Ahmad Adi

Chronic central ghrelin infusion reduces blood pressure and heart rate despite increasing appetite and promoting weight gain in normotensive and hypertensive rats

Acute studies showed that ghrelin acts on the central nervous system (CNS) to reduce blood pressure (BP), heart rate (HR) and sympathetic activity. However, the long-term CNS cardiovascular actions of ghrelin are still unclear. We tested whether chronic intracerebroventricular (ICV) infusion of ghrelin causes sustained reductions in BP, HR and whether it alters baroreceptor sensitivity (BRS) and autonomic input to the heart. A cannula was placed in the lateral ventricle of male Sprague-Dawley (SD) rats for ICV infusions via osmotic minipump (0.5 μl/h). BP and HR were measured 24-h/day by telemetry. After 5 days of control measurements, ghrelin (0.21 nmol/h) or saline vehicle were infused ICV for 10 days followed by a 5-day post-treatment period. Chronic ICV ghrelin infusion increased food intake (22±3 to 26±1 g/day) leading to ~50 g body weight gain. BP fell slightly during ghrelin infusion while HR decreased by ~26 bpm. In control animals BP and HR increased modestly. ICV Ghrelin infusion caused a 50% reduction in sympathetic tone to the heart but did not alter BRS. We also tested if the depressor responses to ICV ghrelin infusion were enhanced in spontaneously hypertensive rats (SHR) due to their high basal sympathetic tone. However, we observed similar BP and HR responses compared to normotensive rats. These results indicate that ghrelin, acting via direct actions on the CNS, has a sustained effect to lower HR and a modest impact to reduce BP in normotensive and hypertensive animals despite increasing appetite and body weight.

Role of Proopiomelanocortin Neuron Stat3 in Regulating Arterial Pressure and Mediating the Chronic Effects of Leptin

Although signal transducer and activator of transcription 3 (Stat3) is a key second messenger by which leptin regulates appetite and body weight, its role in specific neuronal populations in metabolic regulation and in mediating the chronic effects of leptin on blood pressure is unknown. The current study tested the hypothesis that Stat3 signaling in proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on mean arterial pressure (MAP), as well as on glucose regulation, energy expenditure, and food intake. Stat3flox/flox mice were crossed with POMC-Cre mice to generate mice with Stat3 deletion specifically in POMC neurons (Stat3flox/flox/POMC-Cre). Oxygen consumption (VO2), carbon dioxide respiration (VCO2), motor activity, heat production, food intake, and MAP were measured 24 hours/d. After baseline measurements, leptin was infused (4 &mgr;g/kg per min, IP) for 7 days. Stat3flox/flox/POMC-Cre mice were hyperphagic, heavier, and had increased respiratory quotients compared with control Stat3flox/flox mice. Baseline MAP was not different between the groups, and chronic leptin infusion reduced food intake similarly in both groups (27 versus 29%). VO2, VCO2, and heat production responses to leptin were not significantly different in control and Stat3flox/flox/POMC-Cre mice. However, leptin-mediated increases in MAP were completely abolished, and blood pressure responses to acute air–jet stress were attenuated in male Stat3flox/flox/POMC-Cre mice. These results indicate that Stat3 signaling in POMC neurons is essential for leptin-mediated increases in MAP, but not for anorexic or thermogenic effects of leptin.

Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons.

Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 &mgr;g/kg per minute) for 7 days. Compared with control IRS2flox/flox mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 versus 35±1 g and 3.6±0.5 versus 3.8±0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110±2 versus 102±2 mm Hg and 641±9 versus 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g per day), and had higher MAP and heart rate (108±2 mm Hg and 659±9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2flox/flox and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects.

Psychosocial interventions for disruptive behavioural problems in children living in low- and middle-income countries: study protocol of a systematic review.

