Knockout of apolipoprotein A-I decreases parenchymal and vascular ß-amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

AIMS: Apolipoprotein A-I (apoA-I), the principal apolipoprotein associated with high-density lipoproteins in the periphery, is also found at high concentrations in the cerebrospinal fluid. Previous studies have reported either no impact or vascular-specific effects of apoA-I knockout (KO) on ß-amyloid (Aß) pathology. However, the putative mechanism(s) by which apoA-I may influence Aß deposition is unknown. METHODS: We evaluated the effect of apoA-I deletion on Aß pathology, Aß production and clearance from the brain in the Tg2576 mouse model of Alzheimer's disease (AD). RESULTS: Contrary to previous reports, deletion of the APOA1 gene significantly reduced concentrations of insoluble Aß40 and Aß42 and reduced plaque load in both the parenchyma and blood vessels of apoA-I KO × Tg2576 mice compared to Tg2576 animals. This was not due to decreased Aß production or alterations in Aß species. Levels of soluble clusterin/apoJ were significantly higher in neurons of apoA-I KO mice compared to both wildtype (WT) and apoA-I KO × Tg2576 mice. In addition, clearance of Aß along intramural periarterial drainage pathways was significantly higher in apoA-I KO mice compared to WT animals. CONCLUSION: These data suggest that deletion of apoA-I is associated with increased clearance of Aß and reduced parenchymal and vascular Aß pathology in the Tg2576 model. These results suggest that peripheral dyslipidaemia can modulate the expression of apolipoproteins in the brain and may influence Aß clearance and aggregation in AD.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Auscultate, palpate and tap: time to re-evaluate.

AIM: To determine the accuracy of current methods of heart rate (HR) assessment. METHODS: All participants palpated a simulated pulsating umbilicus (UMB), listened to a tapping rate (TAP) and auscultated a simulated HR (AUSC). A simulated HR of 54, 88 and 128 beats per minute (bpm) was randomised for all methods. RESULTS: Twenty-nine healthcare staff participated in this study. Correct assessment of HR of 54 bpm as being within the 0-59 range occurred in 17.2% UMB, 17.2% TAP and 31% AUSC and was obtained in <10 seconds by 48.3%, 65.5% and 62.1%, respectively. A rate of 88 bpm was correctly assessed as within the 60-100 range in 82.8% UMB, 79.3% TAP and 79.3% AUSC and was obtained in <10 seconds by 55.2%, 58.6% and 55.2%, respectively. A rate of 128 bpm was identified as >100 bpm by 96.6% UMB, 93.1% TAP, and 93.1% AUSC and was obtained in <10 seconds by 51.7%, 55.2% and 62.1%, respectively. CONCLUSION: Current methods in assessing rates below 60 bpm are inaccurate and may overestimate HR. We recommend that these methods alone should not be relied upon in neonatal resuscitation and objective assessment of heart rate should be readily available at all newborn resuscitations.

A National Survey on the Diagnosis and Treatment of Paediatric Growth Hormone Deficiency.

Many countries have established regulations regarding growth hormone (GH) treatment in children, to standardise care and reduce cost. In this study, we describe current practice in Ireland surrounding child measurement and the approach to diagnosis of GH deficiency. A questionnaire was sent to 139 paediatricians in Ireland and 35 (9 paediatric endocrinologists) responded. Only 13 (37.1%) use the recommended 2-person technique for measuring children under 2. Amongst GH prescribers, there were a variety of GH Stimulation Tests used, sex steroid priming was used by 8 (80%) and the general cut off for a passed test was consistent (7ng/ml). Brand rotation (n=5, 50%) and cost (n=3, 30%) were the most common criteria for deciding the formulation of GH prescribed. We recommend that departments review their child measurement technique and equipment. We also advise the establishment of national guidelines for the use of GH, and a prospective registry for GH treated children.

Are you also what your mother eats? Distinct proteomic portrait as a result of maternal high-fat diet in the cerebral cortex of the adult mouse.

