Placental IGF-I, IGFBP-1, zinc, and iron, and maternal and infant anthropometry at birth

Aim: To correlate placental protein levels of insulin‐like growth factor (IGF)‐I and insulin‐like growth factor binding protein (IGFBP)‐1, with previously determined levels of IGF‐I and IGF‐II mRNA expression, and the micronutrients zinc and iron, and maternal and newborn anthropometry. Methods: Placental samples were collected from rural field sites in Pakistan. Samples were divided into small and large for gestational age groups (SGA and LGA, respectively). IGFBP‐1 levels were assessed using Western immunoblotting. IGF‐I protein levels were assessed using ELISA techniques. IGF mRNA expression, zinc, and iron, were quantified as previously described and were used for comparative purposes only. Results: Thirty‐three subjects were included (SGA, n = 12; LGA n = 21). Higher levels of IGFBP‐1 were seen in the SGA group (p < 0.01). IGFBP‐1 correlated positively with maternal and infant triceps skin‐fold thickness in the LGA and SGA groups, respectively (p < 0.05). Significantly lower IGF‐I protein levels were seen in the SGA group. IGF‐I levels correlated significantly with maternal and newborn anthropometry. IGFBP‐1 correlated significantly with IGF‐II mRNA expression (p < 0.05). Conclusion: Placental protein levels of IGF‐I and IGFBP‐1 appear to be associated with maternal anthropometry. Maternal anthropometry may thus influence IGFBP‐1 and IGF‐I levels and may possibly be used for screening of pregnancies, with the potential for timely identification of these high‐risk pregnancies.     

Ontogeny of ghrelin, obestatin, preproghrelin, and prohormone convertases in rat pancreas and stomach

The processing of preproghrelin in the stomach by prohormone convertase (PC) 1/3 produces ghrelin and possibly obestatin. In the neonate, the pancreas is also a major source of ghrelin. We compared the ontogeny of preproghrelin, ghrelin, obestatin, and PCs in the stomach and pancreas from rat embryos (day 21) and neonates (days 1, 6, 13, 21, and 28) by immunohistochemistry. In stomach, preproghrelin positive cells were present from embryonic day 21 and were in excess of ghrelin cells. The number of ghrelin positive cells progressively increased with age. When preproghrelin cells were immunoreactive for ghrelin, they were also immunoreactive for obestatin and PC1/3. In pancreas, we only found 0 to 2 preproghrelin positive cells per islet and each of these cells was also positive for ghrelin and obestatin. None of the ghrelin positive cells stained for insulin, but we observed ghrelin positive/glucagon negative and ghrelin positive/glucagon positive cells. Ghrelin positive cells contained PC1/3 or PC2. In summary, in stomach, an excess of preproghrelin positive cells compared with ghrelin/PC1/3 positive cells suggests that PC1/3 determines preproghrelin processing to ghrelin. In pancreas, the colocalization of PC1/3 or PC2 in ghrelin positive cells points to a role for both PCs in preproghrelin processing.     

The interrelationships of glycemic control measures: HbA1c, glycated albumin, fructosamine, 1,5-anhydroglucitrol, and continuous glucose monitoring

Beck R, Steffes M, Xing D, Ruedy K, Mauras N, Wilson DM, Kollman C, the Diabetes Research in Children Network (DirecNet) Study Group. The interrelationships of glycemic control measures: HbA1c, glycated albumin, fructosamine, 1,5‐anhydroglucitrol, and continuous glucose monitoring. Objectives: To describe the interrelationships of glycemic control measures: hemoglobin A1c (HbA1c), glycated albumin, fructosamine, 1,5‐anhydroglucitrol (1,5‐AG), and continuous glucose monitoring (CGM) in children and adolescents with type 1 diabetes. Methods: In total, 26 subjects of age 4–17 had HbA1c measurement followed within 14 d by three laboratory measures of glycemia and the collection of CGM glucose data (N = 21). Results: Glycated albumin and fructosamine levels had a higher correlation with each other than with HbA1c. The correlation of 1,5‐AG with HbA1c was lower (absolute r value = 0.25). All four measures had a similar degree of correlation with CGM‐measured mean glucose (absolute r value = 0.50–0.56) and with hyperglycemic area under the curve (AUC) at 180 mg/dL (0.50–0.60). Conclusion: Each of the four measures (i.e., HbA1c, glycated albumin, fructosamine, and 1,5‐AG) had a similar correlation with mean glucose and hyperglycemic AUC‐180. 1,5‐AG did not correlate with hyperglycemic AUC‐180 better than did HbA1c.     

