Diagnostic specificity of the insular cortex abnormalities in first-episode psychotic disorders

Volume reductions of the insular cortex have been described in schizophrenia, but it remains unclear whether other psychotic disorders such as affective psychosis also exhibit insular cortex abnormalities. In this study, we used magnetic resonance imaging to investigate the gray matter volume of the anterior (short) and posterior (long) insular cortices in 162 first-episode patients with various psychotic disorders (46 schizophrenia, 57 schizophreniform disorder, 34 affective psychosis, and 25 other psychoses) and 62 age- and gender-matched healthy comparison subjects. Patients with schizophrenia showed bilateral volume reduction of the anterior and posterior insular cortices compared with controls, but the remaining first-episode psychosis subgroups had normal insular volumes. The volumes of these insular subregions were significantly smaller in schizophrenia patients than in patients with schizophreniform disorder or affective psychoses. There was no association between the insular cortex volume and daily dosage or type of antipsychotic medication in any patient group. These findings suggest that the widespread volume reduction of the insular cortex is specific to established schizophrenia, implicating its role in the neurobiology of clinical characteristics associated with schizophrenia.     

Effects of intracerebroventricular injection of naloxone on operant feeding and drinking in pigs

Operant feeding and drinking to satiation were studied in prepubertal pigs deprived of food or water for 18 hours and then given intracerebroventricular (ICV) injections of a solution of naloxone hydrochloride. In feeding tests there was no difference in the amount of food consumed, or in the rate at which reinforcements were obtained, between pigs given ICV injections of 0.4 or 0.8 mg naloxone and those receiving a control injection of saline. However, in drinking tests, injection of both 0.2 and 0.4 mg naloxone significantly (p less than 0.01) reduced the quantity of water drunk and slowed the rate at which reinforcements were obtained. No significant effects on operant water intake were seen after intravenous injection of 0.4 mg naloxone.     

An in vivo technique for investigating electrophysiological effects of centrally administered drugs on single neurons and network behaviour

Single neuronal juxtacellular recording with simultaneous cortical electroencephalogram (EEG) in whole-animal preparations in vivo has allowed the study of the behaviour of individual neurons in relation to whole brain activity. Data on single neuron firing, neural synchrony, network behaviour and their responses to pharmacological agents can be obtained with dual recordings. However, pharmacological effects on cellular and network activity during paired single-unit recordings have not been possible due to the difficulties in maintaining recordings of two cells for a prolonged period. Here, we describe a method of maintaining stable dual cell juxtacellular recordings from distinct brain regions, allowing the assessment of single unit activity before, during and after the intracerebroventricular (ICV) injection of drugs. Data collection using this technique allows correlation both between the two cells and with whole-brain EEG, and their responses to pharmacological interventions. This is particularly useful for the investigation of the effects of anti-epileptic drugs on animal models of epilepsy, where single unit activity of two cells from distinct regions can be correlated with each other and with whole-brain activity during pre-ictal, ictal and interictal states. We also describe standardised analytical methods of quantifying cell firing patterns, the rhythmicity of individual neurons and the synchronicity of firing between two neurons in ictal and interictal periods and their responses to drug exposure.     

Intracerebroventricular delivery of glucocerebrosidase reduces substrates and increases lifespan in a mouse model of neuronopathic Gaucher disease

Gaucher disease is caused by a deficit in the enzyme glucocerebrosidase. As a consequence, degradation of the glycolipids glucosylceramide (GluCer) and glucosylsphingosine (GluSph) is impaired, and their subsequent buildup can lead to significant pathology and early death. Type 1 Gaucher patients can be treated successfully with intravenous replacement enzyme, but this enzyme does not reach the CNS and thus does not ameliorate the neurological involvement in types 2 and 3 Gaucher disease. As one potential approach to treating these latter patients, we have evaluated intracerebroventricular (ICV) administration of recombinant human glucocerebrosidase (rhGC) in a mouse model of neuronopathic Gaucher disease. ICV administration resulted in enzyme distribution throughout the brain and alleviated neuropathology in multiple brain regions of this mouse model. Treatment also resulted in dose-dependent decreases in GluCer and GluSph and significantly extended survival. To evaluate the potential of continuous enzyme delivery, a group of animals was treated ICV with an adeno-associated viral vector encoding hGC and resulted in a further extension of survival. These data suggest that ICV administration of rhGC may represent a potential therapeutic approach for type 2/3 Gaucher patients. Preclinical evaluation in larger animals will be needed to ascertain the translatability of this approach to the clinic.     

