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Preterm infants are extremely vulnerable to a range of morbidities and mortality. Underdeveloped cardiac, respiratory, gastrointestinal, and immune systems in the preterm period increase the risk of necrotizing enterocolitis (NEC), a serious disease of the gut. NEC affects 5–12% of very–low birth-weight infants, leads to surgery in 20–40% of cases, and is fatal in 25–50% of cases. There are multiple factors that may contribute to NEC, but the exact cause is not yet fully understood. Severe cases can result in intestinal resection or death, and the health care costs average >$300,000/infant when surgical management is required. Different types of nutrition may affect the onset or progression of NEC. Several studies have indicated that bovine milk–based infant formulas lead to a higher incidence of NEC in preterm infants than does human milk (HM). However, it is not clear why HM is linked to a lower incidence of NEC or why some infants fed an exclusively HM diet still develop NEC. An area that has not been thoroughly explored is the use of semielemental or elemental formulas. These specialty formulas are easy to digest and absorb in the gut and may be an effective nutritional intervention for reducing the risk of NEC. This review summarizes what is known about the factors that contribute to the onset and progression of NEC, discusses its health care cost implications, and explores the impact that different formulas and HM have on this disease.

Preclinical studies reveal associations between intestinal ganglioside content and inflammatory bowel disease (IBD). Since a low level of ganglioside is associated with higher production of proinflammatory signals in the intestine, it is important to determine safety and bioavailability of dietary ganglioside for application as a potential therapeutic agent.Healthy volunteers (HVs; n = 18) completed an 8-week supplementation study to demonstrate safety and bioavailabity of ganglioside consumption. HVs were randomized to consume a milk fat fraction containing 43 mg/d ganglioside or placebo, and patients with IBD (n = 5) consumed ganglioside supplement in a small pilot study. Plasma gangliosides were characterized using reverse-phase liquid chromatography-QQQ mass spectrometry. Intestinal permeability was assessed by oral lactulose/mannitol, and quality of life was assessed by quality of life in the IBD questionnaire.There were no adverse events associated with dietary ganglioside intake. Ganglioside consumption increased ( P.05) plasma content of total GD3 by 35% over 8 weeks. HVs consuming ganglioside exhibited a 19% decrease in intestinal permeability ( P = .04). Consumption of ganglioside was associated with a 39% increase ( P.01) in emotional health and a 36% improvement ( P.02) in systemic symptoms in patients with IBD.Impaired intestinal integrity characteristic of IBD results in increased permeability to bacterial antigens and decreased nutrient absorption. Intestinal integrity may be improved by dietary treatment with specific species of ganglioside. Ganglioside is a safe, bioavailable dietary compound that can be consumed to potentially improve quality of life in patients with IBD and treat other disorders involving altered ganglioside metabolism. This study was registered at clinicaltrials.gov as NCT02139709.

Summary Background & aims Energy is essential for the treatment and recovery of children admitted to Pediatric Intensive Care Units (PICU). There are significant immediate and long-term health consequences of both under- and over-feeding in this population. Energy requirements of critically ill children vary depending on age, nutritional status, sepsis, fever, pharmacotherapy, and duration and stage of critical illness. This study aimed to determine the incidence of over- and under-feeding and to compare hospital outcomes between these feeding categories. Secondary outcomes were collected to describe the association between feeding categories and biochemistries (serum lactate, triglycerides, C-reactive protein). Methods An ethics approved retrospective study of children admitted to PICU was performed. All intubated patients admitted to PICU (2008–2013) were included, except those in which an IC test was not feasible. Data collection included demographics, the primary outcome variable reported as under feeding ( 110% MREE) determined through comparison of measured resting energy expenditure (MREE) using indirect calorimetry (IC) to actual energy intake based on predicted basal metabolic rate (PBMR) and clinical outcomes mechanical ventilation and PICU length of stay (LOS). Data were analysed with descriptive methods, ANOVA and linear regression models. Results A total of 139 patients aged 10 (range 0.03–204) months were included. Sixty (43%) were female and 77 (55%) were admitted after a surgical procedure. A total of 210 IC tests were conducted showing a statistically significant difference between MREE measurements and PBMR (p = 0.019). Of the 210 measurements, only 26 measures (12.4%) demonstrated appropriate feeding, while 72 (34.3) were underfed and 112 (53.3%) were overfed. Children who were overfed had significantly longer PICU LOS (median 45.5, IQR 47.8 days) compared to those children in the appropriately fed (median 21.0, IQR 54.5 days), and underfed groups (median 16.5, IQR 21.3 days). There was a mean difference between the over and under feeding category and ventilation days after adjusting for age and PRISM score (p = 0.026), suggesting decreased mechanical ventilation days for underfed. Children who were underfed had significantly higher CRP (median 75.5, IQR 152.8 mg/L) compared to those children in the appropriately fed (median 57.8, IQR 90.9 mg/L) and overfed groups (median 22.4, IQR 56.2 mg/L). Conclusions This retrospective study confirms that estimations of energy expenditure in critically ill children are inaccurate leading to unintended under and overfeeding. Importantly under feeding seems to be associated with fewer mechanical ventilation days and PICU LOS. Further research is required to elucidate the role of optimal nutrition in altering clinical variables in this population.

