Kim Jachno

Histamine‐induced increases in cyclic AMP levels in bovine adrenal medullary cells

1 The effect of histamine on cellular cyclic AMP levels in cultured bovine adrenal medullary cells has been studied. 2 Histamine (0.3–30 μm) increased cyclic AMP levels transiently, with a maximal response after 5 min, a smaller response after 20 min, and no increase seen after 80 or 180 min. The EC50 at 5 min was approximately 2 μm. Histamine had no effect on cyclic AMP release from the cells over 5 min, but increased it after 90 min. 3 The cyclic AMP response to 5 μm histamine was reduced by 45% by 1 μm mepyramine and by almost 30% by 1 μm cimetidine, and was abolished by the combination of both antagonists. Cimetidine at 100 μm did not inhibit the response to histamine more than 1 μm cimetidine. The H3‐receptor antagonist, thioperamide (1 μm), had no effect on the response to histamine. 4 The H1‐receptor agonist, 2‐thiazolylethylamine (5–100 μm) and the H2‐receptor agonist, dimaprit (5–100 μm), each induced a cyclic AMP response, and gave more‐than‐additive responses when combined. The H3 agonist (R)α‐methylhistamine (100 μm) had no effect either on its own or in combination with either the H1 or the H2 agonist. The response to 100 μm 2‐thiazolylethylamine was unaffected by cimetidine (100 μm). 5 The cyclic AMP responses to 5μm histamine, 100 μm thiazolylethylamine and 100 μm dimaprit were each weakly enhanced in the presence of 1 mm 3‐isobutyl‐1‐methylxanthine. The response to dimaprit was enhanced more than 10 fold in the presence of 0.3 μm forskolin, while the responses to histamine and thiazolylethylamine were weakly enhanced. 6 The cyclic AMP response to 5 μm histamine was partially reduced in the absence of extracellular Ca2+, and the residual response was fully antagonized by 1 μm cimetidine and was unaffected by 1 μm mepyramine. In the absence of Ca2+, the cyclic AMP response to 100 μm thiazolylethylamine was abolished, while that to 100 μm dimaprit was unaffected. 7 Reincubation of 5 μm histamine solutions with a second set of chromaffin cells, following prior incubation with another set of cells, induced a cyclic AMP response in the fresh cells. This response was reduced by a combination of mepyramine and cimetidine to the same degree as the response to fresh 5 μm histamine solutions. 8 The results indicate that histamine increases cellular cyclic AMP levels in bovine chromaffin cells by three mechanisms: by acting on H1 receptors, by acting on H2 receptors, and by an interaction between H1 and H2 receptors. The H1 response does not require concomitant activation of H2 receptors, is fully dependent on extracellular Ca2+, does not depend on secreted chromaffin cell products, and is not due to reduced cyclic AMP degradation or export. The H2 cyclic AMP response is the first functional response reported for H2 receptors on chromaffin cells, is independent of Ca2+, is not due to reduced cyclic AMP export or degradation, and is likely to be mediated via a direct action through Gs. The role of these different mechanisms in the regulation of cyclic AMP‐dependent processes in chromaffin cells by histamine is under investigation.

Nasogastric hydration versus intravenous hydration for infants with bronchiolitis: a randomised trial.

