A molecular dynamics study of viscosity in ionic liquids directed by quantitative structure-property relationships.

A computational study into the molecular origin of viscosity in ionic liquids via a combined quantitative structure-property relationship (QSPR) and molecular dynamics (MD) approach is presented. QSPR models are developed for ionic liquids containing the bis[(trifluoromethyl)sulfonyl]imide (TFSI) anion using literature data. The best models thus developed are used to identify persistently well-correlating molecular descriptors for further investigation by MD. By modifying the force field of a simple ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF(6)], the efficacy of the charged partial surface area (CPSA) descriptor is examined. Finally, by building QSPR models from the MD data and calculations derived from the CPSA descriptor, potential routes for improved prediction of ionic liquid viscosity are proposed.

Cyclosporine A for the treatment of new-onset insulin-dependent diabetes mellitus.

It is not known whether early immunosuppressive treatment can preserve long-term endogenous insulin secretion in subjects with insulin-dependent diabetes mellitus. In the present study, clinical remissions during the first year and C-peptide production for 3 years were followed after 43 subjects with newly diagnosed insulin-dependent diabetes mellitus were randomly assigned to a cyclosporine A treatment group for 4 months or to a control group. Of the six cyclosporine A-treated subjects who had remissions, five were 19 years of age or younger, compared with two of the four in the control group. C-peptide production was present in 98% of all subjects after 4 months, in 88% after 1 year, and in 43% after 3 years. There were no significant differences in numbers of subjects with C-peptide production or in mean hemoglobin A1 levels, between cyclosporine A-treated and control subjects after 3 years. Cyclosporine A treatment of subjects with newly diagnosed insulin-dependent diabetes mellitus for a period of 4 months does not have the ability to preserve residual beta-cell function.

Impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborn infants.

Our objective was to investigate whether notification of high-risk status for type 1 diabetes in newborn infants results in an increased maternal-parenting stress level when compared with notification of low-risk status for type 1 diabetes. Maternal parenting stress level was assessed at 5-7 weeks postpartum (baseline) and was reassessed 4-5 months after parents were informed of their newborn infants' genetic screening results (follow-up). Parenting stress level was measured using the total stress score (TSS) of the Parenting Stress Index/Short Form. The outcome variable, change in TSS, was calculated by subtracting the baseline TSS from the follow-up TSS. Demographic variables such as maternal race, maternal age, maternal education level, maternal marital status, child's birth order, and total family income were assessed through a structured phone interview at the time of baseline assessment. The risk factor of interest was the child's human leukocyte antigen (HLA) status for type 1 diabetes, i.e., whether child was at a high or moderate (combined into "high") genetic risk or at a low genetic risk for type 1 diabetes. A sample of 88 mothers (23 with a high-risk child and 65 with a low-risk child) was evaluated. Baseline median TSSs were 65 and 74 for mothers of low-risk infants and mothers of high-risk infants, respectively. Both groups' median TSS decreased between baseline and follow-up. No significant differences were found between change in TSS and maternal age, race, education level, marital status, total family income, or child's birth order. Although the median decrease in TSS was smaller in mothers with a high-risk child when compared with mothers of a low-risk child, this difference was not statistically significant. We did not find an association between newborn's HLA status and change in maternal TSS. The results of this study suggest that notification of high-risk status for type 1 diabetes in newborn infants may not result in an increased level of parenting stress among mothers.

Short-term effects of postural drainage with clapping vs autogenic drainage on oxygen saturation and sputum recovery in patients with cystic fibrosis.

To compare the short-term effects of postural drainage with clapping (PD) and autogenic drainage (AD) on oxygen saturation, pulmonary function, and sputum recovery, we studied ten patients with cystic fibrosis (CF) randomly treated with PD or AD on separate days. Pulse oximetry was monitored and sputum was collected during and for 1 h following each treatment. Pulmonary function was measured before and then 1, 15, and 60 min after each treatment. There was no significant difference in the amount of sputum recovered with AD (14.0 +/- 3.5 g) vs PD (10.4 +/- 3.0 g) and no significant differences in pulmonary function occurred. Oxygen saturation during PD fell from 93.3 +/- 0.7% to 91.2 +/- 0.8% (p < 0.01) and required 15 min following treatment to return to baseline. Oxygen saturation did not fall during AD and increased to 94.5 +/- 0.7% by 1 h following treatment (baseline, 93.3 +/- 0.8%; p < 0.01). We conclude that AD is less likely to produce oxygen desaturation and may be better tolerated by patients with CF, while producing similar benefits in sputum clearance.

Evaluation of a weight management intervention program in adolescents with insulin-dependent diabetes mellitus.