Introduction Disruptive behaviour disorders (DBDs) are among the most common forms of child psychopathology and have serious long-term academic, social, and mental health consequences worldwide. Psychosocial treatments are the first line of evidence-based treatments for DBDs, yet their effectiveness often varies according to patient sociodemographic characteristics, practice setting, and implementation procedures. While a large majority of the worlds children live in low- and middle-income countries (LMIC), most studies have evaluated psychosocial treatments for DBDs in high-income Anglo countries. Methods and analysis The primary objective of this systematic review is to assess the effects of psychosocial treatments for DBDs in children and adolescents (under age 18) diagnosed with oppositional defiant disorder, conduct disorder, or other disruptive behavioural problems living in LMIC. The secondary objectives are to: (1) describe the range and types of psychosocial treatments used to address DBDs in LMIC and (2) identify key dissemination and implementation factors (adaptation processes, training/supervision processes, and financial costs). All controlled trials comparing psychosocial treatments versus waiting list, no treatment, or treatment as usual in children living in LMIC will be included. Studies will be identified using the methods outlined in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines without restrictions on language, publication type, status, or date of publication. The primary outcome measures will be disruptive behavioural problems (eg, oppositionality, defiance, aggression or deceit). Secondary outcomes will be positive mental health outcomes (eg, prosocial behaviour), function impairment, institutionalisation (or hospitalisation), academic outcomes and caregiver outcomes. Ethics and dissemination This study uses data from published studies; therefore ethical review is not required. Findings will be presented in a published manuscript. Trial registration number PROSPERO CRD42014015334.

Psychosocial interventions for disruptive behaviour problems in children in low- and middle-income countries: A systematic review and meta-analysis

BACKGROUND Most of the evidence for psychosocial interventions for disruptive behaviour problems comes from Western, high-income countries. The transferability of this evidence to culturally diverse, low-resource settings with few mental health specialists is unknown. METHODS We conducted a systematic review with random-effects meta-analysis of randomized controlled trials examining the effects of psychosocial interventions on reducing behaviour problems among children (under 18) living in low- and middle-income countries (LMIC). RESULTS Twenty-six randomized controlled trials (representing 28 psychosocial interventions), evaluating 4,441 subjects, met selection criteria. Fifteen (54%) prevention interventions targeted general or at-risk populations, whereas 13 (46%) treatment interventions targeted children selected for elevated behaviour problems. Most interventions were delivered in group settings (96%) and half (50%) were administered by non-specialist providers. The overall effect (standardized mean difference, SMD) of prevention studies was -0.25 (95% confidence interval (CI): -0.41 to -0.09; I2 : 78%) and of treatment studies was -0.56 (95% CI: -0.51 to -0.24; I2 : 74%). Subgroup analyses demonstrated effectiveness for child-focused (SMD: -0.35; 95% CI: -0.57 to -0.14) and behavioural parenting interventions (SMD: -0.43; 95% CI: -0.66 to -0.20), and that interventions were effective across age ranges. CONCLUSIONS Our meta-analysis supports the use of psychosocial interventions as a feasible and effective way to reduce disruptive behaviour problems among children in LMIC. Our study provides strong evidence for child-focused and behavioural parenting interventions, interventions across age ranges and interventions delivered in groups. Additional research is needed on training and supervision of non-specialists and on implementation of effective interventions in LMIC settings.

Homozygosity analysis in subjects with autistic spectrum disorder

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder that results in social and communication impairments, as well as repetitive and stereotyped patterns. Genetically, ASD has been described as a multifactorial genetic disorder. The aim of the present study was to investigate possible susceptibility loci of ASD, utilizing the highly consanguineous and inbred nature of numerous families within the population of Saudi Arabia. A total of 13 multiplex families and 27 affected individuals were recruited and analyzed using Affymetrix GeneChip(®) Mapping 250K and 6.0 arrays as well as Axiom arrays. Numerous regions of homozygosity were identified, including regions in genes associated with synaptic function and neurotransmitters, as well as energy and mitochondria-associated genes, and developmentally-associated genes. The loci identified in the present study represent regions that may be further investigated, which could reveal novel changes and variations associated with ASD, reinforcing the complex inheritance of the disease.

Screening for Mutations in ABCC8 and KCNJ11 Genes in Saudi Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) Patients

The autosomal recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is associated with mutations in either ABCC8 or KCNJ11 genes. In the present study, we describe the clinical features and results of genetic analysis of 13 Saudi Arabian patients with PHHI. Clinically, most patients presented with infantile seizures and/or developmental delay, with a subset of patients who were also found to have abnormal brain imaging and electrophysiological studies. Interestingly no coding pathogenic mutations were identified in these two genes by direct sequencing. However, two splice variants were identified in ABCC8 gene in two patients, and a large deletion of exons 1-22 of the ABCC8 gene was identified in three patients. Our data shows that large deletions in ABCC8 gene are the common genetic mechanism in the Saudi population.