Contribution of local regeneration of glucocorticoids to tissue steroid pools.

11ß-Hydroxysteroid dehydrogenase 1 (11ßHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11ßHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11ßHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11ßHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- mice, showing the importance for whole-body 11ßHSD1 reductase activity. Disruption of liver 11ßHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11ßHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11ßHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

The Canadian Neuromuscular Disease Registry 2010-2019: A Decade of Facilitating Clinical Research Througha Nationwide, Pan-NeuromuscularDisease Registry.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Local atomic order and hierarchical polar nanoregions in a classical relaxor ferroelectric.

The development of useful structure-function relationships for materials that exhibit correlated nanoscale disorder requires adequately large atomistic models which today are obtained mainly via theoretical simulations. Here, we exploit our recent advances in structure-refinement methodology to demonstrate how such models can be derived directly from simultaneous fitting of 3D diffuse- and total-scattering data, and we use this approach to elucidate the complex nanoscale atomic correlations in the classical relaxor ferroelectric PbMg1/3Nb2/3O3 (PMN). Our results uncover details of ordering of Mg and Nb and reveal a hierarchical structure of polar nanoregions associated with the Pb and Nb displacements. The magnitudes of these displacements and their alignment vary smoothly across the nanoregion boundaries. No spatial correlations were found between the chemical ordering and the polar nanoregions. This work highlights a broadly applicable nanoscale structure-refinement method and provides insights into the structure of PMN that require rethinking its existing contentious models.

Decreasing case fatality rate following invasive pneumococcal disease, North East England, 2006-2016.

Declining mortality following invasive pneumococcal disease (IPD) has been observed concurrent with a reduced incidence due to effective pneumococcal conjugate vaccines. However, with IPD now increasing due to serotype replacement, we undertook a statistical analysis to estimate the trend in all-cause 30-day case fatality rate (CFR) in the North East of England (NEE) following IPD. Clinical, microbiological and demographic data were obtained for all laboratory-confirmed IPD cases (April 2006-March 2016) and the adjusted association between CFR and epidemiological year estimated using logistic regression. Of the 2510 episodes of IPD included in the analysis, 486 died within 30 days of IPD (CFR 19%). Increasing age, male sex, a diagnosis of septicaemia, being in ⩾1 clinical risk groups, alcohol abuse and individual serotypes were independently associated with increased CFR. A significant decline in CFR over time was observed following adjustment for these significant predictors (adjusted odds ratio 0.93, 95% confidence interval 0.89-0.98; P = 0.003). A small but significant decline in 30-day all-cause CFR following IPD has been observed in the NEE. Nonetheless, certain population groups remain at increased risk of dying following IPD. Despite the introduction of effective vaccines, further strategies to reduce the ongoing burden of mortality from IPD are needed.

Antenatal dexamethasone treatment transiently alters diastolic function in the mouse fetal heart.

Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5 to E15.5. To test the direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affected by dexamethasone treatment in either genotype. Dexamethasone treatment transiently decreased the myocardial deceleration index (MDI; a marker of diastolic function), in control fetuses at E15.5, with recovery by E17.5, 2 days after cessation of treatment. MDI was lower in SMGRKO than in control fetuses and was unaffected by dexamethasone. The transient decrease in MDI was associated with repression of cardiac GR in control fetuses following dexamethasone treatment. Measurement of glucocorticoid levels in fetal tissue and hypothalamic corticotropin-releasing hormone (Crh) mRNA levels suggest complex and differential effects of dexamethasone treatment upon the hypothalamic-pituitary-adrenal axis between genotypes. These data suggest potentially detrimental and direct effects of antenatal glucocorticoid treatment upon fetal heart function.

Establishing and developing a Teenage and Young Adult dermatology clinic with embedded specialist psychological support.

Skin conditions are common in adolescence and impart considerable psychological burden. The Department of Health has identified the specialized needs of adolescents transitioning from paediatric to adult services as a priority, yet there are few dedicated transitional clinics in the UK providing appropriate psychosocial support. We have established a monthly Teenage and Young Adult (TYA) dermatology clinic dedicated to managing teenagers and young adults with skin disease alongside open-access psychological support. Demographic data and Teenagers' Quality of Life Index (T-QoL) measures were recorded for all patients in 2016. To evaluate patient experience, two online surveys were conducted. Statistically significant improvements in the T-QoL were recorded for patients with the most common skin condition (eczema) attending for repeat assessment by the psychologist. Patients reported high satisfaction rates in both patient experience surveys. These results demonstrate that specialized adolescent care both is well received and can improve outcomes for these patients.