This study evaluated the effectiveness of a family-based, multidisciplinary, behavior-modification program (SHAPEDOWN) adapted for obese adolescents with insulin-dependent diabetes mellitus (IDDM), a unique and understudied population. Eleven test subjects participated in the SHAPEDOWN program, and 9 comparison subjects received standard nutrition care for subjects with IDDM. Mean age of the experimental and control subjects was 13.9 and 15.2 years, respectively, and the two groups were 121% and 126% overweight, respectively. The program comprised 14 weekly sessions in which subject and parents participated in separate groups taught by a dietitian, a psychologist, and a child health associate. Data were collected at baseline, at 3 months, and at 15 months. Compared with standard treatment, the intervention significantly increased body image. Self-esteem improved clinically in four subjects in the experimental group but in only one subject in the standard treatment group. Change in percent overweight at 15 months was -3% for the experimental group and +0.9% for the standard treatment group; however, the difference was not statistically significant. This mean loss in percent overweight of subjects is comparable with that reported in a nondiabetic group in which age and percent overweight were similar. The change in percent overweight from baseline to 15 months in the two groups combined shows a positive correlation with triceps skinfold thickness and a negative correlation with obesity-related behavior. Changes in glycated hemoglobin were not significantly different. We conclude that this program proved effective in improving body image and self-esteem in obese adolescents with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Tocopheryl polyethylene glycol 1000 succinate therapy for vitamin E deficiency during chronic childhood cholestasis: neurologic outcome.

Treatment of the vitamin E deficiency neurologic syndrome in children with chronic cholestasis is hampered by the very poor intestinal absorption of available forms of vitamin E, thus requiring prolonged treatment with intramuscular injections of vitamin E in many patients. D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble investigational form of vitamin E that is well absorbed during cholestasis. We studied the effect of TPGS therapy on the neurologic function in 12 children with vitamin E deficiency (aged 9 months to 6 years) with prolonged forms of neonatal cholestasis. Each child had failed to respond to up to 100 to 200 IU/kg/d of standard oral preparations of vitamin E. Treatment with 15 to 25 IU/kg/d TPGS for a mean of 19.3 months normalized the biochemical indices of vitamin E status and was well tolerated by all patients. Neurologic function, assessed by serial neurologic examinations, remained normal during therapy in the two children with no neurologic symptoms younger than age 3 years at onset of therapy. Neurologic function, which had deteriorated before this study, improved in six of seven patients with symptoms who were younger than 3 years and in all three with symptoms older than 3 years. TPGS appears to be a safe and effective form of orally administered vitamin E for use in children with chronic cholestasis who are unresponsive to available oral preparations of vitamin E.

Role of respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis.

To determine the frequency of respiratory syncytial virus (RSV) as the cause of hospitalization for acute pulmonary exacerbations in young infants with cystic fibrosis (CF), and to assess the clinical effects of RSV infections, we prospectively followed 48 children with a diagnosis of CF after identification by newborn screening. At a mean follow-up age of 28.8 months (range 5 to 59), 18 infants (38%) had been hospitalized a total of 30 times for acute respiratory distress. At the time of admission, 18 infants (60%) were less than 12 months, 8 (27%) between 12 and 24 months, and 4 more than 2 years of age. The RSV was identified in seven hospitalized infants, as determined by fluorescent antibody, immunoassay, or culture. Before admission with RSV infection, one of the seven infants had chronic respiratory signs, none had Brasfield chest x-ray scores below 20, and a previous throat culture was positive for Staphylococcus aureus in one infant. Hospitalizations were prolonged (mean duration 22 days), and were characterized by significant morbidity, with three infants (43%) requiring mechanical ventilation and five infants (71%) requiring home oxygen therapy for persistent hypoxemia at discharge. At a mean follow-up age of 26 months, these infants more frequently have chronic respiratory signs (p less than 0.01) and lower chest radiograph scores (p less than 0.05) than other CF infants. These findings demonstrate that RSV is an important cause of early acute respiratory tract morbidity in young infants with CF, and suggest the need for studying new strategies to implement early and aggressive antiviral therapy in young infants with CF.

A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus.

Various agents have been tried in subjects with newly diagnosed Type 1 (insulin-dependent) diabetes mellitus in an attempt to preserve Beta-cell function. In this double-blind study, nicotinamide or placebo were given for one year to 35 children and adolescents with newly-diagnosed Type 1 diabetes. All subjects were within six weeks of diagnosis and were between the ages of 6 and 18 years. Nicotinamide, a poly-(ADP-ribose) synthetase inhibitor, was given in a dose of 100 mg/year of age up to a maximum of 1.5 g/day. There were no initial differences between the 17 control and the 18 test subjects in relation to mean age, sex distribution, or severity at onset. Mean insulin dosages and HbA1 values were similar for the two groups during the year of study. Fasting and glucagon-stimulated C-peptide levels were similar for the control and nicotinamide treated groups at the beginning and after 4 and 12 months. There were no differences in remission rates between the two groups. Nicotinamide, at this dosage, does not preserve residual insulin secretion in subjects with newly diagnosed Type 1 diabetes.

