Chapter 1. The Historical Roots of Paediatric Gastroenterology, Hepatology, and Nutrition.

The last 50 years have seen the establishment of paediatric gastroenterology, hepatology, and nutrition (PGHAN) as a well-recognised and thriving clinical specialty throughout most of Europe, and further afield. This has happened, in part, through the existence of the European Society for Paediatric Gastroenterology and Nutrition (ESPGHAN) as a forum for those interested in this branch of children's medicine. To illustrate the pan-European roots of PGHAN, some key scientific and medical events, discoveries, and inventions relevant to 3 common clinical problems-diarrhoea, jaundice, and infant-feeding-have been chosen to survey the historical development of the ways in which each was understood and treated within the changing thinking and practice of past times. Together they are used to trace the prehistory of ESPGHAN and provide a background against which to explain the genesis of the Society and how its spheres of clinical and scientific interest came to be defined.

State of the art of growth standards.

Growth charts have become widely used, if not universal, tools for the assessment of the growth and health of children. In 2006, the WHO published a set of charts designed to represent standards to which all the world's children should aspire. They were produced in response to the apparent variability in the patterns of child growth documented worldwide, and with the aim of creating a prescriptive standard based on best feeding advice. Our modern understanding and use of growth references arose out of the application of technology, mathematics and charting to the biology of growth in the 19th century. As means of summarizing normal development, modern growth standards have replaced Renaissance conceptions of human form based on idealized proportions in harmony with the cosmos, and the simple reference to key developmental milestones first noted by the ancients. The WHO growth standards are the culmination of a search for a human ideal based on 20th century biology. However, while they may be the 'best' standards based on contemporary feeding advice, they are 'provisional' because all developmental processes in biology, including body growth, are plastic and permit a flexibility of life course trajectories in response to epigenetic, nutritional and other environmental conditions.

Neonatal visual evoked potentials in infants born to mothers prescribed methadone.

OBJECTIVE: Drug misuse in pregnancy is associated with impaired infant visual development. Pilot data showed abnormal flash visual evoked potentials (VEPs) in neonates exposed to methadone in utero, but results were confounded by intrauterine growth restriction, gestation, and ongoing drug misuse. This large cohort study aimed to clarify the effects on neonatal flash VEPs of maternal drug misuse in pregnancy, including prescription of substitute methadone and subsequent development of neonatal abstinence syndrome. METHODS: This was a prospective cohort study. Flash VEPs were recorded within 3 days of birth from 100 healthy infants of drug-misusing mothers prescribed substitute methadone during pregnancy and 50 comparison infants matched for birth weight, gestation, and socioeconomic deprivation. VEP morphology was classified as mature, typical, or immature, and amplitudes and implicit times of the major waveform components measured. Drug exposure was determined by maternal history, maternal and infant urine, and meconium toxicology. RESULTS: VEPs from maternal drug-exposed infants were more likely to be of immature waveform (P < .001) and were smaller in overall amplitude (median 27 µV vs 39 µV, P < .001) compared with non-drug-exposed infants. Most infants were exposed to illicit drugs in addition to prescribed methadone; differences in VEP parameters were independently associated with maternal prescribed methadone and persisted after correcting for birth weight, cigarette smoking, and excess in utero alcohol exposure. CONCLUSIONS: In utero exposure to prescribed substitute methadone is associated with altered flash VEPs in the newborn period and these infants may warrant early clinical visual assessment.

Kinderheilkunde and continental connections in child health: the "Glasgow school revisited"--again.

The last two hundred years or so have seen the transformation of medical practice from a clinical art to the application of science to the diagnosis and treatment of disease. There has been a historical debate about how the use of technology and discoveries of the laboratory have become integrated within medical practice. In trying to understand the evolution of "scientific medicine," this has generally focused on the tensions between the differing cultures, persons, and professions of the "laboratory" and "clinic" and sought to explain how they were resolved within specific institutions. This paper looks again at the "Glasgow School" (the subject of a number of seminal papers on this subject) and the forces that shaped it, by exploring the career of Leonard Findlay, whose training in Glasgow, and in Berlin (where he worked in a department in which science and medicine were integrated), defined a style of clinical medicine that formed the model for a new sort of university department of medicine in which clinicians and scientists worked side by side, albeit under the leadership of the former. As a clinician exposed in Berlin to the emerging new sciences of nutrition, microbiology, and immunology, which were particularly relevant to the care of sick children, Findlay created in Glasgow a department of medical pediatrics, which owed less to local factors, figures, and forces and more to his experience in Germany.

Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity.