GHB614 × T304-40 × GHB119 × COT102 Cotton: Protein Expression Analyses of Field-Grown Samples.

Food and feed safety assessment is not enhanced by performing protein expression analysis on stacked trait products. The expression levels of six proteins in cotton matrices from four single cotton events and three conventionally stacked trait cotton products are reported. Three proteins were for insect control; two proteins confer herbicide tolerance; and one protein was a transformation-selectable marker. The cotton matrices were produced at three U.S., five Brazil, and two Argentina field trials. Similar protein expression was observed for all six proteins in the stacked trait products and the single events. However, when two copies of the bar gene were present in the stacked trait products, the expression level of phosphinothricin acetyl transferase herbicide tolerance was additive. Conventional breeding of genetically engineered traits does not alter the level or pattern of expression of the newly introduced proteins, except when multiple copies of the same transgene are present.

An unusual case of alpha-1-antitrypsin deficiency: SZ/Z.

A female patient was first seen at age 65 due to a diagnosis of alpha-1-antitrypsin deficiency (AATD). She was a lifelong non-smoker, with no significant history of second hand smoke exposure. There was no prior family history of AATD or liver disease. Her serum AAT concentration was measured on two occasions and in both cases, concentration was <0.21 g/L. The patient was referred for genetic testing to determine her SERPINA1 (the gene responsible for AATD) genotype. Three deficiency alleles were identified: she was heterozygous for S, a mild deficiency allele, and homozygous for Z, a severe deficiency allele. This case represents unusual convergence of three pathogenic SERPINA1 variants in a single individual. We report the investigations used to clarify her unusual genotype and propose non-crossover gene conversion as the likely mechanism.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Coupling of emergent octahedral rotations to polarization in (K,Na)NbO3 ferroelectrics.

Perovskite potassium sodium niobates, K1-xNaxNbO3, are promising lead-free piezoelectrics. Their dielectric and piezoelectric characteristics peak near x = 0.5, but the reasons for such property enhancement remain unclear. We addressed this uncertainty by analyzing changes in the local and average structures across the x = 0.5 composition, which have been determined using simultaneous Reverse Monte Carlo fitting of neutron and X-ray total-scattering data, potassium EXAFS, and diffuse-scattering patterns in electron diffraction. Within the A-sites, Na cations are found to be strongly off-centered along the polar axis as a result of oversized cube-octahedral cages determined by the larger K ions. These Na displacements promote off-centering of the neighboring Nb ions, so that the Curie temperature and spontaneous polarization remain largely unchanged with increasing x, despite the shrinking octahedral volumes. The enhancement of the properties near x = 0.5 is attributed to an abrupt increase in the magnitude and probability of the short-range ordered octahedral rotations, which resembles the pre-transition behavior. These rotations reduce the bond tension around Na and effectively soften the short Na-O bond along the polar axis - an effect that is proposed to facilitate reorientation of the polarization as external electric field is applied.

11ß-hydroxysteroid dehydrogenase type 1 has no effect on survival during experimental malaria but affects parasitemia in a parasite strain-specific manner.

Malaria is a global disease associated with considerable mortality and morbidity. An appropriately balanced immune response is crucial in determining the outcome of malarial infection. The glucocorticoid (GC) metabolising enzyme, 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1) converts intrinsically inert GCs into active GCs. 11ß-HSD1 shapes endogenous GC action and is immunomodulatory. We investigated the role of 11ß-HSD1 in two mouse models of malaria. 11ß-HSD1 deficiency did not affect survival after malaria infection, but it increased disease severity and parasitemia in mice infected with Plasmodium chabaudi AS. In contrast, 11ß-HSD1 deficiency rather decreased parasitemia in mice infected with the reticulocyte-restricted parasite Plasmodium berghei NK65 1556Cl1. Malaria-induced antibody production and pathology were unaltered by 11ß-HSD1 deficiency though plasma levels of IL-4, IL-6 and TNF-α were slightly affected by 11ß-HSD1 deficiency, dependent on the infecting parasite. These data suggest that 11ß-HSD1 is not crucial for survival of experimental malaria, but alters its progression in a parasite strain-specific manner.

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.

Serotype-specific differences in short- and longer-term mortality following invasive pneumococcal disease.