Type 1 diabetes mellitus: etiology, presentation, and management

This article reviews our current understanding of the etiology, presentation, and management of type 1 diabetes. The discussion includes a review of the natural history of diabetes, the complex relationship between genetic and environmental risk for type 1 diabetes, and current methods for prediction of type 1 diabetes. The article also reviews the current management of children who have new-onset type 1 diabetes, age-appropriate management goals, and diabetes complications. Finally, the article discusses the future of diabetes screening programs and the progress toward the ultimate goal of curing type 1 diabetes.     

The effect of antenatal betamethasone on cord blood concentrations of retinol-binding protein, transthyretin, transferrin, retinol, and vitamin E

We assessed the effect of short-term (less than or equal to 1 week) and prolonged (greater than 1 week) exposure to antenatal betamethasone on umbilical cord serum concentrations of retinol-binding protein (serum t 1/2 = 12 h), transthyretin (t 1/2 = 2 days), transferrin (t 1/2 = 8 days), retinol (vitamin A), and vitamin E in appropriate-for-gestational-age preterm newborn infants of less than 36 weeks' gestation. A group of 30 infants whose mothers received a single course of betamethasone less than or equal to 1 week prior to delivery had significantly elevated mean retinol-binding protein and transthyretin but not transferrin concentrations when compared with a group of 30 gestational age- and birth weight-matched infants with no exposure to antenatal betamethasone. A group of eight infants whose mothers received multiple (more than two) weekly courses of betamethasone prior to delivery had significantly elevated mean serum concentrations of all three proteins when compared with eight gestational age- and weight-matched control infants with no betamethasone exposure. Serum retinol and vitamin E concentrations were measured in a group of 21 infants exposed to short-term prenatal betamethasone and were significantly greater than in a group of 21 control infants without steroid exposure. We conclude that antenatal steroids increase the umbilical cord serum concentrations of retinol-binding protein, transthyretin, transferrin, retinol, and vitamin E. The effect on the various serum proteins is dependent on the duration of exposure to steroids.     

FISH analyses for alterations in chromosomes 1, 2, 3, and 11 define high-risk groups in neuroblastoma

BACKGROUND: The prognostic chromosomal markers 1p loss and MYCN amplification (MNA) are only present in a subgroup of approximately 30% of neuroblastomas. To further characterize high and low risk subsets we investigated alterations in chromosome arms 3p and 11q, additional changes in 1p and MYCN as well as the somy-status of chromosome 1 in the same sample. PROCEDURE: Fluorescence in situ hybridization (FISH) was used as an alternative technique to PCR/LOH- or comparative genomic hybridization (CGH) analyses. Alterations in chromosomes 3p and 11q were investigated in 182 unselected tumors, 1p loss and MNA in 174 and 179 of these, respectively. The somy-status of chromosome 1 was determined in 165 tumors as it highly correlates with the tumor ploidy. RESULTS: Alterations in the four chromosomal regions were found in the following frequencies: 3p26: 19%, 11q23: 29%, 1p36: 29%, MNA: 19%. Fifty-two percent of all cases displayed structural aberrations in at least one chromosomal region, 83% in stage 4 and 30% in stages 1-3, 4s. All aberrations were thus correlated with stage 4 disease but were also present in a substantial subset of localized and 4s tumors. Trisomy of chromosome 1 was found in 38% of the tumors, disomy or tetrasomy in 62%. Patients with alterations in any of the four chromosomes and di/tetrasomy 1 showed a significantly increased age at diagnosis. Loss in 1p and MNA were closely associated with each other, as well as 3p and 11q aberrations but not the groups 1p/MNA versus 3p/11q. Only a small portion of trisomic tumors showed aberrations in at least one of the four chromosomal regions (14%) in contrast to the majority of the di/tetrasomic cases (74%). As already known the MYCN status discriminated between good and poor outcome in localized and metastatic stage 4 tumors. In addition alterations in 1p or 11q, deletion in 3p and di/tetrasomy 1 were associated with an unfavorable prognosis in MYCN single copy tumors of stages 1-3, 4s. Multivariate analysis revealed 11q alterations and MNA as the most important chromosomal prognostic factors in all stages. CONCLUSION: FISH analyses for chromosomal alterations in 3p and 11q as well as in 1p and MYCN allows to define different groups with an increased risk for disease progression.     

