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1.  Pharmacology of reflex blinks in the rat: a novel model for headache research 
Migraineurs are highly sensitive to the nitric oxide donor glyceryl trinitrate which triggers attacks in many sufferers. In animal studies, glyceryl trinitrate increases neuronal activity in the trigeminovascular pathway and elevates neurotransmitter levels in the brainstem. Many migraineurs also display alterations in blink reflexes, known to involve brainstem circuits. We investigated the effect of GTN on evoked blinks in the anaesthetised rat to determine whether such reflexes may prove useful as the basis for a novel animal model to evaluate potential anti-migraine therapeutic agents.
In anaesthetised rats the electromyogram associated with the reflex blink evoked by corneal airpuff was recorded. Rats were infused with glyceryl trinitrate, sumatriptan plus glyceryl trinitrate or vehicle control. Changes in the magnitude of the reflex blink-associated electromyogram following these treatments were measured.
Glyceryl trinitrate potentiated the evoked reflex blink-associated EMG response from 2 h after infusion. That effect was abolished by simultaneous infusion of sumatriptan with glyceryl trinitrate.
These results show that simple skin surface measurements of evoked electromyographic activity in the rat can reliably detect the evoked blink reflex that can be potentiated by nitric oxide donors. This novel model may be an effective tool for evaluating putative anti-migraine therapeutic agents.
PMCID: PMC5074984  PMID: 27770405
Migraine; Blink reflex; Nitric oxide donor; Sumatriptan
2.  Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics 
British Journal of Pharmacology  2014;171(10):2508-2527.
The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators.
This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit
PMCID: PMC4008996  PMID: 24283624
TRPV1; TRPV4; TRPM2; TRPM3; TRPM8; TRPA1; pain; inflammation; nerve injury
3.  Predicting the Concentration of Verotoxin-Producing Escherichia coli Bacteria during Processing and Storage of Fermented Raw-Meat Sausages 
A model to predict the population density of verotoxigenic Escherichia coli (VTEC) throughout the elaboration and storage of fermented raw-meat sausages (FRMS) was developed. Probabilistic and kinetic measurement data sets collected from publicly available resources were completed with new measurements when required and used to quantify the dependence of VTEC growth and inactivation on the temperature, pH, water activity (aw), and concentration of lactic acid. Predictions were compared with observations in VTEC-contaminated FRMS manufactured in a pilot plant. Slight differences in the reduction of VTEC were predicted according to the fermentation temperature, 24 or 34°C, with greater inactivation at the highest temperature. The greatest reduction was observed during storage at high temperatures. A population decrease greater than 6 decimal logarithmic units was observed after 66 days of storage at 25°C, while a reduction of only ca. 1 logarithmic unit was detected at 12°C. The performance of our model and other modeling approaches was evaluated throughout the processing of dry and semidry FRMS. The greatest inactivation of VTEC was predicted in dry FRMS with long drying periods, while the smallest reduction was predicted in semidry FMRS with short drying periods. The model is implemented in a computing tool, E. coli SafeFerment (EcSF), freely available from EcSF integrates growth, probability of growth, and thermal and nonthermal inactivation models to predict the VTEC concentration throughout FRMS manufacturing and storage under constant or fluctuating environmental conditions.
PMCID: PMC3993284  PMID: 24561587
4.  Separation of cognitive impairments in attention deficit hyperactivity disorder into two familial factors 
Archives of general psychiatry  2010;67(11):1159-1167.
Attention deficit hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots, or whether separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations.
To determine, using a multivariate familial factor analysis approach, whether one or more familial factors underlie the slow and variable reaction times (RTs), impaired response inhibition and choice impulsivity that are associated with ADHD.
An ADHD and control sibling-pair design.
Belgium, Germany, Ireland, Israel, Spain, Switzerland and the United Kingdom.
The sample consisted of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with ADHD combined subtype), and 345 control participants.
Main Outcome Measures
Performance on a four-choice RT task, a go/no-go inhibition task and a choice-delay task.
The final model consisted of two familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98-100% of the familial influences on mean RT and RT variability. The second smaller factor, reflecting 12.5% of the familial variance of ADHD, captured 62-82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model, due to poor fit.
