Hyperglycemia is associated with simultaneous alterations in electrical brain activity in youths with type 1 diabetes mellitus.

OBJECTIVE: To assess the association between hyperglycemia and electrical brain activity in type 1 diabetes mellitus (T1DM). METHODS: Nine youths with T1DM were monitored simultaneously and continuously by EEG and continuous glucose monitor system, for 40 h. EEG powers of 0.5-80 Hz frequency bands in all the different brain regions were analyzed according to interstitial glucose concentration (IGC) ranges of 4-11 mmol/l, 11-15.5 mmol/l and >15.5 mmol/l. Analysis of variance was used to examine the differences in EEG power of each frequency band between the subgroups of IGC. Analysis was performed separately during wakefulness and sleep, controlling for age, gender and HbA1c. RESULTS: Mean IGC was 11.49 ± 5.26 mmol/l in 1253 combined measurements. IGC>15.5 mmol/l compared to 4-11 mmol/l was associated during wakefulness with increased EEG power of low frequencies and with decreased EEG power of high frequencies. During sleep, it was associated with increased EEG power of low frequencies in all brain areas and of high frequencies in frontal and central areas. CONCLUSIONS: Asymptomatic transient hyperglycemia in youth with T1DM is associated with simultaneous alterations in electrical brain activity during wakefulness and sleep. SIGNIFICANCE: The clinical implications of immediate electrical brain alterations under hyperglycemia need to be studied and may lead to adaptations of management.

Differences in infantile growth patterns in Turner syndrome girls with and without spontaneous puberty.

OBJECTIVE: The role of prepubertal estrogen in child growth was modeled using Turner's syndrome, comparing growth patterns of girls who later did or did not enter puberty spontaneously. The hypothesis was that TS patients with normal prepubertal estrogen levels would have a different growth pattern from those with subnormal estrogen levels. STUDY DESIGN: Growth data from 78 full-term patients with Turner's syndrome were collected retrospectively. 24/78 later developed spontaneous puberty, (+Pub), and their growth data were compared to TS patients without spontaneous puberty (-Pub). A nonlinear mixed model was fitted using the bi-exponential model. RESULTS: The growth velocity difference between the -Pub and +Pub groups suggests an early infantile growth advantage in the -Pub group, which disappears before the end of the first year of life; growth velocity remains similar (+/- 1 cm/y) for the next 6 years and declines at age 7-8 years in the +Pub group faster than it does in the -Pub group. Bi-exponential analysis showed that both the 1st (restrictive) and 2nd exponent (forward) were different (p = 0.0003). CONCLUSIONS: Comparison of girls with or without spontaneous puberty suggests a role for estrogen in child growth. Estrogens restrict infantile growth, as well as growth during the mid-childhood spurt.

Type 1 diabetes in Jewish Ethiopian immigrants in Israel: HLA class II immunogenetics and contribution of new environment.

The interrelationship between human leukocyte antigen immunogenetics and environmental factors and their contribution to the emergence of type 1 diabetes (T1D) were studied in Jewish immigrants from Ethiopia in Israel. This community displays high incidence of T1D, and is unique both by its ethnic segregation and its rapid exposure to a new environment after the immigration. The study population consisted of 152 Ethiopian Jews living in Israel, 33 with T1D and 119 unrelated controls. Human leukocyte antigen class II susceptible and protective alleles in the Jewish Ethiopian patients were similar to those in patients of other ethnic groups in Israel and in non-Jewish Ethiopian patients, with a few exceptions. Three haplotypes were markedly associated with diabetes in Jewish Ethiopian patients: DRB1*0301 DQA1*05 DQB1*02 (OR 4.4, p < 0.001); DRB1*0404 DQA1 03 DQB1*0302 (OR 19.2, p = 0.006), and DRB1*0405 DQA1*03 DQB1*0302 (OR 87.8, p < 0.001). The highly susceptible allele DRB1*0301 was more common in the general Ethiopian population (25.2%) than in all other ethnic groups in Israel, which may render this community prone to the disease. The age at onset of disease in patients with two susceptible haplotypes was negatively correlated with the duration of living in Israel (r = -0.621, p = 0.04). We concluded that ongoing exposure of genetically predisposed immigrants from Ethiopia to diabetogenic environmental factors eventually leads to a high incidence of overt diabetes in this ethnic group.

