Colleen O'Leary

A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis

Abstract Background: Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients. Objective: To compare Sativex with placebo in relieving symptoms of spasticity due to MS. Methods: A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy. Results: The primary endpoint was a spasticity 0–10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (≥30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: −1·3 versus −0·8 points (change from baseline, p=0·035); and 36% versus 24% (responders, p=0·040). These were supported by the time to response (ITT: p=0·068; PP: p=0·025) analyses, carer global impression of change assessment (p=0·013) and timed 10-meter walk (p=0·042). Among the subjects who achieved a ≥30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity. Discussion and conclusions: The 0–10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.

Health professionals' knowledge, practice and opinions about fetal alcohol syndrome and alcohol consumption in pregnancy

Objective: To measure the knowledge, attitudes and practices of health professionals regarding fetal alcohol syndrome (FAS) and alcohol use during pregnancy.

Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.

Neuregulin‐1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N‐methyl‐d‐aspartate receptor antagonists MK‐801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK‐801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N‐acetylaspartate and GABA were determined using high‐performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor‐activating effects of acute PCP. Subchronic MK‐801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance‐related behaviours observed in vehicle‐treated mutants. No phenotypic differences were demonstrated in N‐acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia‐relevant processes including the effects of psychotomimetic N‐methyl‐d‐aspartate receptor antagonists.

Analysis of lectin binding to glycolipid complexes using combinatorial glycoarrays

Glycolipids are major components of the plasma membrane, interacting with themselves, other lipids, and proteins to form an array of heterogeneous domains with diverse biological properties. Considerable effort has been focused on identifying protein binding partners for glycolipids and the glycan specificity for these interactions, largely achieved through assessing interactions between proteins and homogenous, single species glycolipid preparations. This approach risks overlooking both the enhancing and attenuating roles of heterogeneous glycolipid complexes in modulating lectin binding. Here we report a simple method for assessing lectin-glycolipid interactions. An automatic thin-layer chromatography sampler is employed to create easily reproducible arrays of glycolipids and their heterodimeric complexes immobilized on a synthetic polyvinyl-difluoride membrane. This array can then be probed with much smaller quantities of reagents than would be required using existing techniques such as ELISA and thin-layer chromatography with immuno-overlay. Using this protocol, we have established that the binding of bacterial toxins, lectins, and antibodies can each be attenuated, enhanced, or unaffected in the presence of glycolipid complexes, as compared with individual, isolated glycolipids. These findings underpin the wide-ranging influence and importance of glycolipid-glycolipid cis interactions when the nature of protein-carbohydrate recognition events is being assessed.

Prenatal Alcohol Exposure and Language Delay in 2-Year-Old Children: The Importance of Dose and Timing on Risk

OBJECTIVE. The aim of this study was to investigate the association of dose and timing of prenatal alcohol exposure with early language acquisition. METHODS. We examined language delay in a randomly selected, population-based sample of Western Australian children born in 1995–1996 whose mothers had agreed to participate in a longitudinal study on health-related behaviors and who had completed the 2-year questionnaire (N = 1739). Information on alcohol consumption was collected at 3 months after birth for four periods; the three months pre-pregnancy and for each trimester separately. Prenatal alcohol exposure was grouped into none, low, moderate-heavy and binge (>5) based on the total quantity consumed per week, quantity consumed per occasion, and frequency of consumption. The communication scale from the Ages & Stages Questionnaire was used to evaluate language delay. Logistic regression analysis was used to generate odds ratios and 95% confidence intervals, adjusted for confounding factors. RESULTS. There was no association between low levels of alcohol consumption and language delay at any time period, although there was a nonsignificant 30% increase in risk when moderate-to-heavy levels of alcohol were consumed in the third trimester. Children exposed to a binge pattern of maternal alcohol consumption in the second trimester had nonsignificant, three-fold increased odds of language delay, with a similar estimate following third trimester alcohol exposure after controlling for covariates. CONCLUSIONS. This study did not detect an association between low levels of prenatal alcohol exposure and language delay when compared with women who abstained from alcohol during pregnancy. A nonsignificant threefold increase in the likelihood of language delay was seen in children whose mothers binged during late pregnancy. However, the small numbers of women with a binge-drinking pattern in late pregnancy limited the power of this study; studies analyzing larger numbers of children exposed to binge drinking in late pregnancy are needed.

Molecular Evidence Supports the Role of Dogs as Potential Reservoirs for Rickettsia felis

Rickettsia felis causes flea-borne spotted fever in humans worldwide. The cat flea, Ctenocephalides felis, serves as vector and reservoir host for this disease agent. To determine the role of dogs as potential reservoir hosts for spotted fever group rickettsiae, we screened blood from 100 pound dogs in Southeast Queensland by using a highly sensitive genus-specific PCR. Nine of the pound dogs were positive for rickettsial DNA and subsequent molecular sequencing confirmed amplification of R. felis. A high prevalence of R. felis in dogs in our study suggests that dogs may act as an important reservoir host for R. felis and as a potential source of human rickettsial infection.