Invasive pneumococcal disease (IPD), caused by infection with Streptococcus pneumoniae, has a substantial global burden. There are over 90 known serotypes of S. pneumoniae with a considerable body of evidence supporting serotype-specific mortality rates immediately following IPD. This is the first study to consider the association between serotype and longer-term mortality following IPD. Using enhanced surveillance data from the North East of England we assessed both the short-term (30-day) and longer-term (⩽7 years) independent adjusted associations between individual serotypes and mortality following IPD diagnosis using logistic regression and extended Cox proportional hazards models. Of the 1316 cases included in the analysis, 243 [18·5%, 95% confidence interval (CI) 16·4-20·7] died within 30 days of diagnosis. Four serotypes (3, 6A, 9N, 19 F) were significantly associated with overall increased 30-day mortality. Effects were observable only for older adults (⩾60 years). After extension of the window to 12 months and 36 months, one serotype was associated with significantly increased mortality at 12 months (19 F), but no individual serotypes were associated with increased mortality at 36 months. Two serotypes had statistically significant hazard ratios (HR) for longer-term mortality: serotype 1 for reduced mortality (HR 0·51, 95% CI 0·30-0·86) and serotype 9N for increased mortality (HR 2·30, 95% CI 1·29-4·37). The association with serotype 9N was no longer observed after limiting survival analysis to an observation period starting 30 days after diagnosis. This study supports the evidence for associations between serotype and short-term (30-day) mortality following IPD and provides the first evidence for the existence of statistically significant associations between individual serotypes and longer-term variation in mortality following IPD.

Social cognitive theory mediators of physical activity in a lifestyle program for cancer survivors and carers: findings from the ENRICH randomized controlled trial.

BACKGROUND: Despite increasing numbers of cancer survivors and evidence that diet and physical activity improves the health of cancer survivors, most do not meet guidelines. Some social cognitive theory (SCT)-based interventions have increased physical activity behavior, however few have used objective physical activity measures. The Exercise and Nutrition Routine Improving Cancer Health (ENRICH) randomized controlled trial reported a significant intervention effect for the primary outcome of pedometer-assessed step counts at post-test (8-weeks) and follow-up (20-weeks). The aim of this study was to test whether the SCT constructs operationalized in the ENRICH intervention were mediators of physical activity behavior change. METHODS: Randomized controlled trial with 174 cancer survivors and carers assessed at baseline, post-test (8-weeks), and follow-up (20-weeks). Participants were randomized to the ENRICH six session face-to-face healthy lifestyle program, or to a wait-list control. Hypothesized SCT mediators of physical activity behavior change (self-efficacy, behavioral goal, outcome expectations, impediments, and social expectations) were assessed using valid and reliable scales. Mediation was assessed using the Preacher and Hayes SPSS INDIRECT macro. RESULTS: At eight weeks, there was a significant intervention effect on behavioral goal (A = 9.12, p = 0.031) and outcome expectations (A = 0.25, p = 0.042). At 20 weeks, the intervention had a significant effect on self-efficacy (A = 0.31, p = 0.049) and behavioral goal (A = 13.15, p = 0.011). Only changes in social support were significantly associated with changes in step counts at eight weeks (B = 633.81, p = 0.023). Behavioral goal was the only SCT construct that had a significant mediating effect on step counts, and explained 22 % of the intervention effect at 20 weeks (AB = 397.9, 95 % CI 81.5-1025.5). CONCLUSIONS: SCT constructs had limited impact on objectively-assessed step counts in a multiple health behavior change intervention for cancer survivors and their carers. Behavioral goal measured post-intervention was a significant mediator of pedometer-assessed step counts at 3-months after intervention completion, and explained 22 % of the intervention effect. Future research should examine the separate impact of goals and planning, as well as examining mediators of behavior maintenance in physical activity interventions targeting cancer survivors. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials registry ANZCTRN1260901086257 .

Television advertising, not viewing, is associated with negative dietary patterns in children.

BACKGROUND: Children's exposure to unhealthy food marketing is a contributor to poor diets and weight gain. Television food advertising, in particular, has been the focus of research and policy discussions. OBJECTIVES: We aimed to quantify the specific impact of television advertising, as distinct from television viewing generally, on children's usual diet. Methods Four hundred seventeen Australian children aged 10-16 participated in an online survey, which assessed television viewing habits and consumption of 12 frequently advertised unhealthy foods/drinks. Consumption of these foods/drinks was dichotomized (less weekly, weekly or more) and summed (1 point for each item consumed weekly or more) to give cumulative consumption scores. RESULTS: After adjusting for age and socioeconomic status, there was strong evidence of an increase in unhealthy food score (P < 0.001), drink score (P = 0.002) and food/drink combined score (P < 0.001), with increasing commercial television viewing. CONCLUSIONS: The link between television viewing and poor diet was strongest for children who watched the most commercial television, and those who were actually exposed to advertisements embedded within programs. This association between advertisement exposure and poor diet emphasizes the need for public policy intervention to reduce children's food advertising exposures.

Predictors of the frequency of Australian children's consumption of unhealthy foods.

