Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings.

AIM: This study measured autoantibodies against tissue transglutaminase (anti-tTG) to detect untreated coeliac disease in children with type 1 diabetes and their siblings. METHODS: Anti-tTG was measured in prospectively collected sera from 169 children at the onset of diabetes, 88 of their siblings and 96 matched control children. Coeliac disease was confirmed with a small intestinal biopsy. RESULTS: Coeliac disease was diagnosed in five children before diabetes onset. A further 12 children were diagnosed after diabetes onset, without any gastrointestinal symptoms, and 11 of these had anti-tTG at the onset of diabetes, with the remaining child showing seroconversion within 6 months. Hence, all the children with both diseases had anti-tTG at or before diabetes diagnosis, and the prevalence of coeliac disease was 10.1%. Moreover, 6.8% of the siblings and 3.1% of the control children had elevated levels of anti-tTG. None of the siblings reported any coeliac-related symptoms, despite being positive for anti-tTG, and coeliac disease has so far been biopsy confirmed in 4.5%. CONCLUSION: Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. All diabetes children and their siblings should be tested and followed for the presence of anti-tTG and coeliac disease.

Fetal, developmental, and parental influences on cystatin C in childhood: the Uppsala Family Study.

BACKGROUND: The aim was to identify determinants (biomedical and social characteristics of children and their parents) of cystatin C levels in healthy children drawn from a population sample. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 425 pairs of consecutive full siblings born 1987-1995 in Uppsala were identified using the Swedish Medical Birth Registry and invited with their parents for examination in 2000-2001. OUTCOME: Serum cystatin C level was log-transformed and analyzed using random-effects models. MEASUREMENTS: The examination in parents and children consisted of a nonfasting blood sample, anthropometry, and questionnaires about lifestyle and socioeconomic position. Tanner stage was used for assessment of pubertal status. RESULTS: In age-, height-, and body mass index-adjusted analyses, cystatin C level increased by 2.6% (95% CI, 0.3%-4.8%) higher in Tanner stage 2 vs 1 girls, and 1.6% (95%CI, 0.2%-3.1%) lower in boys than girls. For every 10% increase in maternal cystatin C level, offspring cystatin C level increased by 3.0% (95% CI, 2.2%-3.8%); the equivalent effect for paternal cystatin C level was 2.1% (95% CI, 1.3%-2.9%). Lower maternal education was associated with a 2.4% (95% CI, 0.3%-4.6%) higher cystatin C level in their offspring. LIMITATIONS: Cross-sectional study design, missing cystatin C values for subset of parents, lack of urinary measurements, no gold-standard measurement of glomerular filtration rate. CONCLUSIONS: There are intergenerational associations of cystatin C level in families in line with previous reports of heritability of kidney disease. Lower maternal education is associated with higher cystatin C levels in their children. Further studies of healthy children are needed to explore the biological mechanisms for these findings. If cystatin C is measured, these studies will need to record pubertal stages.

Increased perinatal intracranial pressure and brainstem dysfunction predict early puberty in boys with myelomeningocele.

BACKGROUND: Children with myelomeningocele (MMC) run an increased risk of developing early or precocious puberty (E/PP). AIM: To identify risk factors for E/PP in boys with MMC. METHODS: Boys born between 1970 and 1992, treated for MMC at the University Children's Hospital, Uppsala, were identified. Thirty-eight boys were eligible to be included. Medical records were examined retrospectively. Early puberty was defined as pubertal signs before the age of 10 years and 2 months. Precocious puberty was defined as the appearance of these signs before 9 years of age. Increased intracranial pressure perinatally was defined as wide sutures, bulging fontanelles and increased/increasing head circumference at birth and/or during the first week after birth. Early brainstem dysfunction was defined as severe and persistent feeding and respiratory problems before the age of 3 months despite proper control of the hydrocephalus. RESULTS: Of the 38 boys, 8 (21%) had E/PP, which was strongly associated with increased intracranial pressure perinatally and also with early brainstem dysfunction. Multivariate regression analysis showed early brainstem dysfunction to have the highest explanatory value regarding the occurrence of early puberty. CONCLUSION: Increased intracranial pressure perinatally and brainstem dysfunction early in life are strong predictors of E/PP in boys with MMC.

Enterovirus markers and serum CXCL10 in children with type 1 diabetes.

