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.

Wernicke-Korsakoff syndrome not related to alcohol use: a systematic review.

OBJECTIVE: Although Wernicke-Korsakoff syndrome (WKS) is a common condition, diagnosis remains difficult. WKS not associated with alcohol is rare and thought to present differently to alcohol-related WKS. We conducted a systematic review of WKS not related to alcohol to enhance understanding of WKS not related to alcohol and WKS in general. METHODS: A systematic review was conducted of case reports, published in English, of Wernicke's encephalopathy and WKS in patients without a history of alcohol-use disorder. Main data sources: MEDLINE, Index Medicus. Eligible cases totaled 623. Publication dates ranged from 1867 to 2014. Comparisons of clinical presentation were made with published data on samples comprising, almost exclusively, alcohol-related WKS. RESULTS: A wide array of illnesses precipitated WKS. When diagnosis of WKS was performed postmortem, non-alcohol-related cases presented a similar number of signs of the classic triad as alcohol-related cases (p=0.662, Cohen's w=0.12) but more signs when diagnosed antemortem (p<0.001, Cohen's w=0.46). The most common sign was altered mental state. Korsakoff syndrome or ongoing memory impairment was reported in 25% of non-alcohol-related WKS, although cognitive status was not explicitly reported in many cases. When duration of memory impairment was reported, 56% had clinically obvious memory impairment lasting beyond the period of acute presentation. Non-alcohol-related WKS was more often associated with female gender, younger age, shorter duration of precipitating illness and better survival rate compared to alcohol-related WKS. CONCLUSIONS: Thiamine deficiency in the absence of an alcohol-use disorder can cause the full clinical spectrum of WKS, including chronic cognitive impairment and Korsakoff syndrome.

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.

Rhinal cortex asymmetries in patients with mesial temporal sclerosis.

PURPOSE: The rhinal cortex, comprising the entorhinal (ErC) and perirhinal (PrC) cortices, is one component of the limbic system that may be affected in patients with epilepsy and other temporal lobe pathologies. This study extended quantitative examination of the limbic system through development and validation of volumetric protocols to measure the ErC and PrC. METHODS: Volumes were calculated from MRI studies using ANALYZE 7.5 and based on detailed anatomical definitions developed for the study. Subjects were 61 temporal lobe epilepsy patients with mesial temporal sclerosis (MTS: 33 left, 28 right) and 20 neurologically normal controls. Inter-rater reliabilities for the ErC and PrC volume protocols were found to be high (range 0.86-0.92). RESULTS: Ipsilateral hippocampal volume was reduced in patients with MTS, while contralateral volume did not differ significantly from controls. In the patients, rhinal cortex volumes were reduced as a function of laterality of disease. The pattern of correlations between ErC and PrC differed between disease groups. Hippocampal and rhinal cortex volumes were not significantly correlated. A significant four-way interaction was found between side of MTS, hemisphere, structure and handedness. CONCLUSIONS: This quantitative study demonstrates reliable in vivo evidence of morphometric changes in ErC and PrC in a substantial number of patients with unilateral MTS. The relationship observed between handedness, structure and disease status may suggest a role for cerebral dominance in modulating the expression of MTS.

Impact of severity of substance use disorder on symptomatic and functional outcome in young individuals with first-episode psychosis.

OBJECTIVE: To investigate whether severity of substance use disorder is independently associated with 15-month symptomatic or functional outcome in young individuals with first-episode psychosis. METHOD: Ninety-two individuals aged 15 to 30 years with first-episode psychosis participated in a 15-month prospective follow-up study. DSM-IV criteria were used to diagnose psychotic disorders, and DSM-III-R criteria were used to diagnose substance use disorder (abuse or dependence). Measures of outcome included severity of positive and negative symptoms, quality of life, and level of social functioning. Data were collected between March and July 2001 at a specialist first-episode psychosis service and between January and December 1997 at 2 generic mental health services. RESULTS: Multiple linear regression showed that heavy substance use disorder was significantly associated with more severe positive symptoms at 15 months after controlling for the effects of gender, duration of untreated psychosis, and medication adherence (vs. no substance use disorder, p = .006; vs. mild substance use disorder, p = .023). Heavy substance use disorder was also significantly associated with poorer social functioning at 15 months after controlling for the effects of gender, duration of untreated psychosis, medication adherence, and positive symptoms (vs. no substance use disorder, p = .025; vs. mild substance use disorder, p = .047). Heavy substance use disorder was not associated with negative symptoms or quality of life after controlling for the effects of potential confounding variables. CONCLUSION: Heavy but not mild substance use disorder appears to be independently associated with poorer symptomatic and functional outcome in young patients with first-episode psychosis.

Quality Of Life And Disability In Alcohol And Drug Dependent Patients Undergoing Treatment At Depaul House

Quality of life and disability are important indices that may help change the perception, treatment and care of those with alcohol or drug dependence problem. A cross-sectional survey was done among 25 drug and 25 alcohol dependents consecutively admitted to a community based residential withdrawal service in Melbourne, Australia to assess their quality of life and disabilities using the World Health Organisation Quality of Life (WHOQoL)-Bref and the World Health Organisation Disability Assessment Scale (WHODAS) questionnaires. The quality of life of the sample population was found to be significantly poorer than the general population. The scores on quality of life and disability measurements in the group of patients with alcohol dependence were similar to the other drug dependent group.

