-six mothers of first-grade children (ninety-one boys, eighty-five girls) enrolled in rural public schools. RESULTS: Both maternal depression and SES were found to moderate the permissive parenting style/child obesity association, but not the authoritarian/child obesity association. For depressed mothers, but not for non-depressed mothers, more permissive parenting was predictive of child obesity. Similarly more permissive parenting was predictive of child obesity among higher SES mothers, but not for lower SES mothers. CONCLUSIONS: Maternal depression and SES interact with permissive parenting style to predict child obesity. Future research should examine the relationship among these variables using a longitudinal design.

Parental feeding practices predict authoritative, authoritarian, and permissive parenting styles.

BACKGROUND: Our goal was to identify how parental feeding practices from the nutrition literature link to general parenting styles from the child development literature to understand how to target parenting practices to increase effectiveness of interventions. Stand-alone parental feeding practices could be targeted independently. However, parental feeding practices linked to parenting styles require interventions treating underlying family dynamics as a whole. OBJECTIVE: To predict parenting styles from feeding practices and to test three hypotheses: restriction and pressure to eat are positively related whereas responsibility, monitoring, modeling, and encouraging are negatively related to an authoritarian parenting style; responsibility, monitoring, modeling, and encouraging are positively related whereas restriction and pressure to eat are negatively related to an authoritative parenting style; a permissive parenting style is negatively linked with all six feeding practices. DESIGN: Baseline data of a randomized-controlled intervention study. SUBJECTS/SETTING: Two hundred thirty-nine parents (93.5% mothers) of first-grade children (134 boys, 105 girls) enrolled in rural public schools. MEASURES: Parental responses to encouraging and modeling questionnaires and the Child Feeding Questionnaire, as well as parenting styles measured by the Parenting Styles and Dimensions Questionnaire. STATISTICAL ANALYSES: Correlation and regression analyses. RESULTS: Feeding practices explained 21%, 15%, and 8% of the variance in authoritative, authoritarian, and permissive parenting, respectively. Restriction, pressure to eat, and monitoring (negative) significantly predicted an authoritarian style (Hypothesis 1); responsibility, restriction (negative), monitoring, and modeling predicted an authoritative style (Hypothesis 2); and modeling (negative) and restriction significantly predicted a permissive style (Hypothesis 3). CONCLUSIONS: Parental feeding practices with young children predict general parenting styles. Interventions that fail to address underlying parenting styles are not likely to be successful.