The prolyl hydroxylase inhibitor GSK1120360A reduces early brain injury, but protection is not maintained in a neonatal rat model of hypoxic ischaemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) in newborns is associated with high morbidity and mortality, with many babies suffering long-term neurological deficits. Currently, treatment options are limited to therapeutic hypothermia, which is not appropriate for use in all babies. Previous studies have shown protective effects of increasing the transcription factor-hypoxia-inducible factor-1 (HIF-1) in animal models, by using mild hypoxia or compounds that act as prolyl hydroxylase inhibitors (PHIs). Here, we aimed to examine the neuroprotective actions of an orally active, small molecule PHI, GSK1120360A in a neonatal rat model of hypoxia-ischemia (HI) compared to another PHI, desferrioxamine (DFX). Sprague-Dawley rats underwent HI surgery on postnatal day 7 (P7), where unilateral carotid artery occlusion was performed followed by hypoxia (8% oxygen, 3 h). Initial testing showed that GSK1120360A and erythropoietin levels were detectable in plasma at 6 h following oral exposure to GSK1120360A. For the short-term neuroprotection study, pups were assigned to receive either saline (s.c), desferrioxamine (DFX-200 mg/kg, s.c), methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. Histological analysis showed that GSK1120360A in this setting reduced brain injury size 7 days after HI, compared to the methylcellulose vehicle control group. DFX had no significant effect on injury size compared to saline group at the same 7 day timepoint. In the long-term neuroprotection study, pups were randomly assigned to be administered methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. On P42, rats underwent behavioural testing using the forelimb grip strength, grid walking and novel object recognition tasks, and brains were collected for histological analysis. Long-term behavioural deficits were observed in grid walking, grip strength and novel object recognition tests after HI which were not improved in the GSK1120360A treatment group compared to the methylcellulose group. Similarly, there was no improvement in injury size on P42 in the GSK1120360A study group compared to the methylcellulose group. Here, we have shown that GSK1120360A can reduce brain injury at 7 days but that this neuroprotective benefit is not maintained when examined at 5 weeks after HI.

From ectodermal dysplasia to selective tooth agenesis.

The history and the lessons learned from hypohidrotic ectodermal dysplasia (HED) may serve as an example for the unraveling of the cause and pathogenesis of other ectodermal dysplasia syndromes by demonstrating that phenotypically identical syndromes (HED) can be caused by mutations in different genes (EDA, EDAR, EDARADD), that mutations in the same gene (EDA) can lead to different phenotypes (HED and selective tooth agenesis) and that mutations in genes further downstream in the same signaling pathway (NEMO) may modify the phenotype quite profoundly (incontinentia pigmenti (IP) and HED with immunodeficiency). But it also demonstrates that diligent phenotype characterization and classification is extremely helpful in uncovering the underlying genotype. We also present a new mutation in the EDA gene which causes selective tooth agenesis and demonstrates the phenotype variation that can be encountered in the ectodermal dysplasia syndrome (HED) with the highest prevalence worldwide.

Course of substance misuse and daily tobacco use in first-episode psychosis.

BACKGROUND: Study of the course of substance misuse and daily tobacco use in first-episode psychosis may enhance detection and treatment of these substance-related problems. METHODS: This 15-month follow-up study examined the course of substance misuse and daily tobacco use in 103 individuals treated for first-episode psychosis. RESULTS: Three-quarters (72.6%) of patients with lifetime substance misuse, or half (51.5%) of all patients, continued substance misuse (primarily cannabis) during the 15-month follow-up period. There was a significant reduction in the rate of any substance misuse (70.9% versus 53.4%) but not daily tobacco use (76.7% versus 75.7%) between baseline and 15-month follow-up. Patients who continued substance misuse showed a significant reduction in the severity and frequency of substance use between baseline and follow-up. Patients who continued substance misuse were more likely to be younger, male and single, less likely to have completed secondary school, and more likely to have had more severe cannabis use prior to entry to treatment compared to patients who ceased substance misuse. DISCUSSION: A significant proportion of young patients treated for first-episode psychosis are at risk of mental and physical health problems associated with substance misuse and/or regular tobacco use.

Patterns and predictors of substance use disorders and daily tobacco use in first-episode psychosis.

OBJECTIVE: To investigate the patterns and predictors of substance use disorders (SUD) and daily tobacco use in first-episode psychosis (FEP). METHOD: In this study, consecutive admissions of 126 patients with an initial presentation for FEP were recruited from three psychiatric services. Each patient was assessed with a comprehensive assessment package in order to collect demographic information, to diagnose psychotic disorders and SUD, to estimate the duration of untreated psychosis and to assess premorbid functioning and the severity of psychiatric symptoms. RESULTS: The rates of lifetime SUD and daily tobacco use were 71% and 77%, respectively. The onset of SUD pre-dated the onset of positive psychotic symptoms in 91% of relevant cases. In multivariate analyses, male gender, younger age, Australian birth and unemployed status were the most consistent demographic predictors of SUD and daily tobacco use. There were no associations found between SUD and symptom severity, premorbid adjustment, psychotic disorder diagnosis or hospitalization. CONCLUSIONS: Male gender and younger age are reliable predictors of SUD in FEP. Patients with and without SUD appear to have similar clinical characteristics at initial presentation.

