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1.  Comparison of Colour Duplex Ultrasound with Computed Tomography to Measure the Maximum Abdominal Aortic Aneurysmal Diameter 
Introduction. Maximum diameter of an abdominal aortic aneurysm (AAA) is the main indication for surgery. This study compared colour duplex ultrasound (CDU) and computed tomography (CT) in assessing AAA diameter. Patients and Methods. Patients were included if they had both scans performed within 90 days. Pearson's correlation coefficient, paired t-test, and limits of agreement (LOA) were calculated for the whole group. Subgroup analysis of small (<5.0 cm), medium (5.0–6.5 cm), and large (>6.5 cm) aneurysms was performed. A P value of <0.05 was considered statistically significant. Results. 389 patients were included, giving 130 pairs of tests for comparison. Excellent correlation was in the whole group (r = 0.95) and in the subgroups (r = 0.94; 0.69; 0.96, resp.). Small LOA between the two imaging modalities was found in all subgroups. Conclusion. Small aneurysms can be accurately measured using CDU. CDU is preferable for small AAAs, but cannot supplant CT for planning aortic intervention.
PMCID: PMC4258918  PMID: 25506431
2.  Heat Stress Increases Long-term Human Migration in Rural Pakistan 
Nature climate change  2014;4:182-185.
Human migration attributable to climate events has recently received significant attention from the academic and policy communities (1-2). Quantitative evidence on the relationship between individual, permanent migration and natural disasters is limited (3-9). A 21-year longitudinal survey conducted in rural Pakistan (1991-2012) provides a unique opportunity to understand the relationship between weather and long-term migration. We link individual-level information from this survey to satellite-derived measures of climate variability and control for potential confounders using a multivariate approach. We find that flooding—a climate shock associated with large relief efforts—has modest to insignificant impacts on migration. Heat stress, however—which has attracted relatively little relief—consistently increases the long-term migration of men, driven by a negative effect on farm and non-farm income. Addressing weather-related displacement will require policies that both enhance resilience to climate shocks and lower barriers to welfare-enhancing population movements.
PMCID: PMC4132829  PMID: 25132865
3.  Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver 
To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m −2·min−1) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.
PMCID: PMC4187063  PMID: 25104497
nonalcoholic fatty liver disease; Type 2 diabetes; glucocorticoids; fatty acid metabolism
4.  Putative cortical dopamine levels affect cortical recruitment during planning☆ 
Neuropsychologia  2013;51(11):2194-2201.
Planning, the decomposition of an ultimate goal into a number of sub-goals is critically dependent upon fronto-striatal dopamine (DA) levels. Here, we examined the extent to which the val158met polymorphism in the catechol O-methyltransferase (COMT) gene, which is thought to primarily alter cortical DA levels, affects performance and fronto-parietal activity during a planning task (Tower of London). COMT genotype was found to modulate activity in the left superior posterior parietal cortex (SPC) during planning, relative to subtracting, trials. Specifically, left SPC blood oxygenation level-dependent (BOLD) response was reduced in groups with putatively low or high cortical DA levels (COMT homozygotes) relative to those with intermediate cortical DA levels (COMT heterozygotes). These set of results are argued to occur either due to differences in neuronal processing in planning (and perhaps subtracting) caused by the COMT genotype and/or the cognitively heterogeneous nature of the TOL, which allows different cognitive strategies to be used whilst producing indistinguishable behavioural performance in healthy adults. The implications of this result for our understanding of COMT′s effect on cognition in health and disease are discussed.
•Planning performance is influenced by cortical dopamine levels.•Genetic polymorphisms in the COMT gene affect cortical dopamine levels.•We examined the effect of COMT genotype of the neural correlates of planning.•Putatively high and low dopamine led to reduced parietal activity during planning.
