The effects of gamma-hydroxybutyrate, baclofen and GABAB receptors on brain activity and sleep in mice and humans

Currently, there is an increased interest in γ-hydroxybutyric acid (GHB) and its effects onsleep. This compound, sometimes referred to as 'rape drug', was recently approved as atreatment for the sleep disorder narcolepsy. Although several studies suggest that GHBinduces slow-wave sleep duration and improves sleep quality by increasing EEG slow-waveactivity, others question its ability to induce physiological sleep. GHB's mechanism of actionis still unclear, although in vivo and in vitro it seems to act at high doses as a low-affinityagonist of GABAB receptors. Furthermore, the role GABAB receptors play in sleep and theelectroencephalogram (EEG) is largely unknown.The aim of this project was therefore to investigate the effects of GHB on sleep and EEG, theinvolvement of GABAB receptors in mediating these effects, as well as the intrinsic role ofeach GABAB receptor subunit in the regulation of sleep. Thus, we administered GHB andbaclofen (BAC, a high-affinity agonist at GABAB receptor) to mice lacking the different GABABreceptor subunits and to healthy human volunteers.Our results, both in mice and humans, showed that GHB produced slow waves exclusivelythrough the stimulation of GABAB receptors, but did not induce physiological sleepnecessary to reduce sleep need and to increase cognitive performance. Unlike GHB, BACaffected the homeostatic regulation of sleep (sleep need) and induced a delayedhypersomnia. Finally, GABAB receptor and its subunits seem to play an important role insleep and in particular its circadian distribution.

Training referential communicative skills to individuals with autism spectrum disorder: a pilot study

Summary. The present study reports the effects of referential communication training in individuals formally diagnosed with autism spectrum disorder (ASD). Participants were 20 children with ASD (M age = 14.3 yr., SD = 4.2; 6 girls, 14 boys) in the role of speakers and 20 control children, who acted as listeners. They were all enrolled in mainstream compulsory education. Inclusion/exclusion criteria were defined according to the clinical diagnosis of ASD, the presence or absence of additional or associated disability, previous training in referential communication, and any drug treatment. Speakers were randomly assigned to one of two groups (trained vs untrained). Linguistic age, cognitive level, and autistic symptoms were analyzed, respectively, with the Peabody Picture Vocabulary Test (PPVT), the Wechsler Intelligence Scale (WISCR or WAISIII), and the Autistic Behavior Checklist (ABC). Communicative abilities were analyzed through two indexes related to message complexity and self-regulation. The trained group was trained in referential communication tasks (task analysis, role taking, and task evaluation), while the untrained group took part in a communicative game but without any specific communicative training. The results showed that the complexity of emitted messages had improved statistically significantly in the trained group as an effect of training. Ecological referential communication is shown to be an appropriate paradigm for studying the communicative process and its products and could be used to develop and implement a training program focused on those skills in which individuals with ASD are most deficient.

Family burden related to clinical and functional variables of people with intellectual disability with and without a mental disorder

Few studies have been found that to assess the factors that explain higher levels of familyburden in adults with intellectualdisability (ID) and intellectualdisability and mental disorders (ID-MD). The aims of this study were to assess familyburden in people with ID and ID-MD and to determine which sociodemographic, clinical and functionaldisabilityvariables account for familyburden. The sample is composed of pairs of 203 participants with disability and their caregivers, of which 33.5% are caregivers of people with ID and 66.5% of ID-MD. Assessments were performed using scales of clinical and functionaldisability as the following instruments: Weschler Adult Intelligence Scale-III (WAIS-III), Inventory for Client and Agency Planning (ICAP), Psychiatric Assessment Schedule for Adults with Development Disability (PAS-ADD checklist), Disability Assessment Schedule of the World Health Organization (WHO-DAS-II) and familyburden (Subjective and Objective FamilyBurden Inventory - SOFBI/ECFOS-II). People with ID-MD presented higher levels of functionaldisability than those with ID only. Higher levels of familyburden were related to higher functionaldisability in all the areas (p < 0.006-0.001), lower intelligence quotient (p < 0.001), diagnosis of ID-MD (p < 0.001) and presence of organic, affective, psychotic and behavioral disorders (p < 0.001). Stepwise multiple regression showed that behavioral problems, affective and psychotic disorder, disability in participation in society, disability in personal care and presence of ID-MD explained more than 61% of the variance in familyburden. An integrated approach using effective multidimensional interventions is essential for both people with ID and ID-MD and their caregivers in order to reduce familyburden.