OBJECTIVE: Preterm infants show reduced retinal sensitivity at term corrected age compared with newborn term infants. We tested the hypothesis that retinal sensitivity in preterm infants is improved by early, high-dose vitamin A. STUDY DESIGN: We report a double-blind, randomized controlled trial of infants <32 weeks' gestation and/or <1501 g birth weight. Supplemented infants received additional intramuscular vitamin A 10 000 IU 3 times weekly from day 2 for a minimum of 2 weeks or until establishment of oral feeding. Hepatic stores were assessed by relative dose response (RDR). The primary outcome measure was cone-corrected dark-adapted retinal rod sensitivity measured by electroretinogram at 36 weeks' postmenstrual age (PMA). RESULTS: Eighty-nine infants (42 supplemented and 47 controls) were recruited. Plasma retinol was higher in supplemented infants at 7 and 28 days (median, 1.0 vs 0.5 µmol/L and 0.7 vs 0.6 µmol/L; P < .001 and .03, respectively). Neither plasma retinol nor RDR differed between groups at 36 weeks' PMA. Retinal sensitivity was greater in supplemented infants (-0.81 vs -0.61 log cd • s • m(-2); P < .03) and was not related to RDR. CONCLUSIONS: Early high-dose intramuscular vitamin A supplementation for infants at risk of retinopathy of prematurity improves retinal function at 36 weeks' PMA.

A short history of infant feeding and growth.

Our modern understanding of infant nutrition and feeding arose out of a constellation of scientific discoveries made more than 100 years ago. With the emergence of chemistry and physiology in the late 18th century, the analysis of foods, metabolic and energy balance studies, calorimetry, cell theory and measurements of growth and digestive function, became integrated to provide a coherent model of how organisms grow and are nourished. The interaction, with clinicians and public health professionals, of those working in these 'new' areas of the biological science, led to the application of safe and effective ways of feeding babies and of monitoring their growth and development, in the face of, and in response to, high infant mortality and morbidity.

10-year cognition in preterms after random assignment to fatty acid supplementation in infancy.

OBJECTIVE: To test the hypothesis that long-chain polyunsaturated fatty acid (LCPUFA) supplementation in infancy would improve cognition into later childhood (after 9 years) at both general and specific levels. METHODS: A comprehensive cognitive battery was completed by 107 formerly preterm infants (mean age: 128 months). As infants, they had been assigned randomly to receive LCPUFA-supplemented (N = 50) or control (N = 57) formula, between birth and 9 months; the docosahexaenoic acid level (DHA) in the supplemented formulas was 0.5%. In addition to randomized comparisons, we planned supplementary analyses to examine the effects of both gender and feeding group (those receiving some maternal breast milk versus those receiving none). RESULTS: There were no significant differences between randomized diet groups on any cognitive measure. There was significant interaction between gender and supplementation; girls only showed beneficial effects of LCPUFAs on literacy. Significant interaction also occurred between feeding group and supplementation; increases of 0.7 SD in verbal IQ, full-scale IQ, and memory scores were found for the LCPUFA group, but only for infants who received only formula and no maternal breast milk. CONCLUSIONS: The results of this post-9-year cognitive follow-up study in a randomized trial of LCPUFA-supplemented formula for preterm infants suggest no overall group effects but indicate that gender-specific and diet-specific effects may exist. The data provide some evidence that LCPUFAs are a key factor in the cognitive benefits of breast milk. Caution is advised in data interpretation because of the small groups used.

Use of stable isotopes to measure the metabolic activity of the human intestinal microbiota.

The human intestinal microbiota is a complex biological system comprising a vast repertoire of microbes with considerable metabolic activity relevant to both bacterial growth and host health. Greater strides have been made in the analysis of microbial diversity than in the measurement of functional activity, particularly in vivo. Stable isotope probing offers a new approach by coupling measurements of metabolic activity with microbial identification. Using a low-enrichment labeling strategy in vitro, this study has identified metabolically active bacterial groups via magnetic-bead capture methodology and stable isotope ratio analysis. Using five probes (EUB338, Bac303, Bif164, EREC482, and Clep866), changes in the activities of key intestinal microbial groups were successfully measured by exploiting tracers of de novo RNA synthesis. Perturbation of the nutrient source with oligofructose generated changes in the activity of bifidobacteria as expected, but also in the Bacteroides-Prevotella group, the Eubacterium rectale-Clostridium coccoides group, and the Clostridium leptum subgroup. Changes in activity were also observed in response to the medium type. This study suggests that changes in the functional activity of the gut microbiota can be assessed using tracers of de novo nucleic acid synthesis combined with measurement of low isotopic enrichment in 16S rRNA. Such tracers potentially limit substrate bias because they are universally available to bacteria. This low-enrichment labeling approach does not depend on the commercial availability of specific labeled substrates and can be easily translated to in vivo probing experiments of the functional activity of the microbiota in the human gut.