Colorectal carcinoma in children, adolescents, and young adults

The authors conducted a retrospective evaluation of patients younger than 30 years with colorectal carcinoma in Argentina. Patients were divided into group 1 (patients treated at pediatric institutions from 0 to 20 years of age, n = 14) and group 2 (patients from 21 to 30, n = 7, treated at adult centers). Group 1 had significantly more advanced disease and a poorer prognosis. Six patients (2/14 in group 1 and 4/7 in group 2) survive disease-free. Thirteen patients died of progressive disease, 1 died of a non-tumor-related cause, and 1 is still on treatment. Patients younger than 20 years have a poorer prognosis, probably because of advanced disease on presentation.     

Relation of age, race, and allotype to immunoglobulin subclass concentrations

Concentrations of IgG1, IgG2, and total IgG were measured by a solid phase radioimmunoassay in sera from 36 healthy adults and 114 healthy children. As expected, IgG2 and total IgG had a positive correlation with age in children. In addition to age, several other factors were associated with significant differences in serum subclass concentrations. Female children had higher concentrations of IgG1 than males, and black subjects had significantly higher concentrations of IgG1, IgG2, and total IgG than whites. Although Km(1) and Gm(23) immunoglobulin allotypes had no relation to subclass concentrations when tested as single factors, the Km(1) allotype interacted significantly with race so that Km(1)-positive black children had higher IgG2 concentrations than other subjects. Our findings may explain, in part, recent observations of an association of the Km(1) allotype with altered immune responses of blacks to certain vaccines containing bacterial polysaccharides. In addition, our data indicate the need to control factors such as sex, race, and allotype in studies of subclass concentrations or immune responses.     

Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia

Heme oxygenase-1 (HO-1) is a stress-induced enzyme that catalyses the oxidation of heme to biliverdin. The primary deficiency of this enzyme has been shown in HO-1 knockout mice, and is characterized by intrauterine death and chronic inflammation. The first case of human HO-1 deficiency was reported in 1999. Human HO-1 deficiency has been observed to involve the endothelial cells more severely, resulting in hemolysis and disseminated intravascular coagulation. We report another case of human HO-1 deficiency in a young girl with congenital asplenia, who presented with severe hemolysis, inflammation, nephritis, which was refractory to therapy with corticosteroids, cyclophosphamide, and rituximab.     

