Pitfalls of pharmacoepidemiology.
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Adolescent↗
Biomedical subjects
J A Kaye
Publications and source records attributed to J A Kaye.
Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis.
OBJECTIVE: To compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel. DESIGN: Cohort and case-control analyses derived from the General Practice Research Database. SETTING: UK general practices, January 1993 to December 1999. PARTICIPANTS: Women aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel. MAIN OUTCOME MEASURES: Relative incidence (cohort study) and odds ratios (case-control study) as measures of the relative risk of venous thromboembolism. RESULTS: The adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged. CONCLUSIONS: These findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.
Adolescent↗
The Oregon brain aging study: neuropathology accompanying healthy aging in the oldest old.
OBJECTIVE: To describe the relationship between neuropathologic aging and longitudinal measures of cognitive function in healthy oldest old individuals. METHODS: Nondemented individuals without cardiovascular or other age-associated diseases of age > or =85 years were followed until death. Regional postmortem measures of senile plaque (SP) and neurofibrillary tangle (NFT) severity were examined in relationship to clinical status, cognitive measures, and rate of cognitive change. RESULTS: Among 19 healthy individuals, 10 became demented or had incipient dementia develop. Clinical status and rate of change in cognitive scores correlated with increasing brain lesion burden, particularly in neocortical regions. Compared to demented individuals, nondemented individuals had few or no neocortical NFT (p = 0.009) or SP (p = 0.001). There was a strong correlation between rate of cognitive change on Mini-Mental State Examination (MMSE) and neocortical NFT (r = 0.859, p = 0.001). The few NFT and SP in nondemented patients had a predilection for limbic areas. CONCLUSIONS: These results support a continuum in which AD is infrequent in the healthy, cognitively stable, oldest old. The minimal abnormalities in cognitively stable individuals are consistent with the notion that preclinical pathologic AD precedes obvious cognitive impairment. Longitudinal cognitive testing shows an increased burden of neuropathologic changes in those who have cognitive decline but are not functionally impaired and do not meet criteria for the diagnosis of dementia. The strong relationship between cumulative pathologic changes and rate of cognitive decline suggests that these lesions may have clinical consequences at any age and are not likely to be benign senescent changes.
Aged↗
Methods for discerning disease-modifying effects in Alzheimer disease treatment trials.
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Alzheimer Disease↗
The incidence of breast cancer in the General Practice Research Database compared with national cancer registration data.
Breast cancer incidence rates in the UK from 1990 to 1996 among women aged 35-69 estimated from the General Practice Research Database (GPRD) were closely similar to those reported by the Office for National Statistics from cancer registration data (ONS). The GPRD is a valuable and up-to-date resource for further study of the incidence of breast cancer in the UK as well as changes in cancer treatment and their relation to survival trends.
Adult↗
Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease.
OBJECTIVES: To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). DESIGN: Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n = 14; mean age, 70 years), old healthy elderly (OHE) (n = 14; mean age, 90 years), and subjects with AD (n = 14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. RESULTS: Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. CONCLUSIONS: In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.
Aged↗
Factors associated with brain donation among optimally healthy elderly people.
BACKGROUND: Consent rates for brain donation were examined in 140 healthy elderly participants of the Oregon Brain Aging Study, a longitudinal study of successful aging. Subjects were initially selected for good health. The study population had a relatively high education level, a high socioeconomic status, and were predominantly white. METHODS: At each annual examination, a project physician asked participants to consider brain donation. This analysis examined variables that may affect the rate of brain donation consent: age, gender, education, socioeconomic status, marital status, religiosity, cognitive status, depression, and functional status. RESULTS: Of these variables only age was a meaningful factor. CONCLUSION: The oldest old participants (> or =85 years of age) were more likely to consent to donation than the younger participants (65-84 years of age).
Age Factors↗
Age-related brain changes associated with motor function in healthy older people.