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.

Randomized controlled trial of a brief behavioural intervention for reducing hepatitis C virus risk practices among injecting drug users.

AIM: To develop and evaluate a brief intervention for reducing risk behaviours associated with HCV transmission in injecting drug users (IDU). DESIGN: Randomized controlled trial of an individually tailored brief behavioural intervention (BBI) (experimental) versus a standardized educational intervention (control). SETTING: Specialist drug treatment facility in Melbourne, Australia. PARTICIPANTS: One hundred and forty-five IDU (aged 18 or over, injecting at least weekly in the preceding 6 months) recruited and randomized to the experimental condition (n = 73) or the control condition (n = 72). INTERVENTIONS: The BBI was based on the Blood-Borne Virus Transmission Risk Assessment Questionnaire (BBV-TRAQ)-a standardized blood-borne virus risk assessment instrument comprising injecting risk, sexual risk and other skin penetration risk subscales. The BBV-TRAQ was used to identify individual HCV risk practices and to tailor the 30-minute experimental BBI. Control participants received a standardized HCV educational session, using current educational materials. MAIN OUTCOME MEASURES: BBV-TRAQ subscale and total scores and measures of participant satisfaction. RESULTS: One hundred and twenty-four participants (86%) were followed-up at 4 weeks (+/-7 days). Analyses revealed a significant reduction in HCV risk behaviours for both groups at 1-month follow-up, with participants in the experimental BBI condition reporting higher overall satisfaction with the intervention compared to the control group. CONCLUSIONS: Both groups reported significant reductions in risk behaviour, indicating that while BBI methods hold promise for HCV education and prevention, they were not demonstrated to be more effective than the provision of standard educational materials. Future research could evaluate the efficacy of the BBV-TRAQ as a risk behaviour intervention and counselling tool in clinical, NSP and peer education settings.

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.

Buprenorphine dosing regime for inpatient heroin withdrawal: a symptom-triggered dose titration study.

The study aimed to identify the range of buprenorphine doses required to comfortably alleviate symptoms in patients undergoing inpatient heroin withdrawal using a symptom-triggered titration dosing regime, and to identify the patient characteristics that impact upon the buprenorphine dose requirements. The study was conducted in two Australian inpatient withdrawal units, recruiting 63 dependent, injecting heroin users with no recent methadone treatment, dependence on other drugs, or other active medical or psychiatric conditions. In a single (patient) blinded case series, placebo or 2 mg sublingual buprenorphine tablets was administered four times a day according to severity of withdrawal (assessed with Subjective Opiate Withdrawal Scale). Up to 16 mg buprenorphine was available over the first 4 days of the admission, up to 8 mg on day 5, and placebo continued until day 6. Thirty-two subjects completed the dosing regime, with mean (+/-S.D.) daily doses of 3.8+/-2.8 on day 1, 5.8+/-3.2 on day 2, 4.8+/-3.3 on day 3, 2.3+/-2.6 on day 4, 0.8+/-1.3 on day 5, and a total dose of 17.4+/-9.7. Higher buprenorphine doses were required by those patients with more severe psychosocial dysfunction, women, those with more frequent heroin use, and those with more severe dependence on heroin at intake. A dosing regime using sublingual buprenorphine tablets for short inpatient heroin withdrawal is proposed.

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.

Validation of MRI measurement of cardiac output in the dog: the effects of dobutamine and minoxidil.

The use of magnetic resonance imaging (MRI) for the measurement of cardiac output parameters in anesthetized adult male beagle dogs has been validated against a widely accepted thermodilution method. Using a multislice cine gradient echo MRI method to acquire images of the entire heart, left ventricular lumen volumes were measured at systole and diastole in seven animals. Cardiac output correlated well (R 2 = 0.88) with thermodilution measurements made in a parallel manner, both before and during acute stimulation with the inotrope dobutamine. In a chronic study of changes in cardiac morphology and function brought about by the antihypertensive minoxidil, MRI reliably detected the expected increases in stroke volume (28%) and cardiac output (58%) resulting from neural reaction to decreased blood pressure. Left ventricular lumen enlarged as well in response to fluid retention and plasma volume increase. Two in four minoxidil-treated animals also developed clear MRI-visible pericardial effusion.

New pharmacotherapies for alcohol dependence.

Two pharmacotherapies recently introduced in Australia, acamprosate and naltrexone, provide a major advance in the treatment of severe alcohol dependence, a common condition leading to a considerable burden of illness and major costs to the community. Acamprosate and naltrexone reduce alcohol intake, and increase the likelihood and prolong the duration of abstinence (Level I evidence). Compared with naltrexone, the benefits of acamprosate have been confirmed in a larger number of studies involving larger numbers of patients with longer durations of follow-up. Unlike naltrexone, acamprosate appears to achieve a sustained benefit. There is no known interaction effect between alcohol and acamprosate or naltrexone. Both drugs are well tolerated, although naltrexone blocks the action of opioid analgesics. Adjunctive psychosocial treatment with close follow-up is required for acamprosate and recommended for naltrexone. As yet, no studies have reported a reduction in mortality following the use of any pharmacotherapy for alcohol dependence.