BACKGROUND Bronchiolitis is the most common lower respiratory tract infection in infants and the leading cause of hospital admission. Hydration is a mainstay of treatment, but insufficient evidence exists to guide clinical practice. We aimed to assess whether intravenous hydration or nasogastric hydration is better for treatment of infants. METHODS In this multicentre, open, randomised trial, we enrolled infants aged 2-12 months admitted to hospitals in Australia and New Zealand with a clinical diagnosis of bronchiolitis during three bronchiolitis seasons (April 1-Oct 31, in 2009, 2010, and 2011). We randomly allocated infants to nasogastric hydration or intravenous hydration by use of a computer-generated sequence and opaque sealed envelopes, with three randomly assigned block sizes and stratified by hospital site and age group (2-<6 months vs 6-12 months). The primary outcome was length of hospital stay, assessed in all randomly assigned infants. Secondary outcomes included rates of intensive-care unit admission, adverse events, and success of insertion. This trial is registered with the Australian and New Zealand clinical trials registry, ACTRN12605000033640. FINDINGS Mean length of stay for 381 infants assigned nasogastric hydration was 86·6 h (SD 58·9) compared with 82·2 h (58·8) for 378 infants assigned intravenous hydration (absolute difference 4·5 h [95% CI -3·9 to 12·9]; p=0·30). Rates of admission to intensive-care units, need for ventilatory support, and adverse events did not differ between groups. At randomisation, seven infants assigned nasogastric hydration were switched to intravenous hydration and 56 infants assigned intravenous hydration were switched to nasogastric hydration because the study-assigned method was unable to be inserted. For those infants who had data available for successful insertion, 275 (85%) of 323 infants in the nasogastric hydration group and 165 (56%) of 294 infants in the intravenous hydration group required only one attempt for successful insertion. INTERPRETATION Intravenous hydration and nasogastric hydration are appropriate means to hydrate infants with bronchiolitis. Nasogastric insertion might require fewer attempts and have a higher success rate of insertion than intravenous hydration. FUNDING Australian National Health and Medical Research Council, Samuel Nissen Charitable Foundation (Perpetual), Murdoch Childrens Research Institute, Victorian Government.

Accuracy of PECARN, CATCH, and CHALICE head injury decision rules in children: a prospective cohort study

BACKGROUND Clinical decision rules can help to determine the need for CT imaging in children with head injuries. We aimed to validate three clinical decision rules (PECARN, CATCH, and CHALICE) in a large sample of children. METHODS In this prospective observational study, we included children and adolescents (aged <18 years) with head injuries of any severity who presented to the emergency departments of ten Australian and New Zealand hospitals. We assessed the diagnostic accuracy of PECARN (stratified into children aged <2 years and ≥2 years), CATCH, and CHALICE in predicting each rule-specific outcome measure (clinically important traumatic brain injury [TBI], need for neurological intervention, and clinically significant intracranial injury, respectively). For each calculation we used rule-specific predictor variables in populations that satisfied inclusion and exclusion criteria for each rule (validation cohort). In a secondary analysis, we compiled a comparison cohort of patients with mild head injuries (Glasgow Coma Scale score 13-15) and calculated accuracy using rule-specific predictor variables for the standardised outcome of clinically important TBI. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614000463673. FINDINGS Between April 11, 2011, and Nov 30, 2014, we analysed 20 137 children and adolescents attending with head injuries. CTs were obtained for 2106 (10%) patients, 4544 (23%) were admitted, 83 (<1%) underwent neurosurgery, and 15 (<1%) died. PECARN was applicable for 4011 (75%) of 5374 patients younger than 2 years and 11 152 (76%) of 14 763 patients aged 2 years and older. CATCH was applicable for 4957 (25%) patients and CHALICE for 20 029 (99%). The highest point validation sensitivities were shown for PECARN in children younger than 2 years (100·0%, 95% CI 90·7-100·0; 38 patients identified of 38 with outcome [38/38]) and PECARN in children 2 years and older (99·0%, 94·4-100·0; 97/98), followed by CATCH (high-risk predictors only; 95·2%; 76·2-99·9; 20/21; medium-risk and high-risk predictors 88·7%; 82·2-93·4; 125/141) and CHALICE (92·3%, 89·2-94·7; 370/401). In the comparison cohort of 18 913 patients with mild injuries, sensitivities for clinically important TBI were similar. Negative predictive values in both analyses were higher than 99% for all rules. INTERPRETATION The sensitivities of three clinical decision rules for head injuries in children were high when used as designed. The findings are an important starting point for clinicians considering the introduction of one of the rules. FUNDING National Health and Medical Research Council, Emergency Medicine Foundation, Perpetual Philanthropic Services, WA Health Targeted Research Funds, Townsville Hospital Private Practice Fund, Auckland Medical Research Foundation, A + Trust.