Lack of correlation between disease activity and decreased stimulated secretion of IL-10 in lymphocytes from patients with celiac disease.

BACKGROUND: Celiac disease (CD) is commonly believed to be a predominantly Th1 disease. However, the exact balance between the Th1 and Th2 arms, as well as the correlation to clinical parameters, remains unclear. The aim was to assess the Th1/Th2 cytokine profile and its correlation to clinical parameters in active and non-active CD patients. METHODS: Peak, total secretion and secretory pattern of the Th1 cytokines (IFN-gamma and IL-2) and Th2 cytokines (IL-4 and IL-10) were determined in resting and stimulated peripheral blood mononuclear cells (PBMC) from 19 CD patients with active and non-active disease and 20 normal controls. RESULTS: Peak and total secretion of IL-10 were significantly reduced in CD patients compared with normal controls. This was due to a persistently flat secretory pattern of IL-10 over time in CD patients. In addition, IFN-gamma/IL-10 and the IL-2/IL-10 ratios of peak and total secretion were higher in patients than in controls. In contrast, peak, total secretion and secretory pattern of IL-2, IFN-gamma and IL-4 were comparable in patients and controls as well as the IL-2/IL-4 and IFN-gamma/IL-4 ratios. No difference in the cytokine secretion or Th1/Th2 ratio was found between active and non-active patients or between pediatric and adult patients. CONCLUSIONS: These data indicate that the Thl/Th2 balance in CD is shifted towards Th1 cytokines because of a down-regulated IL-10 secretion. The aberrant profile of cytokine secretion of these patients is not associated with clinical parameters and suggests an inherent defect in IL-10 secretion in CD.

The relation between adrenal function and the severity of bronchial hyperresponsiveness in children as measured by the methacholine provocation test.

BACKGROUND: There is no satisfactory explanation why some individuals experience severe attacks of asthma, yet others, exposed to similar stimuli, have a milder form of the disease. OBJECTIVE: We tested the hypothesis that children with more severe disease may have relative adrenal insufficiency compared to the children with milder disease. PATIENTS AND METHODS: Sixteen children with chronic asthma aged 8-16 years old were studied. Adrenal function was evaluated by the 24-h excretion of urinary free cortisol (UFC) before and after ACTH stimulation, and by plasma cortisol levels before and 60 min after ACTH administration. The severity of bronchial hyperresponsiveness was evaluated by the methacholine provocation test. RESULTS: Nine children had 20% fall in forced expiratory volume in 1 sec (FEV1) after a provocative concentration (PC20FEV1) of methacholine > or =2.5 mg/ml and were considered as having mild-moderate bronchial hyperresponsiveness (Group A). Seven children had a PC20FEV1 of < or =1.25 mg/ml and were considered as having severe bronchial hyperresponsiveness (Group B). No significant difference was found between the peak plasma cortisol response to ACTH between the two groups (634+/-182 and 586+/-137 nmol/l, respectively). However, there was a significant statistical difference (p <0.01) in the 24-h UFC response to ACTH between the children from Group A (345+/-107 nmol/m2 ) and the children from Group B (161+/-125 nmol/m2). CONCLUSIONS: Based on the low levels of 24-h UFC secretion in severely asthmatic children in our study, we propose the encouragement of provision of a short course of inhaled steroids to be kept at home for the emergency therapy of those children identified as having high-risk asthma.

Laparoscopic evaluation and management of nonpalpable testis in children.

We evaluated the outcome of children with nonpalpable testis managed and treated laparoscopically in our department over a 6-year period. One hundred nine boys aged 12 months to 14 years were included in the study; most were between the ages of 12 months and 18 months. Diagnostic laparoscopy and eventual orchiectomy were performed in 50 patients (45.8%) with atrophic testicles. A normal sized intraabdominal testicle was found in 59 patients (54.1%). Seven of the intra-abdominal testicles were bilateral (6.4%), and 12 were located in the vicinity of the inguinal ring (11%). All patients underwent both the first and second stages of the Fowler-Stephens procedure, except for those whose testicles were located in the vicinity of the internal inguinal ring. They underwent an immediate one-stage laparoscopic-assisted orchiopexy without difficulty. Only two patients had atrophic testicles observed in the scrotal area after the complete Fowler-Stephens procedure (3.4%). The good results reported in most series establish the laparoscopic management of the nonpalpable testis as "state of the art," with results superior to those obtained with the open technique regarding morbidity, complication rate, and length of hospital stay.