Objective. To determine if early pre- and postoperative enteral feeding was associated with improved postoperative outcomes in infants with hypoplastic left heart syndrome undergoing the Norwood procedure. Study Design. Retrospective chart review of infants undergoing stage 1 surgical palliation for hypoplastic left heart syndrome. Results. Baseline demographics were similar between infants who received preoperative enteral nutrition (n = 17) and those who did not (n = 23). Infants who received no enteral nutrition had higher preoperative serum lactate levels (3.7 ± 2.1 vs 2.5 ± 0.8 mmol/L, P = .02). Postoperative length of stay, days of parenteral nutrition, and progression of enteral nutrition did not differ between groups. Postoperative length of stay was positively correlated with postoperative number of days from first to full enteral nutrition (r = .6; P < .0005) and day at full enteral nutrition (r = .6; P < .0005) but not day of first enteral nutrition (r = .15; P = .382). Conclusion. While current evidence indicates benefit of early enteral feeding, no association was found between preoperative enteral nutrition and postoperative outcomes measured. Further research using feeding algorithms may help inform care of these complex infants.

This study aimed to determine the prevalence of inadequate serum 25-hydroxyvitamin D (25(OH)D) levels in a pediatric Canadian cystic fibrosis (CF) population and to assess the effectiveness of a vitamin D supplementation protocol on improving vitamin D status. A secondary objective was to analyze factors that may be associated with inadequate 25(OH)D levels.Vitamin D supplementation, 25(OH)D levels, and factors hypothesized to be associated with 25(OH)D levels were collected through a retrospective chart review (2010 and 2011) of 96 patients (1-18 years) at one CF clinic in Canada. Adequacy of 25(OH)D was set at ≥75 nmol/L. Patients with inadequate 25(OH)D levels in 2010 were prescribed an additional 1000 IU/d for levels60 nmol/L or 400 IU/d for levels 60-75 nmol/L.Inadequate 25(OH)D levels were observed in 26% of patients in 2010 and 23% in 2011. After supplementation was increased for those with inadequate 25(OH)D levels in 2010 (n = 20), a significant increase in 25(OH)D levels was observed in 2011 (P = .03). Adequate status was achieved in 50% of these patients (n = 10). Age was significantly negatively associated with 25(OH)D levels in both years (P = .002). Percentage of forced expiratory volume in 1 second was significantly positively associated with 25(OH)D levels in 2011 (P = .03).While vitamin D supplementation was effective at increasing serum 25(OH)D, this protocol did not achieve optimal serum 25(OH)D levels in 25% of the population. Increasing age had the strongest association with 25(OH)D. Current supplementation protocols may require reevaluation based on emerging evidence and revised Cystic Fibrosis Foundation guidelines.

The immune system of preterm infants is immature, placing them at increased risk for serious immune-related complications. Human milk provides a variety of immune protective and immune maturation factors that are beneficial to the preterm infant's poorly developed immune system. The most studied immune components in human milk include antimicrobial proteins, maternal leukocytes, immunoglobulins, cytokines and chemokines, oligosaccharides, gangliosides, nucleotides, and long-chain polyunsaturated fatty acids. There is growing evidence that these components contribute to the lower incidence of immune-related conditions in the preterm infant. Therefore, provision of these components in human milk, donor milk, or formula may provide immunologic benefits.

Clinicians believe nutrition support is important; however, delivery of enteral nutrition may be delayed or interrupted due to a lack of guidelines or perceived contraindications to administration. The aim of this national survey was to examine the knowledge and perceived barriers among clinicians which prevent enteral nutrition administration to PICU patients.The survey consisted of 23 questions (19 primary and four branching). The survey was validated using a semistructured pilot test by three pediatric critical care intensivists and two pediatric critical care registered dietitians external to the study team.The survey was electronically distributed to clinicians in all PICUs across Canada.One hundred sixty-two PICU clinicians, including 96 staff intensivists, eight clinical assistants, 36 fellows, and 22 registered dietitians from PICUs across Canada.None.The survey was administered from January to March 2013. The response rate was 50% (55 staff intensivists, two clinical assistants, nine fellows, and 15 registered dietitians). There was high variability among clinicians regarding reasons to delay the onset of enteral nutrition or interrupt enteral nutrition administration. High variability (70% agreement and10% disagreement or vice versa) was found for some reasons to delay or interrupt enteral nutrition, including lactates (rising or2 or4 mmol/L), high gastric residual volumes, CT/MRI scans, and hypoplastic left heart syndrome. Sixty-eight percent of PICU clinicians reported no written feeding protocol to be in place.Overall, there is high variability among clinicians regarding acceptable procedural and clinical barriers to enteral nutrition administration; this may be improved by a standardized feeding protocol. Therefore, further research must be conducted to provide clinicians with evidence to support their practices for enteral nutrition administration.

The transition from trainee to career clinician-scientist can be a stressful and challenging time, particularly for those entering the less established role of nonphysician clinician-scientist. These individuals are typically PhD-prepared clinicians in the allied health professions, who have either a formal or informal joint appointment between a clinical institution and an academic or research institution. The often poorly defined boundaries and expectations of these developing roles can pose additional challenges for the trainee-to-career transition.It is important for these trainees to consider what they want and need in a position in order to be successful, productive, and fulfilled in both their professional and personal lives. It is also critical for potential employers, whether academic or clinical (or a combination of both), to be fully aware of the supports and tools necessary to recruit and retain new nonphysician clinician-scientists. Issues of relevance to the trainee and the employer include finding and negotiating a position; the importance of mentorship; the value of effective time management, particularly managing clinical and academic time commitments; and achieving work-life balance. Attention to these issues, by both the trainee and those in a position to hire them, will facilitate a smooth transition to the nonphysician clinician-scientist role and ultimately contribute to individual and organizational success.