The findings suggest the existence of two familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the two cognitive impairments is consistent with recent theoretical models – a developmental model and an arousal-attention model – on two separable underlying processes in ADHD. Future research that tests the familial model within a developmental framework may inform developmentally-sensitive interventions.
PMCID: PMC3770932  PMID: 21041617
5.  The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ 
Psychological medicine  2010;41(4):861-871.
Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.
Multivariate familial models were run on data from 1265 individuals aged 6–18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice–delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI).
Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41–0.71) and IQ (rF=−0.25 to −0.49). The association between ADHD and cognitive performance was largely independent (80–87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ.
The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.
PMCID: PMC3430513  PMID: 20522277
ADHD; cognitive; heritability; IQ; intermediate phenotype
6.  The relationship between patients' experiences of continuity of cancer care and health outcomes: a mixed methods study 
British Journal of Cancer  2008;98(3):529-536.
It is difficult to define continuity of care or study its impact on health outcomes. This study took place in three stages. In stage I we conducted qualitative research with patients, their close relatives and friends, and their key health professionals from which we derived a number of self completion statements about experienced continuity that were tested for reliability and internal consistency. A valid and reliable 18-item measure of experienced continuity was developed in stage II. In stage III we interviewed 199 patients with cancer up to five times over 12 months to ascertain whether their experiences of continuity were associated with their health needs, psychological status, quality of life, and satisfaction with care. The qualitative data revealed that experienced continuity involved receiving consistent time and attention, knowing what to expect in the future, coping between service contacts, managing family consequences, and believing nothing has been overlooked. Transitions between phases of treatment were not associated with changes in experienced continuity. However, higher experienced continuity predicted lower needs for care, after adjustment for other potential explanatory factors (standardised regression coefficients ranging from −0.12 (95% CI −0.20, −0.05) to −0.32 (95% CI −0.41, −0.23)). Higher experienced continuity may be linked to lower health care needs in the future.
PMCID: PMC2243159  PMID: 18231111
continuity of care; cohort study; cancer; service delivery; transitions in care
7.  A questionnaire survey of patient acceptability of optic disc imaging by HRT II and GDx 
PMCID: PMC1772129  PMID: 15090433
patient acceptability; GDx; HRT II; optic disc imaging
8.  Spontaneous orbital haemorrhage following cardiac angioplasty 
PMCID: PMC1724082  PMID: 11501524
9.  Prevalence of risk factors for cardiovascular disease in Canadians 55 to 74 years of age: results from the Canadian Heart Health Surveys, 1986-1992 
BACKGROUND: By 2016, the proportion of Canadians older than 65 years of age will increase to 16%, and there will be an increase in the absolute number of cases of cardiovascular disease in older Canadians. The Canadian Heart Health Surveys database provides information about this population upon which health policy related to cardiovascular disease can be based. This paper presents for the first time population-based data on the risk factors for cardiovascular disease in older Canadians. METHODS: Canadians from all 10 provinces participated in surveys of cardiovascular risk factors; health insurance registries were used as sampling frames. In each province, probability samples of 2200 adults 18 to 74 years old not living in institutions, on reserves or in military camps were asked to participate in interviews and to undergo testing at clinics for major risk factors for cardiovascular disease. RESULTS: A total of 2739 men (response rate 70%) and 2617 women (response rate 66%) aged 55 to 74 years participated in the survey and also provided follow-up clinical measurements at the clinic. Overall, 52% of participants were hypertensive, 26% had isolated systolic hypertension, and 30% had a total blood cholesterol level of 6.2 mmol/L or greater. Rates of current smoking were lower in women than men (17% v. 22%). Overall, 87% of men and 78% of women who were current smokers smoked at least 10 cigarettes per day. Only slightly more than half of participants exercised at least once a week for at least 15 minutes, and almost half had a body mass index of 27 or greater. In only 4% was no major risk factor for cardiovascular disease detected. INTERPRETATION: Significant numbers of older Canadians have one or more major risk factors for cardiovascular disease. Many of these risk factors are amenable to modification.
