Qualitative Exploration Toward the Development of a Parent-Rated Scale for Insomnia in Children with Autism Spectrum Disorder.

Toward the development of a new parent-rating for insomnia, this multi-site qualitative study explored sleep problems and related impacts in children with autism spectrum disorder (ASD) and their families. To ensure content validity of the measure, we conducted six focus groups with caregivers (N = 25) of 24 children (age 3 to 18 years) with ASD. Based on parent report, all children had a history of mild or greater insomnia. The focus group transcripts were systematically coded to identify major themes. Verbatim comments from caretakers were used to generate 134 candidate items. Further review by the research team and an expert panel followed by individual cognitive interviews with 12 parents reduced the item bank to 40. The thematic analysis of focus group transcripts identified 7 categories: (1) Trouble falling asleep; (2) trouble staying asleep; (3) early morning waking; (4) bedtime routines; (5) parental strategies for bedtime management; (6) impact of sleep problems on the child; and (7) impact of sleep problems on the family. The Flesch Kincaid Grade Level of the 40-item version was 7.2 (seventh grade reading level). Insomnia in children with ASD shares features in common with insomnia in the general pediatric population. However, perhaps owing to autistic features such as insistence on sameness, sensory sensitivities, communication impairments, insomnia in children with ASD appears to have unique behavioral manifestations. Content validity and item clarity of the 40-item bank were supported by expert panel review and cognitive interviews with caregivers of children with ASD.

The Home Situations Questionnaire-PDD version: factor structure and psychometric properties.

BACKGROUND: The Home Situations Questionnaire (HSQ) is a caregiver-rated scale designed to assess behavioural non-compliance in everyday settings that has been used in several studies in typically developing children. Currently there is no accepted measure of behavioural non-compliance in children with pervasive developmental disorders (PDDs). METHODS: Investigators of the Research Units on Pediatric Psychopharmacology Autism Network modified the HSQ for children with PDDs by adding five items (making 25 total items), and used it as the primary outcome measure in a clinical trial. In the current investigation, we examined the factor structure and psychometric properties of the modified scale, the HSQ-PDD. RESULTS: An exploratory factor analysis with oblique rotations yielded two factors: 'Socially Inflexible' (14 items) and 'Demand-Specific' (six items). Item content of both factors appeared to fit well with the rubric of PDDs. Internal consistency, using Cronbach's alpha statistic, was 0.90 for 'Socially Inflexible', and 0.80 for 'Demand-Specific.' The obtained sub-scales and HSQ-PDD Total score showed moderate correlations with selected sub-scales of the Aberrant Behavior Checklist, Child and Adolescent Symptom Inventory, and Children's Yale-Brown Obsessive Compulsive Scale, and low correlations with the Vineland Adaptive Behavior sub-scales. CONCLUSIONS: The HSQ-PDD appears to be well suited for children with PDDs, although the Demand-Specific sub-scale may benefit from addition of more items. We provided sub-scale means and standard deviations for this relatively severe group of children with PDDs, and discussed the factor structure with respect to previous research.

Therapeutic modulation of growth-promoting activity in platelets from diabetics.

Proliferation of vascular smooth muscle is thought to be involved in the major diabetic complication atherosclerosis. We have previously reported an increase of growth-promoting activity (GA) in platelets from insulin-dependent diabetics. In this study, GA was measured in the platelet extract (PE) from eight diabetic patients who had been treated by conventional insulin therapy. Vascular smooth muscle cells from rat aorta were cultured and used as an assay system for GA. Incorporation of [3H]thymidine into DNA of cultured cells was stimulated by diabetic PE significantly more (P less than .05) than by normal PE. Diabetic PE incubated with cells for 4 days increased cell numbers significantly more (P less than .05) than normal PE. These abnormalities were corrected by long-term intensive insulin treatments (continuous subcutaneous insulin infusion and Pen infuser). The decrease of platelet extract GA appeared to correlate with the amount of insulin administered before meals as short-acting boluses, whereas the level of basal or long-acting insulin appeared to correlate with an increase of PE GA. Thus, the growth-promoting potential of platelets can be normalized by intensive insulin therapy. The relationship of insulin levels to this activity needs further evaluation.

Effects of continuous subcutaneous insulin infusion versus multiple injections on insulin receptors in insulin-dependent diabetics.