Most patients with type 1 diabetes are considered to have a T-cell mediated autoimmune disease. The chemokine CXCL10 promotes the migration of activated T-cells. Virus infections might contribute to the pathogenesis of type 1 diabetes and enterovirus protein and/or genome have been detected in beta-cells from a majority of tested newly diagnosed children with type 1 diabetes. The chemokine CXCL10 is induced in human islet cells by enterovirus infections in vivo and in vitro, but is not expressed in islets from normal organ donors. Since CXCL10 is a chemokine known to be induced by virus infections and/or cellular damage, our aim was to study if levels of CXCL10 are elevated in serum from children with type 1 diabetes and whether it correlates to the presence of enterovirus markers. CXCL10, neutralizing antibody titer rises against certain enterovirus, and antibodies against GAD65 were measured in serum, and enterovirus PCR was performed on whole blood from 83 type 1 diabetes patients at onset, 48 siblings and 69 controls. CXCL10 was also measured in serum from 46 patients with proven enterovirus infection and in serum from 46 patients with other proven virus infections. The CXCL10 serum levels were not elevated in children at onset of type 1 diabetes and there was a considerable overlap between the groups with 99 (8-498) pg/ml in serum from children with type 1 diabetes, 120 (17-538) pg/ml in serum from controls, and 117 (7-448) pg/ml in siblings of the children with type 1 diabetes. The CXCL10 serum levels in patients with proven enterovirus infection were slightly increased compared to the levels in the other groups, 172 (0-585) pg/ml but there was no statistically significant difference. In contrast, CXCL10 serum levels in patients with other proven virus infections were clearly elevated 418 (34-611) pg/ml. Despite that elevated CXCL10 levels have been demonstrated in some groups of patients with type 1 diabetes, in this study the mean CXCL10 serum levels were not elevated in patients with type 1 diabetes neither in patients with proven enterovirus infection. In contrast, in patients with other virus infections the CXCL10 levels were elevated, presumably reflecting the severity or the site of infection. This suggests that local production of CXCL10 in the affected organ cannot be measured reproducible in serum and that its potential use in clinical practice is limited.

Influence of test weighing before/after nursing on breastfeeding in preterm infants.

PURPOSE: Swedish hospitals apply various regimens for preterm infants' nutrition in connection with their mothers' establishment of breastfeeding. Milk intake is assessed either by test weighing before and after breastfeeding or by observing the infant's suckling behavior (ie, clinical indices). These differing policies may lead to differences in infants' feeding progress. The purpose of this study was to compare effects on breastfeeding and weight gain of preterm infants, depending on whether the volume of breast milk intake when suckled in the hospital was estimated by "clinical indices" or determined by test weighing. SUBJECTS: Sixty-four infants treated at a unit applying test weighing were compared with 59 infants treated at a unit assessing milk intake by "clinical indices." DESIGN AND METHODS: A retrospective, descriptive, and comparative design was used to explore the consequences of different nutrition regimens. Data were obtained from a review of hospital medical records. PRINCIPAL RESULTS: The infants treated at the hospital where test weighing was practiced attained exclusive breastfeeding at an earlier postmenstrual age (PMA) and were also discharged at an earlier PMA. However, the 2 study units were alike regarding the proportion of infants attaining exclusive breastfeeding, the postnatal age when this occurred, and the weight pattern in hospital. CONCLUSION: To establish breastfeeding in preterm infants, test weighing before and after breastfeeding and gradual reduction of supplementation are both applicable regimens. Mothers can be encouraged to choose either of them, although test weighing may help infants attain exclusive breastfeeding at an earlier PMA.

Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.

CONTEXT: Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING: A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION: The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE: We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS: The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION: Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

Concern for privacy in relation to age during physical examination of children: an exploratory study.