PMCID: PMC3808120  PMID: 23911779
Dopamine; Planning; Catechol O-methyltransferase (COMT); Inverted-U; fMRI
5.  Temporal Association of HLA-B*81:01- and HLA-B*39:10-Mediated HIV-1 p24 Sequence Evolution with Disease Progression 
Journal of Virology  2012;86(22):12013-12024.
HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.
PMCID: PMC3486481  PMID: 22933291
6.  Passively Transmitted gp41 Antibodies in Babies Born from HIV-1 Subtype C-Seropositive Women: Correlation between Fine Specificity and Protection 
Journal of Virology  2012;86(8):4129-4138.
HIV-exposed, uninfected (EUN) babies born to HIV-infected mothers are examples of natural resistance to HIV infection. In this study, we evaluated the titer and neutralizing potential of gp41-specific maternal antibodies and their correlation with HIV transmission in HIV-infected mother-child pairs. Specific gp41-binding and -neutralizing antibodies were determined in a cohort of 74 first-time mother-child pairs, of whom 40 mothers were infected with HIV subtype C. Within the infected mother cohort, 16 babies were born infected and 24 were PCR negative and uninfected at birth (i.e., exposed but uninfected). Thirty-four HIV-uninfected and HIV-unexposed mother-child pairs were included as controls. All HIV-positive mothers and their newborns showed high IgG titers to linear epitopes within the HR1 region and to the membrane-proximal (MPER) domain of gp41; most sera also recognized the disulfide loop immunodominant epitope (IDE). Antibody titers to the gp41 epitopes were significantly lower in nontransmitting mothers (P < 0.01) and in the EUN babies (P < 0.005) than in HIV-positive mother-child pairs. Three domains of gp41, HR1, IDE, and MPER, elicited antibodies that were effectively transmitted to EUN babies. Moreover, in EUN babies, epitopes overlapping the 2F5 epitope (ELDKWAS), but not the 4E10 epitope, were neutralization targets in two out of four viruses tested. Our findings highlight important epitopes in gp41 that appear to be associated with exposure without infection and would be important to consider for vaccine design.
PMCID: PMC3318605  PMID: 22301151
7.  Virological and Immunological Factors Associated with HIV-1 Differential Disease Progression in HLA-B*58:01-Positive Individuals ▿ †  
Journal of Virology  2011;85(14):7070-7080.
Molecular epidemiology studies have identified HLA-B*58:01 as a protective HIV allele. However, not all B*58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B*58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24Gag and Nef, respectively. Failure to target the TW10 epitope in one B*58:01-positive individual was associated with low CD4+ counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B*58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4+ counts (P = 0.04), but not lower viral loads, than non-B*58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B*58:01 allele.
PMCID: PMC3126593  PMID: 21613398
8.  Mild cognitive impairment in Parkinson disease 
Neurology  2010;75(12):1062-1069.
In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.
The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.
A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.
A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9). Regarding cognitive profiles, 11.3% (9.7–13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0–9.9) as amnestic single-domain, 4.8% (3.8–6.1) as amnestic multiple-domain, and 1.3% (0.9–2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.
MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.
= amnestic multiple-domain MCI;
= amnestic single-domain MCI;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= mild cognitive impairment;
= Mini-Mental State Examination;
= nonamnestic multiple-domain MCI;
= nonamnestic single-domain MCI;
= Parkinson disease;
= Parkinson's Disease Cognitive Rating Scale;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2942065  PMID: 20855849
9.  Adenovirus-Based Vaccines: Comparison of Vectors from Three Species of Adenoviridae ▿  
Journal of Virology  2010;84(20):10522-10532.