Plastic modifications within inhibitory control networks induced by practicing a stop-signal task: an electrical neuroimaging study.

INTRODUCTION: Inhibitory control refers to our ability to suppress ongoing motor, affective or cognitive processes and mostly depends on a fronto-basal brain network. Inhibitory control deficits participate in the emergence of several prominent psychiatric conditions, including attention deficit/hyperactivity disorder or addiction. The rehabilitation of these pathologies might therefore benefit from training-based behavioral interventions aiming at improving inhibitory control proficiency and normalizing the underlying neurophysiological mechanisms. The development of an efficient inhibitory control training regimen first requires determining the effects of practicing inhibition tasks. METHODS: We addressed this question by contrasting behavioral performance and electrical neuroimaging analyses of event-related potentials (ERPs) recorded from humans at the beginning versus the end of 1 h of practice on a stop-signal task (SST) involving the withholding of responses when a stop signal was presented during a speeded auditory discrimination task. RESULTS: Practicing a short SST improved behavioral performance. Electrophysiologically, ERPs differed topographically at 200 msec post-stimulus onset, indicative of the engagement of distinct brain network with learning. Source estimations localized this effect within the inferior frontal gyrus, the pre-supplementary motor area and the basal ganglia. CONCLUSION: Our collective results indicate that behavioral and brain responses during an inhibitory control task are subject to fast plastic changes and provide evidence that high-order fronto-basal executive networks can be modified by practicing a SST.

Community pharmacist intervention in depressed primary care patients (PRODEFAR study): randomized controlled trial protocol.

Background: Treatment of depression, the most prevalent and costly mental disorder, needs to be improved. Non-concordance with clinical guidelines and non-adherence can limit the efficacy of pharmacological treatment of depression. Through pharmaceutical care, pharmacists can improve patients' compliance and wellbeing. The aim of this study is to evaluate the effectiveness and costeffectiveness of a community pharmacist intervention developed to improve adherence and outcomes of primary care patients with depression. Methods/design: A randomized controlled trial, with 6-month follow-up, comparing patients receiving a pharmaceutical care support programme in primary care with patients receiving usual care. The total sample comprises 194 patients (aged between 18 and 75) diagnosed with depressive disorder in a primary care health centre in the province of Barcelona (Spain). Subjects will be asked for written informed consent in order to participate in the study. Diagnosis will be confirmed using the SCID-I. The intervention consists of an educational programme focused on improving knowledge about medication, making patients aware of the importance of compliance, reducing stigma, reassuring patients about side-effects and stressing the importance of carrying out general practitioners' advice. Measurements will take place at baseline, and after 3 and 6 months. Main outcome measure is compliance with antidepressants. Secondary outcomes include; clinical severity of depression (PHQ-9), anxiety (STAI-S), health-related quality of life (EuroQol-5D), satisfaction with the treatment received, side-effects, chronic physical conditions and sociodemographics. The use of healthcare and social care services will be assessed with an adapted version of the Client Service Receipt Inventory (CSRI). Discussion: This trial will provide valuable information for health professionals and policy makers on the effectiveness and cost-effectiveness of a pharmaceutical intervention programme in the context of primary care. Trial registration: NCT00794196

Effects of intranasal administration of synthetic (4-28)human atrial natriuretic peptide to normal volunteers.

The effects of intranasal administration of increasing doses of synthetic human natriuretic peptide (4-28 hANP) were studied in six healthy volunteers. The peptide was administered as a nasal spray at doses of 50, 100, 200, and 500 micrograms in ascending order at 48-h intervals. Vehicle was administered by the same route randomly between any two of the doses. Intranasal hANP administration had no effect on either blood pressure, heart rate (HR), or hematocrit. Diuresis did not change consistently, whereas natriuresis tended to rise with vehicle as well as with hANP administration. This was attributed to the infusion of isotonic saline during the experiment. There was no significant increase in plasma ANP levels after intranasal administration of any of the different doses. Thus, no evidence that the atrial natriuretic peptide tested (4-28 hANP) can cross the nasal mucosal barrier was found.