Background: Comparison of estimated energy requirements using predictive equations (PBMR) to measured resting energy requirements (MREE) using indirect calorimetry is not widely investigated in the pediatric lung transplant (LTx) population. In this population, optimal nutrition delivery may promote appropriate weight gain post-transplantation. The purpose of this case series was to evaluate the difference between predicted and measured energy requirements pre- and post- transplant by comparing PBMR calculated by the World Health Organization (WHO) equation and MREE by indirect calorimetry. The secondary aim was to determine if the diagnosis of Cystic Fibrosis (CF) influenced energy expenditure. It was predicted that the majority of LTx children would have higher MREE than PBMR (denoted as % PBMR). The % PBMR value is relative to MREE. Methods and findings: After exclusion, there were 7 LTx patients (n=5 male, n=4 CF, median age 11.55, age range: 4-16 y) and 14 measurements (7 repeated measures). Measurements were conducted pre- or post- transplant. Pre-LTx patients (n=4 patients, n=2 CF) exhibited a median 106% PBMR (interquartile range: 24%). Post-LTx patients (n=3 patients, n=2 CF) exhibited a median 105% PBMR (24%). The median % PBMR did not differ significantly between CF and non-CF LTx children irrespective of transplant status (113% (22%), 103% (19%), respectively, P=0.12). Conclusion: These results suggest that MREE was higher than PBMR; the WHO equation may underestimate energy requirements for pre- and post-LTx children. There was a trend towards decreasing energy requirements post-LTx. In children post-LTx, the diagnosis of CF may not affect energy requirements.

OBJECTIVES: Serum C-reactive protein (CRP) has been used as a systemic inflammatory response (SIR) marker in the critical ill, including children after cardiopulmonary bypass surgery. Ventricular assist devices (VAD) have been increasingly used as a bridge support to heart transplantation in children. We aimed to examine the profiles of CRP in children receiving VAD support. METHODS: Charts of 13 children receiving Berlin Heart EXCOR ® from 2005 to 2009 were reviewed. The data obtained prior to and during VAD support included: CRP, white blood cells, inotropes and steroid use, VAD mode and duration of VAD support. Ten patients received left VAD (LVAD) and 3 biventricular VAD (BiVAD). RESULTS: The median duration of VAD support was 59 days (ranged 3–678 days). Pre-VAD CRP was 35 ± 51 mg/l and increased to 109 ± 59 mg/l on days 1–3 after the VAD implantation (P = 0.01), then gradually decreased to 28 ± 28 mg/l by 4 months and normalized by 5 months (P < 0.0001). CRP was higher in BiVAD than in LVAD patients throughout the study period (P = 0.003). CRP positively correlated with the doses of the epinephrine and norepinephrine and the monocyte counts, and negatively correlated with the lymphocyte count. The lymphocyte count was 2.5 ± 0.4 × 10 9 /l prior to implantation, and decreased to 2.1 ± 1.3 × 10 9 /l on days 1– 3( P= 0.5) and then to 0.6 ± 0.1 × 10 9 /l by 6 months (P= 0.08). It tended to be lower in BiVAD patients (P= 0.06). CONCLUSIONS: SIR exists in children prior to VAD support. VAD implantation is associated with a significant and prolonged increase in CRP and a decrease in lymphocyte count, indicating a suppressed immune function, being more pronounced in BiVAD patients.

Inflammatory and metabolic response is an important factor to determine clinical outcomes. However, it remains unknown in children undergoing heart transplantation (HTx). We examined the perioperative changes in the inflammatory and metabolic response markers C-reactive protein (CRP) and prealbumin (PA) in 38 heart-transplanted children. Data obtained prior to and within one month after HTx included CRP, PA, total and differential white blood cell counts, doses of inotropes and immunosuppressants, cultures of blood and body fluids, duration of cardiopulmonary bypass (CPB), aortic cross clamp and donor heart ischemia, and days in the intensive care unit (ICU) and hospital. CRP was 32±49 mg/L before HTx, increased to 130±55 mg/L on postoperative day 1-2, and decreased to 21±31 mg/L by one month after HTx. PA was 0.15±0.06 g/L before HTx, decreased to 0.12±0.03 g/L on postoperative day 1-2, and then gradually increased to 0.21±0.10 g/L by one month after HTx. Postoperative CRP positively correlated with epinephrine dosage and CPB duration. PA positively correlated with age. In conclusion, inflammatory and metabolic response is present before HTx and acutely intensified after HTx. It may be mainly influenced by CPB duration and cardiovascular function status.

