CFTR and colorectal cancer susceptibility: an urgent need for further studies.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in cystic fibrosis, a multiorgan disease characterized by aberrant epithelial cell fluid secretion. Recent studies describe a connection between CFTR malfunctioning and a heightened susceptibility to colorectal cancer (CRC). Here, we outline these links and suggest directions for further studies.

The role of self-reported and physiological stress in nocebo hyperalgesia.

Negative expectations can increase pain sensitivity, leading to nocebo hyperalgesia. However, the physiological and psychological factors that predispose individuals to this phenomenon are still not well understood. The present study examined whether stress induced by a social stressor affects nocebo hyperalgesia, and whether this effect is mediated by self-reported and physiological stress responses. We recruited 52 healthy participants (15 men) who were randomly assigned to either the Trier Social Stress Test (TSST) or a control condition (a friendly version of the TSST). Nocebo hyperalgesia was induced using negative suggestions combined with a validated pain conditioning paradigm. We assessed self-reported (anxiety and stress) and physiological (cortisol, alpha-amylase, heart rate, and skin conductance) responses to stress. Both groups exhibited significant nocebo hyperalgesia. The stress group showed higher levels of anxiety, self-reported stress, and cortisol levels compared to the control group while no significant differences were found in other physiological markers. The stress and control groups did not differ in the magnitude of nocebo hyperalgesia, but anxiety levels partially mediated the effects of the stress test on nocebo hyperalgesia. Our findings suggest that an external social stressor does not directly affect nocebo hyperalgesia, but that increased anxiety due to the stressor enhances its magnitude. Thus, it may be worthwhile to investigate whether reducing stress-related anxiety in clinical settings would help alleviate nocebo effects.

Simple 2,4-diacylphloroglucinols as classic transient receptor potential-6 activators--identification of a novel pharmacophore.

The naturally occurring acylated phloroglucinol derivative hyperforin was recently identified as the first specific canonical transient receptor potential-6 (TRPC6) activator. Hyperforin is the major antidepressant component of St. John's wort, which mediates its antidepressant-like properties via TRPC6 channel activation. However, its pharmacophore moiety for activating TRPC6 channels is unknown. We hypothesized that the phloroglucinol moiety could be the essential pharmacophore of hyperforin and that its activity profile could be due to structural similarities with diacylglycerol (DAG), an endogenous nonselective activator of TRPC3, TRPC6, and TRPC7. Accordingly, a few 2-acyl and 2,4-diacylphloroglucinols were tested for their hyperforin-like activity profiles. We used a battery of experimental models to investigate all functional aspects of TRPC6 activation, including ion channel recordings, Ca(2+) imaging, neurite outgrowth, and inhibition of synaptosomal uptake. Phloroglucinol itself was inactive in all of our assays, which was also the case for 2-acylphloroglucinols. For TRPC6 activation, the presence of two symmetrically acyl-substitutions with appropriate alkyl chains in the phloroglucinol moiety seems to be an essential prerequisite. Potencies of these compounds in all assays were comparable with that of hyperforin for activating the TRPC6 channel. Finally, using structure-based modeling techniques, we suggest a binding mode for hyperforin to TRPC6. Based on this modeling approach, we propose that DAG is able to activate TRPC3, TRPC6, and TRPC7 because of higher flexibility within the chemical structure of DAG compared with the rather rigid structures of hyperforin and the 2,4-diacylphloroglucinol derivatives.

The interaction of ethnicity and chronic disease as risk factors for osteoporotic fractures: a comparison in Canadian Aboriginals and non-Aboriginals.