We compared continuous subcutaneous insulin infusion (CSII) versus multiple injections (MI) in the treatment of insulin-dependent diabetes mellitus (IDDM) to assess the effect of glucose control on monocyte insulin receptors. Each IDDM patient (n = 8) was treated for 2 mo by MI (HS Ultralente and AC boluses of regular insulin) and for 2 mo by CSII in a randomized fashion. Prestudy preprandial/postprandial blood glucose levels were 199 +/- 33/261 +/- 28 mg/dl and improved to 124 +/- 12/156 +/- 13 mg/dl during MI and to 115 +/- 11/151 +/- 11 mg/dl during CSII. Glycosylated hemoglobin before the study was 10.1 +/- 0.5% and decreased to 8.8 +/- 0.4 and 8.3 +/- 0.3% during MI and CSII, respectively. The specific 125I-labeled insulin binding to circulating monocytes in a group of nonobese controls (n = 17) was 4.6 +/- 0.2%. In our poorly controlled diabetics during conventional therapy, the 125I-insulin binding was decreased to 3.7 +/- 0.3 (P less than .025). This was not significantly affected by MI despite good glucose control (4.0 +/- 0.3%). With CSII, however, good glucose control was associated with normalization of 125I-insulin binding to monocytes (4.7 +/- 0.27%). The affinity of the insulin receptors was normal before the study and was not affected by either MI or CSII. In conclusion, these observations demonstrate that in IDDM, intensive therapy by MI and CSII resulted in similar good glucose control, but only CSII resulted in normalization of insulin receptors on circulating monocytes.

Continuous subcutaneous insulin infusion (Mill-Hill Infuser) versus multiple injections (Medi-Jector) in the treatment of insulin-dependent diabetes mellitus and the effect of metabolic control on microangiopathy.

The present study was designed to compare continuous subcutaneous insulin infusion (CSII) using the Mill-Hill Infuser (Muirhead Medical Products Ltd., London, England) with multiple injections (MI) using the Medi-Jector (Derata Corporation, Minneapolis, Minnesota) in the treatment of insulin-dependent diabetes mellitus (IDDM), and to assess the effect of glucose control on diabetes complications. Twelve diabetic subjects were treated 3 mo with CSII and 3 mo with MI (bedtime ultralente and premeal boluses of regular insulin) in a randomized fashion. Prestudy preprandial/postprandial glucose levels were 147-215 mg/dl and improved to 108-138 mg/dl during CSII, and to 115-139 mg/dl during MI with glycosylated hemoglobin of 12.9%, 9.1%, and 8.7%, respectively. This improved glucose control with either CSII or MI was associated with an increase in sural nerve conductivity from 42.9 to 45 m/s and a decrease in proteinuria from 1.9 to 0.5 g/24 h. The 24-h insulin dose consisted of 45 U before the study, 44 U during CSII, and 56 U during MI. After the study, seven patients opted to continue with the Mill-Hill Infuser, and five with the Medi-Jector. We conclude the following: (1) treatment with both the Mill-Hill Infuser and the Medi-Jector was well accepted by the patients and resulted in similar improvement in measured blood glucose and glycosylated hemoglobin; (2) this improved metabolic control was associated with an increased nerve conductivity and a decreased protein excretion; and (3) MI required 20% more insulin than CSII to achieve similar glycemic control.

Abnormalities of platelet-derived growth factors in insulin-dependent diabetes.

Platelets are involved in homeostasis of the vascular wall at various levels. An important feature of this involvement is the potential for platelet proliferation. Platelets from normal subjects contain platelet-derived growth factor (PDGF), epithelial growth factor (EGF), and transforming growth factor. We have detected the presence of an excessive growth-promoting activity in the heated supernatant fraction derived from the platelets of young, insulin-dependent diabetics. This activity is most pronounced when measured in cultures of smooth muscle cells and fibroblasts. This activity may be further separated into cationic and anionic fractions by ion exchange chromatography of the platelet-rich supernatant. The cationic factor corresponds to PDGF, whereas the anionic factor appears to be identical to EGF. Chronic, intensive insulin therapy normalizes the excessive growth-promoting activity of platelets from diabetics. Further studies are needed to evaluate the differential release of those growth-promoting factors found in platelets of normal subjects and in patients with vascular disease.

Comparing parent and teacher ratings of social competence and problem behaviors.

A comparison between parent and teacher ratings of 109 school children on the French version of the Nisonger Child Behavior Rating Form, which measures social competence and problem behaviors of children with developmental disabilities, was conducted. Results indicated no significant differences between parent and teacher ratings on the two social competence subscales and two problem behavior subscales. Ratings differed significantly on three problem behavior subscales: (a) Conduct Problem, (b) Insecure/Anxious, and (c) Hyperactive. These results may be indicative of complementary information according to the context (home vs. school). Also, results support the premise that it is important to collect information from multiple sources in order to obtain a complete and global assessment of the child's problem behavior/psychopathology.