Thidiazuron effects on shoot growth, return bloom, fruit set and nutrition of apples

Apple (Malus domestica Borkh.) trees, cultivars Gala and Fuji, were sprayed at full bloom with thidiazuron (TDZ) at doses of 0, 5, 10, or 20 g ha-1 of a.i. in order to evaluate its effects on plant growth and development, return bloom, fruit set, nutrition, and fruit yield. Fruit set increased with TDZ dose in 'Gala' but not in 'Fuji'. TDZ did not affect fruit yield in any cultivar. In 'Gala', the return bloom was reduced in about 50% at TDZ doses of 10 or 20 g ha-1. TDZ increased shoot growth in both cultivars. In leaves, TDZ decreased the concentration of Ca and Mg in 'Gala' and of Mg in 'Fuji', but did not affect the chlorophyll content, leaf area, length, width, and dry mass per cm² regardless of cultivar. In fruits, the effect of TDZ varied according to the portion evaluated. Highest doses of TDZ decreased the concentration of Ca and K in 'Gala' and of K in 'Fuji' in the entire fruits (flesh + skin); in the skin, highest doses of TDZ reduced the levels of N, Ca, and Mg in both cultivars, in addition to the level of K in 'Fuji'.

Effects of dietary protein on lipid metabolism in high fructose fed humans.

BACKGROUND & AIMS: It has been reported that a high protein diet improves insulin sensitivity and reduces ectopic lipids in animals and humans with the metabolic syndrome. We therefore tested the hypothesis that a high dietary protein content may stimulate whole body lipid oxidation and alter post-prandial triglyceride (TG) after fructose ingestion. METHODS: The post-prandial metabolism of 8 young males was studied after two 6-day periods of hyper-energetic, high fructose diet (HiFruD), and after two 6-day periods of hyper-energetic high fructose high protein diet (HiFruHiProD). The order with which these periods were applied was randomized. At the end of each period, either a low protein, (13)C fructose test meal (Fru meal) or a high protein, (13)C fructose test meal (HiPro Fru meal) was administered. This resulted in the monitoring of metabolic parameters at 4 occasions in random order: a) with Fru meal ingested after HiFruD, b) with HiPro Fru meal ingested after HiFruD, c) with Fru meal ingested after HiFruHiProD or d) with HiPro Fru meal ingested after HiFruHiProD. On each occasion, post-prandial TG concentrations were monitored, energy expenditure and substrate metabolism were measured by indirect calorimetry, and fructose-induced gluconeogenesis was evaluated by measuring plasma (13)C-labeled glucose. RESULTS: TG responses to fructose ingestion were significantly higher after a hyper-energetic HiFruHiProD and after HiPro Fru meals than after a Fru meal ingested after a hyper-energetic HiFruD. Compared to low protein meals, high protein meals increased post-prandial energy expenditure, inhibited post-prandial lipid oxidation, and enhanced fructose-induced gluconeogenesis. These effects were similar with HiFruD and HiFruHiProD. CONCLUSIONS: Dietary proteins did not increase lipid oxidation and increased fructose-induced post-prandial TG in healthy humans fed an hyper-energetic, high fructose diet.

Effects of plant population and nitrogen fertilizer on yield and efficiency of maize-bean intercropping

Nitrogen supply and plant population are basic parameters for cereal-legume intercropping. In order to study plant population and nitrogen fertilizer effects on yield and yield efficiency of maize-bean intercropping, a field experiment was established. Three bean plant populations and three nitrogen levels were used. Maize dry matter accumulation decreased with increases in bean plant population. Competitive effect of intercrop beans on maize yields was high at higher plant populations, being decreased by nitrogen fertilizer; application of 50 kg ha-1 N was very efficient in increasing maize cob yield. Intercropping significantly decreased harvest index of beans in all plant population and nitrogen fertilizer situations. The efficiency of intercropping, compared to sole cropping, was evidenced by the values obtained for Land Equivalent Ratio (LER) for biomass, cob and pod yields that increased with increases in bean plant populations and nitrogen fertilizer levels.

Effects of a short-term overfeeding with fructose or glucose in healthy young males.