OBJECTIVES: To explore whether physicians behave differently regarding ethics and respect for privacy depending on children's age. We explored whether physician behaviours contributed to child uneasiness. STUDY DESIGN: Observational study of 21 children (0-12 years; 18 boys; mean age 3.2) undergoing evaluation for inguinal hernia. Specific physician-initiated verbal and nonverbal behaviours were coded from digital video discs of the consultations. RESULTS: Physician intrusiveness (i.e. approaching the child suddenly or in an uninvited way) during the physical examination was related to concurrent child uneasiness (r = 0.42, p < 0.06) and lasted through the postexamination phase of the consultation (r = 0.52, p < 0.01). Child mood during the examination strongly predicted postexamination mood (r = 0.69, p < 0.0001). Neither the total number of physician-initiated positive behaviours or privacy-related behaviours was associated with child age. Negative physician behaviours were strongly related to negative mood in the child (r = 0.72, p < 0.0001) at the close of the consultation. CONCLUSION: Although physicians were more likely to provide information to older than younger children, their behaviours regarding privacy did not differ by child age. We found that intrusiveness was rather common and related to child uneasiness that has implications for the ethical practice and a child's willingness to be examined.

Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency.

CONTEXT: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH). OBJECTIVE: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls. DESIGN AND SETTING: A randomized, controlled, long-term multicenter trial was conducted in Sweden. INTERVENTION: Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated. SUBJECTS: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population. MAIN OUTCOME MEASURES: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS. RESULTS: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. CONCLUSION: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

Effects of being born small for gestational age on long-term intellectual performance.

Size at birth has been associated repeatedly with increased risk of cardiovascular morbidity and mortality later in life. However, there is accumulating evidence to suggest an association between being born small for gestational age (SGA) and increased risk of lower intelligence, poor academic performance, low social competence and behavioural problems, compared with individuals born appropriate for gestational age. Crude neurological handicaps, such as cerebral palsy, are extremely rare in children born SGA at term. Such handicaps are more common in very premature children. However, there does appear to be an increase in the risk for non-severe neurological dysfunction in individuals born SGA. Intellectual performance is evaluated in young children in several different ways, including standardized tests such as Weschler's Intelligence Scale - Revised, and teachers and parents' reports. In adulthood, indirect variables such as education and occupation are used in addition to standardized tests. It may be possible to modify the effects of SGA on intellectual development by breast feeding the baby for more than 6 months. Nutrient-enriched formula does not have any advantages when it comes to intellectual development, and induces a risk of rapid weight gain and eventually overweight. Growth hormone treatment may also have some effect on intelligence quotient.

Effects on isolated human pancreatic islet cells after infection with strains of enterovirus isolated at clinical presentation of type 1 diabetes.

Enterovirus (EV) infections have been associated with the pathogenesis of type 1 diabetes (T1D). They may cause beta-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Evidence for EV involvement have been presented in several studies, EV-IgM antibodies have been reported in T1D patients, EV-RNA has been found in the blood from T1D patients at onset, and EV have been isolated from newly diagnosed T1D. Our aim was to study infections with EV isolates from newly diagnosed T1D patients in human pancreatic islets in vitro. Two of them (T1 and T2) originated from a mother and her son diagnosed with T1D on the same day, the other two (A and E) were isolated from a pair of twins at the time of diagnosis of T1D in one of them. Isolated human pancreatic islets were infected and viral replication, viability and degree of cytolysis as well as insulin release in response to high glucose were measured. All four EV isolates replicated in the islet cells and virus particles and virus-induced vesicles were seen in the cytoplasm of the beta-cells. The isolates varied in their ability to induce cytolysis and to cause destruction of the islets and infection with two of the isolates (T1 and A) caused more pronounced destruction of the islets. Infection with the isolate from the healthy twin boy (E) was the least cytolytic. The ability to secrete insulin in response to high glucose was reduced in all infected islets as early as 3 days post infection, before any difference in viability was observed. To conclude, strains of EV isolated from T1D patients at clinical presentation of T1D revealed beta-cell tropism, and clearly affected the function of the beta-cell. In addition, the infection caused a clear increase in the number of dead cells.

Ethics takes time, but not that long.