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

The impact of behaviour problems on caregiver stress in young people with autism spectrum disorders.

BACKGROUND: The purpose of this study was to examine the correlates of caregiver stress in a large sample of young people with autism spectrum disorders (ASDs). Two main objectives were to: (1) disentangle the effects of behaviour problems and level of functioning on caregiver stress; and (2) measure the stability of behaviour problems and caregiver stress. METHODS: Parents or teachers of 293 young people with ASDs completed measures of stress, behaviour problems and social competence. Parents also completed an adaptive behaviour scale. Eighty-one young people were rated twice at a 1-year interval. RESULTS: Parents and teachers did not perfectly agree on the nature and severity of behaviour problems. However, both sets of ratings indicated that behaviour problems were strongly associated with stress. Conduct problems in particular were significant predictors of stress. Adaptive skills were not significantly associated with caregiver stress. Parental reports of behaviour problems and stress were quite stable over the 1-year interval, much more so than teacher reports. Parent ratings suggested that behaviour problems and stress exacerbated each other over time. This transactional model did not fit the teacher data. CONCLUSION: Results of this study suggested that it is a specific group of externalized behaviours that are the most strongly associated with both parent and teacher stress. Results were discussed from methodological and conceptual perspectives.

Glucagon-cortisol interactions on glucose turnover and lactate gluconeogenesis in normal humans.

To determine the mechanism for cortisol enhancement of glucagon-stimulated overall hepatic glucose output (OHGO), we employed the glucose-insulin clamp technique with infusions of [6-3H]glucose and [U-14C]lactate and measured OHGO, glucose utilization, and the turnover and incorporation of lactate in plasma glucose in normal volunteers under four experimental conditions: 1) normoglucagonemia (approximately 150 pg/ml)- normocortisolemia (approximately 14 micrograms/dl); 2) isolated hyperglucagonemia (approximately 550 pg/ml); 3) isolated hypercortisolemia (approximately 32 micrograms/dl); and 4) combined hyperglucagonemia-hypercortisolemia. Isolated hyperglucagonemia caused initial increases in OHGO and lactate gluconeogenesis, which were maximal at 1 h (23.9 +/- 1 and 2.7 +/- 0.4 mumol.kg-1.min-1, respectively) but remained significantly above values in control experiments through 5 h (10.3 +/- 0.7 vs. 8.2 +/- 1.1, P less than 0.03; 2.2 +/- 0.4 vs. 1.2 +/- 0.3, mumol.kg-1.min-1, P less than 0.04, respectively). Hypercortisolemia has no effect on OHGO but increased lactate gluconeogenesis after 3 h. Superimposition of hypercortisolemia on hyperglucagonemia did not further increase OHGO (11.1 +/- 0.7 vs. 10.3 +/- 0.7 mumol.kg-1.min-1, P = NS) but augmented lactate gluconeogenesis additively (isolated hyperglucagonemia = 0.96, isolated hypercortisolemia = 0.98; combined = 2.02 mumol.kg-1.min-1). Neither glucagon nor cortisol affected lactate turnover or glucose utilization. We conclude that glucagon has a persistent effect on OHGO largely accounted for by increased gluconeogenesis. Cortisol augments glucagon-stimulated gluconeogenesis in an additive manner best explained by changes in gluconeogenic enzymes rather than in substrate availability. Finally, the fact that cortisol increased gluconeogenesis without affecting glucose utilization suggests that the liver is more sensitive to the diabetogenic effects of cortisol than are peripheral tissues.

Are caregivers' reports of motivation valid? Reliability and validity of the Reiss Profile MR/DD.

BACKGROUND: Sensitivity theory proposes that there are wide individual differences in what motivates people with intellectual disability. The Reiss Profile MR/DD is a rating scale that measures 15 fundamental motives. This study examined the internal consistency and interrater reliability of the 15 subscales as well as the validity of motivational profiles. METHOD: The study consisted of two distinct but related steps. First, the interrater reliability of the rating scale was established by having pairs of raters evaluate 48 individuals. Second, raters were presented with three different motivational profiles and asked to identify which one corresponded to the individual they had rated 4 weeks earlier. RESULTS: Results indicated good internal consistency (average alpha=0.84), significant variability in the interrater reliability (average intraclass correlation coefficient=0.52), and excellent validity (95% of the correct profiles were chosen). Average discrepancies between pairs of raters are presented. CONCLUSIONS: Interrater reliability is an important topic for professionals working in the field of intellectual disability and results are discussed in terms of the factors that affect it. This is the first published study to report on the interrater reliability of the Reiss Profile MR/DD.