Nutrition in infancy and long-term risk of obesity: evidence from 2 randomized controlled trials.

BACKGROUND: Growth acceleration as a consequence of relative overnutrition in infancy has been suggested to increase the risk of later obesity. However, few studies have investigated this association by using an experimental study design. OBJECTIVE: We investigated the effect of early growth promotion on later body composition in 2 studies of infants born small for gestational age (weight <10th percentile in study 1 and <20th percentile in study 2). DESIGN: We reviewed a subset of children (n = 153 of 299 in study 1 and 90 of 246 in study 2) randomly assigned at birth to receive either a control formula or a nutrient-enriched formula (which contained 28-43% more protein and 6-12% more energy than the control formula) at 5-8 y of age. Fat mass was measured by using bioelectric impedance analysis in study 1 and deuterium dilution in study 2. RESULTS: Fat mass was lower in children assigned to receive the control formula than in children assigned to receive the nutrient-enriched formula in both trials [mean (95% CI) difference for fat mass after adjustment for sex: study 1: -38% (-67%, -10%), P = 0.009; study 2: -18% (-36%, -0.3%), P = 0.04]. In nonrandomized analyses, faster weight gain in infancy was associated with greater fat mass in childhood. CONCLUSIONS: In 2 prospective randomized trials, we showed that a nutrient-enriched diet in infancy increased fat mass later in childhood. These experimental data support a causal link between faster early weight gain and a later risk of obesity, have important implications for the management of infants born small for gestational age, and suggest that the primary prevention of obesity could begin in infancy.

In the balance: weighing babies and the birth of the infant welfare clinic.

The nineteenth century saw the incorporation of technology, such as the stethoscope, microscope, and thermometer, into clinical medicine. An instrument that has received less attention in the history of the role of technology in medicine is the weighing balance, or scale. Although not new to nineteenth-century medicine, it played an important part in the rise of the numerical method and its application to the development and shaping of pediatrics. This article explores the origin and development of the weighing of babies. During its clinical and scientific adoption, this simple procedure was refined and applied in a number of increasingly sophisticated and far-reaching ways: as a measure of the dimensions of the fetus and newborn, as an index of the viability of the newborn, as a means of estimating milk intake, as a way of distinguishing normality from abnormality, as a summary measure of infant health, and as an instrument of mass surveillance. In so doing it changed the way in which medical care was delivered to infants.

Prevalence of Helicobacter pylori vacA, cagA and iceA genotypes in South African patients with upper gastrointestinal diseases.

Clinical response to Helicobacter pylori infection may be determined by specific virulence-associated genotypes which varies geographically. The aim of this study was to investigate the diversity of putative virulence markers of H. pylori; cagA, vacA and iceA in the Eastern Cape Province of South Africa. One hundred H. pylori strains obtained from dyspeptic patients were used. Gastric biopsies were obtained from 254 dyspeptic patients. H. pylori was cultured and strains were studied. Bacterial genotypes cagA, vacA (s and m subtypes) and iceA were analysed by PCR using specific primers. CagA was identified in 90% of the strains investigated. Fifty-eight of the 100 strains had the vacA signal sequence genotype s1 and 26 had subtype s2. Combined vacA s1/s2 was detected in 16 of the strains. VacA middle region analysis showed that 8 (8%) strains were m1 while 50 were m2. Combined vacA m1/m2 was detected in 36 of the strains. s1m2 (20%) and s2m2 (20%) genotypes were the most common allelic combinations of the vacA gene among the strains. Multiple vacA genotypes were detected in this study. Twenty-six percent of the strains identified had both iceA1 and iceA2. All our strains tested positive for the ureC (glmM) gene. This study reveals a high prevalence of vacA, cagA and iceA2.

The 10-year follow-up of a randomised trial of long-chain polyunsaturated fatty acid supplementation in preterm infants: effects on growth and blood pressure.