HLA typing was performed on 384 individuals of an isolated population of 1,500 people with a.familial aggregate of lymphoma and immunodeficiency cases. Eighty-five % of the total population were descendants of the founding couple. First cousin marriages were common. There was a three-fold or higher increase of the following haplotypes as compared to the frequencies in Sheffield: HLA-A28, Bw35, HLA-A28, B18, HLA-A10, B18, HLA-A2, B18, HLA-A11, Bw40 and HLA-A11, B7. The frequency of HLA-A1, B8 was low (5.4%). The most common genotype was HLA-A2, B12/A2, B12 followed by HLA-A2, B12/A28, Bw35. We found 30 HLA homozygous individuals, of these 15 were HLA-A2, B12/A2, B12. There were two possible HLA cross-overs which may be confirmed and three postulated cross-overs which can never be confirmed as one or both parents of the individuals in question are deceased. Some of the haplotypes could be traced back to the first, second and third generations, i.e. to the first half of the nineteenth century. No single haplotype or antigen was shared by the patients.

In order to further elucidate the genetics of Graves' disease, we studied two families with several affected members, as well as tested the degree to which HLA haplotypes were shared in affected sibpairs. Further, we sought to identify the disease related haplotypes by determining the haplotypes shared among affected parent-child combinations. In one family, two affected sibs differed at four possible parental HLA haplotypes; no evidence of recombination was observed which could account for the result. In the other family, five siblings were affected. Four out of the five affected sibs shared the maternal haplotype HLA-A11, Bw51, Cw5, Cw-, DRw5, Bfs, GLO1, whereas three shared the paternal haplotype HLA-A1, B8, Cw-, DRw3, BfS and GLO1. Looking at haplotype sharing, two pairs of sibs were found to be HLA identical, whereas the fifth sib shared one haplotype with one of these pairs but not with the other. Out of 14 (eight of our own and six from the literature) affected sibpairs examined, nine were found to be HLA identical and four shared one haplotype, suggesting that the contribution of both paternal haplotypes may be necessary for the susceptibility to the disease. Fourteen parent-child combinations were studied; in only three out of 13 in which the shared haplotype could be ascertained was the haplotype B8 positive; this distribution is similar to controls. However, of the remaining 10 combinations which did not share a B8 positive haplotype, five were B8 positive at one or the other of the non-shared haplotypes.

One hundred and thirty members of a family with 33 cases of Dystrophia myotonica (Dm) were tested for various genetic markers including Km, Jk, Lu and Se. All individuals tested were Lua negative, but many were heterozygous for the other markers. Except for two cases all patients with Dm were positive for Km3 and Jka and they were secretors. Assuming the genes are linked and that the order of the loci is Km, Jk, Lu, Se, Dm, then there were 22 meioses informative for Dm and in 10 of these a recombination must have occurred between two of the five loci. Looking at individual pairs of loci, there were no recombinations between Km and Jk in seven informative meioses, three recombinations out of 10 meioses informative for Jk/Se, no recombinations between Se and Dm in five informative meioses and three recombinations out of 12 meioses informative for Jk/Dm.

Introduction: The transfer of children from the pediatric cardiac intensive care unit (PCICU) to the ward is a time of great anxiety for the parents of children and medical vulnerability for children who are receiving complex therapies. Hypothesis: We assessed the hypothesis that parental presence at bedside transfer rounds would reduce parental anxiety and improve patient safety following transfer of children from PCICU to the ward. Methods: We undertook a randomized controlled trial of children discharged from the PCICU to the ward. Consenting parents were randomized to be absent (control group) or present (intervention group) at multidisciplinary face to face bedside transfer rounds. The primary outcome measure was parental stress measured by the validated Spielberger’s State -Trait Anxiety Inventory (STAI) pre and post transfer. Secondary outcome measures included unplanned readmission to the PCICU, medication errors and emergency calls to the ward. We excluded patients being transferred between intensive care units. Results: We enrolled 230 subjects (control group n=93, intervention group n=91, failed to complete study n= 46). The 2 groups were matched with respect to gender (male 46% control vs 54% intervention), age (median age control 1.9 yrs (range 0.02 to 16.3) vs intervention 0.9 (0.02 to 17), parental age 32 yrs (18-64) vs 33 (20-60), parental years of schooling 15.5 years ( 7-26) vs 15 (9-24), presence of medical co-morbidities (33% each group). There was significantly greater reduction in trait (p=0.004, state (p=0.01) and total anxiety (p=0.0012) pre and post transfer in the intervention group vs the control group. There were no differences in minor medication errors (36 vs 33), unplanned PCICU re-admissions (11 vs 12) and emergency ward calls(7 vs 8) Conclusions: Parental presence at face to face multidisciplinary transfer rounds from the PCICU is associated with reduced parental anxiety without change in medication errors, readmission rates or emergency calls to the ward. Reduced parental anxiety may improve parental satisfaction with their child’s care.

Nutrition support is often delayed or interrupted. The aim of this study is to identify reasons for and quantify time spent without nutrition in a mixed medical-surgical-cardiac pediatric intensive care unit (PICU).Data were prospectively collected to describe the patient cohort (anthropometrics and diagnostic category) and nutrition practices (time to nutrition initiation; frequency, duration, and causes of interruptions; and overall caloric intake). Descriptive statistics were used; comparisons of groups were performed using an independent t test and P.05 as significance.The mean (standard deviation) time to nutrition initiation was 22.8 (16.6) hours following admission; 35% of patients were initiated after24 hours. Nutrition was interrupted 1.2 (2.0) times per patient. Time spent without nutrition due to interruptions was 11.6 (23.0) hours, up to 102 hours. Patients spent 42.4% (28.2%) of their median (range) PICU admission of 2.9 days (0.25-39 days) without any form of nutrition. Patients aged 0-6 months had a significantly higher mean number and duration of interruptions (P = .001 and P.001, respectively) compared with children6 months. Interruptions due to surgery and planned extubation lasted significantly longer than all other interruptions (P.001 and P = .001, respectively). Pediatric Risk of Mortality (PRISM) III scores were not correlated with percentage of length of stay spent without nutrition (r = 0.137).Prolonged time to nutrition initiation and interruptions in delivery caused pediatric patients to spend a high proportion of admission without nutrition support, preventing most from meeting energy requirements. Further research addressing specific patient outcomes is required to define optimal initiation times and appropriate procedural-specific fasting times.