Maternal Alcohol Use and Sudden Infant Death Syndrome and Infant Mortality Excluding SIDS

BACKGROUND: Improvements in the rate of infant mortality (death in first year of life) have not occurred in recent years. This study investigates the association between maternal alcohol-use disorder and sudden infant death syndrome (SIDS) and infant mortality not classified as SIDS using linked, population-based health and mortality data. METHODS: Exposed mothers were identified through the presence of an International Classification of Diseases 9/10 alcohol diagnosis, a proxy for alcohol-use disorder, recorded on health, mental health, and/or drug and alcohol datasets (1983–2005). Comparison mothers without an alcohol diagnosis were frequency matched to exposed mothers on maternal age within maternal race and year of birth of their children. All offspring with their birth recorded on the Midwives Notification System compose the exposed (n = 21 841) and comparison (n = 56 054) cohorts. Cases of SIDS (n = 303) and infant mortality excluding SIDS (n = 598) were identified through linkage with the Western Australian Mortality Register. Analyses were conducted by using Cox regression and results presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: The highest risk of SIDS occurred when a maternal alcohol diagnosis was recorded during pregnancy (aHR 6.92, 95% CI 4.02–11.90) or within 1 year postpregnancy (aHR 8.61, 95% CI 5.04–14.69). An alcohol diagnosis recorded during pregnancy more than doubled the risk of infant deaths (excluding SIDS) (aHR 2.35, 95% CI 1.45–3.83). Maternal alcohol-use disorder is attributable for at least 16.41% (95% CI 9.73%–23.69%) of SIDS and 3.40% (95% CI 2.28%–4.67%) of infant deaths not classified as SIDS. CONCLUSIONS: Maternal alcohol-use disorder is a significant risk factor for SIDS and infant mortality excluding SIDS.

High-throughput lectin magnetic bead array-coupled tandem mass spectrometry for glycoprotein biomarker discovery

Alterations in protein glycosylation occur during development and progression of many diseases, hence glycomics and glycoproteomics have emerged as important tools in glycobiomarker discovery. High‐throughput glycan profiling can now be achieved with the recent developments in MS‐based techniques. To enable identification and rapid monitoring of glycosylation changes in serum proteins, we developed a semi‐automated high‐throughput glycoprotein biomarker discovery platform termed lectin magnetic bead array‐coupled tandem mass spectrometry (LeMBA‐MS) which includes (i) effective single‐step serum glycoprotein isolation using a panel of 20 individual lectin‐coated magnetic beads in microplate format, (ii) on‐bead trypsin digestion, and (iii) nanoLC‐MS/MS with lectin exclusion list. With use of appropriate sequence databases, LeMBA‐MS can detect glycosylation changes regardless of the species. By spiking known amounts of titrated ovalbumin to a serum sample, we report nanomolar sensitivity, and linearity of response of LeMBA‐MS using concanavalin A‐coupled beads. Neuraminidase treatment led to reduction of binding to sialic acid‐binding lectins. Interestingly, we found that desialylation caused increased binding of haptoglobin and hemopexin to mannose‐specific lectins, pointing to the importance of identifying a signature of lectin‐binding. High‐throughput LeMBA‐MS to generate glycosylation signatures will facilitate glycobiomarker discovery. LeMBA can be coupled to down‐stream detection platforms for validation, making it a truly versatile platform.

Health professionals addressing alcohol use with pregnant women in Western Australia: barriers and strategies for communication

Health professionals have an important role to play in preventing prenatal alcohol exposure. In 2006 qualitative data were collected from 53 health professionals working in primary care in metropolitan and regional Western Australia. Thematic analysis was used to elucidate barriers in addressing prenatal alcohol use and the strategies used to overcome them. Health professionals identified strategies for obtaining alcohol use information from pregnant women but they are not recognizing moderate alcohol intake in pregnant women. Study limitations are noted and the implications of the results are discussed. This research was funded by the Health Promotion Foundation of Western Australia.

Molecular evidence of Rickettsia felis infection in dogs from northern territory, Australia

The prevalence of spotted fever group rickettsial infection in dogs from a remote indigenous community in the Northern Territory (NT) was determined using molecular tools. Blood samples collected from 130 dogs in the community of Maningrida were subjected to a spotted fever group (SFG)-specific PCR targeting the omp B gene followed by a Rickettsia felis-specific PCR targeting the glt A gene of R. felis. Rickettsia felis omp B and glt A genes were amplified from the blood of 3 dogs. This study is the first report of R. felis infection in indigenous community dogs in NT.