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1.  Cardiometabolic disease risk and HIV status in rural South Africa: establishing a baseline 
BMC Public Health  2015;15:135.
To inform health care and training, resource and research priorities, it is essential to establish how non-communicable disease risk factors vary by HIV-status in high HIV burden areas; and whether long-term anti-retroviral therapy (ART) plays a modifying role.
As part of a cohort initiation, we conducted a baseline HIV/cardiometabolic risk factor survey in 2010–2011 using an age-sex stratified random sample of ages 15+ in rural South Africa. We modelled cardiometabolic risk factors and their associations by HIV-status and self-reported ART status for ages 18+ using sex-stratified logistic regression models.
Age-standardised HIV prevalence in women was 26% (95% CI 24-28%) and 19% (95% CI 17–21) in men. People with untreated HIV were less likely to have a high waist circumference in both women (OR 0.67; 95% CI 0.52-0.86) and men (OR 0.42; 95% CI 0.22-0.82). Untreated women were more likely to have low HDL and LDL, and treated women high triglycerides. Cardiometabolic risk factors increased with age except low HDL. The prevalence of hypertension was high (40% in women; 30% in men).
Sub-Saharan Africa is facing intersecting epidemics of HIV and hypertension. In this setting, around half the adult population require long-term care for at least one of HIV, hypertension or diabetes. Together with the adverse effects that HIV and its treatment have on lipids, this may have serious implications for the South African health care system. Monitoring of the interaction of HIV, ART use, and cardiometabolic disease is needed at both individual and population levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1467-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4335669
South Africa; Rural; Cardiometabolic risk; HIV/AIDS
2.  Heightened D3 Dopamine Receptor Levels in Cocaine Dependence and Contributions to the Addiction Behavioral Phenotype: A Positron Emission Tomography Study with [11C]-(+)-PHNO 
Neuropsychopharmacology  2013;39(2):321-328.
The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [11C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7–240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [11C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [11C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [11C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [11C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in ⩾2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.
PMCID: PMC3870773  PMID: 23921256
[11C]-(+)-PHNO; [11C]raclopride; Addiction & Substance Abuse; D3 receptor; decision-making; Dopamine; Imaging; Clinical or Preclinical; impulsiveness; Psychostimulants; D2/3 dopamine receptor; [11C]-(+)-PHNO; [11C]raclopride; cocaine dependence; impulsiveness; risky decision making
3.  Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans 
Neuropsychopharmacology  2013;39(2):415-424.
Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [11C]-(+)-PHNO ([11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [11C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [11C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [11C]-(+)-PHNO binding in D2 and D3-rich areas (−12.0 and −15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [11C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.
PMCID: PMC3870776  PMID: 23954846
addiction and substance abuse; dopamine; imaging; clinical or preclinical; neurotransmitters; nicotine; PET; tobacco; ventral tegmental area; tobacco; PET; dopamine; ventral tegmental area; nicotine
4.  Image Derived Input Function for [18F]-FEPPA: Application to Quantify Translocator Protein (18 kDa) in the Human Brain 
PLoS ONE  2014;9(12):e115768.
In [18F]-FEPPA positron emission topography (PET) imaging, automatic blood sampling system (ABSS) is currently the gold standard to obtain the blood time activity curve (TAC) required to extract the input function (IF). Here, we compare the performance of two image-based methods of IF extraction to the ABSS gold standard method for the quantification of translocator protein (TSPO) in the human brain. The IFs were obtained from a direct delineation of the internal carotid signal (CS) and a new concept of independent component analysis (ICA). PET scans were obtained from 18 healthy volunteers. The estimated total distribution volume (VT) by CS-IF and ICA-IF were compared to the reference VT obtained by ABSS-IF in the frontal and temporal cortex, cerebellum, striatum and thalamus regions. The VT values estimated using ICA-IF were more reliable than CS-IF for all brain regions. Specifically, the slope regression in the frontal cortex with ICA-IF was r2 = 0.91 (p<0.05), and r2 = 0.71 (p<0.05) using CS-IF.
PMCID: PMC4280118  PMID: 25549260
5.  Validation, Replication, and Sensitivity Testing of Heckman-Type Selection Models to Adjust Estimates of HIV Prevalence 
PLoS ONE  2014;9(11):e112563.
