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Aims: To estimate current and future specialist neurologist demand and supply to assist with health sector planning., Methods: Current demand for the neurology workforce in New Zealand was assessed using neuroepidemiological data. To assess current supply, all New Zealand neurology departments were surveyed to determine current workforce and estimate average neurologist productivity. Projections were made based on current neurologists anticipated retirement rates and addition of new neurologists based on current training positions. We explored several models to address the supply-demand gap., Results: The current supply of neurologists in New Zealand is 36 full-time equivalents (FTE), insufficient to meet current demand of 74 FTE. Demand will grow over time and if status quo is maintained the gap will widen., Conclusions: Pressures on healthcare dollars are ever increasing and we cannot expect to address the identified service gap by immediately doubling the number of neurologists. Instead we propose a 12-year strategic approach with investments to enhance service productivity, strengthen collaborative efforts between specialists and general service providers, moderately increase the number of neurologists and neurology training positions, and develop highly skilled non-specialists including trained.

An observational case-control study was conducted to investigate risk factors for confirmed bovine tuberculosis (bTB) infection in cattle reacting positively to the single intradermal comparative cervical test (SICCT) in Northern Ireland in the years 1998, 2002 and 2006. Macroscopic lesions were detected at slaughter (positive visible lesion (VL) status) in 43.0% of reactor cattle, whilst 45.3% of those sampled were confirmed as bTB positive due to the presence of lesions or positive histopathology/mycobacterial culture (positive bTB status). In 97.5% of the reactors, the VL status and bTB status were either both negative or both positive. Generalized linear mixed model analyses were conducted on data of 24,923 reactor cattle with the variables herd identifier, local veterinary office (DVO) and abattoir being used as random effects within all the models generated at univariable and multivariable level. The other variables within the dataset were used as fixed effects. Significant risk factors associated with VL status and bTB status at multivariable level (p<0.05) included age at death, breed, sex, test year, net increase in skin thickness at bovine tuberculin injection site, epidemiological status of skin test, total number of reactors at the disclosure test, mean herd size and prior response to the skin test. These risk factors are likely related to the time since infection, the strength of the challenge of infection and the susceptibility of the animal. These findings are important as the detection of visible lesions and the confirmation of bTB are an integral part of the overall bTB control programme in Northern Ireland and the veterinary meat inspection and hygiene programme. The visible lesion status and bTB status of an animal can affect the way in which bTB breakdowns are managed, since failure to detect visible lesions and recovery of Mycobacterium bovis can lead to a less stringent follow-up after other risk factors have been taken into account., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with drug-induced adverse events. The information gained may contribute to systems biology disease models.

Advances in systems biology have allowed the development of a highly characterized systems pharmacology model to study mechanisms of drug-induced hepatotoxicity. In this issue of CPT, Yang et al. describe a model, DILIsym, used to characterize mechanisms of hepatotoxicity of troglitazone. Their modeling approach has provided new insight into troglitazone-induced hepatotoxicity in humans but is not associated with hepatotoxicity in rats, consistent with preclinical data for this drug.

Internet search logs provide an abundant source of data that can be explored for purposes such as identifying drug exposure-adverse event relationships. The methodology to rigorously conduct such evaluations is not well characterized, and the utility of such analyses is not well defined. In this issue, White and colleagues propose an approach using Internet search logs for this purpose and compare it to parallel analyses conducted using the US Food and Drug Administration's spontaneous reporting database.

Multiple sclerosis (MS) is an immune-driven, demyelinating disease of the central nervous system (CNS). Although many types of immune cells are involved in disease progression, activated monocytes are believed to be one of the first to arrive to the brain and initiate inflammation. However, little is known about how the two main monocyte subsets, CD14(++)CD16(-) and CD14(+)CD16(+), are involved in MS. To understand how the phenotype and responses of these monocyte subsets are altered during MS, total monocytes and the purified monocyte subsets from healthy subjects (n=29) and MS patients (n=20) were characterized ex vivo and stimulated in vitro with lipopolysaccharide (LPS). The ex vivo analyses showed that total monocytes from MS patients had significantly elevated levels of CD40, CD86, HLA-DR, CD64 and C-C motif chemokine receptor 2 (CCR2), and this elevation was most marked on CD16(+) monocytes. In vitro stimulation with LPS led to an increase in CD86, HLA-DR, CD64 and IL-6 production by monocytes from MS patients. Furthermore, in purified cultures, CD14(+) monocytes were found to be the main producers of IL-10 while CD16(+) monocytes produced more IL-12. In monocytes from MS patients, both subsets produced substantially more IL-6, and the production of IL-10 by the CD16(+) subset was also significantly elevated compared with healthy monocytes. Together these findings highlight the important contribution of the CD16(+) monocyte subset in driving inflammatory responses during MS.

