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.

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.

Growth hormone dose-dependent pubertal growth: a randomized trial in short children with low growth hormone secretion.

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. METHODS: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH(67)) given as one (GH(67×1); n = 35) or two daily injections (GH(33×2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33×1); n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height. RESULTS: Pubertal heightSDSgain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33×1), 0.41, p < 0.05). AHSDS was greater on GH(67) (GH(67×1), -0.84; GH(33×2), -0.83) than GH(33) (-1.25, p < 0.05), and heightSDSgain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS. CONCLUSION: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once- and twice-daily GH(67) regimens. © 2014 S. Karger AG, Basel.

Risks of malignant and non-malignant tumours in tall women treated with high-dose oestrogen during adolescence.

BACKGROUND/AIM: High-dose oestrogen treatment has been used to reduce growth in tall adolescent girls. The long-term safety with regard to cancer has not been clarified. Our aim was to study if this growth reduction therapy affects cancer risk later in life. METHODS: A cohort study of 369 (172 treated, 197 untreated) Swedish women who in 1973-1993 were assessed for tall adolescent stature was designed. Data were collected from university hospital records, patient questionnaires, and the Swedish Cancer Register. RESULTS: Risks are presented as odds ratios (ORs) with 95% confidence intervals comparing treated to untreated subjects. In treated subjects, the overall OR for having a tumour (malignant or non-malignant) was 1.7 (0.8-3.8). The ORs were 2.3 (0.4-12.8) for breast tumours, 0.8 (0.2-2.6) for gynaecological tumours, and 6.1 (1.04-∞) for melanoma. When limiting to malignant tumours, the crude ORs were of similar magnitude. CONCLUSION: The OR for any melanoma was higher in treated than in untreated women, suggesting an increased risk of melanoma associated with high-dose oestrogen treatment during adolescence. Although the risk estimates were increased for overall tumours, breast tumours, malignant gynaecological tumours, and malignant melanoma, these associations were not statistically significant. Our results need to be verified in a larger cohort.

Does growth hormone treatment influence pubertal development in short children?

AIM: To study the influence of growth hormone (GH) treatment on the initiation and progression of puberty in short children. METHODS: This prospective, randomized, controlled study included 124 short children (33 girls) who received GH treatment (Genotropin®; Pfizer Inc.) from a mean age of 11 years until near adult height [intent-to-treat (ITT) population]. Children were randomized into three groups: controls (n = 33), GH 33 µg/kg/day (n = 34) or GH 67 µg/kg/day (n = 57). Prepubertal children at study start constituted the per-protocol (PP) population (n = 101). Auxological measurements were made and puberty was staged every 3 months. Serum sex-steroid concentrations were assessed every 6 months. RESULTS: No significant differences were found between the groups, of both PP and ITT populations, in time elapsed from start of treatment until either onset of puberty, age at start of puberty or age at final pubertal maturation in either sex. In the ITT population, pubertal duration was significantly longer in GH-treated girls, and maximum mean testicular volume was significantly greater in GH-treated boys than controls, but there were no differences in testosterone levels between the groups. CONCLUSION: GH treatment did not influence age at onset of puberty and did not accelerate pubertal development. In boys, GH treatment appeared to increase testicular volume.

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.

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.

Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children.

BACKGROUND/AIMS: To evaluate effects of growth hormone (GH) treatment on behaviour and psychosocial characteristics in short-stature children. METHODS: 99 referred prepubertal non-familiar short-stature children (32 GH deficiency; 67 idiopathic short stature) aged 3-11 years, randomized to fixed or individual GH doses and their parents completed questionnaires (Child Behaviour Checklist, Birleson Depression Self-Report Scale, Abbreviated Parent-Teacher Questionnaire, I Think I Am, Well-Being Visual-Analogue Scales for Short-Stature Children) at baseline (BL) and after 3, 12, and 24 months. RESULTS: At BL, children showed higher levels of internalizing behaviour (p < 0.001), lower levels of externalizing behaviour (p < 0.006) and self-esteem (p < 0.001) compared to reference values. During GH treatment, behavioural measures (p < 0.001) and depression (p < 0.01) changed towards the mean of the population within the first 3 months and remained improved to 24 months. Self-esteem improved at all time points (p < 0.001), and in all subgroups, as did well-being dimensions stability and mood (p < 0.05). Multiple regression analysis showed that greater improvements were related to lower BL value, height gain, higher maximal GH value, being older, and being male. CONCLUSION: On GH treatment, prepubertal short children significantly improved on behavioural, depression, and psychosocial evaluations over a 2-year period of GH treatment. Most change occurred within the first 3 months, which highlights this short period as important not only for growth and metabolic changes but also for behaviour and psychosocial improvements following GH treatment.