BACKGROUND: Time and communication are important aspects of the medical consultation. Physician behavior in real-life pediatric consultations in relation to ethical practice, such as informed consent (provision of information, understanding), respect for integrity and patient autonomy (decision-making), has not been subjected to thorough empirical investigation. Such investigations are important tools in developing sound ethical praxis. METHODS: 21 consultations for inguinal hernia were video recorded and observers independently assessed global impressions of provision of information, understanding, respect for integrity, and participation in decision making. The consultations were analyzed for the occurrence of specific physician verbal and nonverbal behaviors and length of time in minutes. RESULTS: All of the consultations took less than 20 minutes, the majority consisting of 10 minutes or less. Despite this narrow time frame, we found strong and consistent association between increasing time and higher ratings on all components of ethical practice: information, (beta = .43), understanding (beta = .52), respect for integrity (beta = .60), and decision making (beta = .43). Positive nonverbal behaviors by physicians during the consultation were associated particularly with respect for integrity (beta =.36). Positive behaviors by physicians during the physical examination were related to respect for children's integrity. CONCLUSION: Time was of essence for the ethical encounter. Further, verbal and nonverbal positive behaviors by the physicians also contributed to higher ratings of ethical aspects. These results can help to improve quality of ethical practice in pediatric settings and are of relevance for teaching and policy makers.

Risk of high blood pressure among young men increases with the degree of immaturity at birth.

BACKGROUND: Survivors of preterm birth constitute a new generation of young adults, but little is known about their long-term health. We investigated the association between gestational age (GA) and risk of high blood pressure (HBP) in young Swedish men and whether GA modified the risk of HBP; ie, whether HBP was related to being born small for gestational age (SGA). METHODS AND RESULTS: This population-based cohort study included 329 495 Swedish men born in 1973 to 1981 who were conscripted for military service in 1993 to 2001. Multivariate linear- and logistic-regression analyses were performed. Main outcome measures were systolic and diastolic BPs at conscription. Linear-regression analyses showed that systolic BP increased with decreasing GA (regression coefficient -0.31 mm Hg/wk, P<0.001). Systolic and diastolic BPs both increased with decreasing birth weight for GA, but the association with systolic BP was most evident (regression coefficient -0.67 mm Hg per SD score in birth weight for GA, P<0.001). Compared with men born at term (GA, 37 to 41 weeks), the adjusted odd ratios (95% confidence intervals [CIs]) for high systolic BP (> or =140 mm Hg) were as follows: moderately preterm (33 to 36 weeks), 1.25 (1.19 to 1.30); very preterm (29 to 32 weeks), 1.48 (1.30 to 1.68); and extremely preterm (24 to 28 weeks), 1.93 (1.34 to 2.76). Being SGA was associated only with an increased risk of high systolic BP among men born at 33 weeks or later. The risk estimates for high diastolic BP (> or =90 mm Hg) increased with decreasing GA, but the risk reached significance only among men born moderately preterm. CONCLUSIONS: Preterm birth, a common pregnancy complication, is a risk factor for HBP in young men. The risk of high systolic BP associated with birth weight for GA is modified by GA, suggesting that perinatal contributions to BP elevation later in life may be induced by different biological pathways.

Fetal, developmental, and parental influences on childhood systolic blood pressure in 600 sib pairs: the Uppsala Family study.

BACKGROUND: Little is known about the contribution of maternal and paternal factors to the inverse association between birth weight and later blood pressure in human offspring. A study of within- and between-family associations of birth weight with blood pressure, which collected data on both parents, would address this gap in our knowledge. METHODS AND RESULTS: The study examined families composed of mother, father, and 2 full sibs delivered between 38 and 41 weeks' gestation within 36 months of each other. A total of 1967 families meeting our inclusion criteria were contacted and 602 were examined (children 5 to 14 years old, 1998 to 2000). Birth weight and gestational age were available from obstetric records. Systolic blood pressure in childhood was inversely associated with birth weight within families (-2.3 mm Hg/kg, 95% CI -4.4 to -0.3) after adjustment for gestational age, sex, height, and weight at examination. The between-family effect (-1.5 mm Hg/kg, -3.1 to 0.0) was strengthened on adjustment for maternal and paternal height and weight, whereas adjustment for paternal and maternal systolic blood pressure at examination independently attenuated the effect. CONCLUSIONS: The existence of an inverse association of birth weight with systolic blood pressure within families (adjusted for height and weight at examination) demonstrates that factors that vary between pregnancies in the same woman (including fetal genotype) can influence the later blood pressure of offspring. We conclude that this apparent fetal programming effect on blood pressure will not be eliminated solely by interventions aimed at modifying growth and cumulative nutritional status from conception through childhood or other fixed characteristics of future mothers.

Growth, puberty, and final height in children with Type 1 diabetes.