Glycine receptor (GlyR) antibodies have been identified in patients with rigidity and hyperekplexia, but the clinical phenotype associated with these antibodies has not been fully elucidated. The clinical features in two additional patients with GlyR antibodies are described. A 55-year-old man presented with stimulus-induced hyperekplexia and rigidity in the lower limbs and trunk. He initially responded to benzodiazepines, but presented after 18 months with severe, painful, prolonged spasms associated with supraventricular and ventricular arrhythmias, hypoventilation and oxygen desaturation requiring intubation. He improved following treatment with clonazepam, baclofen and immunomodulatory therapies. A 58-year-old woman presented with stiffness in the legs and hyperekplexia associated with hypoventilation, at times leading to loss of consciousness. She responded to benzodiazepines and has remained in remission. The clinical picture associated with GlyR antibodies includes autonomic dysfunction, cardiac arrhythmias and hypoventilation. It is important to recognise these serious complications early to limit mortality from this treatable condition., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Background: Surveying volunteer members of a multiple sclerosis registry is a very cost-effective way of assessing the impact of the disease on life outcomes. However, whether the data from such a study can be generalised to the whole population of persons living with MS in a country or region is unclear., Methods: Here we compare the demographic and disease characteristics of participants in one such study, the Australian Multiple Sclerosis Longitudinal Study (AMSLS), with two well-characterised MS prevalence studies with near-complete ascertainment of MS in their study regions., Results: Although some differences were found, these largely represented the effects of geography (sex ratios) and local factors (national immunomodulatory therapy prescribing requirements), and the cohorts were otherwise comparable. Overall, despite comprising only 12-16% of MS cases in Australia, the AMSLS is highly representative of the MS population., Conclusions: Therefore with some minor caveats, the AMSLS data can be generalised to the whole Australasian MS population. Volunteer disease registries such as this can be highly representative and provide an excellent convenience sample when studying rare conditions such as MS.

Selected demographic features and trends in bovine tuberculosis (BTB) from 1995 to 2010 are described for the countries of the UK and the Republic of Ireland, using standardised definitions and measures. All countries experienced a reduction in the number of cattle and herds and in the proportion of dairy herds, while average herd size increased. In general, the trends indicate a stable situation of very low BTB prevalence in Scotland and, over most of the period, a rising prevalence in England and Wales. The prevalence in the Republic of Ireland declined while Northern Ireland experienced both a rise and fall. Differences in demography, BTB programme structure and test results were noted, particularly between the island of Ireland and Great Britain. Further investigation of these differences may provide valuable insights into risk factors for BTB and optimisation of existing BTB programmes.

The growing significance of bioinformatics and systems biology in drug safety research requires a system of adverse-event classification that goes beyond a simple vocabulary. This opinion piece outlines the need for development of an ontology-based framework of describing adverse drug reactions (ADRs) and describes the potential applications for such a framework.

Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ≥70 years of age. High-risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.

Serum agglutination (SAT), complement fixation (CFT), indirect ELISA (iELISA), competitive ELISA (cELISA), Rose Bengal (RBT) and EDTA-modified agglutination (EDTA) tests were used in parallel on serological samples from 19,935 cattle in 301 herds. The study herds were selected according to putative exposure to Brucellaabortus with cases defined by bacteriological culture or test agreement. No single test identified all infected cattle and, at diagnostic thresholds, relative sensitivity was highest in the iELISA (67.9%) or RBT (78.1%), using bacteriological culture or test agreement, respectively, to define cases. As screening tests, the relative sensitivity of the SAT was highest (75.9% by culture or 84.9% by test agreement), with an optimal threshold of 31 IU. The relative specificity of the diagnostic tests ranged from 99.6% (SAT 31IU) to 100% (iELISA, RBT and CFT). The trial confirmed the value of the SAT as a screening test and the value of parallel testing., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

With a persistent trend of increasing emergency department (ED) volumes every year, services are intensifying. Thus, improving the timeliness of delivering emergency care should be a primary focus, both from an operational and from a research perspective. Much has been published on factors associated with delays in emergency care, and the next phase in this area of research will focus on exploring interventions to improve the timeliness of care. On June 1, 2011, Academic Emergency Medicine held a consensus conference titled "Interventions to Assure Quality in the Emergency Department." This article summarizes the findings of the breakout session that investigated interventions to improve the timeliness of emergency care. This article will explore the background on the concept of timeliness of emergency care, the current state of interventions that have been implemented to improve timeliness, and specific questions as a framework for a future research agenda., (© 2011 by the Society for Academic Emergency Medicine.)