PMCID: PMC1230716  PMID: 10551206
10.  Knowledge and awareness of risk factors for cardiovascular disease among Canadians 55 to 74 years of age: results from the Canadian Heart Health Surveys, 1986-1992 
BACKGROUND: Cardiovascular disease is the leading cause of death and disability in older people, who account for an increasing proportion of Canada's population. Knowledge and awareness of risk factors is essential for changes in behaviour, yet little is known about these issues in older people. The Canadian Heart Health Surveys database provides a unique resource to examine knowledge and awareness of cardiovascular risk factors in older Canadians. METHODS: This descriptive cross-sectional study used data from the Canadian provinces' Heart Health Surveys, for the years 1986 to 1992. Sampling within each province consisted of stratified, 2-stage, replicated probability samples; 4976 people 55 to 74 years of age were included in the present analysis. Knowledge and awareness of cardiovascular risk factors was determined from the survey question "Can you tell me what are the major causes of heart disease or heart problems?" Blood pressure was measured during a home visit; anthropometric and blood measurements were obtained during a clinic visit. Cardiovascular health status was determined by self-reporting. RESULTS: Smoking and stress or worry were mentioned as major causes of heart disease by the greatest proportion of participants (41% and 44% respectively); hypertension was mentioned by only 16%. Men and women did not differ in their awareness of high blood cholesterol (cited by 23% of participants), smoking (41%), excess weight (30%) or lack of exercise (28%) as causes of heart disease. A greater proportion of women than men were aware of hypertension (19% v. 12%) and heredity (31% v. 17%) as major causes of heart disease. Awareness of risk factors was consistently lower in the older age group (65-74 v. 55-64 years). Among women, there was greater awareness of the respective risk factors as causes of heart disease among those who were smokers (60% v. 35% of nonsmokers), those who had a body mass index (BMI) of 25 or greater (38% v. 24% of those with a BMI less than 25) and those who were hypertensive (22% v. 17% of those without hypertension). Those who had experienced a heart attack had greater awareness of the major causes of heart disease than those who had not; this pattern was stronger among women than among men. Of those in whom elevated cholesterol level was identified during the course of the study, 62% of men and 67% of women were unaware of their cholesterol status. Of those in whom high blood pressure was diagnosed, 43% of men and 33% of women were unaware of their hypertensive status. INTERPRETATION: Awareness of the major causes of cardiovascular disease is low among older Canadians, especially among men and in those 65 to 74 years of age.
PMCID: PMC1230715  PMID: 10551207
11.  Trends in the prevalence and treatment of hypertension in Halifax County from 1985 to 1995 
BACKGROUND: The objective of this study was to document changes in the prevalence and treatment of hypertension in Halifax County from 1985 to 1995 in an effort to observe, at the population level, the consequences of the availability of new antihypertensive medications. METHODS: The study population comprised a random sample of Halifax County residents, aged 25-64 years, who responded to the 1985 and 1995 surveys of the Halifax County MONICA Project and residents who responded to the Nova Scotia Health Survey conducted in 1995. Data from the two 1995 surveys were pooled. Information on hypertension awareness and use of medication were obtained through questionnaires, and blood pressure was measured according to a standard protocol, using phase I and V of Korotkoff sounds as respective markers for systolic and diastolic pressures. Uncontrolled hypertension was defined as a systolic pressure of 140 mm Hg or greater and a diastolic pressure of 90 mm Hg or greater. Changes in the prevalence of hypertension, prescribing trends and medication costs were examined, and the association between the type of antihypertensive treatment and characteristics of the respondents with self-reported hypertension was investigated by multivariate logistic regression. RESULTS: Of the 917 people interviewed in 1985 and the 1338 in 1995, 274 (29.9%) and 356 (26.6%), respectively, reported a history of hypertension. When age was controlled for, the proportion of respondents reporting hypertension did not differ between survey years or between men and women. The proportion of treated respondents who had uncontrolled hypertension increased between 1985 and 1995, from 32.6% to 57.4% among men and from 38.0% to 42.6% among women. An increase was seen in the use of calcium-channel blockers (from 2.1% to 19.7%) and angiotensin-converting-enzyme inhibitors (from 5.2% to 25.4%); the proportion of patients receiving combination therapy or diuretics decreased (from 39.6% to 15.6% and from 31.3% to 17.2% respectively). These changes were associated with an increase in the average daily cost of medication from $0.48 to $0.85 per patient. INTERPRETATION: The shift to new antihypertensive drugs was not associated with improved blood pressure control, but it was associated with an increase in average medication costs per patient. Uncontrolled hypertension remains a public health problem.
PMCID: PMC1230618  PMID: 10513276

Results 1-12 (12)