Stanley Zlotkin

Vitamin D–deficiency rickets among children in Canada

Background: Based on regional and anecdotal reports, there is concern that vitamin D–deficiency rickets is persistent in Canada despite guidelines for its prevention. We sought to determine the incidence and clinical characteristics of vitamin D–deficiency rickets among children living in Canada. Methods: A total of 2325 Canadian pediatricians were surveyed monthly from July 1, 2002, to June 30, 2004, through the Canadian Paediatric Surveillance Program to determine the incidence, geographic distribution and clinical profiles of confirmed cases of vitamin D-deficiency rickets. We calculated incidence rates based on the number of confirmed cases over the product of the length of the study period (2 years) and the estimates of the population by age group. Results: There were 104 confirmed cases of vitamin D– deficiency rickets during the study period. The overall annual incidence rate was 2.9 cases per 100 000. The incidence rates were highest among children residing in the the north (Yukon Territory, Northwest Territories and Nunavut). The mean age at diagnosis was 1.4 years (standard deviation [SD] 0.9, min–max 2 weeks–6.3 years). Sixty-eight children (65%) had lived in urban areas most of their lives, and 57 (55%) of the cases were identified in Ontario. Ninety-two (89%) of the children had intermediate or darker skin. Ninety-eight (94%) had been breast-fed, and 3 children (2.9%) had been fed standard infant formula. None of the breast-fed infants had received vitamin D supplementation according to current guidelines (400 IU/d). Maternal risk factors included limited sun exposure and a lack of vitamin D from diet or supplements during pregnancy and lactation. The majority of children showed clinically important morbidity at diagnosis, including hypocalcemic seizures (20 cases, 19%). Interpretation: Vitamin D–deficiency rickets is persistent in Canada, particularly among children who reside in the north and among infants with darker skin who are breast-fed without appropriate vitamin D supplementation. Since there were no reported cases of breast-fed children having received regular vitamin D (400 IU/d) from birth who developed rickets, the current guidelines for rickets prevention can be effective but are not being consistently implemented. The exception appears to be infants, including those fed standard infant formula, born to mothers with a profound vitamin D deficiency, in which case the current guidelines may not be adequate to rescue infants from the vitamin D-deficient state.

Micronutrient Sprinkles to Control Childhood Anaemia

Over 750 million children have iron-deficiency anemia. A simple powdered sachet may be the key to addressing this global problem

Intravenous nitrogen and energy intakes required to duplicate in utero nitrogen accretion in prematurely born human infants.

In order to determine the intravenous energy and nitrogen intakes required to achieve intrauterine rates of nitrogen accretion and growth, 30 studies were completed in 22 premature infants who were provided with various intakes of amino acids and energy (glucose +/- lipid) by peripheral vein infusion. At constant nitrogen intake, increasing energy intake (as lipid) from 50 to 80 nonprotein kcal/kg/day resulted in significant increases in nitrogen retention and weight gain. Increasing nitrogen intake from 494 to 655 mg/kg/day at constant low energy intake (mean = 53 kcal/kg/day) had no effect on nitrogen retention or weight change; however, at higher energy intakes (mean = 81 kcal/kg/day) increasing nitrogen intake correlated significantly with increasing nitrogen retention. At energy intakes greater than 70 kcal/kg/day the major determinant of nitrogen retention was nitrogen intake. When energy intake was greater than 70 kcal/kg/day, the infusion of nitrogen providing 430 to 560 mg/kg/day (2.7 to 3.5 gm protein/kg/day) resulted in the duplication of intrauterine nitrogen accretion rates.

A cross-sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home

We performed a cross-sectional evaluation of deep vein thrombosis (DVT) related to the use of central venous lines (CVLs) in all pediatric patients receiving home total parenteral nutrition at our institution (N = 12). All children (5 months to 17 years of age) were examined with bilateral upper limb venography. All CVLs were flushed daily with heparin (200 units). At the time of evaluation, 49 CVLs had been placed in the 12 children. Of the 39 CVLs removed, 27 (66%) were blocked; venograms had not been previously obtained except of one child. Eight children had clinical evidence of superficial collateral circulation in the upper portion of the chest and the upper extremities; five had intermittent symptoms of superior vena cava obstruction. On venography, 8 of the 12 children had extensive evidence of DVT; two were unilateral and six bilateral. Five children were treated with warfarin (0.12 to 0.28 mg/kg per day) to achieve an international normalized ratio of 1.4 to 1.8. Neither bleeding nor further CVL-related DVT has occurred. We conclude that the risk of CVL-related DVT in children requiring home total parenteral nutrition is high, and that venography should be performed early in the event of CVL blockage. A multicenter, controlled trial assessing optimal warfarin therapy in this patient population is indicated.