The rapid evolution of large biological, pharmacological, and chemical databases has led to optimism that such data resources can be leveraged for prediction of drug action based on molecular descriptors of the drug. Challenges to realize this possibility include organization of each type of database in a manner that allows extraction of information across disparate data sources and the linkage of information across the biological, pharmacological, and chemical domains.

During 2005, a field survey of badger activity was carried out to evaluate differences between two areas with different levels of bovine tuberculosis (annual herd incidences of 16% and 4%) and to assess the awareness of herd keepers in relation to badgers. A random selection of herd keepers was interviewed and their farm land surveyed for the presence of badgers. The survey end point for each farm was the discovery of an active badger sett. Participation was very high in both areas (>80%). Evidence of badger activity was recorded on a higher proportion of farms in the area with a high tuberculosis herd incidence. However, when the difference in quality of agricultural land within each area was taken into account, a statistically significant association was not demonstrated. This suggests that the quality of agricultural land is a major determinant in the location of active badger setts. Nevertheless, the study did demonstrate the potential for increased exposure of cattle to badgers in the high incidence area. Herd keepers accurately identified the presence of badger setts on their land (positive predictive value=97%) but herd keepers reporting the absence of badger setts/activities on their land were found to be less accurate. Overall, the conclusions from this study tend to reflect the findings observed in other studies., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and active surveillance to monitor drug safety. This effort will require the active collaboration of scientists in the pharmaceutical industry, academe, and the National Institutes of Health, as well as those at the FDA, to reach its full potential. Here, we describe the approaches and goals for the mechanism-based drug safety assessment and prediction program.

An epidemiological investigation was undertaken of 41 bovine brucellosis outbreaks that occurred within a 10-month period, in a region where eradication measures appeared to be succeeding. The primary outbreak comprised three herds with significant within-herd spread and a high probability of multiple abortions. Direct contact between cattle at pasture was the most likely means of between-herd transmission for most (71%) outbreaks, with an attack rate of 28.1% in herds immediately neighbouring the primary outbreak herds and 11.3% in the next concentric ring of farms. Resolution of the incident was attributed to a rapid response by the veterinary authorities, detailed epidemiological investigations, repeated, prolonged testing of contact herds and employment of parallel testing., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

Aims: The aim of this project was to employ interdepartmental and cross district health board collaboration to reach a regional consensus on the management of patients who may benefit from carotid endarterectomy., Methods: All regional stroke physicians, neurologists, and vascular surgeons met to review relevant literature and local audits and to discuss best management strategies suited to the region., Results: A consensus statement was agreed upon and is presented here along with a summary of the supporting scientific evidence., Discussion: Regional interdisciplinary collaboration proved an effective way to reach a carotid endarterectomy management consensus across a wider geographical area that is served by a single vascular surgery department. This approach could serve as a model for other regional initiatives.

Selection of a drug dose in pediatrics is generally based on no or incomplete pharmacokinetic data. Traditionally, allometric, or scaling, techniques have been used; however, they have inherent limitations and may not make optimal use of the drug-specific clinical pharmacokinetic information that is available. Modeling is a tool that holds promise. The future challenge is to create a structured approach to determining pediatric doses for new therapeutic agents.

This study used techniques in Geographical Information Systems (GIS) to explore the spatial patterns of bovine tuberculosis (TB) in the whole island of Ireland over an 11-year period. This is the first time that data pertaining to TB from the Republic of Ireland and Northern Ireland have been collated and examined in an all-Ireland context. The analyses were based on 198, 156 point locations representing active farms with cattle in Northern Ireland and the Republic of Ireland between the years 1996 and 2006. The results consist of a series of maps giving a visual representation of cattle populations and associated detected bTB levels on the island of Ireland over this time interval.