OBJECTIVE: To identify the MRI imaging findings associated with motor changes in healthy older people. DESIGN: A cross-sectional study. SETTING: A study of neurologic function in very healthy older people, the Oregon Brain Aging Study. PARTICIPANTS: Clinical and MRI data were examined in 50 very healthy older subjects (mean age = 85.1, SD = 7.2 years). MEASUREMENTS: Clinical measures (finger tapping, hand opening and closing, steps and time to walk 30 feet and timed standing on one foot) were dependent variables in multiple regression analyses using age and the following MRI measures as independent variables: total brain volume (TBV)/intracranial volume; ventricular volume/TBV; periventricular high signal/TBV; deep high signal/TBV. RESULTS: The number of steps and the time to walk 30 feet were each associated with periventricular high signal (steps: r = .58, P < .001; time: r = .60, P < .001) and ventricular volume (steps: r = .54, P < .001; time: r = .58, P < .001). These associations remained significant after adjusting for age. None of the other clinical variables was associated with the MRI volumes. CONCLUSIONS: Gait measures were associated significantly with periventricular high signal and ventricular volume. These CNS changes contribute to the cause of these important markers of aging.
Aged↗
Age-related differences in global-local processing: stability of laterality differences but disproportionate impairment in global processing.
Visual processing of global and local features differentially engages the right and left hemispheres and requires different allocations of spatial attention. To further understand the decline in visual cognition and visual attention with age, we studied the performance of healthy young subjects and healthy elders on a global-local figures task. The results showed that elders processed global images more quickly when presented in the left visual field and local images in the right visual field, similarly to the young controls. However, we did observe a significant impairment in the elders' ability to process global figures compared with local figures, despite there being no overall difference between global and local processing speed among the young. It is thought that this age-related decline in global processing is related to the narrowed attentional field that can be demonstrated in other age-related visual processing declines such as visual search and useful field of view.
Adult↗
The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.
OBJECTIVE: To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature. METHODS: An attempt was made to identify all English and non-English-language articles in which G. biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, or National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system-active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis. RESULTS: Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 (P<.0001). This modest effect size translated into a 3% difference in the Alzheimer Disease Assessment Scale-cognitive subtest. CONCLUSIONS: Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.
Alzheimer Disease↗
FDA licensure of NEUMEGA to prevent severe chemotherapy-induced thrombocytopenia.
This paper discusses background information and the body of clinical data that has been accumulated to demonstrate the efficacy and safety of NEUMEGA (recombinant human interleukin 11) when used to prevent severe chemotherapy-induced thrombocytopenia and reduce the need for platelet transfusions in patients with nonmyeloid malignancies. NEUMEGA is recommended to be used at a dose of 50 microg/kg s.c. once daily starting the day after chemotherapy ends until a platelet count of 50,000 cells/microl is achieved after the expected nadir.
Antineoplastic Agents↗
The rate of progression of Alzheimer's disease in the later stages: evidence from the Severe Impairment Battery.
This study describes changes in cognitive function in patients who are typically excluded from longitudinal studies due to their inability to complete most standardized batteries. Thirty-three patients with moderate to severe Alzheimer's disease were assessed by means of the Severe Impairment Battery (SIB), Mini Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and measures of functional status. Follow-up evaluations were conducted, and annual rates of change were calculated. Patients with severe cognitive impairment demonstrated rates of progression similar to patients who were moderately impaired at initial evaluation. Rates of decline on the SIB were unrelated to baseline cognitive function, and annual rate of decline in Year 1 was not correlated with disease progression in the subsequent year. This study demonstrates that, with appropriate assessments, severely impaired patients can exhibit a range of performance and rates of decline that are comparable to those of moderately impaired patients.
Aged↗
A randomized trial of recombinant human interleukin-11 following autologous bone marrow transplantation with peripheral blood progenitor cell support in patients with breast cancer.
