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Biomedical subjects

Jeffrey A Johnson

Publications and source records attributed to Jeffrey A Johnson.

At least 19 recordsLinked to original sources
PubMed2007

Developmental exposure to methylmercury alters learning and induces depression-like behavior in male mice.

To investigate the long-term effects of developmental exposure to methylmercury (MeHg), pregnant mice were exposed to at 0.5 mg MeHg/kg/day via drinking water from gestational day 7 until day 7 after delivery. The behavior of offspring was monitored at 5-15 and 26-36 weeks of age using an automated system (IntelliCage) designed for continuous long-term recording of the home cage behavior in social groups and complex analysis of basic activities and learning. In addition, spontaneous locomotion, motor coordination on the accelerating rotarod, spatial learning in Morris water maze, and depression-like behavior in forced swimming test were also studied. The analysis of behavior performed in the IntelliCage without social deprivation occurred to be more sensitive in detecting alterations in activity and learning paradigms. We found normal motor function but decreased exploratory activity in MeHg-exposed male mice, especially at young age. Learning disturbances observed in MeHg-exposed male animals suggest reference memory impairment. Interestingly, the forced swimming test revealed a predisposition to depressive-like behavior in the MeHg-exposed male offspring. This study provides novel evidence that the developmental exposure to MeHg can affect not only cognitive functions but also motivation-driven behaviors.

Alkaline Phosphatase↗
PubMed2006

Utilization of diabetes medication and cost of testing supplies in Saskatchewan, 2001.

The purpose of this study was to describe the patterns of antidiabetic medication use and the cost of testing supplies in Canada using information collected by Saskatchewan's Drug Plan (DP) in 2001. The diabetes cohort (n = 41,630) included individuals who met the National Diabetes Surveillance System (NDSS) case definition. An algorithm was then used to identify subjects as having type 1 or type 2 diabetes. Among those identified as having type 2 diabetes (n = 37,625), 38% did not have records for antidiabetic medication in 2001. One-third of patients with type 2 diabetes received monotherapy. Metformin, alone or in combination with other medications, was the most commonly prescribed antidiabetic medication. Just over one-half of the all patients with diabetes had a DP records for diabetes testing supplies. For individuals (n = 4,005) with type 1 diabetes, 79% had a DP record for supplies, with an average annual cost of 472 +/- 560 dollars. For type 2 diabetes, 50% had records for testing supplies, with an average annual cost of 122 +/- 233 dollars. Those individuals with type 2 diabetes who used insulin had higher testing supply costs than those on oral antidiabetic medication alone (359 vs 131 dollars; p < 0.001).

Adult↗
PubMed2006

Assessing responsiveness of generic and specific health related quality of life measures in heart failure.

BACKGROUND: Responsiveness, or sensitivity to clinical change, is an important consideration in selection of a health-related quality of life (HRQL) measure for trials or clinical applications. Many approaches can be used to assess responsiveness, which may affect the interpretation of study results. We compared the relative responsiveness of generic and heart failure specific HRQL instruments, as measured both by common psychometric indices and by external clinical criteria. METHODS: We analyzed data collected at baseline and 6-weeks in 298 subjects with heart failure on the following HRQL measures: EQ-5D (US, UK, and VAS Scoring), Kansas City Cardiomyopathy Questionnaire (KCCQ) (Clinical and Overall Summary Score), and RAND12 (Physical and Mental Component Summaries). Three external indicators of clinical change were used to classify subjects as improved, deteriorated, or unchanged: 6-minute walk test, New York Heart Association (NYHA) class, and physician global rating of change. Four responsiveness statistics (T-test, effect size, Guyatt's responsiveness statistic, and standardized response mean) were used to evaluate the responsiveness of the select measures. The median rank of each HRQL measure across responsiveness indices and clinical criteria was then determined. RESULTS: Average age of subjects was 60 years, 75 percent were male, and had moderate to severe heart failure symptoms. Overall, the KCCQ Summary Scores had the highest relative ranking, irrespective of the responsiveness index or external criterion used. Importantly, we observed that the relative ranking of responsiveness of the generic measures (i.e. EQ-5D, RAND12) was influenced by both the responsive indices and external criterion used. CONCLUSION: The disease specific KCCQ was the most responsive HRQL measure assessing change over a 6-week period, although generic measures provide information for which the KCCQ is not suitable. The responsiveness of generic HRQL measures may be affected by the index used, as well as the external criterion to classify patients who have clinically change or remained stable.