Treatment of vitamin E deficiency during chronic childhood cholestasis with oral d-alpha-tocopheryl polyethylene glycol-1000 succinate.

Treatment of vitamin E deficiency during chronic childhood cholestasis is hampered by the poor intestinal absorption of available oral preparations of vitamin E when bile flow is severely impaired; thus parenteral vitamin E has been the only effective therapy for many children with this problem. We studied the intestinal absorption, efficacy, and safety of a water-soluble oral form of vitamin E, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), in 22 children (7 mo to 19 yr old) with severe cholestasis and vitamin E deficiency who were unresponsive to massive oral doses (100-200 IU/kg.day) of dl-alpha-tocopherol. The results of oral vitamin E tolerance tests showed that TPGS was well absorbed in virtually all study subjects, that TPGS intestinal absorption was superior to that of dl-alpha-tocopherol, and that TPGS absorption in teenage children with chronic cholestasis was similar to that of normal adults. In addition, 1.7% +/- 1.6% (mean +/- SD) of the administered polyethylene glycol 1000 contained in the TPGS was absorbed and excreted in the urine of the 13 subjects analyzed, compared with 3.0% +/- 1.3% in 4 normal adults. A chronic oral dose of 15-25 IU/kg.day of TPGS corrected the biochemical vitamin E deficiency state over 1-19 mo (mean, 10.6 mo) of TPGS therapy. No clinical or biochemical evidence of gastrointestinal, renal, hepatic, or hematologic toxicity was demonstrated. This study suggests that TPGS administered orally in a dose of 15-25 IU/kg.day may be a safe and effective form of vitamin E for prevention and correction of vitamin E deficiency during severe childhood cholestasis.

Diagnosis of pre-type I diabetes.

Islet cell antibodies were found in 71 of 1169 first-degree relatives (6.1%) from 448 families who had a proband with type I diabetes. Seven children have since become insulin dependent. All had islet cell antibodies and were followed up prospectively with measurement of first-phase insulin production during intravenous glucose tolerance testing. In this group the statistical probability of developing type I diabetes within 12 months with 95% confidence was found to be 59% to 100% when the first-phase insulin secretion was less than 25 microU/mL. The identification of the prediabetes time period should allow an opportunity for intervention in the underlying disease process to determine if the onset of type I diabetes can be altered.

Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening.

To understand better the events associated with the initiation of lung disease in young children with cystic fibrosis (CF), we prospectively performed a longitudinal study examining the early bacteriologic, immunologic, and clinical courses of 42 children with CF diagnosed after identification by neonatal screening. Serial evaluations included history and physical examination, chest radiographs, throat cultures for bacteria, and determinations of serum immunoglobulin levels and circulating immune complexes. At a mean follow-up age of 27 months, 19% of the children had serial throat cultures positive for Pseudomonas aeruginosa; the first positive culture was found at a mean age of 21 months. In three infants the initial P. aeruginosa isolates were mucoid. As determined by typing with a DNA probe, serial P. aeruginosa isolates from each patient were identical over time but were genetically distinct from isolates recovered from other patients. Of 11 infants with P. aeruginosa, nine (82%) had previous isolates of Staphylococcus aureus or Haemophilus influenzae; all had received prior antibiotic therapy. In comparison with other infants with CF, children with P. aeruginosa grown on serial throat cultures more frequently had daily cough (p less than 0.01), lower chest radiograph scores (p less than 0.05), and elevated levels of circulating immune complexes (p less than 0.01). None of the study infants had persistent hypogammaglobulinemia or hypergammaglobulinemia. We conclude that (1) S. aureus and H. influenzae remain the isolates most frequently recovered from infants with CF; (2) initial recovery of P. aeruginosa by throat culture is often preceded by the onset of chronic respiratory signs; (3) elevations of circulating immune complexes can occur early, often after the initial recovery of P. aeruginosa; and (4) early P. aeruginosa isolates are genetically distinct, demonstrating the lack of cross-colonization in this newborn population.

Autosomal dominant polycystic kidney disease in childhood: a longitudinal study.

