A Prospective Open Trial of Guanfacine in Children with Pervasive Developmental Disorders

Objective: A common complaint for children with pervasive developmental disorder (PDD) is hyperactivity. The purpose of this pilot study was to gather preliminary information on the efficacy of guanfacine in children with PDD and hyperactivity. Methods: Children with PDD accompanied by hyperactivity entered the open-label trial if there was a recent history of failed treatment with methylphenidate or the child did not improve on methylphenidate in a multisite, placebo-controlled trial. Results: Children (23 boys and 2 girls) with a mean age of 9.03 (±3.14) years entered the open-label trial. After 8 weeks of treatment, the parent-rated Hyperactivity subscale of the Aberrant Behavior Checklist (ABC) went from a mean of 31.3 (±8.89) at baseline to 18.9 (±10.37) (effect size = 1.4; p < 0.001). The teacher-rated Hyperactivity subscale decreased from a mean of 29.9 (±9.12) at baseline to 22.3 (±9.44) (effect size = 0.83; p < 0.01). Twelve children (48%) were rated as Much Improved or Very Much Improved on the Clinical Global Impressions– Improvement. Doses ranged from 1.0 to 3.0 mg/day in two or three divided doses. Common adverse effects included irritability, sedation, sleep disturbance (insomnia or midsleep awakening), and constipation. Irritability led to discontinuation in 3 subjects. There were no significant changes in pulse, blood pressure, or electrocardiogram. Conclusions: Guanfacine may be useful for the treatment of hyperactivity in children with PDD. Placebocontrolled studies are needed to guide clinical practice

Evaluation of Important Treatment Parameters in Supraphysiological Thermal Therapy of Human Liver Cancer HepG2 Cells

This study was aimed at simulating the effect of various treatment parameters like heating rate (HR), peak temperature (PT) and hold/total treatment time on the viability of human liver cancer HepG2 cells subjected to different thermal therapy conditions. The problem was approached by investigating the injury kinetics obtained using experimentally measured viability of the cells, heated to temperatures of 50–70°C for 0–9 min at HRs of 100, 200, 300 and 525°C min(−1). An empirical expression obtained between the activation energy (E) and HR was extended to obtain the E values over a broad range of HRs from 5 to 600°C min(−1) that mimic the actual conditions encountered in a typical thermal therapy protocol. Further, the effect of the HR (5–600°C min(−1)) and PT (50–85°C) on the cell survival was studied over a range of hold times. A significant drop in survival from 90% to 0% with the simultaneous increase in HR and PT was observed as the hold time increased from 0 to 5 min. For complete cell death, the hold time increased with the increase in the HR for a given PT, while the total time showed presence of minima for 60, 65 and 70°C at HRs of 50, 100 and 200°C min(−1), respectively

Risperidone Treatment of Autistic Disorder: Longer-Term Benefits and Blinded Discontinuation After 6 Months

Objective: Risperidone is effective for short-term treatment of aggression, temper outbursts, and self-injurious behavior in children with autism. Because these behaviors may be chronic, there is a need to establish the efficacy and safety of longer-term treatment with this agent. Method: The authors conducted a multisite, two-part study of risperidone in children ages 5 to 17 years with autism accompanied by severe tantrums, aggression, and/or self-injurious behavior who showed a positive response in an earlier 8-week trial. Part I consisted of 4-month open-label treatment with risperidone, starting at the established optimal dose; part II was an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal. Primary outcome measures were the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression improvement scale. Results: Part I included 63 children. The mean risperidone dose was 1.96 mg/day at entry and remained stable over 16 weeks of open treatment. The change on the Aberrant Behavior Checklist irritability subscale was small and clinically insignificant. Reasons for discontinuation of part I included loss of efficacy (N=5) and adverse effects (N=1). The subjects gained an average of 5.1 kg. Part II included 32 patients. The relapse rates were 62.5% for gradual placebo substitution and 12.5% for continued risperidone; this difference was statistically significant. Conclusions: Risperidone showed persistent efficacy and good tolerability for intermediate-length treatment of children with autism characterized by tantrums, aggression, and/or self-injurious behavior. Discontinuation after 6 months was associated with a rapid return of disruptive and aggressive behavior in most subjects

Dynamic GABAergic afferent modulation of AgRP neurons

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior

A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia.

Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia

Gastrointestinal Symptoms in a Sample of Children with Pervasive Developmental Disorders

Objective To evaluate gastrointestinal (GI) problems in a large, well-characterized sample of children with pervasive developmental disorders (PDDs). Methods One hundred seventy two children entering one of two trials conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network were assessed comprehensively prior to starting treatment and classified with regard to GI symptoms. Results Thirty nine (22.7%) were positive for GI problems, primarily constipation and diarrhea. Those with GI problems were no different from subjects without GI problems in demographic characteristics, measures of adaptive functioning, or autism symptom severity. Compared to children without GI problems, those with GI problems showed greater symptom severity on measures of irritability, anxiety, and social withdrawal. Those with GI problems were also less likely to respond to treatment