Adult↗
PubMed2006

Electrophilic chemicals but not UV irradiation or reactive oxygen species activate Nrf2 in keratinocytes in vitro and in vivo.

The NF-E2-related factor 2 (Nrf2) transcription factor is a potent inducer of cytoprotective genes, which encode--among others--enzymes that detoxify reactive oxygen species (ROS). As we demonstrated a crucial role of Nrf2 in the prevention of skin carcinogenesis, it is of interest to identify Nrf2-activating factors in keratinocytes. For this purpose, keratinocytes from mice transgenic for an Nrf2-responsive reporter gene were analyzed. Electrophilic compounds activated the reporter in keratinocytes, and induced nuclear translocation of Nrf2 and the expression of known Nrf2 target genes. This is biologically relevant, as we show that Nrf2-mediated gene expression protects keratinocytes from the toxicity of these substances. By contrast, hydrogen peroxide, glucose oxidase, UVA, and UVB irradiation had no effect, although these treatments strongly increased the levels of intracellular ROS. To verify these results in vivo, transgenic reporter mice with and without functional Nrf2 alleles were topically treated with electrophilic chemicals or irradiated with UVB. Electrophiles but not UVB activated the reporter in an Nrf2-dependent manner. These results provide the basis for the identification of novel Nrf2 activators in keratinocytes with therapeutic potential for skin tumor prevention.

Active Transport, Cell Nucleus↗
PubMed2006

Longitudinal validation of a modified Edmonton symptom assessment system (ESAS) in haemodialysis patients.

BACKGROUND: Health-related quality of life (HRQL) is an important outcome in the treatment of end-stage renal disease (ESRD) and appears to be highly associated with patient self-report of symptom burden. This study examines the longitudinal validity of the modified Edmonton symptom assessment system (ESAS) to determine the impact of change in symptom burden on the change in HRQL of haemodialysis (HD) patients. METHODS: 261 haemodialysis patients completed the Kidney Disease Quality of Life-Short Form (KDQOL-SF) and the ESAS at baseline and at 6 months. RESULTS: The change in overall symptom distress score was strongly correlated with the change in KDQOL-SF subscales symptom/problem list (R=-0.73, P<0.01), effects of kidney disease (R=-0.53, P<0.01), and burden of kidney disease (R=-0.46, P<0.01) as well as overall physical health composite (R=-0.58, P<0.01) and overall mental health composite (R=-0.68, P<0.01). The change in symptom burden, as described by the ESAS, accounted for 46% of the change in the mental HRQL and 34% of the change in the physical HRQL. There was no correlation between baseline demographics, comorbidity or changes in biochemical markers with changes in either the ESAS or HRQL scores. CONCLUSION: The modified ESAS is a simple, valid tool for the longitudinal assessment of physical and psychological symptom burden in ESRD and is responsive to change in HD patients. The use of this symptom assessment scale and improved management of patient symptoms would be expected to positively impact HD patients' HRQL.

Adult↗
PubMed2006

Understanding the determinants of health for people with type 2 diabetes.

