Oesophageal atresia is correctable and survivable in infants less than 1 kg

INTRODUCTION: Management of oesophageal atresia (OA) and trachea-oesophageal fistula (TOF) in babies of low birth weight is challenging especially when associated with other anomalies. Birth weight of <1500 g has previously formed part of a classification system designed to predict outcome, alongside the cardiac status of the patient. Improvements in neonatal care have led to increasing numbers of premature low birth weight infants surviving. The aim of this study was to look at the experience of our institution in the extremely low birth weight (ELBW) patients. METHODS: A retrospective review of our institutions OA database was performed from 1993 to June 2015. Patients of birth weight less than 1000 g were included. A review of our OA/TOF clinical database and notes review established the following; gestation, birth weight, associated anomalies, operative procedures, morbidity and mortality. RESULTS: Of 349 patients with OA across the 22-year period, 9 ELBW patients were identified (<1000 g). Six males and three females. Gestational age ranged from 23 to 34 weeks and median birth weight was 815 g ranging from 630 to 950 g. Overall survival was 56 % (5/9). There were double the numbers of ELBW OA/TOF patients seen in the second half of the study period presumably the result of improving neonatal care. Seven patients had type C OA with TOF and underwent emergency TOF ligation, two had concomitant oesophageal repair. One of these patients died from NEC; the other survived. Of the five who had isolated TOF ligation three died-two from cardiac disease and one from prematurity. Both type A patients survived and after initial gastrostomy placement one had a primary delayed repair, the other a gastric transposition. All three babies under 800 g died-one from cardiac disease the others from conditions indicative of their prematurity-necrotising enterocolitis and intraventricular haemorrhage. CONCLUSIONS: 50 % survival is achievable in OA/TOF under 1 kg and the Spitz classification is still applicable in this group as a whole. However, none of the current classification systems are applicable in infants <800 g who in our study all had poor outcomes. We suggest these should be considered as separate group when predicting outcomes

Continuous monitoring of the bronchial epithelial lining fluid by microdialysis

<p>Abstract</p> <p>Background</p> <p>Contents of the epithelial lining fluid (ELF) of the bronchi are of central interest in lung diseases, acute lung injury and pharmacology. The most commonly used technique broncheoalveolar lavage is invasive and may cause lung injury. Microdialysis (MD) is a method for continuous sampling of extracellular molecules in the immediate surroundings of the catheter. Urea is used as an endogenous marker of dilution in samples collected from the ELF. The aim of this study was to evaluate bronchial MD as a continuous monitor of the ELF.</p> <p>Methods</p> <p>Microdialysis catheters were introduced into the right main stem bronchus and into the right subclavian artery of five anesthetized and normoventilated pigs. The flowrate was 2 μl/min and the sampling interval was 60 minutes. Lactate and fluorescein-isothiocyanate-dextran 4 kDa (FD-4) infusions were performed to obtain two levels of steady-state concentrations in blood. Accuracy was defined as [bronchial-MD] divided by [arterial-MD] in percent. Data presented as mean ± 95 percent confidence interval.</p> <p>Results</p> <p>The accuracy of bronchial MD was calculated with and without correction by the arteriobronchial urea gradient. The arteriobronchial lactate gradient was 1.2 ± 0.1 and FD-4 gradient was 4.0 ± 1.2. Accuracy of bronchial MD with a continuous lactate infusion was mean 25.5% (range 5.7–59.6%) with a coefficient of variation (CV) of 62.6%. With correction by the arteriobronchial urea gradient accuracy was mean 79.0% (57.3–108.1%) with a CV of 17.0%.</p> <p>Conclusion</p> <p>Urea as a marker of catheter functioning enhances bronchial MD and makes it useful for monitoring substantial changes in the composition of the ELF.</p

An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene

This is the final version. Available from the publisher via the DOI in this record.A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.Alzheimer's Society, United KingdomMedical Research Council (MRC)NIH, United States, R01 grantAlzheimer's Research U