Epigenetic silencing of the tumor suppressor genes SPI1, PRDX2, KLF4, DLEC1, and DAPK1 in childhood and adolescent lymphomas

The aim of the study was to investigate the expression and methylation status of seven distinctive genes with tumor suppressing properties in childhood and adolescent lymphomas. A total of 96 patients with Hodgkin Lymphoma (HL, n = 41), Non-Hodgkin Lymphoma (NHL, n = 15), and reactive lymphoid hyperplasia (RLH, n = 40, as controls) are included in the research. The expression status of CDKN2A, SPI1, PRDX2, DLEC1, FOXO1, KLF4 and DAPK1 genes were measured with QPCR method after the RNA isolation from paraffin blocks of tumor tissue and cDNA conversion. DNA isolation was performed from samples with low gene expression followed by methylation PCR study specific to promoter regions of these genes. We found that SPI1, PRDX2, DLEC1, KLF4, and DAPK1 genes are significantly less expressed in patient than the control group (p = 0.0001). However, expression of CDKNA2 and FOXO1 genes in the patient and control groups were not statistically different. The methylation ratios of all genes excluding the CDKN2A and FOXO1 were significantly higher in the HL and NHL groups than the controls (p = 0.0001). We showed that SPI1, PRDX2, DLEC1, KLF4 and DAPK1 genes are epigenetically silenced via hypermethylation in the tumor tissues of children with HL and NHL. As CDKN2A gene was not expressed in both patient and control groups, we conclude that it is not specific to malignancy. As FOXO1 gene was similarly expressed in both groups, its relationship with malignancy could not be established. The epigenetically silenced genes may be candidates for biomarkers or therapeutic targets in childhood and adolescent lymphomas.     

Stones, bones, and heredity

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine–glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined.

Conclusion

These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.     

Thiamine, riboflavin, pyridoxine, and vitamin C status in premature infants receiving parenteral and enteral nutrition

BACKGROUND: There is a paucity of data about water soluble vitamin status in low birthweight infants. Therefore, the authors' objective was to assess current feeding protocols. METHODS: The authors measured serum concentrations for riboflavin, pyridoxine, and vitamin C and functional assays for thiamine and riboflavin longitudinally in 16 premature infants (birthweight, 1,336 +/- 351 g; gestational age, 30 +/- 2.5 weeks) before receiving nutrition (time 1, 2 +/- 1 days), during supplemental or parenteral nutrition (time 2, 16 +/- 10 days) and while receiving full oral feedings (time 3, 32 +/- 15 days). In plasma, vitamin C was measured colorimetrically, and riboflavin and pyridoxine were measured using high-performance liquid chromatography. The erythrocyte transketolase test as a functional evaluation of thiamine and the erythrocyte glutathione reductase test for riboflavin were measured colorimetrically. RESULTS: At time 1, nutrient intake of vitamins were negligible because infants were receiving intravenous glucose and electrolytes only. Intakes differed between time 2 and time 3 for thiamine (510 +/- 280 and 254 +/- 115 microg. kg-1. d-1, respectively), riboflavin (624 +/- 305 and 371 +/- 193 microg. kg-1. d-1, respectively), and pyridoxine (394 +/- 243 and 173 +/- 85 microg/100 kcal, respectively), but not for vitamin C (32 +/- 17 and 28 +/- 12 mg. kg-1. d-1, respectively). Blood levels at times 1, 2, and 3 were for thiamine (4.9 +/- 2.7%, 3.3 +/- 6.6%, and 4.1 +/- 9% erythrocyte transketolase test, respectively), riboflavin (0.91 +/- 0.31, 0.7 +/- 0.3, 0.91 +/- 0.18 erythrocyte glutathione reductase test, respectively), riboflavin (19.5 +/- 17, 23.3 +/- 8.6, 17.6 +/- 10 ng/mL, respectively), pyridoxine (32 +/- 25, 40 +/- 16, 37 +/- 26 ng/mL, respectively), and vitamin C (5.2 +/- 3, 5 +/- 2.2, 10 +/- 5 microg/mL, respectively) and did not differ at those times. CONCLUSIONS: Current intakes of these vitamins, except for possibly vitamin C, during parenteral and enteral nutrition seem to result in adequate plasma concentrations and normal functional indices.     