OBJECTIVE: To test the hypothesis that consumption of infant formulas containing long-chain polyunsaturated fatty acids (LCPUFAs) by preterm infants would favourably influence growth, body composition and blood pressure (BP) at age 10 years. METHODS: This was a follow-up study of a preterm cohort (<35 weeks and birth weight <2000 g) randomly assigned to unsupplemented or LCPUFA-supplemented formulas to 9 months post term. The setting was a research clinic at Yorkhill Hospital for Sick Children, Glasgow, UK. A total of 107 children aged 9-11 years who participated in the original randomised controlled trial (45% follow-up) took part. Main outcome measures were: (1) anthropometry, (2) body composition and (3) BP. RESULTS: There were no differences in growth or BP between randomised groups for the whole cohort. However, girls who had received LCPUFA-supplemented formula were heavier (42.20 (SD 9.61) vs 36.94 (9.46) kg, p=0.05), had greater skin fold thicknesses (biceps 10.7 (3.3) vs 8.5 (3.6) mm, p=0.03; suprailiac 16.7 (8.2) vs 12.0 (7.5) mm, p=0.03) and higher BP (mean 82.2 (8.4) vs 78.1 (6.2) mm Hg, p=0.04: systolic 111.4 (10.1) vs 105.9 (9.0) mm Hg, p=0.04: diastolic 64.8 (8.4) vs 61.1 (5.4) mm Hg, p=0.05). Differences in weight SD score (0.85 (95% CI 0.13 to 1.58), p=0.02), Ln sum of skin fold thicknesses (0.27 (0.02 to 0.52), p=0.04) and BP (mean 4.6 mm Hg (0.43 to 8.84), p=0.03; systolic 6.1 (0.45 to 11.7), p=0.04) remained after adjustment for prerandomisation confounders. Differences in BP were not significant following adjustment for current weight. CONCLUSIONS: Girls born preterm and randomised to LCPUFA-supplemented formula showed increased weight, adiposity and BP at 9-11 years, which might have adverse consequences for later health. No effects were seen in boys. Long-term follow-up of other LCPUFA supplementation trials is required to further investigate this finding.

Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease.

BACKGROUND & AIMS: Childhood-onset inflammatory bowel disease (IBD) might be etiologically different from adult-onset IBD. We analyzed disease phenotypes and progression of childhood-onset disease and compared them with characteristics of adult-onset disease in patients in Scotland. METHODS: Anatomic locations and behaviors were assessed in 416 patients with childhood-onset (276 Crohn's disease [CD], 99 ulcerative colitis [UC], 41 IBD type unclassified [IBDU] diagnosed before seventeenth birthday) and 1297 patients with adult-onset (596 CD, 701 UC) IBD using the Montreal classification. RESULTS: At the time of diagnosis in children, CD involved small bowel and colon (L3) in 51% (138/273), colon (L2) in 36%, and ileum (L1) in 6%; the upper gastrointestinal (GI) tract (L4) was also affected in 51%. In 39%, the anatomic extent increased within 2 years. Behavioral characteristics progressed; 24% of children developed stricturing or penetrating complications within 4 years (vs 9% at diagnosis; P < .0001; odds ratio [OR], 3.32; 95% confidence interval [CI], 1.86-5.92). Compared with adults, childhood-onset disease was characterized by a "panenteric" phenotype (ileocolonic plus upper GI [L3+L4]; 43% vs 3%; P < .0001; OR, 23.36; 95% CI, 13.45-40.59) with less isolated ileal (L1; 2% vs 31%; P < .0001; OR, 0.06; 95% CI, 0.03-0.12) or colonic disease (L2; 15% vs 36%; P < .0001; OR, 0.31; 95% CI, 0.21-0.46). UC was extensive in 82% of the children at diagnosis, versus 48% of adults (P < .0001; OR, 5.08; 95% CI, 2.73-9.45); 46% of the children progressed to develop extensive colitis during follow-up. Forty-six percent of children with CD and 35% with UC required immunomodulatory therapy within 12 months of diagnosis. The median time to first surgery was longer in childhood-onset than adult-onset patients with CD (13.7 vs 7.8 years; P < .001); the reverse was true for UC. CONCLUSIONS: Childhood-onset IBD is characterized by extensive intestinal involvement and rapid early progression.

What is the role of the metabolic activity of the gut microbiota in inflammatory bowel disease? Probing for answers with stable isotopes.

The pathogenesis of inflammatory bowel disease remains obscure. However, there has been increasing interest in the role of the gut microbiota, focusing in particular on the "unculturable majority" of luminal and mucosal bacteria, which until recently have been difficult to study owing to the technical challenges of identification and elucidating function. Bacterial components and metabolites have been implicated in signalling to host immune systems and regulating inflammatory responses. Although the rapid expansion in techniques of molecular microbiology has increased our understanding of bacterial diversity, the tools to assess bacterial metabolic activity, and to link the 2, lag behind. Stable isotope probing is a powerful technique to link the metabolic activity and diversity of "unculturable" bacteria through isotopic labelling of biomarkers such as DNA and RNA. Progression of current stable isotope probing methodology with high-resolution oligonucleotide 16s rRNA probe technology and high precision liquid chromatographic isotope ratio mass spectrometry may facilitate application in human microbial ecology. Progress towards stable isotope probing use in vivo, in concert with other advances in bacterial metabolome analysis, will lead to the development of a dynamic picture of the metabolic activity and diversity of intestinal bacteria in inflammatory bowel disease. Such insights will, over time, lead to fuller understanding of inflammatory bowel disease pathogenesis and the development of targeted therapies to reverse the "dysbiosis" that precedes disease relapse.