The effects of sucrose meal on insulin requirement in IDDM and its modulation by acarbose.

The purpose of the present study was to evaluate the insulin requirement in response to sucrose meal in IDDM and its modulation by a disaccharidase inhibitor, Acarbose. After an overnight fast, the subjects (n = 9) were "hooked" to the artificial pancreas (Biostator) to maintain normoglycemia. Blood glucose and insulin requirement were recorded by the Biostator throughout the experiment. The patients were divided into two groups. In group I, five patients received increasing sucrose load (50, 75 and 100 g) with and without Acarbose 100 mg. After a 50 g sucrose meal with and without Acarbose, the peak postprandial (PP) blood glucose was 118 and 157 mg/dl and the insulin requirement was 3.9 and 7.8 units resulting in free plasma insulin peak of 34 and 59 microU/ml respectively. After a 75 g sucrose meal with and without Acarbose, the peak PC blood glucose was 134 and 166 mg/dl and the insulin requirement was 5.7 and 9.9 units resulting in free plasma insulin peak of 75 and 87 microU/ml. After a 100 g sucrose meal with and without Acarbose the peak PP blood glucose was 131 and 175 mg/dl and the insulin requirement was 6 and 12.8 units resulting in free plasma insulin peak of 50 and 69 microU/ml. In group II, four patients received increasing Acarbose dose with a fixed sucrose load (75 g). The PP blood glucose peaked at 161, 145, 120 and 102 mg/dl after 0, 50, 100, 200 mg of Acarbose respectively. The total insulin requirements were 12.9, 9.6, 4.3 and 3.1 units. The free plasma insulin was decreased by Acarbose treatment while plasma glucagon remained unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous determination of glucose turnover, alanine turnover, and gluconeogenesis in human using a double stable-isotope-labeled tracer infusion and gas chromatography-mass spectrometry analysis.

We have developed and validated a new method to measure simultaneously glucose turnover, alanine turnover, and gluconeogenesis in human, in steady and non-steady states, using a double stable-isotope-labeled tracer infusion and GC-MS analysis. The method is based on the concomitant infusion and dilution of D-[2,3,4,6,6-2H5]glucose and L-[1,2,3-13C3]alanine. The choice of the tracers was done on the basis of a minimal overlap between the ions of interest and those arising from natural isotopic abundances. Alanine was chosen as the gluconeogenic substrate because it is the major gluconeogenic amino acid extracted by the liver and, with lactate, constitutes the bulk of the gluconeogenic precursors. The method was validated by comparing the results obtained during simultaneous infusion of trace amounts of both stable isotope labeled compounds with the radioactive tracers (D-[3-3H]glucose and L-[1,2,3-14C3]alanine) in a normal and a diabetic subject; the radiolabeled tracers were used as the accepted reference procedure. A slight overestimation of glucose turnover (7.3 versus 6.8 in normal and 10.8 versus 9.2 mumol/kg min in diabetic subject) was noticed when the stable isotope-labeled tracers were used. For the basal turnover rate of alanine, similar values were obtained with both methods (6.2 mumol/kg min). For gluconeogenesis, higher values were observed in the basal state with the stable isotopes (0.42 versus 0.21 mumol/kg min); however, these differences disappeared in the postprandial period after the ingestion of a mixed meal. Despite those minor differences, the overall correlation with the reference method was excellent for glucose turnover (r = 0.87) and gluconeogenesis (r = 0.86).(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated hypoisoleucinemia impairs whole body but not hepatic protein synthesis in humans.

It is not known whether an acute decrease in the plasma concentration of any essential amino acid, as occurs during insulin infusion, impairs protein synthesis. To test this hypothesis in humans, selective hypoisoleucinemia or hypothreoninemia was induced by insulin infusion while maintaining normal or elevated plasma concentrations of the other amino acids via their selective infusion. The effects on protein synthesis were assessed using leucine kinetics and fractional synthetic rates of the two hepatic proteins albumin and fibrinogen. Results were compared with those of a combined insulin and complete amino acid infusion. Hypoisoleucinemia increased leucine oxidation (P less than 0.03) and decreased nonoxidative leucine disposal (P less than 0.04) and net leucine balance (P less than 0.03), whereas hypothreoninemia had no effect on any of these parameters. Neither hypoisoleucinemia or hypothreoninemia altered albumin and fibrinogen fractional synthetic rates when compared with the control study. Because of the known relationships between intra- and extracellular amino acid concentrations, the hypoisoleucinemia was most likely associated with a decreased intracellular concentration of isoleucine; such would not be the case for hypothreoninemia. Thus acute limited availability of a single essential amino acid can adversely affect nonhepatic protein synthesis.