A recent study using Heckman-type selection models to adjust for non-response in the Zambia 2007 Demographic and Health Survey (DHS) found a large correction in HIV prevalence for males. We aim to validate this finding, replicate the adjustment approach in other DHSs, apply the adjustment approach in an external empirical context, and assess the robustness of the technique to different adjustment approaches. We used 6 DHSs, and an HIV prevalence study from rural South Africa to validate and replicate the adjustment approach. We also developed an alternative, systematic model of selection processes and applied it to all surveys. We decomposed corrections from both approaches into rate change and age-structure change components. We are able to reproduce the adjustment approach for the 2007 Zambia DHS and derive results comparable with the original findings. We are able to replicate applying the approach in several other DHSs. The approach also yields reasonable adjustments for a survey in rural South Africa. The technique is relatively robust to how the adjustment approach is specified. The Heckman selection model is a useful tool for assessing the possibility and extent of selection bias in HIV prevalence estimates from sample surveys.
PMCID: PMC4234405  PMID: 25402333
6.  Self-denigrating terms 
PMCID: PMC4213260  PMID: 25364345
7.  Raltegravir Has a Low Propensity To Cause Clinical Drug Interactions through Inhibition of Major Drug Transporters: an In Vitro Evaluation 
Raltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series of in vitro experiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 μM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 μM and 18.8 μM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 μM) and MATE2-K (29% inhibition at 100 μM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.
PMCID: PMC3957841  PMID: 24295974
8.  Does intergenerational mobility shape psychological distress? Sorokin revisited 
Drawing from Sorokin's hypothesis that socially mobile individuals are at greater risk of experiencing psychological distress than their non-mobile counterparts, we investigate whether intergenerational occupational mobility influences psychological distress, as measured by the Center for Epidemiologic Studies Depression (CES-D) scale. Using data for men from the Wisconsin Longitudinal Study (WLS) and Sobel's Diagonal Mobility Models, we find little evidence for Sorokin's hypothesis; mobile individuals are no more likely to be psychologically distressed than their non-mobile counterparts. In fact, one group of mobile men – those who left their farming origins – are actually less distressed than the sons who remain as farmers and non-mobile men in higher-ranked social classes. We speculate that this reflects the fact that farming became very arduous during the late 20th century and these mobile sons of farmers appreciate their improved life chances. Our findings suggest that the association between mobility and psychological distress varies across specific class backgrounds and is contingent upon the broader social and economic context.
PMCID: PMC4139926  PMID: 25152556
Sorokin; Mobility effects; Diagonal Mobility Models; Psychological distress
9.  Visualization of Mouse Neuronal Ganglia Infected by Herpes Simplex Virus 1 (HSV-1) Using Multimodal Non-Linear Optical Microscopy 
PLoS ONE  2014;9(8):e105103.
Herpes simplex virus 1 (HSV-1) is a neurotropic virus that causes skin lesions and goes on to enter a latent state in neurons of the trigeminal ganglia. Following stress, the virus may reactivate from latency leading to recurrent lesions. The in situ study of neuronal infections by HSV-1 is critical to understanding the mechanisms involved in the biology of this virus and how it causes disease; however, this normally requires fixation and sectioning of the target tissues followed by treatment with contrast agents to visualize key structures, which can lead to artifacts. To further our ability to study HSV-1 neuropathogenesis, we have generated a recombinant virus expressing a second generation red fluorescent protein (mCherry), which behaves like the parental virus in vivo. By optimizing the application of a multimodal non-linear optical microscopy platform, we have successfully visualized in unsectioned trigeminal ganglia of mice both infected cells by two-photon fluorescence microscopy, and myelinated axons of uninfected surrounding cells by coherent anti-Stokes Raman scattering (CARS) microscopy. These results represent the first report of CARS microscopy being combined with 2-photon fluorescence microscopy to visualize virus-infected cells deep within unsectioned explanted tissue, and demonstrate the application of multimodal non-linear optical microscopy for high spatial resolution biological imaging of tissues without the use of stains or fixatives.
PMCID: PMC4136817  PMID: 25133579
10.  Mapping of a Chromosome 12 Region Associated with Airway Hyperresponsiveness in a Recombinant Congenic Mouse Strain and Selection of Potential Candidate Genes by Expression and Sequence Variation Analyses 
PLoS ONE  2014;9(8):e104234.