The transition from trainee to career clinician-scientist can be a stressful and challenging time, particularly for those entering the less established role of nonphysician clinician-scientist. These individuals are typically PhD-prepared clinicians in the allied health professions, who have either a formal or informal joint appointment between a clinical institution and an academic or research institution. The often poorly defined boundaries and expectations of these developing roles can pose additional challenges for the trainee-to-career transition.It is important for these trainees to consider what they want and need in a position in order to be successful, productive, and fulfilled in both their professional and personal lives. It is also critical for potential employers, whether academic or clinical (or a combination of both), to be fully aware of the supports and tools necessary to recruit and retain new nonphysician clinician-scientists. Issues of relevance to the trainee and the employer include finding and negotiating a position; the importance of mentorship; the value of effective time management, particularly managing clinical and academic time commitments; and achieving work-life balance. Attention to these issues, by both the trainee and those in a position to hire them, will facilitate a smooth transition to the nonphysician clinician-scientist role and ultimately contribute to individual and organizational success.

BACKGROUND Infants with congenital heart lesions who undergo open heart surgery may experience physiologic and metabolic stress in the postoperative period, leading to altered metabolism and hypercatabolism. The purpose of this study was to determine the relationship between energy intake and hospital outcomes during the first 10 days following neonatal open heart surgery. MATERIALS AND METHODS A post hoc analysis of all patients in a prospective randomized controlled trial was performed. Nutrition intake and hospital outcomes were assessed in 32 infants (40 ± 2.2 weeks, 3.4 ± 0.5 kg) in the neonatal and pediatric intensive care units. Infants received parenteral nutrition (PN) for 1-4 days before and 10 days after open heart surgery. Infants were separated into those who received a cumulative energy intake of

Inflammatory and metabolic response is an important factor to determine clinical outcomes. However, it remains unknown in children undergoing heart transplantation (HTx). We examined the perioperative changes in the inflammatory and metabolic response markers C-reactive protein (CRP) and prealbumin (PA) in 38 heart-transplanted children. Data obtained prior to and within one month after HTx included CRP, PA, total and differential white blood cell counts, doses of inotropes and immunosuppressants, cultures of blood and body fluids, duration of cardiopulmonary bypass (CPB), aortic cross clamp and donor heart ischemia, and days in the intensive care unit (ICU) and hospital. CRP was 32±49 mg/L before HTx, increased to 130±55 mg/L on postoperative day 1-2, and decreased to 21±31 mg/L by one month after HTx. PA was 0.15±0.06 g/L before HTx, decreased to 0.12±0.03 g/L on postoperative day 1-2, and then gradually increased to 0.21±0.10 g/L by one month after HTx. Postoperative CRP positively correlated with epinephrine dosage and CPB duration. PA positively correlated with age. In conclusion, inflammatory and metabolic response is present before HTx and acutely intensified after HTx. It may be mainly influenced by CPB duration and cardiovascular function status.

Objectives: Necrotizing enterocolitis (NEC) has high morbidity in premature infants. Hypoxia-ischemia, infection, and enteral feeding are risk factors associated with NEC, whereas feeding human milk is protective. Vasoactive and inflammatory mediators in NEC remain elusive. Gangliosides are found in human milk and enterocyte membranes. An infant bowel model of NEC was developed to test the hypothesis that gangliosides modulate the inflammatory response to infection and hypoxia. Patients and Methods: Viable, noninflamed bowel was obtained from 9 infants between 26 and 40 weeks' gestational age. Infant bowel was treated in culture with Escherichia coli lipopolysaccharide (LPS) and hypoxia in the presence or absence of preexposure to gangliosides. Bowel necrosis and production of nitric oxide, endothelin-1, serotonin, eicosanoids, hydrogen peroxide, and proinflammatory cytokines were measured. Results: Ganglioside preexposure reduced bowel necrosis and endothelin-1 production in response to LPS. Gangliosides suppressed infant bowel production of nitric oxide, leukotriene B4, prostaglandin E2, hydrogen peroxide, interleukin-1β, interleukin-6, and interleukin-8 in response to LPS exposure and hypoxia. Conclusions: A bowel protective effect of gangliosides is indicated by modulation of vasoactive mediators and proinflammatory signal suppression.