OBJECTIVE: We assessed which of a broad range of determinants of health are most strongly associated with health-related quality of life (HRQL) among people with type 2 diabetes. METHODS: Our analysis included respondents from the Canadian Community Health Survey Cycle 1.1 (2000-2001) who were aged 18 years and older and who were identified as having type 2 diabetes. We used regression analyses to assess the associations between the Health Utilities Index Mark 3 and determinants of health. RESULTS: Comorbidities had the largest impact on HRQL, with stroke (-0.11; 95% confidence interval [CI] = -0.17, -0.06) and depression (-0.11; 95% CI = -0.15, -0.06) being associated with the largest deficits. Large differences in HRQL were observed for 2 markers of socioeconomic status: social assistance (-0.07; 95% CI=-0.12, -0.03) and food insecurity (-0.07; 95% CI=-0.10, -0.04). Stress, physical activity, and sense of belonging also were important determinants. Overall, 36% of the variance in the Health Utilities Index Mark 3 was explained. CONCLUSION: Social and environmental factors are important, but comorbidities have the largest impact on HRQL among people with type 2 diabetes.

Aged↗
PubMed2006

Type 2 diabetes does not increase risk of depression.

BACKGROUND: Although diabetes mellitus has a strong association with the presence of depression, it is unclear whether diabetes itself increases the risk of developing depression. The objective of our study was to evaluate whether people with diabetes have a greater incidence of depression than those without diabetes. METHODS: We conducted a population-based retrospective cohort study using the administrative databases of Saskatchewan Health from 1989 to 2001. People older than 20 years with newly identified type 2 diabetes were identified by means of diagnostic codes and prescription records and compared with a nondiabetic cohort. Depression was ascertained via diagnostic codes and prescriptions for antidepressants. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for age, sex, frequency of visits to physicians and presence of comorbidities. RESULTS: We identified 31 635 people with diabetes and 57 141 without. Those with diabetes were older (61.4 v. 46.8 yr; p < 0.001), were more likely to be male (55.4% v. 49.8%; p < 0.001) and had more physician visits during the year after their index date (mean 14.5 v. 5.9; p < 0.001). The incidence of new-onset depression was similar in both groups (6.5 v. 6.6 per 1000 person-years among people with and without diabetes, respectively). Similarity of risk persisted after controlling for age, sex, number of physician visits and presence of prespecified comorbidities (adjusted HR 1.04, 95% CI 0.94- 1.15). Other chronic conditions such as arthritis (HR 1.18) and stroke (HR 1.73) were associated with the onset of depression. INTERPRETATION: Using a large, population-based administrative cohort, we found little evidence that type 2 diabetes increases the risk of depression once comorbid diseases and the burden of diabetes complications were accounted for.

Adult↗
PubMed2006

A meta-analysis of the association between adherence to drug therapy and mortality.

OBJECTIVE: To evaluate the relation between adherence to drug therapy, including placebo, and mortality. DESIGN: Meta-analysis of observational studies. DATA SOURCES: Electronic databases, contact with investigators, and textbooks and reviews on adherence. Review methods Predefined criteria were used to select studies reporting mortality among participants with good and poor adherence to drug therapy. Data were extracted for disease, drug therapy groups, methods for measurement of adherence rate, definition for good adherence, and mortality. RESULTS: Data were available from 21 studies (46,847 participants), including eight studies with placebo arms (19,633 participants). Compared with poor adherence, good adherence was associated with lower mortality (odds ratio 0.56, 95% confidence interval 0.50 to 0.63). Good adherence to placebo was associated with lower mortality (0.56, 0.43 to 0.74), as was good adherence to beneficial drug therapy (0.55, 0.49 to 0.62). Good adherence to harmful drug therapy was associated with increased mortality (2.90, 1.04 to 8.11). CONCLUSION: Good adherence to drug therapy is associated with positive health outcomes. Moreover, the observed association between good adherence to placebo and mortality supports the existence of the "healthy adherer" effect, whereby adherence to drug therapy may be a surrogate marker for overall healthy behaviour.

Drug Therapy↗
PubMed2006

A cross-sectional study of health-related quality of life deficits in individuals with comorbid diabetes and cancer.