In a previous study we determined that BcA86 mice, a strain belonging to a panel of AcB/BcA recombinant congenic strains, have an airway responsiveness phenotype resembling mice from the airway hyperresponsive A/J strain. The majority of the BcA86 genome is however from the hyporesponsive C57BL/6J strain. The aim of this study was to identify candidate regions and genes associated with airway hyperresponsiveness (AHR) by quantitative trait locus (QTL) analysis using the BcA86 strain. Airway responsiveness of 205 F2 mice generated from backcrossing BcA86 strain to C57BL/6J strain was measured and used for QTL analysis to identify genomic regions in linkage with AHR. Consomic mice for the QTL containing chromosomes were phenotyped to study the contribution of each chromosome to lung responsiveness. Candidate genes within the QTL were selected based on expression differences in mRNA from whole lungs, and the presence of coding non-synonymous mutations that were predicted to have a functional effect by amino acid substitution prediction tools. One QTL for AHR was identified on Chromosome 12 with its 95% confidence interval ranging from 54.6 to 82.6 Mbp and a maximum LOD score of 5.11 (p = 3.68×10−3). We confirmed that the genotype of mouse Chromosome 12 is an important determinant of lung responsiveness using a Chromosome 12 substitution strain. Mice with an A/J Chromosome 12 on a C57BL/6J background have an AHR phenotype similar to hyperresponsive strains A/J and BcA86. Within the QTL, genes with deleterious coding variants, such as Foxa1, and genes with expression differences, such as Mettl21d and Snapc1, were selected as possible candidates for the AHR phenotype. Overall, through QTL analysis of a recombinant congenic strain, microarray analysis and coding variant analysis we identified Chromosome 12 and three potential candidate genes to be in linkage with airway responsiveness.
PMCID: PMC4128649  PMID: 25111050
11.  Synthesis and preclinical evaluation of [11C-carbonyl]PF-04457845 for neuroimaging of fatty acid amide hydrolase 
Nuclear medicine and biology  2013;40(6):740-746.
PMCID: PMC3737387  PMID: 23731552
FAAH; positron emission tomography; rodent models; carbon-11; radiotracer
12.  Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase 
Bioorganic & medicinal chemistry  2013;21(14):4351-4357.
Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an 18F-radiotracer designed to image FAAH using positron emission tomography (PET) is described.
Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [18F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17–22% (from [18F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82 nM after a preincubation of 60 min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [18F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [18F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts.
We infer from these results that [18F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.
PMCID: PMC3683374  PMID: 23712084
PET; FAAH; radiosynthesis; fluorine-18; rat; endocannabinoid; anandamide
13.  Weight Change and Depression Among US Young Women During the Transition to Adulthood 
American Journal of Epidemiology  2013;178(1):22-30.
By using data from wave 2 (in 1996) and wave 3 (in 2000–2001) of the US-based National Longitudinal Study of Adolescent Health, we investigated the association between young women's body weight and depression during the transition to adulthood. Respondents (n = 5,243) were 13–18 years of age during wave 2 and 19–25 years of age during wave 3. We used Center for Epidemiologic Studies Depression Scale scores to classify young women as never depressed, consistently depressed, experiencing depression onset, or experiencing depression recovery from wave 2 to wave 3. Results from adjusted multinomial logistic regression models indicated that respondents who experienced significant weight gain were at risk of depression onset. Normal weight (adjusted odds ratio = 2.10, 95% confidence interval: 1.14, 3.84) and overweight (adjusted odds ratio = 1.86, 95% confidence interval: 1.15, 2.99) adolescent girls who were obese by young adulthood, as well as young women who were consistently obese during adolescence and young adulthood (adjusted odds ratio = 1.97, 95% confidence interval: 1.19, 3.26), had roughly twice the odds of depression onset as did young women who were never overweight. We concluded that weight gain and obesity are risk factors for depression onset during the transition to adulthood. Policies prioritizing healthy weight maintenance may help improve young women's mental health as they begin their adult lives.
PMCID: PMC3816342  PMID: 23752915
body weight changes; depression; mental health; obesity; weight gain
15.  Paying pharmacists for patient care 
Canadian Pharmacists Journal : CPJ  2014;147(4):209-232.
Expansion of scope of practice and diminishing revenues from dispensing are requiring pharmacists to increasingly adopt clinical care services into their practices. Pharmacists must be able to receive payment in order for provision of clinical care to be sustainable. The objective of this study is to update a previous systematic review by identifying remunerated pharmacist clinical care programs worldwide and reporting on uptake and patient care outcomes observed as a result.
Literature searches were performed in several databases, including MEDLINE, Embase and International Pharmaceutical Abstracts, for papers referencing remuneration, pharmacy and cognitive services. Searches of the grey literature and Internet were also conducted. Papers and programs were identified up to December 2012 and were included if they were not reported in our previous review. One author performed data abstraction, which was independently reviewed by a second author. All results are presented descriptively.