OBJECTIVE: The aims of this study were to assess the physical growth and pubertal development in a group of diabetic children and to evaluate the effect of height at diagnosis, duration of illness, and degree of glycemic control on final height and sexual maturation. RESEARCH DESIGN: A cohort of 72 Sudanese diabetic children, 7-13 years of age at diagnosis, was followed longitudinally from the onset of diabetes until the attainment of final height. RESULTS: The mean height standard deviation scores (SDS) at diagnosis were 0.04 in boys and -0.15 in girls, which was greater than their genetic target height (GTH). The growth velocity between diagnosis and final height was slow, with significant reduction in pubertal growth spurt. The mean final height attained by these children was lower than their GTH, a finding that contradicts most of the recently published reports. The average age at menarche in girls (15.1 years) and the mean age of full sexual maturation in boys (17.2 years) were significantly delayed in this group of diabetic patients. This retardation in physical growth and pubertal development was positively correlated with the duration of diabetes before the onset of puberty and glycated haemoglobin (HbA1c) concentration. The majority of these patients were thin at diagnosis of diabetes, with median body mass index (BMI) <22, but showed a remarkable, progressive weight gain during puberty, which was more evident in girls. The weight gain was independent of weight at diagnosis and duration of diabetes, but was positively correlated with the daily dose of insulin and HbA1c concentration. CONCLUSION: Conventional therapy of diabetic children is associated with impairment of physical growth and delayed sexual maturation.

Parents' perspectives on research involving children.

Children's participation in research is essential for the development of safe and age-appropriate treatments. However, children's participation is limited. The aim of this study was to determine (1) mothers' and fathers' views on which agencies/persons should evaluate the level of acceptable risk for children and (2) parents' willingness to allow children to participate in research. Medical factors, sociodemographics, and research attitudes were related to willingness. The study used a cross-sectional and longitudinal design with 863 expectant parents (435 women; 428 men) consecutively recruited at gestational week 19 during routine ultrasound examination at 2 hospitals in Uppsala County, Sweden. 123 women at gestational week 34 were followed-up. Parental ratings of agencies/persons' degree of involvement in risk-evaluation for. child research participants and parents' willingness to allow children to participate in research were the main outcome measures. Most parents believed that more pediatric research was needed. Attitudes played a major role in willingness, indicating a potential for information that could modify willingness. Over 80% of mothers and fathers rated the attending physician as needing to be "fully involved" in risk evaluation for research participants. Parents' views contradict current trends in research ethics which place evaluation of risk in the hands of regional agencies. Instead, the majority of parents would like the decision to be individually based on the attending physicians advise. We conclude that children's participation in research could be improved by actively incorporating the attending physician and by educating the public so that research attitudes can be based on accurate information.

High risk of sensorineural hearing loss in men born small for gestational age with and without obesity or height catch-up growth: a prospective longitudinal register study on birth size in 245,000 Swedish conscripts.

BACKGROUND: Several components of the metabolic syndrome coincide with those risk factors linked to sensorineural hearing loss (SNHL). According to the thrifty phenotype hypothesis, the metabolic syndrome can be caused by events during the fetal period. This study tests the thrifty phenotype hypothesis on hearing, using body size at birth and conscription as indirect markers for fetal programming and body mass index as an indicator for the metabolic syndrome. METHODS: Odds ratios were used to analyze birth data regarding body size from birth to conscription as risk factors for hearing loss in 245,092 conscripted Swedish men. FINDINGS: Compared with conscripts born short for gestational age with catch-up growth, those born short with absence of catch-up growth exhibited 134% higher risk of SNHL. Adult short stature was associated with a 50% increased risk. Compared with conscripts with average body mass index, overweight was associated with 30%, obesity with 99%, and overweight if born light for gestational age with 118% higher risk of SNHL. Conscripts born light for gestational age had a 41% increased risk, independent of the later growth pattern. CONCLUSION: The thrifty phenotype hypothesis also seems to be valid for SNHL, meaning that SNHL in adulthood may originate from events during fetal life. SNHL might be a new clinical feature of the metabolic syndrome.

Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset.