One hundred fifty-four children aged eighteen years or younger from 83 families with autosomal-dominant polycystic kidney disease were studied by ultrasonography or excretory urography. Twenty-three children had bilateral renal involvement with at least five cysts (ADPKD), 28 children were classified as suspicious (SADPKD), and 103 children had no renal involvement (NADPKD) detected by ultrasound. Seventy-four percent of the ADPKD children had signs or symptoms compatible with the diagnosis of ADPKD, compared to 34% of the NADPKD and 36% of the SADPKD children (both P less than 0.05). Three of the 23 ADPKD children had elevated serum creatinines at the time of diagnosis, while all of the NADPKD and SADPKD children had normal renal function. Renal area by ultrasonography (width X depth) was greater among the ADPKD children compared to the SADPKD and NADPKD groups (P less than 0.05). On follow-up 30 of the 37 NADPKD children remained NADPKD, three were reclassified as SADPKD, and four progressed to ADPKD after 18 years of age. All of the NADPKD children had normal renal function on follow-up. Overall, 14 children had suspicious ultrasounds at some point with follow-up ultrasonography and ten (71%) progressed to ADPKD. All SADPKD children maintained normal renal function. Eight of 18 ADPKD children had progression of the disease manifested by development of hypertension and/or decreased renal function. Three children progressed to end-stage renal disease. Five ADPKD children were diagnosed before one year of age, two of them via prenatal ultrasonography. One fetus was aborted after documentation of oligohydramnios.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of the course of pre-type I diabetes.

To increase knowledge on the predictability of the onset of insulin-dependent diabetes mellitus (IDDM; type I), we followed 38 subjects less than 18 years of age who had positive results on two or more islet-cell antibody tests and one identical twin who had positive results on one islet-cell antibody test. All 39 patients had longitudinal intravenous glucose tolerance tests to determine the first-phase insulin response (FPIR). Insulin dependence has developed in 10 untreated subjects less than 18 years of age. Of the 10 subjects, insulin dependence developed in eight a mean of 4.6 months after their FPIR fell to less than 30 microU/ml and a mean of 14 months after it fell to less than 46 microU/ml. Nine of the untreated subjects had an FPIR less than 67 microU/ml on at least two occasions and became insulin dependent a mean of 19 months after the value first fell below this level (95% confidence limit = 66.4% to 100%). All but one of the 10 subjects in whom IDDM developed initially had islet-cell antibody levels of greater than 80 JDF units. Insulin autoantibody values at onset were available for 9 of the 10 subjects and were positive (greater than 39 nU/ml) in six. We conclude that the combination of positive results on two islet-cell antibody tests and two diminished FPIRs (less than 67 microU/ml) in subjects less than 18 years of age reliably predicts the onset of IDDM. These data should permit intervention studies to be planned.

Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis.

To determine the frequency of biochemical vitamin E deficiency and of the clinical signs of the vitamin E deficiency neurologic syndrome in children with prolonged neonatal cholestatic disorders, we studied 46 children (aged 1 month to 17.0 years) with chronic forms of intrahepatic neonatal cholestasis and 47 children (aged 4 months to 8.0 years) with extrahepatic biliary atresia. Based on serum vitamin E concentrations and the ratios of serum vitamin E concentration to total serum lipid concentration, 64% of the intrahepatic and 77% of the extrahepatic cholestasis groups were vitamin E deficient. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic function was normal in the vitamin E-sufficient children. We conclude that vitamin E status should be evaluated in infants in whom cholestasis is diagnosed, and effective therapy should be initiated to prevent or treat vitamin E deficiency at an early age.

Multicenter trial of d-alpha-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis.

BACKGROUND: Malabsorption and deficiency of vitamin E causing neurological degeneration are common consequences of chronic childhood cholestatic liver disease. The objective of this study was to determine the long-term efficacy and safety of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) in correcting vitamin E deficiency in children with chronic cholestasis who were unresponsive to other forms of oral vitamin E. METHODS: Sixty vitamin E-deficient children with chronic cholestasis unresponsive to 70-212 IU.kg-1.day-1 of oral vitamin E were entered into a trial at eight centers in the United States. After initial evaluation, treatment was started with 25 IU.kg-1.day-1 of TPGS. Vitamin E status, neurological function quantitated by a specific scoring system, and clinical and biochemical parameters were monitored during therapy. RESULTS: All children responded to TPGS with normalization of vitamin E status. Neurological function, which had deteriorated before entry in the trial, improved in 25 patients, stabilized in 27, and worsened in only 2 after a mean of 2.5 years of therapy. No adverse effects were observed. CONCLUSIONS: TPGS (20-25 IU.kg-1.day-1) appears to be a safe and effective form of vitamin E for reversing or preventing vitamin E deficiency during chronic childhood cholestasis.