Sixty new remunerated programs were identified across Canada, the United States, Europe, Australia and New Zealand, ranging in complexity from emergency contraception counseling to minor ailments schemes and comprehensive medication management. In North America, the average fee provided for a medication review is $68.86 (all figures are given in Canadian dollars), with $23.37 offered for a follow-up visit and $15.16 for prescription adaptations. Time-dependent fees were reimbursed at $93.60 per hour on average. Few programs evaluated uptake and outcomes of these services but, when available, indicated slow uptake but improved chronic disease markers and cost savings.
Remuneration for pharmacists’ clinical care services is highly variable, with few programs reporting program outcomes. Programs and pharmacists are encouraged to examine the time required to perform these activities and the outcomes achieved to ensure that fees are adequate to sustain these patient care activities.
PMCID: PMC4212445  PMID: 25360148
16.  The Unfolding Counter-Transition in Rural South Africa: Mortality and Cause of Death, 1994–2009 
PLoS ONE  2014;9(6):e100420.
The HIV pandemic has led to dramatic increases and inequalities in adult mortality, and the diffusion of antiretroviral treatment, together with demographic and socioeconomic shifts in sub-Saharan Africa, has further changed mortality patterns. We describe all-cause and cause-specific mortality patterns in rural South Africa, analyzing data from the Agincourt health and socio-demographic surveillance system from 1994 to 2009 for those aged 5 years and older. Mortality increased during that period, particularly after 2002 for ages 30–69. HIV/AIDS and TB deaths increased and recently plateaued at high levels in people under age 60. Noncommunicable disease deaths increased among those under 60, and recently also increased among those over 60. There was an inverse gradient between mortality and household SES, particularly for deaths due to HIV/AIDS and TB and noncommunicable diseases. A smaller and less consistent gradient emerged for deaths due to other communicable diseases. Deaths due to injuries remained an important mortality risk for males but did not vary by SES. Rural South Africa continues to have a high burden of HIV/AIDS and TB mortality while deaths from noncommunicable diseases have increased, and both of these cause-categories show social inequalities in mortality.
PMCID: PMC4068997  PMID: 24959714
17.  A Problem-Solving Early Intervention for Stroke Caregivers: One Year Follow-Up 
The study purposes were to assess the efficacy of a caregiver problem-solving intervention (CPSI) on stroke caregiver physical and psychosocial adaptation compared with a wait-list control (WLC) treatment, and to assess the mediation effects of coping on outcomes.
A stress and coping model guided the study design. Outcomes were depression, anxiety, preparedness, life changes, and family functioning. CPSI started during acute rehabilitation and continued 3 months postdischarge. Data were collected at baseline (T1), postintervention (T2), and 6 (T3) and 12 months postdischarge (T4).
Of 255 caregivers, 75% were depressed at baseline. Repeated measures ANOVA of study completers (n = 121) indicated improved T2 depression, life change, and health (ps < .04) favoring the CPSI group. Improvements faded by 6 months. Although no group differences in outcomes were found in the intention-to-treat analysis, growth curve modeling indicated a difference in depression rate of change, favoring the CPSI (p = .04). Perceived health, threat appraisal and rational problem-solving were significant mediators (ps < .05).
Findings provide direction for future interventions to promote and sustain healthy caregiver adaptation.
PMCID: PMC4060889  PMID: 22949276
caregiver; depression; mediators; problem-solving; stroke
18.  Interannual and spatial variability of maple syrup yield as related to climatic factors 
PeerJ  2014;2:e428.
Sugar maple syrup production is an important economic activity for eastern Canada and the northeastern United States. Since annual variations in syrup yield have been related to climate, there are concerns about the impacts of climatic change on the industry in the upcoming decades. Although the temporal variability of syrup yield has been studied for specific sites on different time scales or for large regions, a model capable of accounting for both temporal and regional differences in yield is still lacking. In the present study, we studied the factors responsible for interregional and interannual variability in maple syrup yield over the 2001–2012 period, by combining the data from 8 Quebec regions (Canada) and 10 U.S. states. The resulting model explained 44.5% of the variability in yield. It includes the effect of climatic conditions that precede the sapflow season (variables from the previous growing season and winter), the effect of climatic conditions during the current sapflow season, and terms accounting for intercountry and temporal variability. Optimal conditions for maple syrup production appear to be spatially restricted by less favourable climate conditions occurring during the growing season in the north, and in the south, by the warmer winter and earlier spring conditions. This suggests that climate change may favor maple syrup production northwards, while southern regions are more likely to be negatively affected by adverse spring conditions.