5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions

5-HT has been reported to possess significant effects on cardiac activities, but activation of 5-HTR on the cell membrane failed to illustrate the controversial cardiac reaction. Because 5-HT constantly comes across the cell membrane via 5-HT transporter (5-HTT) into the cytoplasm, whether 5-HTR is functional present on the cellular organelles is unknown. Here we show 5-HTR3 and 5-HTR4 were located in cardiac mitochondria, and regulated mitochondrial activities and cellular functions. Knock down 5-HTR3 and 5-HTR4 in neonatal cardiomyocytes resulted in significant increase of cell damage in response to hypoxia, and also led to alternation in heart beating. Activation of 5-HTR4 attenuated mitochondrial Ca2+ uptake under the both normoxic and hypoxic conditions, whereas 5-HTR3 augmented Ca2+ uptake only under hypoxia. 5-HTR3 and 5-HTR4 exerted the opposite effects on the mitochondrial respiration: 5-HTR3 increased RCR (respiration control ratio), but 5-HTR4 reduced RCR. Moreover, activation of 5-HTR3 and 5-HTR4 both significantly inhibited the opening of mPTP. Our results provided the first evidence that 5-HTR as a GPCR and an ion channel, functionally expressed in mitochondria and participated in the mitochondria function and regulation to maintain homeostasis of mitochondrial [Ca2+], ROS, and ATP generation efficiency in cardiomyocytes in response to stress and O2 tension

5-HT2C Receptors Localize to Dopamine and GABA Neurons in the Rat Mesoaccumbens Pathway

The serotonin 5-HT2C receptor (5-HT2CR) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT2CR is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of γ-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT2CR within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT2CR upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT2CR innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which >50% also contained 5-HT2CR immunoreactivity. Thus, we demonstrate for the first time that the 5-HT2CR colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc-projecting VTA neurons. These data suggest that the 5-HT2CR may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles

Evidence for energy conservation during pubertal growth. A 10-year longitudinal study (EarlyBird 71)

BACKGROUND: Diabetes is closely linked to obesity, and obesity rates climb during adolescence for reasons that are not clear. Energy efficiency is important to obesity, and we describe a temporary but substantial fall in absolute energy expenditure, compatible with improved energy efficiency, during the rapid growth phase of puberty. METHODS: In a longitudinal cohort study lasting 10 years, we measured voluntary energy expenditure as physical activity (PA) by accelerometry, involuntary energy expenditure as resting energy expenditure (REE) by oxygen consumption, body mass index (BMI) and body composition by dual energy X-ray absorptiometry annually on 10 occasions from 7 to 16 years in the 347 children of the EarlyBird study. We used mixed effects modelling to analyse the trends in REE and their relationship to BMI, lean mass (LM), fat mass (FM), age, PA and pubertal stage. RESULTS: Relative REE and total PA fell during puberty, as previously described, but the longitudinal data and narrow age-range of the cohort (s.d.±4m) revealed for the first time a substantial fall in absolute REE during the period of maximum growth. The fall became clearer still when adjusted for FM and LM. The fall could not be explained by fasting insulin, adiponectin, leptin, luteinising hormone or follicle stimulating hormone. CONCLUSIONS: There appears to be a temporary but substantial reduction in energy expenditure during puberty, which is unrelated to changes in body composition. If it means higher energy efficiency, the fall in REE could be advantageous in an evolutionary context to delivering the extra energy needed for pubertal growth, but unfavourable to weight gain in a contemporary environment.International Journal of Obesity advance online publication, 4 October 2016; doi:10.1038/ijo.2016.158.We are grateful to the Bright futures trust, Fountain Foundation, BUPA Foundation, EarlyBird Diabetes Trust and countless individual donors who made this study possible

Distinguishing Type 2 Diabetes from Type 1 Diabetes in African American and Hispanic American Pediatric Patients