Short term arterial remodelling in the aortae of cholesterol fed New Zealand white rabbits shown in vivo by high-resolution magnetic resonance imaging - implications for human pathology.

High-resolution, non-invasive imaging methods are required to monitor progression and regression of atherosclerotic plaques. We investigated the use of MRI to measure changes in plaque volume and vessel remodelling during progression and regression of atherosclerosis in New Zealand White rabbits. Atherosclerotic lesions were induced in the abdominal aorta by balloon injury and cholesterol feeding. MR images (2D) of the abdominal aorta were acquired with cardiac and respiratory gating using a fast spin echo sequence with and without fat-suppression. In an initial study on rabbits treated for 30 weeks we imaged the aortae with a spatial resolution of 250x250 micrometers with a slice thickness of 2 mm and achieved a close correlation between MRI-derived measurements and those made on perfusion pressure-fixed histological sections (r(1) = 0.83, slope p(1) < 0.01). We subsequently imaged 18 rabbits before and periodically during 12 weeks of cholesterol feeding (progression) followed by 12 weeks on normal diet (regression). Aortic wall (atherosclerotic lesion) volume increased significantly during progression and decreased during regression. In contrast, lumen volume increased during progression and did not change during regression. In conclusion, this study confirms that non-invasive, high-resolution MRI can be used to monitor progression and regression of atherosclerosis, each within 3 months and shows, for the first time in a short-term model, that positive remodelling occurs early during progression and persists through regression of atherosclerotic lesions.

A new primate model of focal stroke: endothelin-1-induced middle cerebral artery occlusion and reperfusion in the common marmoset.

The purpose of the present set of studies was to develop a new primate model of focal ischemia with reperfusion for long-term functional assessment in the common marmoset. Initially, the cerebral vascular anatomy of the marmoset was interrogated by Araldite-cast and ink-perfusion methods to determine the feasibility of an intravascular surgical approach. The methods showed that the internal carotid artery was highly tortuous in its passage, precluding the development of an extracranial method of inducing temporary middle cerebral artery occlusion in the marmoset. A pilot dose-response study investigated an intracranial approach of topically applying endothelin-1 (ET-1) to the M2 portion of the middle cerebral artery in a small sample of marmosets for up to 6 hours (n = 2 or 3 per group). Dose-dependent reductions in middle cerebral artery vessel caliber followed by gradual reperfusion were inversely related to increases in corrected lesion volume after ET-1 treatment, relative to vehicle control application. Finally, the functional consequences of ET-1-induced lesions to the M2 vascular territory were assessed up to 24 hours after surgery using the optimal dose established in the pilot study (2.5 nmol/25 microL). ET-1-treated marmosets (n = 4) showed marked contralateral motor deficits in grip strength and retrieval of food rewards and contralateral sensory/motor neglect towards tactile stimulation, relative to their ipsilateral side and vehicle-treated marmosets (n = 4). Strong correlations were shown between contralateral impairments and histopathologic parameters, which revealed unilateral putamen and cortical damage to the middle cerebral artery territory. No deficits were shown on general mobility, and self-care was promptly resumed in ET-1 marmosets after surgery. These results show that this novel model of ischemia with reperfusion in the marmoset has the potential to assess long-term function and to gauge the efficacy of novel therapeutic strategies targeted for clinical stroke.

Use of cyanoacrylate gel as a substitute for dental cement in intracerebroventricular cannulations in rats.

This study was carried out to determine whether cyanoacrylate gel was suitable for use as a substitute for dental cement during brain implant surgery of rats. Intracerebroventricular (ICV) cannulations were performed in 24 rats by two surgeons, one with 3 years' experience in this type of surgery, and one novice, with only basic training performed on cadavers. Each surgeon prepared six randomly allocated animals using dental cement to secure the cannula and six with cyanoacrylate gel. Time to complete surgery was recorded. Wound healing was scored and body weight recorded for each animal every day for 7 days, then on day 14 after surgery. The use of gel led to an overall reduction in surgical time of 8 min (approximately 30%) per animal when compared with dental cement. No significant differences in the animals' recovery (wound healing and body weight) were found between surgeons or techniques. We find the use of cyanoacrylate gel to be a suitable and less time-consuming alternative to dental cement for ICV cannulations in rats.