No systematic studies of the occurrence of Trichinella in wildlife have been carried out in Northern Ireland (NI) in recent years, and the last reports of trichinellosis in livestock and human outbreaks in NI date back to 1979 and 1945, respectively. In this study, covering the period 2003/2004 and 2007/2008, a total of 443 red foxes (Vulpes vulpes) were collected throughout the country and screened for trichinellosis using a modified muscle digest method. One examined animal was found to be infected with larvae from Trichinella spiralis, indicating a national prevalence in NI of Trichinella in foxes of 0.2%. This prevalence compares well to the findings reported from the bordering Republic of Ireland [Rafter, P., Marucci, G., Brangan, P., Pozio, E., 2005. Rediscovery of Trichinella spiralis in red foxes (Vulpes vulpes) in Ireland after 30 years of oblivion. J. Infect. 50, 61-65] and could be a further indication for a sylvatic Trichinella life cycle existing independently from the domestic cycle.

Objective: To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident., Methods: Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques., Results: Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA., Conclusions: Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.

When making the transition from trainee to principal investigator, there are few steps more important than selecting the first independent research project. The project must synthesize the excitement and idealism of contributing to the well-being of humankind and the practical realities of an area of inquiry that is likely to lead to a successful career.

The movement of cattle from herds infected with Brucella abortus was investigated in order to assess the control measures for eradication of brucellosis from the cattle population of Northern Ireland. Using recorded cattle movement data, a historical cohort study was designed and carried out to quantify the risk of seropositivity in bovine animals moved from herds infected with brucellosis. The study found that 3.1% of animals, moved in the 6-month period prior to disclosure of infection in the source herd and subsequently tested, were interpreted as seropositive in their destination herds. The odds of seropositivity were approximately 19 (95% confidence interval: 7.8-46.4) times higher in this cohort compared with animals from herds with no history of infection. A multivariate logistic regression model was constructed to examine factors influencing the risk of seropositivity in the exposed cohort of animals, identifying maternal status (whether the dam had been a brucellosis reactor) and age at leaving the infected herd as the main risk factors.

Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5-6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

A method for the simultaneous determination of R- and S-propranolol and R- and S-hyoscyamine in human plasma was developed, validated and applied to the analysis of samples from a clinical study. Sample preparation was performed by solid-phase extraction of 2 ml of human plasma using Oasis MCX cartridges and the enantioselective separations were achieved using a Chirobiotic V chiral stationary phase. The chromatography was carried out using gradient elution with a mobile phase composed of methanol:acetic acid:triethylamine which was varied from 100:0.05:0.04 to 100:0.05:0.1 (v/v/v) over 30 min and delivered at a flow rate 1 ml/min. The internal standard was R,S-propranolol-d7 and the analytes were quantified using a single quadrupole mass spectrometer employing APCI interface operated in the positive ion mode with single ion monitoring. The enantioselective separation factors, alpha, were 1.15 and 1.07 for S- and R-propranolol and R- and S-hyoscyamine, respectively. The standard curves were linear for all target compounds with coefficients of determination (r2) ranging from 0.9977 to 0.9999. The intra- and inter-day precision and accuracy were

Objective: To assess characteristics of active motor units (MUs) during volitional vastus medialis (VM) activation in adults with symptomatic knee osteoarthritis (OA) across the spectrum of radiographic severity and age-comparable healthy control volunteers., Methods: We evaluated 39 participants (age 65+/-3 years) in whom weight-bearing knee X-rays were assigned a Kellgren & Lawrence (KL) grade (18 with KL grade=0; four each with KL grades=1, 2 and 4; nine with grade 3). Electromyography (EMG) signals were simultaneously acquired using surface [surface EMG (S-EMG)] and intramuscular needle electrodes, and analyzed by decomposition-enhanced spike-triggered averaging to obtain estimates of size [surface-represented MU action potentials (S-MUAP) area], number [MU recruitment index (MURI)] and firing rates [MU firing rates (mFR)] of active MUs at 10%, 20%, 30% and 50% effort relative to maximum voluntary force [maximal voluntary isometric contraction (MVIC)] during isometric knee extension., Results: Knee extensor MVIC was lower in OA participants, especially at higher KL grades (P=0.05). Taking the observed force differences into account, OA was also associated with activation of larger MUs (S-MUAP area/MVICx%effort; P<0.0001). In contrast, the estimated number of active units (MURI/MVICx%effort) changed differently as effort increased from 10% to 50% and was higher with advanced OA (KL=3, 4) than controls (P=0.0002)., Conclusion: VM activation changes at the level of the MU with symptomatic knee OA, and this change is influenced by radiographic severity. Poor muscle quality may explain the pattern observed with higher KL grades, but alternative factors (e.g., nerve or joint injury, physical inactivity or muscle composition changes) should be examined in early OA.

Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs are large molecular weight glycoproteins that embody structural, biochemical, and pharmacologic properties distinct from other biologics or chemically synthesized compounds. Early therapeutic Mabs were murine proteins, and clinical testing of these agents revealed serious immune-mediated toxicities. The side effect profile of murine Mab therapeutic agents restricted the clinical development of these agents to indications with high morbidity and/or mortality (ie, oncology, graft vs host rejection). Advances in genetic engineering and protein expression technologies resulted in the development of Mabs composed either predominately (ie, mouse/human chimeric, "humanized") or completely (ie, "fully human" Mabs) of the human amino acid sequence. The production of chimeric, humanized, and fully human Mabs significantly reduced the immune-mediated toxicities and expanded the utility for these agents in numerous therapeutic areas, particularly in chronic disorders requiring either long-term administration (ie, rheumatoid arthritis) or treatment upon the flare up of disease (Crohn's disease, psoriasis). This review provides an overview of the molecular, biochemical, and pharmacokinetic properties and clinical development history of Mabs and details how these factors currently affect the scope and design of early clinical development strategies for these drug candidates. Emphasis is placed on the criteria for selecting appropriate subject populations for phase I testing of Mabs.

Between 1990 and 2000, 317 herds of cattle in Northern Ireland were identified as being seropositive to Brucella abortus, and 68 per cent of them were attributed to transmission from neighbouring herds or to local spread. Of particular significance were three primary outbreaks in 1997, which resulted in significant secondary and tertiary spread. Three spatial clusters were identified, corresponding to two of the primary outbreaks, and the herd density and within-herd spread were highest in the largest cluster. Abortions in an infected herd and the disease-risk status of the disclosure test were positively associated with an increased within-herd prevalence.

Bovine tuberculosis is endemic in Northern Ireland and a comprehensive eradication scheme has been in operation since 1959. The current programme involves annual testing, extensive computerized tracing, short-interval testing of herds contiguous to outbreaks and compulsory slaughter of positive cattle. Despite initial reductions in disease prevalence, eradication has proved elusive and potential explanatory factors include high cattle density and potential for between-herd contact, the impact of exotic diseases on resource priorities, and significant levels of bovine tuberculosis in a wildlife reservoir, the European badger (Meles meles). Both the role of the infected bovine and that of the badger in spreading disease have to be addressed to ensure progress towards eradication. Current measures are described and future options for enhancing the programme are outlined.

We present the case of a woman who developed respiratory failure in the postoperative period secondary to previously unsuspected motor neurone disease. This case highlights the difficulty in detecting subtle neuromuscular weakness during anaesthetic pre-assessment.

On-line measurement of bulk elemental composition is often best achieved with highly penetrative neutron-gamma techniques. CSIRO has developed and implemented one such technique, neutron inelastic-scattering and thermal-capture analysis (NITA). A distinctive feature of NITA is its use of fast neutron sources to generate inelastic scattering reactions, thus exciting gamma-rays from industrially important elements such as carbon and oxygen. A full-scale prototype for on-line coal quality measurement has been tested under simulated industrial conditions. The effect of sample compositional inhomogeneity and stream thickness will be discussed.

Several studies have reported high rates of depression in multiple sclerosis (MS) with a lifetime prevalence of approximately 50% and an annual prevalence of 20% not uncommon. Concern about the potential of new drug treatments to exacerbate or precipitate depression in MS has led to increased interest in the relation between MS and depression. This review on MS and depression identifies the following key issues: How common is depression in people with MS? Is depression in MS associated with lesions in specific regions of the central nervous system? Is there an increased risk of suicide in MS? Is there a higher than expected incidence of anxiety disorders in MS? Are fatigue and depressed mood related in MS? Is there a relation between depression and cognitive impairment in MS? Which psychosocial variables affect the development of depression in MS? Does treatment with interferon increase the risk of depression? How effective are treatments for MS patients with depression? Each of these issues is briefly reviewed with critical commentary, and some priorities for future research are suggested.