Contributions of gluconeogenesis and glycogenolysis during glucose counterregulation in normal humans.

To estimate the relative contributions of gluconeogenesis and glycogenolysis to the increase in hepatic glucose output (HGO) during glucose counterregulation under conditions simulating clinical insulin hypoglycemia, we induced moderate hypoglycemia (approximately 55 mg/dl) with a continuous infusion of insulin that resulted in physiological hyperinsulinemia (approximately 20 microU/ml) in eight normal volunteers and estimated gluconeogenesis by two methods: an isotopic approach in which appearance of plasma glucose derived from lactate was determined and another approach in which we infused alcohol along with insulin to block gluconeogenesis and used the exogenous glucose required to prevent greater hypoglycemia as an index of gluconeogenesis. Both methods gave similar results. Initially glycogenolysis accounted for approximately 85% of HGO; however, once hypoglycemia became established, the contribution of gluconeogenesis increased progressively to 77 +/- 10 (isotopic method) and 94 +/- 10% (alcohol method) of overall HGO. We conclude that in normal humans during moderate protracted hypoglycemia induced by physiological hyperinsulinemia, gluconeogenesis is the predominant factor responsible for the counterregulatory increase in HGO and that increased gluconeogenesis rather than increased glycogenolysis is the primary mechanism preventing development of greater hypoglycemia.

Determination of leucine and alpha-ketoisocaproic acid concentrations and specific activity in plasma and leucine specific activities in proteins using high-performance liquid chromatography.

Plasma concentrations and 3H and 14C specific activities (specific radioactivities) of leucine and alpha-ketoisocaproate (KIC) and leucine specific radioactivity in hydrolyzed tissue and plasma proteins were determined using an automated isocratic high-performance liquid chromatographic (HPLC) system. Within-day variability of leucine and KIC specific radioactivity in plasma was congruent to 1%, whereas that observed for leucine derived from protein hydrolysis was congruent to 5%. Day-to-day variability of leucine and KIC specific radioactivity in plasma was congruent to 5% and in protein-derived leucine congruent to 6%. In addition, an indirect method is described to measure low specific activities of [3H]- and [14C]leucine derived from the hydrolysis of in vivo labeled proteins with low turnover rates (skeletal muscle and diaphragm). In proteins with higher turnover rates (fibrin, kidney, liver, jejunum and heart muscle), this indirect method gave similar results to the direct HPLC method. Using these methods, fractional protein synthetic rates in a variety of tissues can be accurately determined using radioisotopes of KIC and/or leucine.

Influence of serum Ca concentration on circulating molecular forms of PTH in three species.

The influence of serum calcium concentration on total circulating parathyroid hormone (PTH) and on the relative amount of intact PTH-(1-84) and large carboxyterminal fragments was studied in the canine and bovine species and in man. Serum calcium was modified through infusions of CaCl2 or EDTA and samples obtained in time for the measurement of serum calcium and PTH concentrations. Pools of serum, corresponding to specific serum calcium concentrations, were analyzed by gel chromatography in all species. PTH was measured with a carboxyterminal radioimmunoassay. In basal conditions, total serum PTH was composed mostly of large carboxyterminal fragments, intact PTH-(1-84) representing less than 25% of the hormone in any species. With hypercalcemia, (greater than or equal to 2.0 mg/dl), total serum PTH decreased only to 40% of the original value measured in all species, despite serum calcium concentrations of over 13 mg/dl. The relative amount of intact PTH-(1-84) remained unchanged in the bovine and canine species and slightly decreased in man. Hypocalcemia (less than or equal to 2.0 mg/dl) induced a 300-450% increase in the basal PTH value measured. The relative amount of intact PTH-(1-84) became as or more important than carboxyterminal fragments in the canine species and in man, respectively, and remained slightly less in the bovine species. Despite small quantitative variations between species, these results indicate that changes in serum calcium concentration induced acute modification in PTH secretion or PTH peripheral metabolism, altering the ratio of intact hormone to carboxyterminal fragments in circulation.