In order to better understand the broad applicability of adenovirus (Ad) as a vector for human vaccine studies, we compared four adenovirus (Ad) vectors from families C (Ad human serotype 5 [HAdV-5; here referred to as AdHu5]), D (HAdV-26; here referred to as AdHu26), and E (simian serotypes SAdV-23 and SAdV-24; here referred to as chimpanzee serotypes 6 and 7 [AdC6 and AdC7, respectively]) of the Adenoviridae. Seroprevalence rates and titers of neutralizing antibodies to the two human-origin Ads were found to be higher than those reported previously, especially in countries of sub-Saharan Africa. Conversely, prevalence rates and titers to AdC6 and AdC7 were markedly lower. Healthy human adults from the United States had readily detectable circulating T cells recognizing Ad viruses, the levels of which in some individuals were unexpectedly high in response to AdHu26. The magnitude of T-cell responses to AdHu5 correlated with those to AdHu26, suggesting T-cell recognition of conserved epitopes. In mice, all of the different Ad vectors induced CD8+ T-cell responses that were comparable in their magnitudes and cytokine production profiles. Prime-boost regimens comparing different combinations of Ad vectors failed to indicate that the sequential use of Ad vectors from distinct families resulted in higher immune responses than the use of serologically distinct Ad vectors from the same family. Moreover, the transgene product-specific antibody responses induced by the AdHu26 and AdC vectors were markedly lower than those induced by the AdHu5 vector. AdHu26 vectors and, to a lesser extent, AdC vectors induced more potent Ad-neutralizing antibody responses. These results suggest that the potential of AdHu26 as a vaccine vector may suffer from limitations similar to those found for vectors based on other prevalent human Ads.
PMCID: PMC2950567  PMID: 20686035
10.  Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure 
Virology  2009;396(2):213-225.
It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential “transmission signatures”, we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission.
PMCID: PMC2810538  PMID: 19913270
HIV; subtype C; primary infection; immune escape; reversion
11.  Cardiac risk assessment before the use of stimulant medications in children and youth: A joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry 
The Canadian Journal of Cardiology  2009;25(11):625-630.
Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and pediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac subspecialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.
PMCID: PMC2776560  PMID: 19898693
Attention-deficit hyperactivity disorder; Consensus statement; Pediatric; Population health; Risk; Sudden death
12.  Cardiac risk assessment before the use of stimulant medications in children and youth 
Paediatrics & Child Health  2009;14(9):579-585.
Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and paediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac sub-specialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.
PMCID: PMC2806076  PMID: 21037835
Attention-deficit hyperactivity disorder; Consensus statement; Paediatrics; Population health; Risk; Sudden death
13.  L’évaluation du risque cardiaque avant l’utilisation de stimulants chez les enfants et les adolescents 
Paediatrics & Child Health  2009;14(9):586-592.
Les décisions en matière de réglementation et les documents scientifiques au sujet de la prise en charge du trouble de déficit de l’attention avec hyperactivité (TDAH) soulèvent des questions quant à l’innocuité des médicaments et à l’évaluation convenable à effectuer avant le traitement afin de déterminer la pertinence d’une pharmacothérapie. Ce constat est particulièrement vrai en présence de cardiopathies structurelles ou fonctionnelles. Le présent article contient l’analyse des données disponibles, y compris les publications révisées par des pairs, des données tirées du site Web de la Food and Drug Administration des États-Unis au sujet des réactions indésirables déclarées chez des enfants qui prennent des stimulants, ainsi que des données de Santé Canada sur le même problème. Des lignes directrices consensuelles sur l’évaluation pertinente sont proposées d’après l’apport des membres de la Société canadienne de pédiatrie, de la Société canadienne de cardiologie et de l’Académie canadienne de psychiatrie de l’enfant et de l’adolescent, qui possèdent notamment des compétences et des connaissances précises tant dans le secteur du TDAH que de la cardiologie pédiatrique. Le présent document de principes prône une anamnèse et un examen physique détaillés avant la prescription de stimulants et s’attarde sur le dépistage des facteurs de risque de mort subite, mais il ne contient pas de recommandations systématiques de dépistage électrocardiographique ou de consultations avec un spécialiste en cardiologie, à moins que les antécédents ou que l’examen physique ne le justifient. Le document contient un questionnaire pour repérer les enfants potentiellement vulnérables à une mort subite (quel que soit le type de TDAH ou les médicaments utilisés pour le traiter). Même si les recommandations dépendent des meilleures données probantes disponibles, le comité s’entend pour affirmer que d’autres recherches s’imposent pour optimiser l’approche de ce scénario clinique courant.