The lacI mutant frequency and mutation spectrum were determined in the bone marrow and testes of B6C3F1 lacI transgenic mice exposed by inhalation to ethylene oxide (EO). Groups of male transgenic lacI B6C3F1 mice were exposed to 0, 25, 50, 100 or 200 p.p.m. EO for up to 48 weeks (6 h/day, 5 days/week) and were killed at 12, 24 or 48 weeks of EO exposure for determination of lacI mutant frequency. In the bone marrow, the lacI mutant frequency was significantly increased at the two highest exposure levels (100 and 200 p.p.m.) and at the 48 week exposure time point. The shape of the exposure-response curve for lacI mutant frequency in the bone marrow was non-linear. DNA sequence analysis of the bone marrow mutation spectrum revealed that only AT-->TA transversions occurred at an increased frequency in EO-exposed mice: 25.4% in EO-exposed mice for 48 weeks (200 p.p.m.) compared with 1.4% in air controls. In testes, the lacI mutant frequency was increased at a single exposure level of 200 p.p.m. for 24 weeks. At 48 weeks, the lacI mutant frequency in testes was significantly increased to an equal degree at 25, 50 and 100 p.p.m. EO but not at 200 p.p.m. Analysis of the testes mutation spectrum in air control mice and in mice exposed to 200 p.p.m. EO for 48 weeks revealed that no single mutational type occurred at an increased frequency. In the testes, there was a small increase across all mutational types that was sufficient to increase the overall lacI mutation frequency although not significant individually. The mutation spectrum in testes of EO-exposed mice also revealed that the increased lacI mutant frequency observed at 25 or 50 p.p.m. EO was not due to an increase in mutant siblings (clonality). These data demonstrate that inhalation exposure to EO for up to 48 weeks produces distinct mutagenic responses in bone marrow and testes.

Aims: To describe the transfer of patient information from hospital to general practice and compare the quality of coding of patient diagnoses in hospital and general practice systems., Setting: Wellington Hospital and patients registered with 12 general practitioners (GPs) from two local computerised general practices. Discharge and outpatient letters for the period June to August 2003 were analysed and diagnostic coding compared between letters and electronic health records (EHR) in hospital and general practice. A questionnaire was sent to 167 consultants and 112 GPs from Wellington city region with a 71% response rate., Results: GPs received 55% of 284 discharge letters and 97% of 612 outpatient letters with a mean time of 9.4 days (range 0-70 days) and 14 days (range 0-120 days). The mean number of diagnostic codes recorded in discharge letters was 2.9 per letter, in the GPs' EHR 0.9 per letter, and in the hospital EHR 3.5 per letter. GPs were sent new diagnostic information in 30% of discharge and 36% of outpatient letters. There was more coding agreement between GPs' EHR and discharge letters than between the hospital EHR and discharge letters (65% versus 35%). GPs duplicated coding for 71% of all letters, and 74% of diagnoses were coded within the classification section of the GPs' EHR. More GPs than hospital doctors coded patient diagnoses (85% versus 15%), had any formal training in coding (25% versus 2%), and thought coding improved patient care (75% versus 50%). Most doctors in both groups experienced considerable delay of information flow and favoured an electronic transfer of information., Conclusions: There is delay in information flow from hospital to general practice and poor comparison of diagnostic coding across the two systems. Attitudinal differences and inefficient coding practices will need to be addressed to produce an integrated information system between hospital and general practice.

It has long been observed that patients with Parkinson's disease (PD) can sometimes react and move quickly in response to an external stimulus in a way that they cannot when required to initiate the movement themselves. This curious phenomenon has sometimes been called 'paradoxical kinesis'. The present study was an attempt to demonstrate this phenomenon in patients with PD using an objective and quantifiable experimental procedure. A reaction time task was used in which participants had to press one of two computer keys, either left or right, to save a cartoon person on a computer screen from being run over by a motor car. In one condition, trials started after a traffic light appeared on the computer screen and then changed from red to green. In a second condition, the participants had to first press a third response key which resulted in the traffic light appearing on screen and changing from red to green. Participants also received both these conditions with the addition of a visual cue, an arrow, which told them in advance which direction to respond in (i.e., left or right key) on each trial. The purpose of the visual cue was to separate the effects of motor planning from motor activation. Healthy controls reacted quickest when they initiated trials themselves whereas the PD group were quicker to respond when trials were externally generated. Both groups were quicker under the visual cue condition. The results are discussed in terms of recent research which has suggested that two separate neural systems may be involved in externally generated or stereotyped actions and motor responses which require self-generated or nonroutine decision making.

Qualitative methods such as focus groups, individual interviews, case studies and participant observation were used to complete a needs assessment for a telehealth service in the South Pacific. Participants from the Cook Islands and Fiji were able to identify extensive uses for a telehealth service, but also identified barriers to its implementation. These included the extremely limited telecommunications and electrical infrastructure found in South Pacific countries, the high cost of Internet access and staffing shortages. The effective implementation of a telehealth site will probably require the use of clinician drivers with an interest in telehealth to encourage colleagues less enthusiastic to change their work practices. Telehealth in the South Pacific would improve services across a wide geographical area, but initial and continuing costs would be high due to the lack of infrastructure.