BACKGROUND: Child obesity interventions need to be based on a sound understanding of the factors that influence children's diets. OBJECTIVE: To investigate the relationship between a range of predictor variables and the frequency with which Australian children consume energy-dense, nutrient-poor (EDNP) foods. METHODS: A web panel provider was used to access 1302 parents of Australian children aged 8-14 years who responded to an online survey about their children's diets. Structural equation modelling was conducted to test a model of the factors contributing to the frequency of children's unhealthy food consumption. RESULTS: Of the tested variables, consumption of EDNP foods was primarily influenced by parents' attitudes to these foods, children's pestering behaviours and perceived social norms relating to children's consumption of these products. Both pestering and social norms had significant direct effects on consumption frequency as well as indirect effects via their impact on parents' attitudes to EDNP foods. CONCLUSION: Environmental factors that contribute to both pestering and social norms are likely to be critical considerations in the development of child obesity interventions.

Decreased Npas4 and Arc mRNA Levels in the Hippocampus of Aged Memory-Impaired Wild-Type But Not Memory Preserved 11ß-HSD1 Deficient Mice.

Mice deficient in the glucocorticoid-regenerating enzyme 11ß-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms and pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11ß-HSD1. Aged wild-type mice were separated into memory-impaired and unimpaired relative to young controls according to their performance in the Y-maze. All individual aged 11ß-HSD1-deficient mice showed intact spatial memory. The majority of differentially expressed hippocampal genes were increased with ageing (e.g. immune/inflammatory response genes) with no genotype differences. However, the neuronal-specific transcription factor, Npas4, and immediate early gene, Arc, were reduced (relative to young) in the hippocampus of memory-impaired but not unimpaired aged wild-type or aged 11ß-HSD1-deficient mice. A quantitative reverse transcriptase-polymerase chain reaction and in situ hybridisation confirmed reduced Npas4 and Arc mRNA expression in memory-impaired aged wild-type mice. These findings suggest that 11ß-HSD1 may contribute to the decline in Npas4 and Arc mRNA levels associated with memory impairment during ageing, and that decreased activity of synaptic plasticity pathways involving Npas4 and Arc may, in part, underlie the memory deficits seen in cognitively-impaired aged wild-type mice.

Impact of a nutrition and physical activity intervention (ENRICH: Exercise and Nutrition Routine Improving Cancer Health) on health behaviors of cancer survivors and carers: a pragmatic randomized controlled trial.

BACKGROUND: Physical activity and consuming a healthy diet have clear benefits to the physical and psychosocial health of cancer survivors, with guidelines recognising the importance of these behaviors for cancer survivors. Interventions to promote physical activity and improve dietary behaviors among cancer survivors and carers are needed. The aim of this study was to determine the effects of a group-based, face-to-face multiple health behavior change intervention on behavioral outcomes among cancer survivors of mixed diagnoses and carers. METHODS: The Exercise and Nutrition Routine Improving Cancer Health (ENRICH) intervention was evaluated using a two-group pragmatic randomized controlled trial. Cancer survivors and carers (n = 174) were randomly allocated to the face-to-face, group-based intervention (six, theory-based two-hour sessions delivered over 8 weeks targeting healthy eating and physical activity [PA]) or wait-list control (after completion of 20-week data collection). Assessment of the primary outcome (pedometer-assessed mean daily step counts) and secondary outcomes (diet and alcohol intake [Food Frequency Questionnaire], self-reported PA, weight, body mass index, and waist circumference) were assessed at baseline, 8-and 20-weeks. RESULTS: There was a significant difference between the change over time in the intervention group and the control group. At 20 weeks, the intervention group had increased by 478 steps, and the control group had decreased by 1282 steps; this represented an adjusted mean difference of 1761 steps (184 to 3337; P = 0.0028). Significant intervention effects for secondary outcomes, included a half serving increase in vegetable intake (difference 39 g/day; 95 % CI: 12 to 67; P = 0.02), weight loss (kg) (difference -1.5 kg; 95 % CI, -2.6 to -0.3; P = 0.014) and change in body mass index (kg/m(2)) (difference -0.55 kg/m(2); 95 % CI, -0.97 to -0.13; P = 0.012). No significant intervention effects were found for self-reported PA, total sitting time, waist circumference, fruit, energy, fibre, alcohol, meat, or fat consumption. CONCLUSIONS: The ENRICH intervention was effective for improving PA, weight, body mass index, and vegetable consumption even with the inclusion of multiple cancer types and carers. As an example of successful research translation, the Cancer Council NSW has subsequently adopted ENRICH as a state-wide program. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register identifier: ANZCTRN1260901086257.