BACKGROUND: Numerous studies have identified a reduced health related quality of life (HRQL) in patients that have either diabetes or cancer. We assessed the HRQL burden in patients with these comorbid conditions, postulating that they would have even greater HRQL deficits. METHODS: Data from the Public Use File of the Canadian Community Health Survey (PUF CCHS) Cycle 1.1 (September 2000-November 2001) were used for this analysis. The total sample size of the CCHS PUF is 130,880 individuals. We used the Health Utilities Index Mark 3 (HUI3) to assess HRQL in patients with: 1) comorbid diabetes and cancer, 2) diabetes alone, 3) cancer alone, and 4) no diabetes or cancer. Analysis of covariance was used to compare the mean overall HUI3 score, controlling for age, sex, marital status, body mass index (BMI), physical activity level, smoking status, education level, depression status, and other chronic conditions. RESULTS: We identified 113,587 individuals (87%) with complete data for the analysis. The comorbid diabetes and cancer group were older and a larger proportion reported being obese, inactive, having less than a secondary education and more chronic conditions when compared to the other three cohorts (p < 0.0001). However, the diabetes and cancer cohort was less likely to be depressed (p < 0.0001). Overall HUI3 scores were significantly lower for the diabetes and cancer group (unadjusted mean (SD): 0.67 (0.30)), compared to diabetes (0.78 (0.27)), cancer (0.78 (0.25)), and the reference group (0.89 (0.18)) (p < 0.0001). After adjusting for covariates, the comorbid diabetes and cancer group continued to have significantly lower overall HUI3 scores than the reference group (unstandardized mean difference: -0.11, 95% CI: -0.13 to -.0.09) (p < 0.0001). CONCLUSION: Individuals with diabetes and cancer had a clinically important and significantly lower HRQL than those with either condition alone. A better understanding of the relationship between diabetes and cancer, and their associated comorbidities, complications, and HRQL deficits may have important implications for prevention and management strategies.

Adolescent↗
PubMed2006

Misinterpretation with norm-based scoring of health status in adults with type 1 diabetes.

BACKGROUND: Interpretations of profile and preference based measure scores can differ. Profile measures often use a norm-based scoring algorithm where each scale is scored to have a standardized mean and standard deviation, relative to the general population scores/norms (i.e., norm-based). Preference-based index measures generate an overall scores on the conventional scale in which 0.00 is assigned to dead and 1.00 is assigned to perfect health. Our objective was to investigate the interpretation of norm-based scoring of generic health status measures in a population of adults with type 1 diabetes by comparing norm-based health status scores and preference-based health-related quality of life (HRQL) scores. METHODS: Data were collected through self-complete questionnaires sent to patients with type 1 diabetes. The RAND-36 and the Health Utilities Index Mark 3 (HUI3) were included. RESULTS: A total of 216 (61%) questionnaires were returned. The respondent sample was predominantly female (58.8%); had a mean (SD) age of 37.1 (14.3) years and a mean duration of diabetes of 20.9 (12.4) years. Mean (SD) health status scores were: RAND-36 PHC 47.9 (9.4), RAND-36 MHC 47.2 (11.8), and HUI3 0.78 (0.23). Histograms of these scores show substantial left skew. HUI3 scores were similar to those previously reported for diabetes in the general Canadian population. Physical and mental health summary scores of the RAND-36 suggest that this population is as healthy as the general adult population. CONCLUSION: In this sample, a preference-based measure indicated poorer health, consistent with clinical evidence, whereas a norm-based measure indicated health similar to the average for the general population. Norm-based scoring measure may provide misleading interpretations in populations when health status is not normally distributed.

Adult↗
PubMed2006

Health Utilities Index mark 3 demonstrated construct validity in a population-based sample with type 2 diabetes.