Thirteen nondemented patients with Parkinson's disease (PD) were compared with age-matched controls on two standard tests of implicit learning. A verbal version of the Serial Reaction Time (SRT) task was used to assess sequence learning and an artificial grammar (AG) task assessed perceptual learning. It was predicted that PD patients would show implicit learning on the AG task but not the SRT task, as motor sequence learning is thought to be reliant on the basal ganglia, which is damaged in PD. Patients with PD demonstrated implicit learning on both tasks. In light of these unexpected results the research on SRT learning in PD is reconsidered, and some possible explanations for the sometimes conflicting results of PD patient samples on the SRT task are considered. Four factors which merit further study in this regard are the degree to which the SRT task relies on overt motor responses, the effects of frontal lobe dysfunction upon implicit sequence learning, the effects of cerebellar degeneration, and the degree to which the illness itself has advanced., (Copyright 2001 Academic Press.)

Background and Objective: Nefazodone inhibits CYP3A; therefore coadministration with CYP3A substrates such as terfenadine or loratadine may result in increased exposure to these drugs. A potential pharmacodynamic consequence is electrocardiographic QTc prolongation, which has been associated with torsade de pointes cardiac arrhythmia. Therefore a clinical pharmacokinetic-pharmacodynamic evaluation of this potential interaction was conducted., Methods: A randomized, double-blind, double-dummy, parallel group, multiple-dose design was used. Healthy men and women who were given doses of 60 mg of terfenadine every 12 hours, 20 mg of loratadine once daily, and 300 mg of nefazodone every 12 hours were studied. Descriptive pharmacokinetics (time to maximum concentration, maximum concentration, and area under the plasma concentration-time curve) were used for the examination of interactions among the respective parent drugs and metabolites. QTc prolongation (mean value over the dosing interval) was the pharmacodynamic parameter measured. Kinetic and dynamic analysis was used for the examination of pooled concentration and QTc data with the use of a linear model., Results: Concomitant nefazodone treatment markedly increased the dose interval area under the plasma concentration-time curve of both terfenadine (mean value, 17.3 +/- 8.5 ng. mL/h versus 97.4 +/- 48.9 ng. mL/h; P <.001) and carboxyterfenadine (mean value, 1.69 +/- 0.48 microg. h/mL versus 2.88 +/- 0.53 microg. h/mL; P <.001) and moderately increased the dose interval area under the plasma concentration-time curve of both loratadine (mean value, 31.5 +/- 27.9 ng. h/mL versus 43.7 +/- 25.9 ng. h/mL; P <.014) and descarboethoxyloratadine (mean value, 73.4 +/- 54.9 ng. h/mL versus 81.9 +/- 26.2 ng. h/mL; P <.002). The mean QTc was unchanged with terfenadine alone; however, it was markedly prolonged with concomitant nefazodone and terfenadine (mean [90% confidence interval] prolongation 42.4 ms [34.2, 50.6 ms]; P <.05). Similarly, the mean QTc was unchanged with loratadine alone; however, it was prolonged with concomitant nefazodone and loratadine (21.6 ms [13.7, 29.4 ms]; P <.05). Nefazodone alone did not change mean QTc. QTc was positively correlated with terfenadine plasma concentration (r (2) = 0.21; P =.0001). Similarly, QTc was positively correlated with loratadine plasma concentration (r (2) = 0.056; P =.0008) but with a flatter slope. There was no relationship between QTc and nefazodone plasma concentration during treatment with nefazodone alone (r (2) = 0.002, not significant)., Conclusions: In healthy men and women, concomitant nefazodone treatment at a therapeutic dose increases exposure to both terfenadine and carboxyterfenadine. This increased exposure is associated with marked QTc prolongation, which is correlated with terfenadine plasma concentration. A similar interaction occurs with loratadine, although it is of lesser magnitude. Concomitant administration of nefazodone with terfenadine may have predisposed individuals to the arrhythmia associated with QTc prolongation, torsade de pointes, when terfenadine was available for clinical use. However, a new finding is that in the context of higher than clinically recommended daily doses (20 mg) of loratadine concomitant administration with a metabolic inhibitor such as nefazodone can also result in QTc prolongation.