Background Nutritional support in the critically ill child has not been well investigated and is a controversial topic within paediatric intensive care. There are no clear guidelines as to the best form or timing of nutrition in critically ill infants and children. This is an update of a review that was originally published in 2009. . Objectives The objective of this review was to assess the impact of enteral and parenteral nutrition given in the first week of illness on clinically important outcomes in critically ill children. There were two primary hypotheses: 1. the mortality rate of critically ill children fed enterally or parenterally is different to that of children who are given no nutrition; 2. the mortality rate of critically ill children fed enterally is different to that of children fed parenterally. We planned to conduct subgroup analyses, pending available data, to examine whether the treatment effect was altered by: a. age (infants less than one year versus children greater than or equal to one year old); b. type of patient (medical, where purpose of admission to intensive care unit (ICU) is for medical illness (without surgical intervention immediately prior to admission), versus surgical, where purpose of admission to ICU is for postoperative care or care after trauma). We also proposed the following secondary hypotheses (a priori), pending other clinical trials becoming available, to examine nutrition more distinctly: 3. the mortality rate is different in children who are given enteral nutrition alone versus enteral and parenteral combined; 4. the mortality rate is different in children who are given both enteral feeds and parenteral nutrition versus no nutrition. Search methods In this updated review we searched: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2); Ovid MEDLINE (1966 to February 2016); Ovid EMBASE (1988 to February 2016); OVID Evidence-Based Medicine Reviews; ISI Web of Science - Science Citation Index Expanded (1965 to February 2016); WebSPIRS Biological Abstracts (1969 to February 2016); and WebSPIRS CAB Abstracts (1972 to February 2016). We also searched trial registries, reviewed reference lists of all potentially relevant studies, handsearched relevant conference proceedings, and contacted experts in the area and manufacturers of enteral and parenteral nutrition products. We did not limit the search by language or publication status. Selection criteria We included studies if they were randomized controlled trials; involved paediatric patients, aged one day to 18 years of age, who were cared for in a paediatric intensive care unit setting (PICU) and had received nutrition within the first seven days of admission; and reported data for at least one of the pre-specified outcomes (30-day or PICU mortality; length of stay in PICU or hospital; number of ventilator days; and morbid complications, such as nosocomial infections). We excluded studies if they only reported nutritional outcomes, quality of life assessments, or economic implications. Furthermore, we did not address other areas of paediatric nutrition, such as immunonutrition and different routes of delivering enteral nutrition, in this review. Data collection and analysis Two authors independently screened the searches, applied the inclusion criteria, and performed 'Risk of bias' assessments. We resolved discrepancies through discussion and consensus. One author extracted data and a second checked data for accuracy and completeness. We graded the evidence based on the following domains: study limitations, consistency of effect, imprecision, indirectness, and publication bias. Main results We identified only one trial as relevant. Seventy-seven children in intensive care with burns involving more than 25% of the total body surface area were randomized to either enteral nutrition within 24 hours or after at least 48 hours. No statistically significant differences were observed for mortality, sepsis, ventilator days, length of stay, unexpected adverse events, resting energy expenditure, nitrogen balance, or albumin levels. We assessed the trial as having unclear risk of bias. We consider the quality of the evidence to be very low due to there being only one small trial. In the most recent search update we identified a protocol for a relevant randomized controlled trial examining the impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients; no results have been published. Authors' conclusions There was only one randomized trial relevant to the review question. Research is urgently needed to identify best practices regarding the timing and forms of nutrition for critically ill infants and children.

Human leukocyte antigen (HLA)-DR-positive synovial fibroblasts are frequently observed in rheumatoid arthritis (RA) and may be implicated in the autoimmune reaction because RA is associated with certain HLA-DRB1* alleles. The question of whether components of the class II antigen presentation pathway and specific DRB alleles are efficiently expressed by synovial fibroblasts is germane to this hypothesis. To address this, cultured fibroblast-like synoviocytes (cFLS) were analyzed for constitutive and interferon (IFN)-gamma-induced expression of specific DRB alleles and class II-associated cochaperones. IFN-gamma induction of invariant chain, DM, and DR molecules was observed in all cFLS, but expression of specific DR allotypes was variable. Interestingly, DM-modulated epitopes on RA-associated DR molecules were either absent or delayed, despite strong DM expression and a paucity of major histocompatibility complex/class II-associated invariant chain peptide complexes. Altered expression of specific peptide-dependent epitopes on RA-associated HLA-DR molecules suggests differences in antigen presentation by cFLS, which may have implications for the immunopathogenesis of RA.

The genetic polymorphism of human factor H (beta 1H) was investigated by a combination of isoelectrofocusing and immunoblotting. This simple method is reliable and economical. The allelic frequencies in the Newfoundland population were estimated to be 0.597 and 0.403 for FH*1 and FH*2, respectively (129 individuals typed). No association of factor H types with rheumatoid arthritis was found (111 patients typed).

The HLA-DR4 association with rheumatoid arthritis (RA) was revealed in several pioneering observations by Stastny and others between 1974 and 1980 [1]. It is interesting that even in those early days there was an awareness that DR4 was not just associated with RA but was associated with severity of RA, as will be discussed later. As knowledge of the HLA system advanced and as further studies of RA were undertaken it became evident that the HLA association was by no means straightforward. For example, when it was found that DR4 was supertypic to a series of alleles - the subtypes of DR4 - it was noted that only a few of them were associated with RA; indeed one (DwlO or DRB1*0402) actually appeared to be protective. Later DR1 and DR14 were associated in some studies and DR10 was prominent in others. This confusing situation was considerably clarified when Gregersen et al. in 1987 [2] put forward the “shared epitope hypothesis”. These authors realised, from examination of the amino-acid sequence data that the alleles which were associated with RA all had a similar sequence in the beta chain, QKRAA or QRRAA at positions 70-74. This unifying hypothesis showed that the closest association between HLA and RA is with the shared sequence which lies on the edge of the MHC groove midway along one of its alpha helices. This is referred to as the “shared epitope”. The epitope concept leads into the purpose of this report which is to describe a series of monoclonal antibodies to DR4 and some of its subtypes as well as to the shared epitope. As will be discussed later, these antibodies may be useful in determining prognosis in early cases of RA.