INTRODUCTION: Efforts to develop global methods for absolute fracture risk prediction are currently limited by uncertainty over the validity of these models in non-White populations. Aboriginal Canadians have higher fractures rates than non-Aboriginals. This analysis examined the interaction of ethnicity with diabetes mellitus, disease comorbidity and substance abuse as possible explanatory variables. METHODS: A retrospective, population-based matched cohort study of fracture rates was performed using Manitoba administrative health data (1984-2003). The study cohort consisted of 27,952 registered Aboriginal adults (aged 20 years or older) and 83,856 non-Aboriginal controls (matched three to one for year of birth and gender). Diabetes mellitus, number of ambulatory disease groups (ADGs), substance abuse and incident fractures were based upon validated definitions. Poisson regression analyses of fracture rates modelled the explanatory variables as main effects and two-way interactions with ethnicity. RESULTS: Osteoporotic fracture rates were approximately twofold higher in the Aboriginal cohort (p<0.0001). Diabetes, greater number of ADGs and substance abuse were all more common in the Aboriginal cohort (all p<0.0001). These factors were associated with increased fracture rates (all p<0.0001) and significantly higher population attributable risk percent in the Aboriginal cohort (all p<0.0001). However, no significant interactions between the risk factors and ethnicity were observed (p>0.1 for all interaction effects). CONCLUSION: Greater prevalence of diabetes, comorbidity and substance abuse contributes to higher rates of fracture. The relative risk of fracture for these factors is similar for both Aboriginal and non-Aboriginals despite large differences in absolute fracture risk and risk factor prevalence.

What determines the need for nursing home admission in a universally insured population?

OBJECTIVES: People in lower socio-economic groups are more likely to experience disability and cognitive impairments at earlier ages than those in higher status groups. As a result, the need for nursing home care would be expected to be greater among older people of lower socio-economic status. This study examines the effects of income and education on the probability of nursing home entry in a universally insured elderly population. METHODS: Using a prospective observational study design, a range of predictors of nursing home admission was examined over a three-year period in a representative sample of 7220 residents, aged 60 years or older, in a Canadian province. Individual census records and computerized administrative records of health care utilization were linked to form a database for analysis. RESULTS: An increased risk of institutionalization was associated with older age, male gender, unmarried status and self-reported disability. In addition, lower household income and lower attained education were independently associated with a higher risk of nursing home admission. CONCLUSIONS: These results emphasize the independent role of socio-economic status in accentuating or accelerating the need for institutional care towards the end of life. It is important that these effects are recognized in policies that determine the finance of both nursing home care and formal community-based supportive care.

Assessing ecologic proxies for household income: a comparison of household and neighbourhood level income measures in the study of population health status.

This paper examines the validity of using ecologic measures of socioeconomic status as proxies for individual-level measures in the study of population health. Based on a representative 5% sample of households in a Canadian province, the study integrated three sources of information: administrative records of individual health care utilization, records of deaths and 1986 census records which contained information on household income and average neighbourhood income. Thirteen measures of health status were developed from these sources of information. The hypothesis that risk estimates derived from ecologic income measures will be attenuated relative to estimates obtained from household income was not supported. These results provide evidence for the use of ecologic-level measures of income in studies which do not have access to individual-level income measures.

Widening regional inequality in premature mortality rates in Manitoba.

OBJECTIVE: To describe regional trends in premature mortality in Manitoba. DESIGN: Comparison of all-cause and cause-specific mortality of persons less than age 75 in 11 Regional Health Authority populations over two time periods: 1985-89 and 1990-94. RESULTS: The provincial premature mortality rate declined over the two time periods (4.00/1,000 to 3.72/1,000). Declines were also observed in 9 of 11 regional populations. Premature mortality increased, however, in the 2 regional populations with the highest mortality rates in the first observation period. CONCLUSION: Declining premature mortality in low mortality populations and rising premature mortality in high mortality populations has resulted in a widening of regional mortality rates in Manitoba. Recent policy initiatives in many provinces, including the devolution of authority for the management and delivery of health services and the implementation of population need-based funding formulas to share health care resources among regional health authorities, if implemented, have the potential to partially mitigate the processes producing these widening regional health inequalities.

Age-specific education and income gradients in morbidity and mortality in a Canadian province.