Aims: 1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults., Methods: Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained., Results: Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)-halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6 +/- 52.0 ng ml(-1) [(+)-halofantrine] and 48.5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)- and (-)-halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

Ca(2+)-induced inactivation of L-type Ca(2+) is differentially mediated by two C-terminal motifs of the alpha(1C) subunit, L (1572-1587) and K (1599-1651) implicated for calmodulin binding. We found that motif L is composed of a highly selective Ca(2+) sensor and an adjacent Ca(2+)-independent tethering site for calmodulin. The Ca(2+) sensor contributes to higher Ca(2+) sensitivity of the motif L complex with calmodulin. Since only combined mutation of both sites removes Ca(2+)-dependent current decay, the two-site modulation by Ca(2+) and calmodulin may underlie Ca(2+)-induced inactivation of the channel.

Molecular cloning of the human fibroblast Ca2+ channel pore-forming alpha1C subunit revealed (Soldatov, 1992. Proc. Natl. Acad. Sci. USA 89:4628-4632) a naturally occurring mutation g2254 --> a that causes the replacement of the conservative alanine for threonine at the position 752 at the cytoplasmic end of transmembrane segment IIS6. Using stably transfected HEK293 cell lines, we have compared electrophysiological properties of the conventional alpha(1C,77) human recombinant L-type Ca2+ channel with those of its mutated isoform alpha(1C,94) containing the A752T replacement. Comparative quantification of steady-state availability of the current carried by alpha(1C,94) and alpha(1C,77) showed that A752T mutation prevented a large (approximately 25%) fraction of the current carried by Ca2+ or Ba2+ from fully inactivating. This mutation, however, did not appear to alter significantly the Ca2+-dependence and kinetics of decay of the inactivating fraction of the current or its voltage-dependence. The data suggests that Ala752 at the cytoplasmic end of IIS6 might serve as a molecular determinant of the Ca2+ channel inactivation, possibly regulating the voltage-dependence of its availability.

To determine the effect of age on exposure to the circulating major verapamil metabolites norverapamil, N-dealkylverapamil (D-617), and N-dealkylnorverapamil (D-620), plasma concentrations of verapamil and the three metabolites were determined during the last dose interval of a 14-day administration period of 240 mg of sustained release verapamil once daily in 11 older (aged 65-75 years) and 8 younger (20-28 years) healthy male volunteers. Area under the plasma concentration time curve (AUC) was greater for verapamil (mean +/- S. D.) (2815 +/- 733 older versus 1639 +/- 466 ng/ml.h(-1) young; P <. 0007) and norverapamil (2927 +/- 655 versus 2143 +/- 471 ng/ml. h(-1); P <.007); however, it was not significantly different for D-617 [2386 +/- 772 versus 1894 +/- 418 ng/ml.h(-1); not significantly different (NS)] and N-dealkylnorverapamil (897 +/- 366 versus 757 +/- 104 ng/ml.h(-1); NS) in older as compared with young subjects. These data indicate that impaired verapamil oral clearance previously described in older men does not result in decreased exposure to the formed major metabolites, rather there is increased exposure to norverapamil and the same or a trend toward greater exposure to D-617 as well. This suggests that in addition to the impaired clearance mechanisms for verapamil, which are thought to be primarily mediated by CYP3A, biotransformation processes distal to the formation of norverapamil and D-617 are impaired as well.

The primary objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of tasosartan and atenolol administered alone and concomitantly under steady-state conditions in 17 patients ages 18 to 65 years diagnosed with stage 1 to 2 essential hypertension. After a 3- to 14-day qualification period, all patients received placebo tasosartan on days--1 through 5 and 25 through 34, atenolol alone (50 mg) on days 1 through 5, atenolol (50 mg) + tasosartan (50 mg) on days 6 through 19, and tasosartan (50 mg) alone on days 20 through 24. A PK and PD evaluation of atenolol alone was performed on study day 5. On study day 19, PK and PD of both tasosartan and atenolol were assessed. PK and PD evaluation for tasosartan alone was assessed on study day 24. The coadministration of atenolol + tasosartan did not affect the pharmacokinetics of tasosartan, its major metabolite (enoltasosartan), or atenolol when compared with tasosartan or atenolol administered separately. For area under the change in diastolic blood pressure curve, the reduction was significantly greater after tasosartan + atenolol compared with that after atenolol alone (336 +/- 85 and 190 +/- 71 mmHg.24 h; p < 0.05 for combination and atenolol alone, respectively; mean +/- SEM). Combination therapy also caused a maximal reduction in diastolic blood pressure that is significantly more than with monotherapy with atenolol (-27 +/- 2 mmHg and -20 +/- 2 mmHg, respectively, p < 0.05). The additive effects of tasosartan and atenolol in decreasing diastolic blood pressure may provide a rationale for combination antihypertensive therapy.