Bone mineral density and turnover in children with attention-deficit hyperactivity disorder receiving methylphenidate.

Attention-deficit hyperactivity disorder (ADHD) is the most common behavior disorder among children; methylphenidate is a drug frequently prescribed for the control of its symptoms. One of the potential side effects of methylphenidate that concerns parents is its impact on the growth of children, since the mechanism by which methylphenidate might influence growth is not known. As linear growth is associated with an increase in bone mineral density and turnover, this study was undertaken to evaluate bone mineral density by dual photon absorptiometry and bone turnover by measuring serum bone-specific alkaline phosphatase and the urinary deoxypyridinoline excretion rate in children treated with methylphenidate for 1 to 2 years as compared to a control group. There were no significant differences in bone mineral density at either the lumbar spine or femoral neck in the study group (0.662 +/- 0.04 and 0.735 +/- 0.07 g/cm2, respectively) as compared to the controls (0.675 +/- 0.05 g/cm2 and 0.734 +/- 0.07 g/cm2, respectively). Furthermore, there were no significant differences in serum bone-specific alkaline phosphatase in the study group (58 +/- 22 U/L) as compared to the control children (71 +/- 34 U/L) or in urinary deoxypyridinoline in the study group (34 +/- 38 nM/mM), as compared to the control group (27 +/- 12 nM/mM). In conclusion, our data do not support a significant effect of methylphenidate on bone mineral density turnover in children when used for 1 to 2 years.

Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study.

OBJECTIVE: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. DESIGN: Prospective randomised study. SETTING: Paediatric emergency department in a general hospital. SUBJECTS: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. INTERVENTIONS: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). MAIN OUTCOME MEASURES: Time from arrival at hospital to starting treatment and cessation of seizures. RESULTS: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7. 9 to 8.3). No significant side effects were observed in either group. CONCLUSION: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.

The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux.

We aimed to investigate, by means of dimercaptosuccinic acid (DMSA) scan, the relations between vesicoureteral reflux (VUR) and its degree, pyelonephritis during infancy, and renal parenchymal findings. Seventy-four infants with pyelonephritis, 44 girls and 30 boys (mean age at their first pyelonephritic episode 4.12 months, median 3 months), were enrolled in the study. Voiding cystourethrography (VCU) and ultrasonography (US) were performed within 6 weeks following the infection. DMSA was performed at least 4 months after the urinary tract infection (UTI). The renal parenchymal pathology was defined as focal or multifocal defects or as a split renal uptake of less than 45%. DMSA scintigraphy revealed that 19% (14/74) of the children had renal damage. Renal parenchymal findings were observed only when VUR was present, and its grade was above 3/5. No abnormality was found in 51 renal units without reflux, 9 with VUR grade 1/5, and 54 with grade 2/5. Renal pathology was observed in 9/24 renal units with VUR grade 3, 3/8 with grade 4, and 2/2 with grade 5. No correlation was found between renal parenchymal defects and clinical presentation of the pyelonephritis, type of the microorganism, presence of bacteremia, or the number of recurrent infections. In adequately treated infants, renal damage is probably due to a reflux-associated, preexisting, congenital renal parenchymal pathology and not to the inflammatory process. We suggest that DMSA scintigraphy should not be performed routinely in every infant with UTI and should be reserved primarily for children with VUR grade 3 and above.

Iron deposition in the anterior pituitary in homozygous beta-thalassemia: MRI evaluation and correlation with gonadal function.

OBJECTIVE: Iron deposition in the anterior pituitary continues to pose a serious problem in older patients with homozygous beta-thalassemia particularly in terms of gonadal function. This study aimed to investigate whether iron loading within the pituitary correlated with endocrine function. PATIENTS: 33 patients above 15 years of age, with transfusion-dependent homozygous beta-thalassemia and iron overload were studied. All had been receiving deferoxamine since 1978. DESIGN AND MEASUREMENTS: The endocrine status of the patients was assessed on clinical examination by an endocrinologist, and by a gonadotropin releasing hormone stimulation test. MRI of the pituitary was carried out for each patient. RESULTS: Anterior pituitary function (GnRH stimulation test) correlated well with MRI results. However, no correlation was found between the MRI measurements, the GnRH stimulation test and the clinical status of the patients, as 28 out of the 33 patients achieved normal puberty. CONCLUSIONS: MRI in conjunction with a GnRH stimulation test may be useful in predicting future impairment of pituitary function; however, further studies are needed to assess the effect of chelation therapy on the iron overload in the gland.