Consumption of simple carbohydrates has markedly increased over the past decades, and may be involved in the increased prevalence in metabolic diseases. Whether an increased intake of fructose is specifically related to a dysregulation of glucose and lipid metabolism remains controversial. We therefore compared the effects of hypercaloric diets enriched with fructose (HFrD) or glucose (HGlcD) in healthy men. Eleven subjects were studied in a randomised order after 7 d of the following diets: (1) weight maintenance, control diet; (2) HFrD (3.5 g fructose/kg fat-free mass (ffm) per d, +35 % energy intake); (3) HGlcD (3.5 g glucose/kg ffm per d, +35 % energy intake). Fasting hepatic glucose output (HGO) was measured with 6,6-2H2-glucose. Intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) were measured by 1H magnetic resonance spectroscopy. Both fructose and glucose increased fasting VLDL-TAG (HFrD: +59 %, P < 0.05; HGlcD: +31 %, P = 0.11) and IHCL (HFrD: +52 %, P < 0.05; HGlcD: +58 %, P = 0.06). HGO increased after both diets (HFrD: +5 %, P < 0.05; HGlcD: +5 %, P = 0.05). No change was observed in fasting glycaemia, insulin and alanine aminotransferase concentrations. IMCL increased significantly only after the HGlcD (HFrD: +24 %, NS; HGlcD: +59 %, P < 0.05). IHCL and VLDL-TAG were not different between hypercaloric HFrD and HGlcD, but were increased compared to values observed with a weight maintenance diet. However, glucose led to a higher increase in IMCL than fructose.

Differential effects of GABAB receptor subtypes, {gamma}-hydroxybutyric Acid, and Baclofen on EEG activity and sleep regulation.

The role of GABA(B) receptors in sleep is still poorly understood. GHB (γ-hydroxybutyric acid) targets these receptors and is the only drug approved to treat the sleep disorder narcolepsy. GABA(B) receptors are obligate dimers comprised of the GABA(B2) subunit and either one of the two GABA(B1) subunit isoforms, GABA(B1a) and GABA(B1b). To better understand the role of GABA(B) receptors in sleep regulation, we performed electroencephalogram (EEG) recordings in mice devoid of functional GABA(B) receptors (1(-/-) and 2(-/-)) or lacking one of the subunit 1 isoforms (1a(-/-) and 1b(-/-)). The distribution of sleep over the day was profoundly altered in 1(-/-) and 2(-/-) mice, suggesting a role for GABA(B) receptors in the circadian organization of sleep. Several other sleep and EEG phenotypes pointed to a more prominent role for GABA(B1a) compared with the GABA(B1b) isoform. Moreover, we found that GABA(B1a) protects against the spontaneous seizure activity observed in 1(-/-) and 2(-/-) mice. We also evaluated the effects of the GHB-prodrug GBL (γ-butyrolactone) and of baclofen (BAC), a high-affinity GABA(B) receptor agonist. Both drugs induced a state distinct from physiological sleep that was not observed in 1(-/-) and 2(-/-) mice. Subsequent sleep was not affected by GBL whereas BAC was followed by a delayed hypersomnia even in 1(-/-) and 2(-/-) mice. The differential effects of GBL and BAC might be attributed to differences in GABA(B)-receptor affinity. These results also indicate that all GBL effects are mediated through GABA(B) receptors, although these receptors do not seem to be involved in mediating the BAC-induced hypersomnia.

The Effects of Headcut and Knickpoint Propagation on Bridges in Iowa, TR-541, 2008

The overarching goal of the proposed research was to provide a predictive tool for knickpoint propagation within the HCA (Hungry Canyon Alliance) territory. Knickpoints threaten the stability of bridge structures in Western Iowa. The study involved detailed field investigations over two years in order to monitor the upstream migration of a knickpoint on Mud Creek in Mills County, IA and identify the key mechanisms triggering knickpoint propagation. A state-of-the-art laser level system mounted on a movable truss provided continuous measurements of the knickpoint front for different flow conditions. A pressure transducer found in proximity of the truss provided simultaneous measurements of the flow depth. The laser and pressure transducer measurements led to the identification of the conditions at which the knickpoint migration commences. It was suggested that negative pressures developed by the reverse roller flow near the toe of the knickpoint face triggered undercutting of the knickpoint at this location. The pressure differential between the negative pressure and the atmospheric pressure also draws the impinging jet closer to the knickpoint face producing scour. In addition, the pressure differential may induce suction of sediment from the face. Other contributing factors include slump failure, seepage effects, and local fluvial erosion due to the exerted fluid shear. The prevailing flow conditions and soil information along with the channel cross-sectional geometry and gradient were used as inputs to a transcritical, one dimensional, hydraulic/geomorphic numerical model, which was used to map the flow characteristics and shear stress conditions near the knickpoint. Such detailed flow calculations do not exist in the published literature. The coupling of field and modeling work resulted in the development of a blueprint methodology, which can be adopted in different parts of the country for evaluating knickpoint evolution. This information will assist local government agencies in better understanding the principal factors that cause knickpoint propagation and help estimate the needed response time to control the propagation of a knickpoint after one has been identified.