The Development of Cystathionase Activity During the First Year of Life

Summary: The development of hepatic cystathionase (EC 4.4.1.1) activity is dependent both upon the gestational age of the infant and the postnatal age. Full-term infants are born with greater hepatic cystathionase activity than pre-term infants, and the activity increases rapidly after birth reaching mature levels at about 3 months of age. Prematurely born infants have lower hepatic cystathionase activity at birth and like the full-term, the activity increases after birth. Cystathionase activity is not isolated to the liver. In both premature and full-term infants, it is present in the kidneys and adrenals, but of little significance in the pancreas. These in vitro measurements of cystathionase activity indicate that the premature infant is potentially capable of endogenous cysteine production if provided with adequate methionine.Speculation: We postulate that, if given adequate methionine, the preterm infant may have sufficient cystathionase capacity to produce cysteine in amounts adequate to meet estimated needs.

Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

BACKGROUND & AIMS Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder presenting in the neonatal period. CTE is characterized by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. The objective of this study was to identify the gene responsible for CTE. METHODS A family with 2 children affected with CTE was identified. The affected children are double second cousins providing significant statistical power for linkage. Using Affymetrix 50K single nucleotide polymorphism (SNP) chips, genotyping was performed on only 2 patients and 1 unaffected sibling. Direct DNA sequencing of candidate genes, reverse-transcription polymerase chain reaction, immunohistochemistry, and Western blotting were performed on specimens from patients and controls. RESULTS SNP homozygosity mapping identified a unique 6.5-Mbp haplotype of homozygous SNPs on chromosome 2p21 where approximately 40 genes are located. Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 in affected patients. Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM. Direct sequencing of EpCAM from 2 additional unrelated patients revealed novel mutations in the gene. CONCLUSIONS Mutations in the gene for EpCAM are responsible for CTE. This information will be used to gain further insight into the molecular mechanisms of this disease.

Maintenance of remission in inflammatory bowel disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses.

&NA; The objective was to systematically review the efficacy and safety of n‐3 (omega‐3 fatty acids, fish oil) for maintaining remission in Crohns disease (CD) and ulcerative colitis (UC). Electronic databases were searched systematically for randomized controlled trials of n‐3 for maintenance of remission in inflammatory bowel disease (IBD). Studies of patients of any age group who were in remission at the time of recruitment and were followed for at least 6 months were included. The primary outcome was relapse rate at the end of the follow‐up period. Nine studies were eligible for inclusion; six studies of CD (n = 1039) and three of UC (n = 138). There was a statistically significant benefit for n‐3 in CD (relative risk [RR] 0.77; 95% confidence interval [CI] 0.61–0.98); however, the studies were heterogeneous (I2 = 58%). The absolute risk reduction was −0.14 (95% CI: −0.25 to −0.02). Opinions may vary on whether this is a clinically significant effect. Two well‐done studies with a larger sample size reported no benefit. A sensitivity analysis excluding a small pediatric study resulted in the pooled RR being no longer statistically significant. A funnel plot analysis suggested publication bias for the smaller studies. For UC, there was no difference in the relapse rate between the n‐3 and control groups (RR 1.02; 95% CI: 0.51–2.03). The pooled analysis showed a higher rate of diarrhea (RR 1.36; 95% CI: 1.01–1.84) and symptoms of the upper gastrointestinal tract (RR 1.96; 95% CI: 1.37–2.80) in the n‐3 treatment group. There are insufficient data to recommend the use of omega 3 fatty acids for maintenance of remission in CD and UC. (Inflamm Bowel Dis 2011;)

Effect of Iron Fortification on Malaria Incidence in Infants and Young Children in Ghana: A Randomized Trial