Intranasal midazolam as a treatment of autonomic crisis in patients with familial dysautonomia.

To evaluate the efficacy and safety of intranasal midazolam in the treatment of autonomic crises in children with familial dysautonomia, intranasal midazolam was administered at the hospital to six patients during nine episodes of autonomic crisis. Treatment was successful in seven of nine episodes of autonomic crisis in five of six patients, with a mean interval to response of 9.25 +/- 1.25 minutes. The parents of five patients in whom the treatment was successful were instructed to use midazolam at home. At home, 16 additional episodes were treated by the parents, with successful control achieved in 14 (87%). The mean interval to response was 12.8 +/- 2 minutes. No significant side effects were observed at the hospital or at home after intranasal administration of midazolam. Midazolam, given intranasally, is effective and safe in the management of autonomic crises in patients with familial dysautonomia, either in the hospital or at home by the parents after appropriate instruction.

Sodium potassium adenosine triphosphatase activity in preterm and term infants and its possible role in sodium homeostasis during maturation.

AIM: To investigate sodium (NA(+)) potassium (K(+)) adenosine triphosphatase (ATPase) activity in newborn infants at different gestational ages, to elucidate the mechanism underlying poor renal sodium conservation in preterm infants. METHODS: Fifty three healthy newborn infants, gestational age 30-42 weeks, were studied. Umbilical cord red blood cell Na(+) K(+)ATPase activity, plasma renin activity, and plasma aldosterone activities were measured in all of them. Red blood cell Na(+) K(+)ATPase activity was re-examined in eight preterm infants, one and two weeks after birth. Total and ouabain sensitive ATPase activity was measured spectrophotometrically using a method that couples ATP hydrolysis with NADH oxidation. RESULTS: Red blood cell Na(+) K(+)ATPase activity was significantly lower (p<0.01) in preterm babies with a gestational age below 35 weeks, compared with those with aged 35 weeks and above: 2.3 (0.8) and 6.7 (1.3) nmol NADH/minute/mg protein, respectively. There was no correlation between gestational age, Na(+) K(+)ATPase, plasma renin activity and aldosterone values either in the preterm or term babies. Two weeks after birth, irrespective of gestational age, the enzyme activity of the preterm babies increased to values similar to those observed in the term neonates at birth. CONCLUSION: The differences in sodium homeostasis between term and preterm babies are modulated via changes in Na(+) K(+)ATPase activity.

Defective activation of p21ras in peripheral blood mononuclear cells from patients with insulin dependent diabetes mellitus.

We previously reported that a decreased TCR mediated activity of the GTP-GDP binding p21ras protooncogene is associated with prediabetes in non-obese diabetic (NOD) mice. Furthermore, prevention of autoimmune diabetes is associated with reversal of the p21ras signaling defect in NOD T cells. Based on these animal studies we determined the activation of p21ras in PBMC from patients with Insulin Dependent Diabetes Mellitus (IDDM), Non-Insulin Dependent Diabetes Mellitus (NIDDM) and normal healthy controls. Stimulation by PHA induced a decrease of 3.7 +/- 1.4% and an increase of 2.44 +/- 2.3%, p < 0.02 and 2.6 +/- 1.6%,p < 0.003 in the basal unstimulated p21ras activity in the IDDM, NIDDM and normal control groups, respectively. Expression of p21ras and its regulatory elements, the GTPase activating protein p120ras-GAP and the guanine nucleotide releasing factor (GNRF) hSOS, was comparable in the three groups. The in vitro proliferative response to PHA was comparable in the IDDM and control groups: stimulation index (SI) of 8.6 +/- 2.5 and 9.4 +/- 3.5 respectively, p < 0.44. No correlations were found in the IDDM patients between the degree of p21ras activation and the mitogen induced in vitro proliferative response or the various clinical parameters including age, gender, disease duration, daily insulin requirements and metabolic control. Taken together these data indicate that PBMC from IDDM patients are characterized by a persistent impairment in the activation of their p21ras. They also suggest that p21ras stimulated activity is a sensitive and independent parameter of PBMC activation in these patients.

Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.

BACKGROUND: Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. METHODS: In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. RESULTS: The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. CONCLUSIONS: Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.

Clinical relevance of therapeutic drug monitoring of digoxin and gentamicin in the saliva of children.

Digoxin and gentamicin are widely used in pediatric medicine, and therapeutic monitoring is mandatory because of their narrow margin of safety and wide interpatient and intrapatient pharmacokinetic variabilities. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is often difficult. In 11 children treated with digoxin for various cardiac conditions, and in 24 children treated with gentamicin (14 patients were administered gentamicin three times a day, and 10 once-daily), drugs levels were measured in plasma and saliva. There was no correlation between plasma total or free digoxin concentrations and saliva levels, precluding the clinical use of the saliva test for digoxin. No correlation was found between plasma gentamicin concentrations and saliva levels when the drug was administered three times a day; however, good correlation was found when the drug was administered once-daily (r2 = 0.89, p < 0.0001). Saliva may be used as a noninvasive method of measuring gentamicin serum concentrations to guide dosage adjustments in patients administered the drug once-daily.

Decreased secretion of Th2 cytokines precedes Up-regulated and delayed secretion of Th1 cytokines in activated peripheral blood mononuclear cells from patients with insulin-dependent diabetes mellitus.

Recent evidence suggests that autoimmune animal diabetes is associated with an imbalance between the Th1 and Th2 arms of the cellular immune system. However, limited data is available regarding the Th1/Th2 imbalance in human Insulin dependent diabetes mellitus (IDDM) patients. Therefore, we examined the peak levels, secretory pattern and total cytokine production (calculated as the area under the curve, AUC) of the Th1 cytokines, IL-2 and IFN-gamma, and Th2 cytokines, IL-4 and IL-10, from stimulated peripheral blood mononuclear cells, from 17 IDDM patients and 24 normal controls. In contrast to controls, diabetic patients were characterized by an early, uniformly low secretion of Th2 cytokines, followed by a late increased secretion of Th1 cytokines. This resulted in significant differences in secretory patterns of IFN-gammaIL-2, IL-4 and IL-10 between the two groups; P<0.001, P<0.005, P<0.005 and P<0.001, respectively. No correlation was found in the diabetic patients between any profiles of the cytokines and their various clinical parameters, including age, gender, disease duration, insulin requirements or glycated hemoglobin levels. In conclusion, our data provides the first comprehensive evidence for an independent and persistent impairment of both Th1 and Th2 cytokine secretory patterns in IDDM patients.

Acute iron intoxication: significant differences between sexes.

Iron, one of the common medications in use among children and adults, is the leading cause of pediatric unintentional ingestion fatalities and is not an uncommon poisoning among adults. Accidental ingestion is common because iron-containing compounds are readily available, brightly colored, often sugar coated, and frequently considered harmless vitamins. There are no data on differences between sexes with regard to iron intoxication, and the management of iron overdose is the same for females and males. After oral administration by gavage of the LD50 of iron to Wistar rats, the pharmacokinetics of iron, baseline and peak serum iron levels, and mortality rates were compared between sexes. Prepubertal females died significantly more than males (p < 0.01), pubertal females died significantly earlier than males (p < 0.04), and the same was true among adult rats (p = 0.02). Baseline serum iron levels were not significantly different between prepubertal female and male rats, but female pubertal rats had significantly higher baseline iron levels than males (p = 0.006). After iron administration, females had significantly higher peak serum iron concentrations (p < 0.03). Mechanisms of iron absorption are still not completely known and, probably, there are differences in iron absorption between sexes, which may account for the differences in serum iron levels and mortality rates. While the therapeutic approach in cases of intoxication is individual, iron intoxication, as may be true for other poisonings also, treatments administered to females may need to be different from that given to males.

Incidence of recurrent intussusception following barium versus air enema.

The aim of this study was to determine whether using air enema for acute intussusception is related to a higher rate of recurrence than other methods of treatment. A 10-y (1986-95) retrospective study was performed in a university-affiliated paediatric division. The overall recurrence rate for 97 patients with acute intussusception was 7.8% (10% of whom were treated non-surgically). There were no recurrences following the surgical treatment. In matched groups of patients, no risk factors were found for recurrence following air vs barium enema.