Epidemiological studies suggest an association between maternal obesity and adverse neurodevelopmental outcomes in offspring. Our aim was to compare the global proteomic portrait in the cerebral cortex between mice born to mothers on a high-fat or control diet who themselves were fed a high-fat or control diet. Male mice born to dams fed a control (C) or high-fat (H) diet 4 weeks before conception and during gestation, and lactation were assigned to either C or H diet at weaning. Mice were killed at 19 weeks and their cerebral cortices were analysed using a two-dimensional liquid chromatography-mass spectrometry methodology. In total, 6 695 proteins were identified (q<0.01), 10% of which were modulated in at least one of the groups relative to controls. In silico analysis revealed that mice clustered based on the diet of the mother and not their own diet and that maternal high-fat diet was significantly associated with response to hypoxia/oxidative stress and apoptosis in the cerebral cortex of the adult offspring. Maternal high-fat diet resulted in distinct endophenotypic changes of the adult offspring cerebral cortex independent of its current diet. The identified proteins could represent novel therapeutic targets for the prevention of neuropathological features resulting from maternal obesity.

Afferent and efferent immunological pathways of the brain. Anatomy, function and failure.

Immunological privilege appears to be a product of unique lymphatic drainage systems for the brain and receptor-mediated entry of inflammatory cells through the blood-brain barrier. Most organs of the body have well-defined lymphatic vessels that carry extracellular fluid, antigen presenting cells, lymphocytes, neoplastic cells and even bacteria to regional lymph nodes. The brain has no such conventional lymphatics, but has perivascular pathways that drain interstitial fluid (ISF) from brain parenchyma and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes. ISF and solutes drain along narrow, ∼100 nm-thick basement membranes within the walls of cerebral capillaries and arteries to cervical lymph nodes; this pathway does not allow traffic of lymphocytes or antigen presenting cells from brain to lymph nodes. Although CSF drains into blood through arachnoid villi, CSF also drains from the subarachnoid space through channels in the cribriform plate of the ethmoid bone into nasal lymphatics and thence to cervical lymph nodes. This pathway does allow the traffic of lymphocytes and antigen presenting cells from CSF to cervical lymph nodes. Efferent pathways by which lymphocytes enter the brain are regulated by selected integrins on lymphocytes and selective receptors on vascular endothelial cells. Here we review: (1) the structure and function of afferent lymphatic drainage of ISF and CSF, (2) mechanisms involved in the efferent pathways by which lymphocytes enter the brain and (3) the failure of lymphatic drainage of the brain parenchyma with age and the role of such failure in the pathogenesis of Alzheimer's disease.

The evolving course of HNF4A hyperinsulinaemic hypoglycaemia--a case series.

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations have a well-recognized role in maturity-onset diabetes of the young and have recently been described in congenital hyperinsulinism. A biphasic phenotype has been postulated, with macrosomia and congenital hyperinsulinism in infancy, and diabetes in young adulthood. In this case series, we report three children with HNF4A mutations (two de novo) and diazoxide-responsive congenital hyperinsulinism, highlighting the potential for ongoing diazoxide requirement and the importance of screening for these mutations even in the absence of family history. CASE REPORTS: All patients presented with macrosomia (mean birthweight 4.26 kg) and hyperinsulinaemic hypoglycaemia soon after birth (median age 1 day). All three (age range 7 months to 11 years 10 months) remain on diazoxide therapy, with dose requirements increasing in one patient. There was no prior family history of diabetes, neonatal hypoglycaemia or macrosomia. Parents were screened for HNF4A mutations post-diagnosis and one father was subsequently found to have maturity-onset diabetes of the young. CONCLUSIONS: This case series follows the evolving course of three patients with confirmed HNF4A-mediated congenital hyperinsulinism, highlighting (1) the variable natural history of these mutations, (2) the potential for prolonged diazoxide requirement, even into adolescence, and (3) the need for screening, regardless of family history.

Paediatric type 1 diabetes in Ireland--results of the first national audit.

The aim of this study was to describe the services provided for children with type 1 diabetes in the Republic of Ireland, and to identify a baseline from which services and outcomes might be improved. Lead clinicians in 17 of the 19 centres providing paediatric type 1 diabetes care responded to requests for information from 2012 regarding demographics, patient numbers, diagnostics, outpatient management, multidisciplinary team resources, comorbidity screening, transition policy, clinical guidelines, and use of insulin pumps. The total number of patients attending these centres was 2518. Eight centres initiate insulin pump therapy. Insulin pump usage ranged from 0 to 42% of patients attending each centre. Self reported clinic mean haemoglobin A1c ranged from 8.2 to 9.4% (66.1 to 79.2 mmol/mol). Variation existed in guideline availability, frequency of clinic appointments, age of transition and insulin types used. We recommend a national approach to standardising and improving care for these patients.