PMCID: PMC4060030  PMID: 24949244
Maple syrup; Sugar maple; Climate; Cold hardiness; Acer saccharum; Freeze–thaw events; Yield statistics
19.  The role of perioperative sodium bicarbonate infusion affecting renal function after cardiothoracic surgery 
Cardiac surgery associated acute kidney injury (CSA-AKI) is associated with poor outcomes including increased mortality, length of hospital stay (LOS) and cost. The incidence of acute kidney injury (AKI) is reported to be between 3 and 30% depending on the definition of AKI. We designed a multicenter randomized controlled trial to test our hypothesis that a perioperative infusion of sodium bicarbonate (SB) during cardiac surgery will attenuate the post-operative rise in creatinine indicating renal injury when compared to a perioperative infusion with normal saline. An interim analysis was performed after data was available on the first 120 participants. A similar number of patients in the two treatment groups developed AKI, defined as an increase in serum creatinine the first 48 h after surgery of 0.3 mg/dl or more. Specifically 14 patients (24%) who received sodium chloride (SC) and 17 patients (27%) who received SB were observed to develop AKI post-surgery, resulting in a relative risk of AKI of 1.1 (95% CI: 0.6–2.1, chi-square p-value = 0.68) for patients receiving SB compared to those who received SC. The data safety monitoring board for the trial recommended closing the study early as there was only a 12% probability that the null hypothesis would be rejected. We therefore concluded that a perioperative infusion of SB failed to attenuate the risk of CSA-AKI.
PMCID: PMC4040918  PMID: 24917818
acute kidney injury; cardiovascular surgery; bicarbonate therapy
20.  Distribution of monoamine oxidase proteins in human brain: implications for brain imaging studies 
Positron emission tomography (PET) imaging of monoamine oxidases (MAO-A: [11C]harmine, [11C]clorgyline, and [11C]befloxatone; MAO-B: [11C]deprenyl-D2) has been actively pursued given clinical importance of MAOs in human neuropsychiatric disorders. However, it is unknown how well PET outcome measures for the different radiotracers are quantitatively related to actual MAO protein levels. We measured regional distribution (n=38) and developmental/aging changes (21 hours to 99 years) of both MAOs by quantitative immunoblotting in autopsied normal human brain. MAO-A was more abundant than MAO-B in infants, which was reversed as MAO-B levels increased faster before 1 year and, unlike MAO-A, kept increasing steadily to senescence. In adults, regional protein levels of both MAOs were positively and proportionally correlated with literature postmortem data of MAO activities and binding densities. With the exception of [11C]befloxatone (binding potential (BP), r=0.61, P=0.15), correlations between regional PET outcome measures of binding in the literature and MAO protein levels were good (P<0.01) for [11C]harmine (distribution volume, r=0.86), [11C]clorgyline (λk3, r=0.82), and [11C]deprenyl-D2 (λk3 or modified Patlak slope, r=0.78 to 0.87), supporting validity of the latter imaging measures. However, compared with in vitro data, the latter PET measures underestimated regional contrast by ∼2-fold. Further studies are needed to address cause of the in vivo vs. in vitro nonproportionality.
PMCID: PMC3677103  PMID: 23403377
ageing; immunoblotting; monoamine oxidase; positron emission tomography; postmortem human brain
22.  Should vitamin B12 tablets be included in more Canadian drug formularies? An economic model of the cost-saving potential from increased utilisation of oral versus intramuscular vitamin B12 maintenance therapy for Alberta seniors 
BMJ Open  2014;4(5):e004501.
The aim of this study was to estimate the cost-savings attainable if all patients aged ≥65 years in Alberta, Canada, currently on intramuscular therapy were switched to oral therapy, from the perspective of a provincial ministry of health.
Primary care setting in Alberta, Canada.
Seniors of age 65 years and older currently receiving intramuscular vitamin B12 therapy.
Oral vitamin B12 therapy at 1000 μg/day versus intramuscular therapy at 1000 μg/month.
Primary and secondary outcome measures
Cost saving from oral therapy over intramuscular therapy, from the perspective of the Alberta Ministry of Health, including drug costs, dispensing fees, injection administration fees, additional laboratory monitoring and physician visit fees.
Over 5 years, if all Albertans aged 65 years and older who currently receive intramuscular B12 are switched to oral therapy, our model found that $C13 975 883 can be saved. Even if no additional physician visits are billed for among patients receiving intramuscular therapy, $C8 444 346 could be saved from reduced administration costs alone.