A familial aggregate of seven cases of Hodgkin's disease (HD) has been investigated by HLA typing. Over 600 people in the immediate population (i.e. about half) have been HLA typed and haplotypes have been obtained for 95% of them. It was expected that the cases would share a particular HLA haplotype or at least that they would have one or two HLA antigens of the same series in common. However, this was not the case so no simple idea of association of HLA with HD cases was upheld. When antigen frequencies were examined in the whole population, it was found that HLA B18 increased progressively in incidence from 0.08 to 0.4 in successive groups of individuals each one more closely related to the HD cases. Similarly the community with the highest incidence of HD also had the highest incidence of B18. Thus B18, which in the world figures carries the highest relative risk, emerged as important in this study. Of four proposed interpretations of the data, we are most interested in the idea that the important HLA association is at a population level rather than at the level of the individual patient. A hypothesis, based on the concept of a "healthy carrier" for the HD agent, explains how such an association might operate. It is possible that B18-linked complement deficiency could be the basis for such a carrier state.

A C4 haplotype containing C4*A6 without C4*B1 is described. It occurred in the MHC haplotype HLA-A1, Cw5, Bw44, C2*1, BF*S, C4*A6BQO, DR3, GLO 2. This haplotype was observed in five of eight siblings, including the propositus who was in renal failure. The C4A6 was not haemolytically active and this new haplotype is therefore of particular interest since it is functionally equivalent to the rare C4-deficient haplotype C4*AQOBQO.

An association between Graves' disease and the human leukocyte antigen (HLA) system has previously been reported. The disease was more strongly associated with the HLA D locus antigen Dw3 than with HLA B8. Products of the HLA D locus are determined by the interaction of test cells with standard typing lymphocytes, a technically difficult procedure. Recently, it has been possible to type serologically for D locus related (DRw) specificities on peripheral bone marrow-derived (B) lymphocytes. Blood B lymphocytes from 50 unrelated controls and 41 patients with Graves' disease were typed for seven HLA DRw specificities. 28 patients with Graves' disease (68%) were positive for DRw3, in contrast to 14 controls (28%); whereas only 21 patients (50%) were HLA B8 positive, compared with 13 (26%) controls. Thus, positivity for DRw3 afforded a relative risk for Graves' disease of 5.5, whereas that for HLA B8 amounted to 3.0. Additionally, a family with multiple cases of Graves' disease in which the disease was previously shown to be inherited with the haplotype, was linked to DRw2, which suggests that the susceptibility to the disease was inherited in association with that antigen. Two HLA B/glyoxalase recombination events were observed in this family; in both instances HLA DRw followed HLA B. This study thus demonstrates that the disease susceptibility gene for Graves' disease is in strong linkage disequilibrium with DRw3; however, it may be associated with other DRw specificities and inherited within family units in association with them.

Hedgehog serum proteins were studied by physical, chemical and immunological methods. The paper electrophoretic and immunoelectrophoretic patterns did not differ greatly from those of human serum. In paper electrophoresis two beta-bands were found, the beta2-band being the most conspicuous. In the immunoelectrophoretic pattern, the form of the “rapid” lipoprotein-line was found to vary with temperature and duration of storage of serum. Autoradiography showed transferrin in hedgehog serum to be a beta2-globulin. Antibody activity was found in two different fractions after gel filtration or ultracentrifugation of serum, probably representing antibodies of the 19S and 7s types.

1. 1. Hedgehog IgG2 was shown to have a hexose content of 1·05 per cent and a total carbohydrate content of 2·00 per cent. 2. 2. Papain digestion of IgG2 yielded F(ab) 2 Fab and Fc depending on the conditions. Digestion in the presence of 0·1 M cysteine destroyed the Fc fragment. 3. 3. Hedgehog IgG1 induced reversed passive cutaneous anaphylaxis in guinea-pigs. The results with IgG2 were inconclusive. 4. 4. Hedgehog IgG2 bound staphylococcal protein A (Fc binding) while IgG1 did not.

1. 1. Antibodies of IgM class reacting with rabbit red cells were shown to be present in serum from non-immunized hedgehogs. 2. 2. Antibodies of IgM, IgG1 and IgG2 class reacting with rabbit red cells were shown to be present in serum from hedgehogs immunized with the serum sickness antigen (sheep red cells). 3. 3. Antibody activity to rabbit red cells was not demonstrated in hedgehog IgA.

The phagocytosis and intracellular killing of Staphylococcus aureus by humans granulocytes in the presence of immunoglobulin preparations have been examined. Isolated IgG from pooled human serum induced phagocytosis and intracellular killing of bacteria. F(ab')2 fragments had no significant effect, indicating that the Fc piece of the IgG molecule is of importance not only for the phagocytosis but also for the intracellular killing of bacteria. Isolated IgM stimulated the phagocytosis to a minor extent, with no enhancement of the bactericidal activity.