Is the NHS best practice tariff for type 1 diabetes applicable in the Irish context?

The National Health Service in the UK has identified thirteen key standards of paediatric diabetes care. Funding depends on services meeting these standards. The aim of this study was to determine if these standards are applicable in an Irish setting. All patients attending the diabetes service during 2012 were included. Patient charts, electronic appointments, nursing notes and computerised results were used to ascertain relevant information for comparison with the NHS standards. Patients attended a mean 2.97 (SD 0.7) medical and 2.2 (SD 2.9) nursing appointments per year, with a median additional contacts of 8 nurse phone calls (range 0 - 125). Most standards were met by this service. In comparing our service to the NHS standard, we have identified a number of areas for improving our service provision. Limited resources and staff shortages make a number of these standards unachievable, namely annual dietetic review and three monthly outpatient appointments.

Difficulties associated with diabetes management during the Junior Certificate examination.

The aim of this study was to describe the adherence to recommended diabetes care during the Junior Certificate, and the utilisation of available allowances for children with type 1 diabetes. Questionnaires were sent within 3 months of the examination to all adolescents and their families attending our service completing the Junior Certificate in June of 2012. Fifteen of the 25 (60%) patients/parents completed the questionnaires. Five (33%) had higher than usual glucose readings during the examination period and three (20%) experienced hypoglycaemia during at least one exam. Nine (60%) never checked capillary glucose levels during the exams. No patients left the examination area to perform diabetes related tasks. Thirteen (86%) brought fast acting glucose into the examination centre while only six (40%) brought a glucometer. Just four (27%) patients availed of the rest breaks allowed and six (40%) felt that their diabetes affected their examination performance.

Priorities, opportunities, and challenges for integrating microorganisms into Earth system models for climate change prediction.

Climate change jeopardizes human health, global biodiversity, and sustainability of the biosphere. To make reliable predictions about climate change, scientists use Earth system models (ESMs) that integrate physical, chemical, and biological processes occurring on land, the oceans, and the atmosphere. Although critical for catalyzing coupled biogeochemical processes, microorganisms have traditionally been left out of ESMs. Here, we generate a "top 10" list of priorities, opportunities, and challenges for the explicit integration of microorganisms into ESMs. We discuss the need for coarse-graining microbial information into functionally relevant categories, as well as the capacity for microorganisms to rapidly evolve in response to climate-change drivers. Microbiologists are uniquely positioned to collect novel and valuable information necessary for next-generation ESMs, but this requires data harmonization and transdisciplinary collaboration to effectively guide adaptation strategies and mitigation policy.

Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.

Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aß), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aß (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

Your diagnosis? Congenital foot drop.

A term infant was noted to have right-sided foot drop. We discuss the role of neurophysiology and diagnostic imaging.

Short stature in child with early-onset diabetes.

We present a girl who initially presented at 12 weeks of age with antibody negative diabetes. Genetic screening for common mutations of monogenic diabetes was negative. She was noted to have short stature at 8 years of age (height <0.4 centile), as well as overlapping toes and distal abnormalities of her fingers. On reevaluation, further investigation revealed an EIF2AK3 mutation, and a diagnosis of Wolcott Rallison syndrome was made. This case highlights the importance of close follow up of patients with neonatal diabetes for the development of syndromic features that may lead to a unifying diagnosis.

Efficacy and user preference of two CO2 detectors in an infant mannequin randomized crossover trial.

Assessment of effective ventilation in neonatal mask ventilation can be difficult. This study aims to determine whether manual ventilation with a T-piece resuscitator containing an inline CO2 detector (either a Pedi-Cap® CO2 detector or a Neo-StatCO2

Parental patterns of use of over the counter analgesics in children.

Over-The-Counter Analgesics (OTCA) account for over a fifth of Irish pharmacy sales. Little is known about patterns of use, specifically in children. This study investigated parents' use of OTCAs in children. A questionnaire exploring use of OTCAs and knowledge of side-effects was distributed to guardians of children attending three GP surgeries in South of Ireland from June-September 2010. The questionnaire was completed by 183 parents (response rate 95%). Many respondents (n = 121, 66.1%) were using analgesics when not required or using an inappropriate analgesic for a child's symptom. Private patients demonstrated better use (n = 31, 40%) than those with Medical Cards (n = 18, 22.5%) (p = 0.016). Identification of potential side-effects was poor, with drowsiness (n = 88, 49%), rash (n = 39, 22%) and nausea (n =3 2, 18%) listed as potential side-effects. Inappropriate use of OTCAs is prevalent in Irish children. Parents need more information and guidance on their use.