PMCID: PMC2806077
Attention-deficit hyperactivity disorder; Consensus statement; Paediatrics; Population health; Risk; Sudden death
14.  The val158met COMT polymorphism's effect on atrophy in healthy aging and Parkinson's disease 
Neurobiology of Aging  2010;31(6):1064-1068.
We investigated whether the val158met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n = 80, ages 18–79) and those with Parkinson's disease (n = 50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3 T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val158met genotype on morphometry. Since the val158met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span.
PMCID: PMC3898476  PMID: 18755526
COMT; Catechol-o-methyltransferase; VBM; Parkinson's disease; Healthy aging; MRI
17.  Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort 
The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.
PMCID: PMC2117467  PMID: 16614029
LRRK2 gene; Parkinson's disease; human genetics
This report examines the structure and function of ARHGAP4, a novel RhoGAP whose structural features make it ideally suited to regulate the cytoskeletal dynamics that control cell motility and axon outgrowth. Our studies show that ARHGAP4 inhibited the migration of NIH/3T3 cells and the outgrowth of hippocampal axons. ARHGAP4 contains an N-terminal FCH domain, a central GTPase activating (GAP) domain and a C-terminal SH3 domain. Our structure/function analyses show that the FCH domain appears to be important for spatially localizing ARHGAP4 to the leading edges of migrating NIH/3T3 cells and to axon growth cones. Our analyses also show that the GAP domain and C-terminus are necessary for ARHGAP4-mediated inhibition of cell and axon motility. These observations suggest that ARHGAP4 can act as a potent inhibitor of cell and axon motility when it is localized to the leading edge of motile cells and axons.
PMCID: PMC2111057  PMID: 17804252
19.  Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial 
Brain  2008;131(9):2376-2386.
Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.
PMCID: PMC2525447  PMID: 18689435
human; transplantation; spinal cord injury; paraplegia
20.  Parkinson's disease and dopaminergic therapy—differential effects on movement, reward and cognition 
Brain  2008;131(8):2094-2105.
Cognitive deficits are very common in Parkinson's disease particularly for ‘executive functions’ associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative ‘on’ and ‘off’ states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1–4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico–striato–thalamo–cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.
PMCID: PMC2494617  PMID: 18577547
Parkinson's disease; reward; task-shift; fMRI; dopamine
21.  Saccadic latency distributions in Parkinson's disease and the effects of l-dopa 
Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. l-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of l-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.
PMCID: PMC1877863  PMID: 16544135
Parkinson's disease; Saccade; Latency; Biomarker; l-dopa
22.  β Blockers in older persons with heart failure: tolerability and impact on quality of life 
Heart  2002;88(6):611-614.
Objective: To determine tolerability and symptom changes associated with the introduction of bisoprolol treatment in older patients with heart failure.
Design: Prospective observational cohort study.
Setting: Geriatric medicine outpatient department of a university hospital.
Patients: 51 patients (mean age 78 years, range 70–89 years) with stable symptomatic heart failure caused by left ventricular systolic dysfunction.
Interventions: Bisoprolol tablets, 1.25–10.0 mg.
Main outcome measures: Tolerability; changes in symptoms and exercise tolerance.
Results: 69% of patients tolerated bisoprolol. Mean tolerated dose was 7.6 mg. There was no change in symptoms or exercise capacity in those who tolerated bisoprolol. Perceived health status and symptoms of anxiety and depression improved during the titration period.
Conclusions: The rate of withdrawal from bisoprolol treatment in older patients with congestive heart failure was twice that previously reported in younger patients. The mean tolerated dose was similar to that found in trials reporting clinical efficacy. There was no evidence of a negative impact on symptoms or exercise capacity in patients who tolerated bisoprolol.