Cohort Profile: The Barwon Infant Study

The modern environment is associated with an increasing burden of non-communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n = 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early-life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2- and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [peter.vuillermin@deakin.edu.au].

Applicability of the CATCH, CHALICE and PECARN paediatric head injury clinical decision rules: pilot data from a single Australian centre

Background Clinical decision rules (CDRs) for paediatric head injury (HI) exist to identify children at risk of traumatic brain injury. Those of the highest quality are the Canadian assessment of tomography for childhood head injury (CATCH), Childrens head injury algorithm for the prediction of important clinical events (CHALICE) and Pediatric Emergency Care Applied Research Network (PECARN) CDRs. They target different cohorts of children with HI and have not been compared in the same setting. We set out to quantify the proportion of children with HI to which each CDR was applicable. Methods Consecutive children presenting to an Australian paediatric Emergency Department with HIs were enrolled. Published inclusion/exclusion criteria and predictor variables from the CDRs were collected prospectively. Using these we determined the frequency with which each CDR was applicable. Results 1012 patients (69.9%) were enrolled with 949 available for analysis. Mean age was 6.8 years (21% <2 years). 95% had initial Glasgow Coma Scale 15. CT rate was 12.8% and neurosurgery rate was 0.7%. No CDR was applicable to all patients. CHALICE was applicable to the most (97%, 95% CI 96% to 98%) and CATCH to the fewest (26%, 95% CI 24% to 29%). PECARN was applicable to 76% (95% CI 70% to 82%) aged <2 years, and 74% (95% CI 71% to 77%) aged 2–<18 years. Conclusions Each CDR is applicable to a different proportion of children with HI. This makes a direct comparison of the CDRs difficult. Prior to selection of any for implementation they should undergo validation outside the derivation setting coupled with an analysis of their performance accuracy, usability and cost effectiveness.

The ontogeny of naïve and regulatory CD4(+) T-cell subsets during the first postnatal year: a cohort study.

As there is limited knowledge regarding the longitudinal development and early ontogeny of naïve and regulatory CD4+ T‐cell subsets during the first postnatal year, we sought to evaluate the changes in proportion of naïve (thymic and central) and regulatory (resting and activated) CD4+ T‐cell populations during the first postnatal year. Blood samples were collected and analyzed at birth, 6 and 12 months of age from a population‐derived sample of 130 infants. The proportion of naïve and regulatory CD4+ T‐cell populations was determined by flow cytometry, and the thymic and central naïve populations were sorted and their phenotype confirmed by relative expression of T cell‐receptor excision circle DNA (TREC). At birth, the majority (94%) of CD4+ T cells were naïve (CD45RA+), and of these, ~80% had a thymic naïve phenotype (CD31+ and high TREC), with the remainder already central naïve cells (CD31− and low TREC). During the first year of life, the naïve CD4+ T cells retained an overall thymic phenotype but decreased steadily. From birth to 6 months of age, the proportion of both resting naïve T regulatory cells (rTreg; CD4+CD45RA+FoxP3+) and activated Treg (aTreg, CD4+CD45RA−FoxP3high) increased markedly. The ratio of thymic to central naïve CD4+ T cells was lower in males throughout the first postnatal year indicating early sexual dimorphism in immune development. This longitudinal study defines proportions of CD4+ T‐cell populations during the first year of postnatal life that provide a better understanding of normal immune development.