A morphological,biochemical, and radioautographic study in rats

Splenectomy has long been an establishmd surgical procedure in various conditions, including trauma. Because total splenectomy has often been correlated with sepsis, every surgeon tries to preserve as much of the injured spleen as possible. Contradictory reports have been published as to whether regeneration of the remaining splenic tissue is possible. In the present study, 28 Sprague-Dawley rats ( 100 g) were divided into four groups. They underwent two-thirds partial splenectomy; the remaining splenic tissue was examined after 1 day, 1 week, 1 month and 3 months postoperatively. The following parameters were determined: weight, length, and protein and deoxyribonucleic acid (DNA) content of the remaining spleen. The incorporation of ³H-thymidine into the remaining spleen tissue was also measured. Histology and radioautography were studied in parallel. Results were compared with control animals that were operated upon but with no partial splenectomy. One day, 1 week, and 1 month following partial splenectomy, a slight increase in weight, length, protein, and DNA content as well as incorporation of the radioisotope into cellular DNA was found. By 3 months after the operation, there was no difference in the above parameters between the experimental animals and controls.Radioautographs indicated that most of the cells containing the isotope were situated in the perinodular areas in the red pulp, accompanied by an increased number of inflammatory cells. We found this cell proliferation mainly along the cut surface of the spleen. The slight increase that was found in all the parameters examined up to 1 month after partial splenectomy is an inflammatory response and not regeneration of the spleen.     

Effect of yearly vaccinations with live,attenuated, cold-adapted,trivalent, intranasal influenza vaccines on antibody responses in children

BACKGROUND: The cold-adapted, trivalent influenza vaccine (CAIV-T) may become an option for annual vaccination. However, there is little information regarding the immune response to repeated immunization with CAIV-T. OBJECTIVE: To determine the antibody response to repeated immunization with CAIV-T and to compare this with the response after the first CAIV-T immunization. DESIGN AND METHODS: Healthy children were offered CAIV-T immunization for 4 consecutive years, and blood samples were taken from a subset in Years 1, 2 and 4. In Year 4, 156 similarly aged children who had not received influenza vaccine previously were immunized with the same CAIV-T. RESULTS: The H3N2 and B components of the CAIV-T induced high antibody titers in Year 1 that were maintained during 4 years. The H1N1 titers were lower than the H3N2 or B titers. Comparison of the group immunized for 4 consecutive years with the group immunized for the first time revealed the following: (1) before immunization yearly immunized subjects were more likely to be seropositive to each of the three vaccine strains than those immunized for the first time (P < 0.05 for each); (2) after immunization the percentage of seropositive subjects to each of the strains was similar; (3) after immunization titers were higher in the subjects immunized for the first time than those immunized yearly (P < 0.05 for H3N2 and B). CONCLUSION: Yearly vaccination with CAIV-T induced high antibody titers, especially to the H3N2 and B strains in the vaccines. The titers in those immunized with CAIV-T for the first time were higher than in those immunized for 4 consecutive years.     

Lessons from fragile X regarding neurobiology, autism, and neurodegeneration

The fragile X mental retardation 1 gene (FMR1) mutation causes two disorders: fragile X syndrome (FXS) in those with the full mutation and the fragile X-associated tremor/ataxia syndrome (FXTAS) in some older individuals with the premutation. FXS is caused by a deficiency of the FMR1 protein (FMRP) leading to dysregulation of many genes that create a phenotype with ADHD, anxiety, and autism. FXTAS is caused by the elevation of FMR1-mRNA to levels 2 to 8 times normal in the premutation. This causes an RNA gain of function toxicity leading to brain atrophy, white matter disease, neuronal and astrocytic inclusion formation, and subsequent ataxia, intention tremor, peripheral neuropathy, and cognitive decline. The neurobiology and pathophysiology of FXS and FXTAS are described in detail.     

Autism: definition, neurobiology, screening, diagnosis

Autism (ie, the autism spectrum disorders) is now recognized in 1 in 150 children. This article highlights the definition, neurobiology, screening, and diagnosis of autism. The genetics, immunology, imaging, and neurophysiology of autism are reviewed, with particular emphasis on areas that impact pediatricians. Early recognition of the social deficits that characterize autism is key to maximizing the potential of these children.     