IMPORTANCE In sub-Saharan Africa, malaria is a leading cause of childhood morbidity and iron deficiency is among the most prevalent nutritional deficiencies. In 2006, the World Health Organization and the United Nations Childrens Fund released a joint statement that recommended limiting use of iron supplements (tablets or liquids) among children in malaria-endemic areas because of concern about increased malaria risk. As a result, anemia control programs were either not initiated or stopped in these areas. OBJECTIVE To determine the effect of providing a micronutrient powder (MNP) with or without iron on the incidence of malaria among children living in a high malaria-burden area. DESIGN, SETTING, AND PARTICIPANTS Double-blind, cluster randomized trial of children aged 6 to 35 months (n = 1958 living in 1552 clusters) conducted over 6 months in 2010 in a rural community setting in central Ghana, West Africa. A cluster was defined as a compound including 1 or more households. Children were excluded if iron supplement use occurred within the past 6 months, they had severe anemia (hemoglobin level <7 g/dL), or severe wasting (weight-for-length z score <-3). INTERVENTIONS Children were randomized by cluster to receive a MNP with iron (iron group; 12.5 mg/d of iron) or without iron (no iron group). The MNP with and without iron were added to semiliquid home-prepared foods daily for 5 months followed by 1-month of further monitoring. Insecticide-treated bed nets were provided at enrollment, as well as malaria treatment when indicated. MAIN OUTCOMES AND MEASURES Malaria episodes in the iron group compared with the no iron group during the 5-month intervention period. RESULTS In intention-to-treat analyses, malaria incidence overall was significantly lower in the iron group compared with the no iron group (76.1 and 86.1 episodes/100 child-years, respectively; risk ratio (RR), 0.87 [95% CI, 0.79-0.97]), and during the intervention period (79.4 and 90.7 episodes/100 child-years, respectively; RR, 0.87 [95% CI, 0.78-0.96]). In secondary analyses, these differences were no longer statistically significant after adjusting for baseline iron deficiency and anemia status overall (adjusted RR, 0.87; 95% CI, 0.75-1.01) and during the intervention period (adjusted RR, 0.86; 95% CI, 0.74-1.00). CONCLUSION AND RELEVANCE In a malaria-endemic setting in which insecticide-treated bed nets were provided and appropriate malaria treatment was available, daily use of a MNP with iron did not result in an increased incidence of malaria among young children. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01001871.

Aspartame: Effect on lunch-time food intake, appetite and hedonic response in children

Two experiments were conducted, each with 20 healthy 9-10-year-old children. After an overnight fast, subjects were given a standardized breakfast at 0830 hrs, the treatments at 1030 hrs, and a lunch containing an excess of foods at 1200 hrs. Visual analog scales of hunger, fullness, and desire to eat were administered 5 min before and 20 and 85 min after treatment. Lunch-time food intake was measured. In experiment 1, either aspartame (34 mg/kg), or the equivalent sweetness of sodium cyclamate, was given in an ice slurry (300 ml) of unsweetened strawberry Kool-Aid with carbohydrate (1.75 g/kg polycose). In experiment 2, drinks (300 ml) contained either sucrose (1.75 g/kg) or aspartame (9.7 mg/kg). In both experiments, significant meal- and time-dependent effects were observed for subjective feelings of hunger, fullness and desire to eat. Treatments, however, did not affect either subjective feelings of appetite or lunch-time food intake. Thus, aspartame consumed without or with carbohydrate, did not affect either hunger or food intake of children when compared with the sweeteners sodium cyclamate and sucrose, respectively.

Hepatic Metallothionein as a Source of Zinc and Cysteine during the First Year of Life

ABSTRACT: Metallothionein, a high cysteine-containing protein, can bind with both essential and nonessential metals and thus play an important role as a metal storage protein and also in the detoxification of toxic metals. Although in the human fetus, levels of trace minerals and metallothionein are very high, their postnatal changes are not well documented. The purpose of the present investigation, therefore, was to quantify the accumulation of metallothionein in premature and full-term infants during the first year of life and to identify factors affecting its accumulation. From 47 postmortem samples, it was determined that hepatic metallothionein levels were highest in newborn premature and full-term infants falling to levels found in older children by 4.4 months of age. Hepatic zinc levels were also highest in the youngest infants, falling with increasing postnatal age. There was a significant positive correlation between zinc and metallothionein at all ages. However, there was a negative correlation between hepatic metallothionein levels and cystathionase activity. Hepatic copper and metallothionein levels were unrelated. The renal concentration of metallothionein, zinc, and copper were significantly lower than corresponding hepatic levels. The fall in hepatic levels of zinc and metallothionein during the first months of life correspond to a period of negative zinc balance and low endogenous cysteine production in the newborn. Thus metallothionein may play an important role as a storage depot for these two essential nutrients during this critical period of active growth.