MRI and visual-evoked potentials in partners of multiple sclerosis patients.

OBJECTIVE: Some epidemiological evidence, particularly concerning the role of Epstein Barr Virus implies that multiple sclerosis (MS) may be transmissible and if correct, this might be revealed by increased prevalence of MS in cohabiting partners. METHODS: We addressed this problem by neurological assessment, visual-evoked potentials (VEP) and magnetic resonance imaging (MRI) in 112 partners of patients with MS in comparison to a control group of 93 individuals with clinically non-significant head or neck pain and in comparison to UK prevalence. RESULTS: We found one instance of conjugal definite MS. Including this case, VEP were abnormal in five instances with either significant delay (n = 3) or increased interocular latency difference (IOLD) (n = 2) in partners of MS patients thus raising the possibility of subclinical optic nerve demyelination. The mean absolute value of IOLD in partners was greater than the value in controls (P = 0.033). There were no significant differences in MRI findings between the two groups. CONCLUSION: The finding of one conjugal pair and abnormal VEP in a further four MS partners could have several explanations. It is compatible with the concept of a transmissible agent, although our observations could be due to several biases as well as the play of chance alone.

Bystander cardiopulmonary resuscitation for paediatric out-of-hospital cardiac arrest in England: An observational registry cohort study.

INTRODUCTION: Bystander cardiopulmonary resuscitation (BCPR) is strongly advocated by resuscitation councils for paediatric out-of-hospital cardiac arrests (OHCAs). However, there are limited reports on rates of BCPR in children and its relationship with return of spontaneous circulation (ROSC) or survival outcomes. OBJECTIVE: We describe the rate of BCPR and its association with any ROSC and survival- to- hospital-discharge. METHODS: We conducted retrospective analysis of prospectively collected paediatric (<18 years of age) OHCA cases in England; we included specialist registry patients treated by emergency medical services (EMS) with known BCPR status and outcome between January 2014 and November 2018. Data included patient demographics, aetiology, witness status, initial rhythm, EMS, season, time of day and bystander status. Associations between BCPR, and any ROSC and survival-to-hospital-discharge outcomes were explored using multivariable logistic regression. RESULTS: There were 2363 paediatric OHCAs treated across 11 EMS regions. BCPR was performed in 69.6% (1646/2363) of the cases overall (range 57.7% (206/367) to 83.7% (139/166) across EMS regions). Only 34.9% (550/1572) of BCPR cases were witnessed. Overall, any ROSC was achieved in 22.8% (523/2289) and survival to hospital discharge in 10.8% (225/2066). Adjusted odds ratio (aOR) for any ROSC was significantly improved following BCPR compared to no BCPR (aOR 1.37, 95% CI 1.03-1.81), but adjusted odds ratio for survival-to-hospital-discharge were similar (aOR 1.01, 95% CI 0.66-1.55). CONCLUSIONS: BCPR was associated with improved rates of any ROSC but not survival-to-hospital-discharge. Variations in EMS BCPR rates may indicate opportunities for regional targeted increase in public BCPR education.

Observation of the decay B- → D(s)((*)+) K- ℓ- ν(ℓ).

We report the observation of the decay B- → D(s)((*)+) K- ℓ- ν(ℓ) based on 342 fb(-1) of data collected at the Υ(4S) resonance with the BABAR detector at the PEP-II e+ e- storage rings at SLAC. A simultaneous fit to three D(s)(+) decay chains is performed to extract the signal yield from measurements of the squared missing mass in the B meson decay. We observe the decay B- → D(s)((*)+) K- ℓ- ν(ℓ) with a significance greater than 5 standard deviations (including systematic uncertainties) and measure its branching fraction to be B(B- → D(s)((*)+) K- ℓ- ν(ℓ)) = [6.13(-1.03)(+1.04)(stat)±0.43(syst)±0.51(B(D(s)))]×10(-4), where the last error reflects the limited knowledge of the D(s) branching fractions.