Natural BMI Reductions and Overestimation of Obesity Trial Effectiveness

The immediate challenge arising from endemically high rates of childhood obesity is to develop, test, and implement effective treatments that reduce its negative consequences on future health and costs. However, there remain no ready “fixes,” as most trials report at most small BMI benefits despite substantial intervention input. Given the opportunity costs of ineffective interventions, public health providers should rightly query value for money if interventions deliver change that barely exceeds natural history and/or is insufficient for health benefit. However, such judgments require knowledge of the natural history of BMI change in community samples of overweight and obese children participating in research studies. Unfortunately, regression to the mean and biases favoring resolution such as the Hawthorne effect seem no less likely in obesity than with any other chronic disease. For example, the most recent Cochrane systematic review of childhood obesity treatment1 included lifestyle trials comparing 2 or more interventions head-to-head, as well as trials comparing interventions with true controls. The former generally concluded that both interventions were equally effective, on the basis of mean reductions occurring within both intervention groups. In contrast, those studies with true controls tended to reveal that the interventions were ineffective, even though average BMI reductions were similar to those observed in the comparative trials. Thus, the meta-analysis of behavioral interventions in trials with true controls revealed only a small favorable between-group effect of −0.06 in BMI z score (95% confidence interval [CI]: −0.12 to −0.01).1 To define intervention success, one should also understand what BMI change equates to improved health. Although this has no definitive answer, and to some extent depends on the baseline value, it is suggested that BMI z score (considered by some a better marker of fat loss than change in BMI, weight, or weight z score) should fall by … Address correspondence to Melissa Wake, MD, Centre for Community Child Health, Royal Children’s Hospital, Flemington Road, Parkville 3052, Australia. E-mail: melissa.wake{at}rch.org.au

Computed tomography for head injuries in children: Change in Australian usage rates over time

Paediatric head injury is a common presentation to the ED. North American studies demonstrate increasing use of computed tomography (CT) brain scan (CTB) to investigate head injury. No such data exists for Australian EDs. The aim of this study was to describe CTB use in head injury over time in eight Australian EDs.

Nasogastric Hydration in Infants with Bronchiolitis Less Than 2 Months of Age

OBJECTIVES To determine whether nasogastric hydration can be used in infants less than 2 months of age with bronchiolitis, and characterize the adverse events profile of these infants compared with infants given intravenous (IV) fluid hydration. STUDY DESIGN A descriptive retrospective cohort study of children with bronchiolitis under 2 months of age admitted for hydration at 3 centers over 3 bronchiolitis seasons was done. We determined type of hydration (nasogastric vs IV fluid hydration) and adverse events, intensive care unit admission, and respiratory support. RESULTS Of 491 infants under 2 months of age admitted with bronchiolitis, 211 (43%) received nonoral hydration: 146 (69%) via nasogastric hydration and 65 (31%) via IV fluid hydration. Adverse events occurred in 27.4% (nasogastric hydration) and 23.1% (IV fluid hydration), difference of 4.3%; 95%CI (-8.2 to 16.9), P = .51. The majority of adverse events were desaturations (21.9% nasogastric hydration vs 21.5% IV fluid hydration, difference 0.4%; [-11.7 to 12.4], P = .95). There were no pulmonary aspirations in either group. Apneas and bradycardias were similar in each group. IV fluid hydration use was positively associated with intensive care unit admission (38.5% IV fluid hydration vs 19.9% nasogastric hydration; difference 18.6%, [5.1-32.1], P = .004); and use of ventilation support (27.7% IV fluid hydration vs 15.1% nasogastric hydration; difference 12.6 [0.3-23], P = .03). Fewer infants changed from nasogastric hydration to IV fluid hydration than from IV fluid hydration to nasogastric hydration (12.3% vs 47.7%; difference -35.4% [-49 to -22], P < .001). CONCLUSIONS Nasogastric hydration can be used in the majority of young infants admitted with bronchiolitis. Nasogastric hydration and IV fluid hydration had similar rates of complications.

Geography does not limit optimal diabetes care: Use of a tertiary centre model of care in an outreach service for type 1 diabetes mellitus

Young people with type 1 diabetes mellitus living in rural and regional Australia have previously been shown to have limited access to specialised diabetes services. The Royal Childrens Hospital Melbourne has been running diabetes outreach clinics to Western Victoria, Australia, for over 13 years. We aim to evaluate this service by comparing the outcomes of three outreach clinics with our urban diabetes clinic at the Royal Childrens Hospital Melbourne.