To test the hypothesis that clinical observations made at patient presentation can distinguish type 2 diabetes (T2D) from type 1 diabetes (T1D) in pediatric patients aged 2 to 18.Medical records of 227 African American and 112 Hispanic American pediatric patients diagnosed as T1D or T2D were examined to compare parameters in the two diseases. Age at presentation, BMI z-score, and gender were the variables used in logistic regression analysis to create models for T2D prediction.The regression-based model created from African American data had a sensitivity of 92% and a specificity of 89%; testing of a replication cohort showed 91% sensitivity and 93% specificity. A model based on the Hispanic American data showed 92% sensitivity and 90% specificity. Similarities between African American and Hispanic American patients include: (1) age at onset for both T1D and T2D decreased from the 1980s to the 2000s; (2) risk of T2D increased markedly with obesity. Racial/ethnic-specific observations included: (1) in African American patients, the proportion of females was significantly higher than that of males for T2D compared to T1D (p<0.0001); (2) in Hispanic Americans, the level of glycated hemoglobin (HbA1c) was significantly higher in T1D than in T2D (p<0.002) at presentation; (3) the strongest contributor to T2D risk was female gender in African Americans, while the strongest contributor to T2D risk was BMI z-score in Hispanic Americans.Distinction of T2D from T1D at patient presentation was possible with good sensitivity and specificity using only three easily-assessed variables: age, gender, and BMI z-score. In African American pediatric diabetes patients, gender was the strongest predictor of T2D, while in Hispanic patients, BMI z-score was the strongest predictor. This suggests that race/ethnic specific models may be useful to optimize distinction of T1D from T2D at presentation

Regionalisation of trauma care in England

Aims We aimed to determine whether there is evidence of improved patient outcomes in Major Trauma Centres following the regionalisation of trauma care in England. Patients and Methods An observational study was undertaken using the Trauma Audit and Research Network (TARN), Hospital Episode Statistics (HES) and national death registrations. The outcome measures were indicators of the quality of trauma care, such as treatment by a senior doctor and clinical outcomes, such as mortality in hospital. Results and Conclusion A total of 20 181 major trauma cases were reported to TARN during the study period, which was 270 days before and after each hospital became a Major Trauma Centre. Following regionalisation of trauma services, all indicators of the quality of care improved, fewer patients required secondary transfer between hospitals and a greater proportion were discharged with a Glasgow Outcome Score of “good recovery”. In this early post-implementation analysis, there were a number of apparent process improvements (e.g. time to CT) but no differences in either crude or adjusted mortality. The overall number of deaths following trauma in England did not change following the national reconfiguration of trauma services. Evidence from other countries that have regionalised trauma services suggests that further benefits may become apparent after a period of maturing of the trauma system

Machine Learning Methods for Prediction of CDK-Inhibitors

Progression through the cell cycle involves the coordinated activities of a suite of cyclin/cyclin-dependent kinase (CDK) complexes. The activities of the complexes are regulated by CDK inhibitors (CDKIs). Apart from its role as cell cycle regulators, CDKIs are involved in apoptosis, transcriptional regulation, cell fate determination, cell migration and cytoskeletal dynamics. As the complexes perform crucial and diverse functions, these are important drug targets for tumour and stem cell therapeutic interventions. However, CDKIs are represented by proteins with considerable sequence heterogeneity and may fail to be identified by simple similarity search methods. In this work we have evaluated and developed machine learning methods for identification of CDKIs. We used different compositional features and evolutionary information in the form of PSSMs, from CDKIs and non-CDKIs for generating SVM and ANN classifiers. In the first stage, both the ANN and SVM models were evaluated using Leave-One-Out Cross-Validation and in the second stage these were tested on independent data sets. The PSSM-based SVM model emerged as the best classifier in both the stages and is publicly available through a user-friendly web interface at http://bioinfo.icgeb.res.in/cdkipred

Pregnant Behind Bars: Meeting the Nutrition Needs of Incarcerated Pregnant Women

The number of women involved in the criminal justice system has increased dramatically over the past 20 years. Due to their marginalized background, incarcerated women have a complex set of health-related needs. This is especially true of those who are pregnant, a particularly vulnerable, high-risk group. Although guidelines have been developed that recommend pregnancy screening, provision of dietary supplements, regular nutritious meals, and nutritional counseling for incarcerated pregnant women, jail policies and health care protocols often fail to heed these recommendations. In this chapter, we discuss the nutritional needs of pregnant incarcerated women as well as breastfeeding in the context of the criminal justice system and consider some of the challenges in developing programming and policies to address these health-related needs. We also present findings from the William & Mary Healthy Beginnings Project, a nutrition intervention program developed for pregnant incarcerated women in Southeastern Virginia. Assessment of this program suggests that through the development of protocols and polices that consider the health-related needs of pregnant women, correctional facilities could play a pivotal role in helping incarcerated women develop healthier habits to better care for themselves and their newborns.https://scholarworks.wm.edu/asbookchapters/1106/thumbnail.jp