While important age-related trends in the use of health care services over the past two decades in Canada have been well described, a comprehensive description of socioeconomic gradients in morbidity and mortality across age cohorts for a representative population has not been accomplished to date in Canada. The objective of this study was to describe age-specific socioeconomic differentials in mortality and morbidity for a representative sample of a single Canadian province. The study sample was formed from the linkage of individual respondent records in the 1986 census to vital statistics records and comprehensive records of health care utilization for a 5% sample of residents of the province of Manitoba. Using two measures of socioeconomic status derived from census responses, attained education and household income, individuals were stratified into age-specific quartile ranks. Based on diagnostic information contained on health care utilization records, the proportion of the sample in treatment during a 12-month observation period was calculated for 15 broadly defined categories of morbidity and tested for differences across socioeconomic quartiles. Mortality was inversely associated with both income and education quartile rank. In the analysis of morbidity, no association between socioeconomic status and treatment prevalence was observed in the majority, no association between socioeconomic status and treatment prevalence was observed in the majority of the 122 age- and disorder-specific strata tested. Of the observed associations, however, negative relationships were dominant, indicating a higher treatment prevalence among individuals of lower attained education or lower household income. Across the age course, negative relationships were most frequently present among young and middle aged adults, those aged 30-64, and were more consistently found for income than for education. The general findings of this study of a representative Canadian population support observations from other developed country settings that socioeconomic differences in relative rates of mortality and morbidity over the life course are greatest in the adult years.

Intensive use of mental health care.

OBJECTIVE: To describe the profile of the intensive use of mental health services over a 4-year period in a population of 1.1 million people. METHODS: Data obtained from computerized hospital separation records and physician reimbursement claims were combined to form patient-based histories of mental health care utilization. Users of mental health services in a 24-month period were hierarchically classified as having a psychotic disorder (ICD-9-CM 295-299) or a nonpsychotic disorder (ICD-9-CM 300-301, 306-309, 311). Intensive use was defined as 12 or more contact months or a minimum of 2 episodes of therapy in the 24-month period. The cohort of intensive users were followed over the subsequent 24-month interval to describe the persistence of intensive use. RESULTS: In the initial observation periods, intensive users constituted 27.4% of individuals in treatment for psychotic disorder and 4.4% of persons in treatment for nonpsychotic disorder. These 2 groups, which represent 7.4% of all users of mental health care, were responsible for 53% of physician services, 72.7% of contacts with psychiatrists, and 64.4% of acute psychiatric bed days in the initial period. In the follow-up period, intensive use status was replicated by 44.6% of the cohort. CONCLUSIONS: The diagnostic and therapeutic characteristics of intensive users of mental health services are heterogeneous. There is substantial persistence of intensive mental health service use over time.

Impact of a nurses' strike on the cesarean birth rate.

OBJECTIVE: Our purpose is to describe the impact of a 31-day nurses' strike on the cesarean birth rate in the province of Manitoba, Canada. STUDY DESIGN: Computerized hospital records, obtained for all births over a 24-month period, were used to identify complications of labor indicating cesarean section, method of delivery, and adverse maternal and newborn outcomes. The strike interval was compared with a 16-month prestrike period. RESULTS: The cesarean section rate in the strike interval, 12.5 per 100 deliveries, was significantly lower than the prestrike rate of 14.6 per 100 deliveries (p < 0.05). Reductions occurred primarily among breech deliveries and among women with a previous cesarean section. No differences were observed in the rates of individual adverse maternal or newborn outcomes. However, the pooled incidence of adverse newborn outcomes was significantly higher during the strike than during the prestrike period (10.2 vs 8.1/100 deliveries, odds ratio 1.27, 95% confidence interval 1.07 to 1.52). CONCLUSION: In response to constraints imposed by a reduced nursing complement, physicians increased the frequency of vaginal birth in breech presentation and among women with previous cesarean section.