Helicobacter pylori isolates recovered from gastric biopsies of patients with gastro-duodenal pathologies in Cameroon: current status of antibiogram.

OBJECTIVE: To determine the prevalence of Helicobacter pylori in patients with gastro-duodenal pathologies and the susceptibility patterns of isolates to the currently recommended antibiotic treatment regimen used in Cameroon. METHODS: Consecutive dyspeptic patients referred to Douala General Hospital, Cameroon for endoscopy were recruited in the study. Gastric biopsies were collected from the patients and H. pylori isolated and identified following standard microbiology and biochemical techniques. Antibiotic susceptibility was determined by disk diffusion and agar dilution methods against clarithromycin, tetracycline, amoxicillin and metronidazole. Data were analysed using chi-square test and significance considered at P < 0.05. RESULTS: Seventy-one (92.2%) of the 77 patients (mean age 44.5 +/- 15.7, range 15-77 years) were positive for H. pylori. The antibiotic susceptibility rates were 56% for tetracycline, 55.3% for clarithromycin, 14.4% for amoxicillin and 6.8% for metronidazole. The prevalence of clarithromycin resistance in males vs. females was 42.1%vs. 46.7%, while for metronidazole it was 89.5%vs. 94.7% (P > 0.05). Antimicrobial susceptibility results also revealed 12 antibiotypes based on resistance to the antimicrobial agents investigated. The resistance pattern, amoxicillin and metronidazole (AMR(R) MET(R)) was the most common (23.7%) amongst the isolates. More than 60% of the isolates exhibited multi-drug resistance to three or four antibiotics. CONCLUSION: Multi-drug resistance is common against the current treatment regimen in Cameroon and, therefore, calls for urgent studies involving newer and broad spectrum antibiotics to address the problem.

Probiotics for necrotizing enterocolitis: a systematic review.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most commonly acquired neonatal intraabdominal emergency and causes significant morbidity and mortality. A proposed strategy for the prevention of NEC is the administration of oral probiotics. Probiotics have been shown to reduce NEC in experimental rat models and have been used in clinical trials. The authors aimed to review the existing data on the use of oral probiotics for the prevention of NEC in preterm infants (age <33 weeks) and those with very low birth weight (VLBW). MATERIALS AND METHODS: Systematic review of randomized controlled trials (RCTs) and quasi-RCTs was performed to find outcome measures of incidence, severity, need for surgery, and mortality in NEC. Electronic searches were performed on Medline and CINAHL databases using key word and subject headings with combinations of the terms "infant, preterm"; "infant, VLBW"; "enterocolitis, necrotizing"; and "probiotics." In addition, citation searches were performed for all potential studies. RESULTS: Six potential RCTs were identified for inclusion, but there were no systematic or Cochrane database reviews identified. One study was discounted because of the use of historical controls, so 5 studies were selected for analysis. Cumulatively, 640 infants were treated with probiotics and 627 were used as control subjects. All of the studies showed a trend toward less NEC in the treatment group. The heterogeneity of probiotic formulations and the timing and methods of interventions in the identified studies made synthesis and comparison of data inappropriate. CONCLUSIONS: The data appear to lend support to the use of oral probiotics for the prevention of NEC in preterm infants and those with VLBW. However, the data are insufficient to comment on their short- and long-term safety. Type of probiotics used, as well as the timing and dosage, are still to be optimized. Further understanding of the pathogenesis of NEC and the mechanisms by which probiotics prevent it may lead to evidence-based treatment strategies.

Evaluation of 13C-urea breath test and fecal antigen immunoassay to detect Helicobacter pylori infection in Gambian infants.

Helicobacter pylori colonization was measured by [13C]-urea breath test in 198 Gambian infants and by fecal enzyme-linked immunosorbent assay in 52 of the 198 at ages 2, 5, and 12 months. By 12 months there was good concordance between tests; 33 of 44 (75%) test results were positive by enzyme-linked immunosorbent assay, and 29 of 44 (66%) test results were positive by urea breath test. H. pylori colonization is common among Gambian infants, and noninvasive tests can provide a reliable means of diagnosis.