Oral B12 therapy has been shown to be an effective therapeutic option for patients with vitamin B12 deficiency, yet only three provinces and the Non-Insured Health Benefits program include oral tablets on their formulary rather than the parenteral preparation. To ensure judicious use of limited health resources, clinicians and formulary committees are encouraged to adopt oral B12 therapy as a clinically and cost-effective first-line therapy for vitamin B12 deficiency.
PMCID: PMC4025453  PMID: 24793247
Health Economics; Primary Care
23.  Causality and headache triggers 
Headache  2013;53(4):628-635.
The objective of this study was to explore the conditions necessary to assign causal status to headache triggers.
The term “headache trigger” is commonly used to label any stimulus that is assumed to cause headaches. However, the assumptions required for determining if a given stimulus in fact has a causal-type relationship in eliciting headaches have not been explicated.
A synthesis and application of Rubin’s Causal Model is applied to the context of headache causes. From this application the conditions necessary to infer that one event (trigger) causes another (headache) are outlined using basic assumptions and examples from relevant literature.
Although many conditions must be satisfied for a causal attribution, three basic assumptions are identified for determining causality in headache triggers: 1) constancy of the sufferer; 2) constancy of the trigger effect; and 3) constancy of the trigger presentation. A valid evaluation of a potential trigger’s effect can only be undertaken once these three basic assumptions are satisfied during formal or informal studies of headache triggers.
Evaluating these assumptions is extremely difficult or infeasible in clinical practice, and satisfying them during natural experimentation is unlikely. Researchers, practitioners, and headache sufferers are encouraged to avoid natural experimentation to determine the causal effects of headache triggers. Instead, formal experimental designs or retrospective diary studies using advanced statistical modeling techniques provide the best approaches to satisfy the required assumptions and inform causal statements about headache triggers.
PMCID: PMC3628761  PMID: 23534872
headache triggers; causality; research design
24.  Predicting Acute Pain after Cesarean Delivery Using Three Simple Questions 
Anesthesiology  2013;118(5):1170-1179.
Interindividual variability in postoperative pain presents a clinical challenge. Preoperative quantitative sensory testing is useful but time consuming in predicting postoperative pain intensity. The current study was conducted to develop and validate a predictive model of acute postcesarean pain using a simple three-item preoperative questionnaire.
A total of 200 women scheduled for elective cesarean delivery under subarachnoid anesthesia were enrolled (192 subjects analyzed). Patients were asked to rate the intensity of loudness of audio tones, their level of anxiety and anticipated pain, and analgesic need from surgery. Postoperatively, patients reported the intensity of evoked pain. Regression analysis was performed to generate a predictive model for pain from these measures. A validation cohort of 151 women was enrolled to test the reliability of the model (131 subjects analyzed).
Responses from each of the three preoperative questions correlated moderately with 24-h evoked pain intensity (r = 0.24-0.33, P < 0.001). Audio tone rating added uniquely, but minimally, to the model and was not included in the predictive model. The multiple regression analysis yielded a statistically significant model (R2 = 0.20, P < 0.001), whereas the validation cohort showed reliably a very similar regression line (R2 = 0.18). In predicting the upper 20th percentile of evoked pain scores, the optimal cut point was 46.9 (z =0.24) such that sensitivity of 0.68 and specificity of 0.67 were as balanced as possible.
This simple three-item questionnaire is useful to help predict postcesarean evoked pain intensity, and could be applied to further research and clinical application to tailor analgesic therapy to those who need it most.
PMCID: PMC3951732  PMID: 23485992
25.  FDG-PET in Semantic Dementia after 6 Months of Memantine: an Open-Label Pilot Study 
To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open label study of memantine in frontotemporal dementia (FTD).
We repeated fluoro-deoxyglucose positron emission tomography (PET) after 6 months of drug use and subjected the data to an SPM analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI).
Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia. The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p<0.002) for 5 participants with semantic dementia. The 2–6 month interval revealed a late increase in normalized metabolic activity in the left insula (p<0.013), right insula (p<0.009), and left anterior cingulate (p<0.005). The right anterior cingulate showed both an initial increase and a delayed, further increase (2–6 month, p<0.016). FBI scores worsened by 43.3%. One participant with semantic dementia opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases.
Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Since one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure.
PMCID: PMC3467357  PMID: 22674572
frontotemporal dementia; metabolism; PET scan; semantic dementia

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