Short adult stature and overweight are associated with poor intellectual performance in subjects born preterm.

BACKGROUND/AIMS: To study the association between preterm birth and adult intellectual performance, with special emphasis on the influence of postnatal growth. METHODS: A population-based cohort study was performed on 272,046 males, born between 1973 and 1978, of whom 248,447 were conscripted for military service between 1991 and 1997. Birth characteristics were obtained from the Swedish Medical Birth Register and information on intellectual performance, final height and BMI were taken from the Swedish Conscript Register. Multiple logistic regression analysis was performed. RESULTS: At conscription, males born preterm had lower results at tests of intellectual performance compared to those born at term. Short adult stature among these males enhanced the risk of low intellectual performance, as compared to those with normal adult stature. Moreover, a high adult BMI in the males born preterm was associated with an increased risk of subnormal performance as compared to those with normal BMI. CONCLUSIONS: Subjects born preterm had poorer intellectual performance than those born at term. Short adult stature or a high BMI was associated with an even higher risk for poor intellectual performance in the subjects born preterm. This indicates the occurrence of common mechanisms underlying growth and cognitive development.

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.

Relationships between ophthalmological and neuropaediatric findings in children adopted from Eastern Europe.

PURPOSE: This study aimed to evaluate and relate visual function, ocular dimensions and neuropaediatric findings in adoptees from Eastern Europe. METHODS: We studied 72 of 99 children, born during 1990-95 and adopted from Eastern Europe to western Sweden during 1993-97. The children (mean age 7.5 years, range 4.8-10.5 years; 41 boys, 31 girls) were examined after a mean period of 5 years post-adoption by a multidisciplinary team. Correlations between ophthalmological findings and neuropaediatric data were analysed. RESULTS: Bivariate and regression analyses indicate a significant positive correlation between visual acuity (VA) and perceptual organization (p < 0.001), as well as between strabismus and verbal comprehension (p < 0.02). Fetal alcohol syndrome (FAS) was correlated with low VA (p < 0.02), subnormal stereovision (p < 0.009) and small optic discs (p < 0.02). Small head circumference was related to low VA (p < 0.015) and small optic discs (p < 0.03). Furthermore, small optic discs were related to low birthweight (p < 0.005) and preterm birth (p < 0.01). Large optic cups were correlated with poorer perceptual organization (p < 0.02). CONCLUSIONS: In this group of adoptees from Eastern Europe, ophthalmological findings were correlated to neuropaediatric findings, especially those arising from prenatal adverse events resulting in growth deficiency and central nervous system damage. Therefore, it is important and valuable with an ophthalmological examination in children adopted from Eastern Europe.

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.

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.

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.

Relation problems in internationally adopted juvenile delinquents.

OBJECTIVE: Internationally adopted delinquents are overrepresented in juvenile Swedish institutions. With the purpose of investigating possible reasons for this overrepresentation, this study compared adopted delinquent adolescents and internationally adopted controls in the structure and functioning of their current relations, especially with their parents. METHODS: Internationally adopted adolescents admitted to institutional care (N=20) and non-delinquent internationally adopted controls (N=21) were compared through: a questionnaire; "family relations", a subscale in I think I am; "Family climate" (from Karolinska Scale of Personality); Individual Schedule of Social Interaction; and an Attachment Test. RESULTS: Bad relations with adoptive parents were more prevalent in internationally adopted delinquents compared to internationally adopted controls. Furthermore, the adopted delinquents and their parents blamed each other for the problems and the adopted delinquents reported physical and emotional abuse. CONCLUSIONS: Internationally adopted delinquents reported more problems in their relationships to their parents than adopted controls did.

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.

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.