OBJECTIVE: To assess the cross-sectional construct validity of the Health Utilities Index mark 3 (HUI3) in type 2 diabetes using population health survey data. STUDY DESIGN AND SETTING: Data used were from 5,134 adult respondents of Cycle 1.1 (2000-2001) of the Canadian Community Health Survey (CCHS) with type 2 diabetes. Analyses of covariance models were used to assess differences in overall and single-attribute HUI3 scores between groups hypothesized a priori to differ in HRQL. The association between health-care resource use (i.e., hospitalizations and physician and emergency room visits) and overall HUI3 scores was assessed using logistic regression models. RESULTS: For overall HUI3 scores, clinically important and statistically significant differences were observed between all groups expected to differ in HRQL. Depression was the comorbidity associated with the largest deficit (-0.17; 95% confidence interval CI=-0.22, -0.12), followed by stroke (-0.15; 95% CI=-0.21, -0.10) and heart disease (-0.08; 95% CI=-0.11, -0.05). Insulin use and comorbidities were associated with clinically important deficits in pain. Overall HUI3 scores were significantly predictive of all three categories of health-care resource use. CONCLUSION: Observed differences between groups contribute further evidence of the construct validity of the HUI3 in type 2 diabetes.

Canada↗
PubMed2006

Educational intervention to reduce falls and fear of falling in patients after fragility fracture: results of a controlled pilot study.

OBJECTIVES: Falls and fear of falling are a major health problem. We sought to determine the effectiveness of an educational intervention in reducing fear of falling and preventing recurrent falls in community-dwelling patients after a fragility fracture. METHODS: One hundred two community-dwelling patients aged 50 years or older who fell and sustained a wrist fracture and were treated at Emergency Departments in Edmonton, Alberta, Canada (2001-2002) were allocated to either standardized educational leaflets and post-discharge telephone counseling regarding fall prevention strategies ("intervention") or attention-controls ("controls"). Main outcomes were fear of falling and recurrent falls 3 months after fracture. RESULTS: Mean age was 67 years and most patients were female (80%). The majority of falls (76%) leading to fracture occurred outdoors. Three months post-fracture, almost half of patients (48%) reported increased fear of falling and 11 of 102 (11%) reported falling again. The intervention did not reduce the fear of falling (43% had increased fear vs. 53% of controls, adjusted P value=0.55) or decrease recurrent falls (17% fell vs. 5% of controls, adjusted P value=0.059) within 3 months of fracture. CONCLUSIONS: An educational intervention undertaken in the Emergency Department was no more effective than usual care in reducing fear of falling or recurrent falls in community-dwelling patients. Future strategies must address a number of dimensions beyond simple education.

Accidental Falls↗
PubMed2006

Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study.

BACKGROUND: Over the past 30 years, the relation between use of sulfonylureas to treat type 2 diabetes and the risk of cardiovascular events has been vigorously debated. The purpose of this study was to determine if the risk of death changes with level of exposure to sulfonylurea drugs. METHODS: This was a retrospective, inception cohort study using administrative data from Saskatchewan Health (1991-1999). The 5795 subjects, identified by their first-ever dispensation for an oral antidiabetic agent, were grouped according to their use of such agents during follow-up. Potential subjects using insulin or combination therapy were excluded. Exposure level was defined by daily dose and degree of adherence. Separate multivariate Cox proportional-hazard models were constructed for each monotherapy group and used to calculate the risk of death associated with higher versus lower exposure category. Disease severity indicators were identified among the administrative data and entered as covariates in each model. The main outcomes were all-cause mortality and death from an acute ischemic event. RESULTS: The mean age of the cohort members was 66.3 (standard deviation [SD] 13.4) years; 43.4% were female; and their mean duration of follow-up was 4.6 (SD 2.1) years. First-generation sulfonylureas were used exclusively by 120 subjects; glyburide, by 4138; and metformin, by 1537. A greater risk of death was associated with higher daily doses of the first-generation sulfonylureas (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.0-4.7) and glyburide (HR 1.3, 95% CI 1.2-1.4), but not metformin (HR 0.8, 95% CI 0.7-1.1). Similar associations were observed for death caused by an acute ischemic event. INTERPRETATION: Higher exposure to sulfonylureas was associated with increased mortality among patients newly treated for type 2 diabetes. The same relation was not observed with metformin. This implies that the manner in which blood glucose concentration is lowered may be as important as achieving recommended glucose targets.

Aged↗
PubMed2006

A rapid and sensitive real-time PCR assay for the K65R drug resistance mutation in SIV reverse transcriptase.