Differential clinical, structural and P300 parameters in schizophrenia patients resistant to conventional neuroleptics

Schizophrenia is a heterogeneous clinical condition that may reflect a variety of biological processes. In particular, treatment-resistant (TR) schizophrenia may have a distinct neurobiological substrate. Within the context of clinical data, a simultaneous study with different imaging techniques could help to elucidate differences in cerebral substrates among schizophrenia patients with different responses to treatment. In the present work we used a set of biological data (basal and longitudinal volumetry, and P300 event-related potential measurements) to compare TR and treatment-responsive chronic schizophrenia patients with healthy controls. The TR patients showed higher baseline clinical scores, a more severe basal profile of brain alterations, as well as a different outcome as regards to volume deficits. These data support the notion that biological substrates vary among groups of different psychotic patients, even when they have the same diagnosis, and that those substrates may be related to the response to treatment.     

Operant feeding and drinking in pigs following intracerebroventricular injection of synthetic cholecystokinin octapeptide

Operant feeding and drinking was investigated in food- or water-deprived pigs following intracerebroventricular (ICV) injection of a saline solution containing synthetic cholecystokinin (CCK) octapeptide. In 17-hour food-deprived animals treated with 0, 5, 10, 20 or 40 units ICV, post-treatment food intake was significantly reduced in a dose-related manner but drinking was unaffected. In 22-hour water-deprived pigs treated with 0, 10 or 40 units CCK octapeptide ICV, no effect on drinking was apparent. Pigs injected intravenously with 40 units following 17 hours food deprivation did not reduce their food intake.     

The dipsogenic effect of intracerebroventricular infusion of hypertonic NaCI in the sheep is mediated mainly by the Na ion

In order to examine the importance of the chloride ion in the dipsogenic effect of intracerebroventricular (ICV) infusion of hypertonic NaCI, the water intake in response to 30-min ICV infusons of hypertonic solutions of different Na salts (0.25 M NaCI, Nal, NaSCN and 0.125 _M Na₂S₂O₃), mannitol (0.5 M) and choline chloride (0.25 M) was studied in the sheep. All solutions of the Na salts caused significant water drinking compared with ICV control infusions of isotonic artificial cerebrospinal fluid (CSF), except Na thiosulphate (Na₂S₂O₃), which was much less effective, even after equilibration of its osmolality with the other sodium solutions by adding mannitol (0.125 M Na₂S₂O₃/o.25 M mannitol). An inconsistent and small intake of water was induced by ICV hypertonic mannitol and choline chloride. It is concluded that the dipsogenic effect of ICV infusion of hypertonic NaCI in the sheep is mainly caused by the increased Na rather than the CI ion concentration or the hyperosmolality in the extracellular fluid of juxtaventricular brain tissue.     

Hypoxic response in newborn rat is attenuated by neurokinin-1 receptor blockade

Substance P (SP) is considered to be involved in the regulation of respiration, in particular when respiratory demands are increased, such as during hypoxic stress. In the present study we have investigated the effects of intracerebroventricular pre-treatment with the selective NK-1 receptor antagonist RP67580 on the respiratory response to hypoxia in 5-day-old rat pups. Basal respiration was not altered by RP67580. When subjected to hypoxia (10% O(2)), rat pups pre-treated with RP67580 were unable to sustain the increased respiratory frequency at 10 min. In situ hybridisation demonstrated increased expression of c-fos mRNA in several brainstem areas following hypoxia. This activation was blocked by the antagonist in the retrotrapezoid nucleus and the rostral ventrolateral medulla, areas known to be involved in the hypoxic ventilatory response. This study corroborates a role of endogenously released SP, mediated via NK-1 receptors, in the sustained response to hypoxia in 5-day-old rat pups and suggests that neurons in the rostral ventrolateral medulla are important in this function. It also represents a further example that neuropeptides are released under stressful conditions.     

Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: a 25-year experience

OBJECTIVE: To analyze the outcome of children with short bowel syndrome (SBS) who required long-term parenteral nutrition (PN). STUDY DESIGN: Retrospective analysis of children (n=78) with SBS who required PN >3 months from 1975 to 2000. Statistics: univariate analysis, Kaplan-Meier method, and Cox proportional regression model were used. RESULTS: We identified 78 patients. Survival was better with small bowel length (SBL) >38 cm, intact ileocecal valve (ICV), intact colon, takedown surgery after ostomy (all P <.01), and primary anastomosis (P <.001). PN-associated early persistent cholestatic jaundice (P <.001) and SBL of <15 cm (P <.01) were associated with a higher mortality. Intestinal adaptation was less likely if SBL <15 cm (P <.05), ICV was removed, colonic resection was done (both P <.001), >50% of colon was resected (P <.05), and primary anastomosis could not be accomplished (P <.01). Survival was 73% (57), and 77% (44) of survivors had intestinal adaptation. CONCLUSIONS: SBL, intact ICV, intestinal continuity, and preservation of the colon are important factors for survival and adaptation. Adaptation usually occurred within the first 3 years. Need for long-term PN does not preclude achieving productive adulthood. Patients with ICV even with <15 cm of SBL and patients with SBL >15 cm without ICV have a chance of intestinal adaptation.     

Biological actions and therapeutic potential of the glucagon-like peptides

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.