We examined HLA association with differentiated thyroid carcinoma in 45 patients from Newfoundland. No association was found. This finding contrasts with the description of an association of thyroid cancer with HLA-DR1 in Italy and Hungary (iodide deficient areas) and with DR7 in the American mid-west. We suggest that iodide deficiency predisposes DR1 + individuals to thyroid cancer and that this risk is negated by iodide sufficiency unless some other risk factor supervenes.

We found the rare properdin factor B(Bf) variant F1 to be present in 11% of 72 patients suffering from insulindependent diabetes (IDDM) compared with 2% among 150 normal controls. BfF1 thus confers a relative risk for IDDM of 5.55. All eight patients and three controls who were BfF1 positive were also HLA-B18 positive, reflecting the strong linkage disequilibrium between these two factors. We suggest that BfF1 marks a ‘diabetogenic’ B18-bearing HLA haplotype. Studies of unselected families with one or more affected members suggest that the B18, BfF1 does not necessarily segregate with IDDM phenotype. This study provides further evidence for the genetic heterogeneity of IDDM.

Although HLA-B27 carries a high relative risk for development of ankylosing spondylitis (AS), most B27 positive individuals do not have spondylitis. One interpretation of this observation is that there may be 2 types of B27, 1 which carries the risk factor and 1 which does not. If this were the case, then with the help of markers closely linked to HLA-B, it might be possible to detect differences between the B27 haplotypes in AS patients and those in healthy probands. We studied 197 members of 18 families with known AS and 110 members of 19 families in which HLA-B27 was present without any known inflammatory spinal disease. HLA antigens A, B, and C and alleles of complement components C2, C4, and Factor B and glyoxalase-1 were determined in all cases. Detailed haplotypes were assigned and their associations with development of the disease were examined. We were unable to identify any distinct HLA-B27 haplotype associated with AS; 2 common haplotypes and several miscellaneous ones were found in both groups. Thinking that the development of AS might be influenced by the other, non-B27 haplotype, we analyzed this and found that there was no detectable influence. The data do not contradict the notion that B27 in whites is a single entity and is itself the susceptibility factor predisposing to the development of ankylosing spondylitis.

Serum IgG, IgA, and IgM concentrations were measued in 120 members of a family with 33 cases of Dystrophia myotonica (Dm) and 27 members who were "possibly affected". The Dm individuals had significantly lower serum concentrations of IgG and IgA (P

The fourth component of complement (C4) has two classes of protein, C4A and C4B, both of which have many allelic forms. The serological determinants Rodgers (Rg1, Rg2) and Chido (Ch1, Ch2, Ch3) are generally associated with C4A and C4B, respectively. The C4B3 allotype has been detected in a single Canadian family that expresses a novel Ch phenotype, Ch:−1, 2, −3. There was no information for the Rg determinants, as the C4A * 2B * 3 haplotype would normally express Rg on the C4A protein. Other C4B3 allotypes in informative families have different Ch phenotypes, and the relationships of these within extended major histocompatibility complex haplotypes are discussed in this paper.

We have studied 25 patients with polyglandular autoimmune disease with respect to HLA antigens. Whereas the combination of insulin dependent diabetes with Graves’disease or atrophic thyroiditis was associated with an increase in HLA–B8, this was not found to be the case for patients with I.D.D.M. and goitrous thyroiditis. However 4/7 of these patients were DRw3 positive in contrast to previously established normal distribution of HLA–B8 in patients with goitrous thyroiditis alone. These data suggest that patients with polyglandular failure may be highly selected for HLA-B8/DRw3 positivity. We also report on two families with polyglandular autoimmune disease; the results suggest that these disorders are not necessarily transmitted with B8/DRw3 bearing haplotypes. In one family both the affected mother and non-affected father were B8 positive. The mother's B8, which was associated with DRw7, BfF and Rga did not appear to be involved in the transmission of disease susceptibility to two affected offspring. The search for complete haplotypic arrangement should be pursued to see whether this uncommon haplotype arrangement is peculiar to autoimmune diseases.

Sera from 305 individuals were typed for factor I, and a new variant, tentatively designated FI* C, was found. All other samples were FIB except for seven samples from Chinese that were of the FI AB phenotype. This suggests that polymorphism of factor I may be rare in Caucasians.

1. 1. Hibernating hedgehogs lysed intracardially injected foreign red cells slower than did non-hibernating hedgehogs. 2. 2. Ten out of nineteen hibernating hedgehogs immunized with sheep red cells formed antibody during hibernation. The latent period was at least 3 weeks. 3. 3. Two hedgehogs immunized twice started to produce antibodies after termination of hibernation. 4. 4. The antibodies formed during hibernation were predominantly of mercaptoethanol sensitive type.

1. 1. The concentration of IgG2 in serum of non-hibernating hedgehogs was fairly constant, 16 mg/ml. During hibernation the concentration fell steadily to reach the lowest value in March–April and then rose again after termination of hibernation. 2. 2. The mean decrease in serum concentration of IgG2 in two hibernating animals studied more closely was 0·05 mg/ml per day. 3. 3. The half-life of IgG2 in non-hibernating hedgehogs was 2·2 days. The half-life was prolonged to as much as 40 days in hibernating animals.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2–1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2* 1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B*2 whilst the Bw22 haplotypes mostly carry C4A*4, C4B*4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2*2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2*2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.