PMCID: PMC1767441  PMID: 12433890
heart failure; old age; bisoprolol; β blocker
23.  Blood pressure response to glucose potassium insulin therapy in patients with acute stroke with mild to moderate hyperglycaemia 
Insulin is neuroprotective in animal stroke models but its effects in acute stroke in humans are unknown. The Glucose Insulin in Stroke Trial (GIST-UK) is a randomised controlled trial investigating the benefits of maintaining euglycaemia in hyperglycaemic patients with acute stroke. Data are reported from a GIST-UK substudy which sought to determine the influence of glucose potassium insulin (GKI) infusion on blood pressure in acute stroke. All adult patients admitted to hospital with acute stroke with hyperglycaemia (plasma glucose 6.1-17 mmol/l) were potentially eligible. Randomised patients received either a GKI infusion (500 ml 10% glucose, 20 mmol potassium chloride, 16 units of insulin) or control therapy with 154 mmol/l (0.9%) saline at 100 ml/h for 24 hours. BM test strip glucose monitoring was performed 2 hourly, blood pressure monitoring 4hourly, and plasma glucose sampling 8 hourly. Insulin concentration in the GKI infusate was altered according to test strip values to maintain test strip values between 4-7 mmol/l in the GKI group. Neurological impairment was determined using the European stroke scale (ESS). 145 patients were studied (73 GKI, 72 control). Mean systolic blood pressure was significantly lower during GKI infusion between 4 hours and 24 hours except at 8 hours. Median total ESS scores improved significantly between admission and day 7 in the GKI group (p<0.001) although there was no significant difference in total ESS score between groups at day 7. The significant reduction of systolic blood pressure in acute stroke associated with GKI therapy was not associated with neurological deterioration and may have been beneficial.

PMCID: PMC1737285  PMID: 11181869
24.  The Ottawa Summit: New Training Parameters for Child and Adolescent Psychiatry at the University of Ottawa 
To develop a renewed and innovative curricula for training and education in child and adolescent psychiatry career for track psychiatry trainees at the University of Ottawa.
Faculty members who were graduates of multiple Canadian training programs, as well as current career child psychiatry trainees of the University of Ottawa program, summarized and reviewed their training and education experiences in a one day summit. This was integrated into overall directions cited by recent literature as well as positions of the Canadian Academy of Child and Adolescent Psychiatry.
A template for new curricula was developed with new focus being placed on normal development, research methodology/evidence based medicine, emergency psychiatry, psychotherapy, and cultural competence.
Curricula renewal is essential, possible, and appropriate in order to produce a Child and Adolescent Psychiatrist who meets the needs of the Canadian public as defined in the CanMeds 2000 project of the RCPSC.
PMCID: PMC2533828  PMID: 19030152
25.  Receptor Usage and Fetal Expression of Ovine Endogenous Betaretroviruses: Implications for Coevolution of Endogenous and Exogenous Retroviruses 
Journal of Virology  2003;77(1):749-753.
Betaretroviruses of sheep include two exogenous viruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group of endogenous viruses known as enJSRVs. The exogenous JSRV and ENTV are the etiological agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal tumor (ENT), respectively. Sheep affected by OPA or ENT do not show an appreciable antibody response to JSRV or ENTV. Consequently, it is conceivable that enJSRV expression in the fetal lamb tolerizes sheep to the related exogenous viruses. In this study, possible mechanisms of interference between the sheep exogenous and endogenous betaretroviruses were investigated. In situ hybridization detected enJSRV RNAs in lymphoid cells associated with the lamina propria of the small intestine and in the thymus of sheep fetuses. Low-level expression of enJSRVs was also detected in the lungs. In addition, expression of enJSRVs was found to block entry of the exogenous JSRV, presumably via mechanisms of receptor interference. Indeed, enJSRVs, like JSRV and ENTV, were found to utilize hyaluronidase-2 as a cellular receptor.
PMCID: PMC140614  PMID: 12477881

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