A structural MRI study of motor conversion disorder: evidence of reduction in thalamic volume.

OBJECTIVE: To investigate potential abnormalities in subcortical brain structures in conversion disorder (CD) compared with controls using a region of interest (ROI) approach. METHODS: Fourteen patients with motor CD were compared with 31 healthy controls using high-resolution MRI scans with an ROI approach focusing on the basal ganglia, thalamus and amygdala. Brain volumes were measured using Freesurfer, a validated segmentation algorithm. RESULTS: Significantly smaller left thalamic volumes were found in patients compared with controls when corrected for intracranial volume. These reductions did not vary with handedness, laterality, duration or severity of symptoms. CONCLUSIONS: These differences may reflect a primary disease process in this area or be secondary effects of the disorder, for example, resulting from limb disuse. Larger, longitudinal structural imaging studies will be required to confirm the findings and explore whether they are primary or secondary to CD.

Transpiration stimulée afin d'améliorer l'équilibre hydro-sodé chez les patients hémodialysés : à propos d'un cas [Stimulated sweating in order to improve the water-and-salt balance in hemodialysis patients. A case report].

Obtaining the desired dry weight in dialysis patients is challenging once residual diuresis has disappeared, considering the trend of increasing dietary salt intake and shortening dialysis time over the last 40 years. We describe the case of a 55-year-old patient of Sudanese origin, who presented excessive interdialytic weight gain and hypertension on maintenance hemodialysis. After failure of conservative measures, a therapy of daily hot water baths of 30minutes each on non-dialysis days was introduced. All clinical parameters improved, including potassium profile. In this article, we review the history, pathophysiological mechanisms, efficacy and possible side effects of this interesting, somewhat forgotten technique.

Differentiating schizoaffective and bipolar I disorder in first-episode psychotic mania.

OBJECTIVE: This study aims to differentiate schizoaffective disorder (SAD) and bipolar-I-disorder (BD) in first-episode psychotic mania (FEPM). METHODS: All 134 patients from an epidemiological first-episode psychosis cohort (N=786) with FEPM and an 18-month follow-up final diagnosis of SAD (n=36) or BD (n=98) were assessed with respect to pre-treatment, baseline and outcome differences. Second, patients with baseline BD who shifted (shifted BD) or did not shift to SAD (stable BD) over the follow-up period were compared regarding pre-treatment and baseline differences. RESULTS: SAD patients displayed a significantly longer duration of untreated psychosis (DUP; effect size r=0.35), a higher illness-severity at baseline (r=0.20) and more traumatic events (Cramer-V=0.19). SAD patients displayed a significantly higher non-adherence rate (Cramer-V=0.19); controlling for time in treatment and respective baseline scores, SAD patients had significantly worse illness severity (CGI-S; partial η(2)=0.12) and psychosocial functioning (GAF; partial η(2)=0.07) at 18-months, while BD patients were more likely to achieve remission of positive symptoms (OR=4.9, 95% CI=1.8-13.3; p=0.002) and to be employed/occupied (OR=7.7, 95% CI=2.4-24.4, p=0.001). The main discriminator of stable and shifted BD was a longer DUP in patients shifting from BD to SAD. CONCLUSIONS: It is difficult to distinguish BD with psychotic symptoms and SAD in patients presenting with FEPM. Longer DUP is related to SAD and to a shift from BD to SAD. Compared to BD, SAD had worse outcomes and higher rates of non-adherence with medication. Despite these differences, both diagnostic groups need careful dimensional assessment and monitoring of symptoms and functioning in order to choose the right treatment.