We have studied the occurrence of enterovirus (EV)-RNA at the onset of childhood type 1 diabetes in all 24 new cases of childhood type 1 diabetes during 1 year in Uppsala county, Sweden. We also studied 24 matched control subjects and 20 siblings of the patients. RNA was isolated from peripheral blood mononuclear cells and EV-RNA detected by RT-PCR. Primers (groups A and B) corresponding to conserved regions in the 5' noncoding region (NCR) of EV were used in the PCRs, and the amplicons were sequenced. By the use of group A primers, EV-RNA was found in 12 (50%) of the 24 type 1 diabetic children, 5 (26%) of 19 siblings, and none of the control subjects. Both patients and siblings showed a higher frequency of EV-RNA compared with the control subjects. The group B primers detected EV-RNA in all three groups but did not show statistically significant differences between the groups. The EV-RNA positivity with the group B primers was 11 (46%) of 24 in the type 1 diabetic children, 11 (58%) of 19 in the siblings, and 7 (29%) of 24 in the control subjects. The significant difference between groups seen with the group A primers but not with the group B primers might indicate the existence of diabetogenic EV strains. The phylogenetic analysis of the PCR products revealed clustering of the sequences from patients and siblings into five major branches when the group A PCR primers were used. With the group B primers, the sequences from patients, siblings, and control subjects formed three major branches in the phylogenetic tree, where 6 of the 7 control subjects clustered together in a sub-branch of CBV-4/VD2921. Seven of the type 1 diabetic children clustered together in another sub-branch of CBV-4/VD2921. Five of the type 1 diabetic children formed a branch together with the CBV-4/E2 strain, four clustered together with CBV-5, and one formed a branch with echovirus serotype. The presence of EV-RNA in the blood cells of most newly diagnosed type 1 diabetic children supports the hypothesis that a viral infection acts as an exogenous factor. In addition, sequencing of the PCR amplicons from the type 1 diabetic children, their siblings, and matched control subjects might reveal differences related to diabetogenic properties of such a virus.

Simultaneous type 1 diabetes onset in mother and son coincident with an enteroviral infection.

Enterovirus (EV) infections have been implicated in the development of type 1 diabetes. (T1D). They may cause beta-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Virus was isolated from a woman at diagnosis of T1D (Tuvemo 1) and in addition, virus was isolated from her son at diagnosis of T1D at the same day (Tuvemo 2). None of the isolates could initially be serotyped by conventional methods. The Tuvemo 1 virus was genotyped and after sub-cultivation it was also serotyped as Coxsackievirus B5. The mother revealed antibodies against GAD65. The boy and the father both revealed a significant increase in neutralization antibody titre against two strains of CBV-4, clearly indicating a recent or ongoing EV infection. In addition, the brother showed such a titre rise against another CBV-4 strain (E2) and against a CBV-5 strain (4429). These results show that the whole family had a proven EV infection at the time of T1D diagnosis of the mother and the 10-years-old boy, indicating that the infection might cause or accelerate the T1D.

Growth Hormone Treatment Improves Cognitive Function in Short Children with Growth Hormone Deficiency.

BACKGROUND/AIMS: We investigated the association between cognition and growth hormone (GH) status and GH treatment in short prepubertal children with broadly ranging GH secretion. METHODS: A total of 99 children (age 3-11 years), 41 with GH deficiency (GHD) and 58 with idiopathic short stature (ISS), were randomized to a fixed dose (43 µg/kg/day) or a prediction model-guided individualized dose (17-100 µg/kg/day) and followed up for 24 months. In a longitudinal and mixed within- and between-subjects study, we examined clinical effect size changes, measured by Cohen's d, in full-scale IQ (FSIQ) and secondary IQ indices. RESULTS: Significant increases giving medium effect size in FSIQ (p = 0.001, Cohen's d = 0.63), performance IQ (p = 0.001, Cohen's d = 0.65) and processing speed (p = 0.005, Cohen's d = 0.71) were found in the GH-deficient group. In contrast, perceptual organization only increased in the ISS group (p = 0.001, Cohen's d = 0.53). Baseline IQ was normally distributed with small but significant differences between the groups: GH-deficient children had lower FSIQ (p = 0.042) and lower performance IQ (p = 0.021). Using multiple regression analysis, 40% of the variance in delta processing speed scores (0-24 months) was explained by GHmax and IGF-ISDS at baseline. CONCLUSION: IQ, specifically fluid intelligence, increased in the GH-deficient children. The pretreatment status of the GH/IGF-I axis was significantly predictive for these changes. © 2015 S. Karger AG, Basel.