Duodenal duplications. Clinical characteristics, embryological hypotheses, histological findings, treatment.

BACKGROUND: The aim of this study was to analyse different clinical aspects and embryologic hypotheses of duodenal duplications. METHODS: Duodenal duplications occurring since 1995 were recorded. The age of the children at the time of diagnosis, the sex, location of the duplication, type of mucosa, clinical signs, associated lesions, and the type of surgical intervention were defined. RESULTS: We identified 5 patients (3 girls and 2 boys) who presented with histological or intraoperative findings of duodenal duplication. Their ages ranged from 4 days to 9 years, with the exception of two prenatal diagnoses. Three children were symptomatic: high intestinal obstruction (1 case), digestive bleeding (2 cases). In 1 case we found a palpable abdominal mass and 1 case was completely asymptomatic (prenatal detection). The abnormality was located on the duodenal concavity, originating from the third part in 2 cases and from the second part in 3 cases. All cases were non communicating types, 4 of which were cystic duplications and 1 was a tube-like variety. The epithelial lining was duodenal mucosa in all patients, but gastric heterotopies were identified in 2 cases. We performed two complete resections and 3 intraduodenal derivations. The outcome was uneventful in 5 cases with an average follow-up of 2 years. CONCLUSION: Duodenal duplications are rare malformations with several anatomical varieties. The preferred treatment for duodenal duplications is complete removal when the location allows it without endangering nearby anatomical structures.     

Day care attendance, respiratory tract illnesses, wheezing, asthma, and total serum IgE level in early childhood

BACKGROUND: It has been hypothesized that day care--related infections may explain the inverse relation between day care attendance in early life and asthma in childhood. OBJECTIVE: To examine the relation between day care attendance or respiratory tract illnesses in the first year of life and wheezing and asthma in the first 4 years of life among children with a parental history of atopy who were followed up from birth. RESULTS: Day care attendance in the first year of life was inversely associated with geometric mean total serum IgE level (12.9 [+/-1 SD = 3.3, 51.4] IU/mL for day care vs 18.5 [[+/-1 SD = 5.3, 64.7] IU/mL for no day care; P =.03) at 2 years of age but not significantly associated with wheezing at or after 2 years of age. Having at least 1 physician-diagnosed lower respiratory tract illness in the first year of life was significantly associated with recurrent wheezing (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.0-4.1) and asthma (OR, 2.5; 95% CI, 1.1-5.5) at 4 years of age, but not with any wheezing (infrequent and frequent) at 3 years or older. Illnesses of the upper respiratory tract (> or = 1 physician-diagnosed upper respiratory tract illness or > or = 3 episodes of nasal catarrh) in the first year of life were associated with any wheezing (frequent and infrequent) between the ages of 1 and 4 years, but not with recurrent wheezing or asthma at 4 years of age. CONCLUSIONS: Our results suggest that among children with a parental history of atopy the protective effect of day care attendance in early life against the development of atopy has begun by 2 years of age, and that a protective effect of day care attendance in early life against wheezing may not be observed until after 4 years of age.     

Congenital hypothyroidism, seasonality and consanguinity in the West Midlands, England

Seasonal variation in the incidence of congenital hypothyroidism (CHT) is reported by some centres. Also, the incidence of CHT varies with ethnic origin. We report our experience in the West Midlands, England. The overall incidence of CHT among 1128 632 neonates screened over 16 years in the West Midlands was 1:2924 live births, but was increased (1:2323; p<0.05) between October and December. In the city of Birmingham between 1981 and 1991, the incidence of CHT was 1:781, 1:5540 and 1:2257 in Pakistani, Indian and North-West European children, respectively; no cases were seen in those from other ethnic groups. Consanguinity among those of Pakistani descent could account for the increased incidence within this population. Identification of the cause of seasonal variation may aid development of preventative strategies.