Macaques infected with simian immunodeficiency virus (SIV) provide a suitable model for assessing the efficacy of antiretroviral (ARV) drug interventions and drug resistance selection associated with treatment. Resistance to the HIV reverse transcriptase inhibitor tenofovir continues to be examined in different treatment strategies in the macaque model. Evaluations of treatment interventions and drug resistance are hampered by the limited sensitivity of conventional population sequencing and the substantial effort involved in testing various tissue compartments in which viruses may reside. Therefore, a sensitive assay that permits simple and rapid testing for drug-resistant viruses would benefit appraisals of ARV treatments using in vivo models. To have this capability, we developed a real-time PCR-based assay for the detection of the SIV K65R reverse transcriptase mutation, a key marker for reduced susceptibility to tenofovir. Evaluations of SIV sequences yielded an assay detection limit mean of 0.4% mutant virus (range = 0.1-2%) in a wild-type background. In testing longitudinal plasma specimens from four SIV-infected macaques that received an active daily regimen of 30 mg/kg of tenofovir subcutaneously, the assay was able to detect K65R-positive viruses in all animals within 1-7 weeks after treatment began. The emerging mutants were initially present at frequencies estimated between 0.4% and 3%, below the detection capability of population sequencing. We propose the SIV K65R real-time PCR assay provides improved sensitivity and simplicity in studying tenofovir resistance in macaque models.

Adenine↗
PubMed2006

Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element.

The transcription factor, nuclear factor E2 (erythroid-derived 2)-related factor 2 (Nrf2), is essential for the induction of a battery of phase II detoxification genes through the antioxidant response element (ARE) that lies in their promoter region. Genes driven by the ARE are up-regulated in response to various stressors of the cellular environment. These genetic changes to the cellular reducing potential may reflect an intrinsic damage response to harmful toxicants. Analysis of transgenic reporter mice following kainate injection revealed selective ARE activation within the damaged hippocampus. Further, 2 x 2 microarray analyses comparing Nrf2 knockout versus wild-type hippocampi unmasked gene changes associated with ion movement and myelination, in addition to alterations to detoxification-related genes. Nrf2 knockout mice were more sensitive to kainate toxicity, as evidenced by elevated seizure severity, seizure duration, hippocampal neuron damage and mortality. Knockout mice injected with kainate displayed altered glial fibrillary acidic protein immunoreactivity and increased microglial infiltration. The wild-type to knockout damage differential was not dependent on the peripheral metabolism of the excitotoxin, was well correlated with increased seizure susceptibility, and was therefore not necessarily the neuroprotective effects of Nrf2. These results combine to support a role for Nrf2 in the neural cell defense response of the adult brain.

Animals↗
PubMed2006

Structured treatment interruptions with tenofovir monotherapy for simian immunodeficiency virus-infected newborn macaques.

We demonstrated previously that prolonged tenofovir treatment of infant macaques, starting early during infection with virulent simian immunodeficiency virus (SIVmac251), can lead to persistently low or undetectable viremia even after the emergence of mutants with reduced in vitro susceptibility to tenofovir as a result of a K65R mutation in reverse transcriptase; this control of viremia was demonstrated to be mediated by the generation of effective antiviral immune responses. To determine whether structured treatment interruptions (STI) can induce similar immunologic control of viremia, eight newborn macaques were infected with highly virulent SIVmac251 and started on a tenofovir STI regimen 5 days later. Treatment was withdrawn permanently at 33 weeks of age. All animals receiving STI fared much better than 22 untreated SIVmac251-infected infant macaques. However, there was a high variability among animals in the viral RNA set point after complete drug withdrawal, and none of the animals was able to achieve long-term immunologic suppression of viremia to persistently low levels. Early immunologic and viral markers in blood (including the detection of the K65R mutation) were not predictive of the viral RNA set point after drug withdrawal. These results, which reflect the complex interactions between drug resistance mutations, viral virulence, and drug- and immune-mediated inhibition of virus replication, highlight the difficulties associated with trying to develop STI regimens with predictable efficacy for clinical practice.

Adenine↗