This study assessed the safety and efficacy of recombinant human interleukin (rhIL)-11 in decreasing platelet transfusion requirements in patients with breast cancer who were undergoing autologous bone marrow transplantation (ABMT) with peripheral blood progenitor cell (PBPC) support. After high-dose therapy with cyclophosphamide, cisplatin, and carmustine, 80 patients were randomized to one of three treatment groups: placebo (26), 25 microg/kg of rhIL-11 (28), and 50 microg/kg of rhIL-11 (26). Of those randomized, 75 (94%) received at least one dose of the masked study drug and the remaining 5 (6%) withdrew consent before study drug administration. In the placebo group, each patient received an average 12.4 (+/-10.2) platelet transfusions vs. 9.2 (+/-5.0) in the 25-microg/kg rhIL-11 group (p = 0.17) and 9.9 (+/-3.5) in the 50-microg/kg rhIL-11 group (p = 0.34). There was no statistically significant difference between the rhIL-11 groups and the placebo group in the median number of days to platelet recovery. Neutrophil and red blood cell recovery were similar for all treatment groups. The imbalance in the number of patients already alloimmunized at study entry in the rhIL-11 groups (12) and in the placebo group (1) may have confounded the primary efficacy assessment. Most adverse events were related to the high-dose chemotherapy. Generally mild edema and minor conjunctival bleeding (grades 1 or 2) were statistically associated with rhIL-11 administration (p < 0.04). There was no association between rhIL-11 and the occurrence of atrial arrhythmias, although there was a suggestion of an association with rhIL-11, 5 of 50 cases vs. 1 of 25 in the placebo group. Two cardiovascular events, tachycardia and hypotension (grade 1 or 2), occurred in the 50-microg/kg rhIL-11 group. The number of patients who discontinued study drug dosing because of an adverse event was distributed across all treatment groups. In summary, rhIL-11 was safe and well tolerated in this study. The results did not demonstrate that rhIL-11 treatment significantly decreased platelet transfusion requirements after high-dose chemotherapy with ABMT and PBPC support.
Adult↗
Verbal fluency task affects gait in Parkinson's disease with motor freezing.
We examined the effects of a simultaneous verbal fluency task on walking in Parkinson's disease (PD) patients with freezing of gait (PD-F) compared to nonfreezing patients (PD-NF) or control subjects (C). Effects of antiparkinsonian medications on gait in PD-F were examined. PD-F patients exhibited a greater increase in the number of steps to complete the walk with verbal fluency, even when the effect of medication was taken into account (mean increase +/- SD): PD-F = 4.2 +/- 4.6, n = 10; PD-NF = 0.1 +/- 1.6, n = 9; C = 1.5 +/- 1.5, n = 19; P = .007. Medications improved walking in PD-F patients by decreasing the number of steps, the time to walk, and freezing. PD-F patients may be more dependent on attention for walking.
Aged↗
Diagnostic challenges in dementia.
As the population ages, increasing numbers of patients will present with dementia. Diagnosis may be very straightforward, as in an individual with dementia secondary to an obvious medical illness. However, the differential diagnosis of dementia may be less clear. Diagnostically challenging cases tend to appear in the setting of dementias that present without distinctive neurologic signs or evidence of medical or neurologic disease, such as Alzheimer's disease or the frontotemporal dementias. A similar diagnostic challenge is seen in dementias that present with neurologic signs but without obvious significant medical disorders, such as the parkinsonian dementias or the vascular dementias. In recent years, the presentations of these dementias have become more sharply drawn on the basis of consensus reviews of clinicopathologic correlations. Because each of these disorders has unique treatment and management strategies, the ability of clinicians to differentiate among these syndromes has become critically important.
Dementia↗
Brain volume preserved in healthy elderly through the eleventh decade.
OBJECTIVE: To determine which brain regions lose volume with aging over time in healthy, nondemented elderly. BACKGROUND: Cross-sectional studies suggest widespread loss of brain volume with aging. These studies may be biased by significant numbers of preclinically demented elderly in the oldest comparison groups. Longitudinal studies may allow closer determination of the effect of aging unaffected by dementia. METHODS: Quantitative volumetric MRI was performed annually on 46 healthy subjects older than age 65 who had maintained cognitive health a mean of 5 years. Comparisons (analysis of variance) were made of rates of volume loss (slopes) divided into 11 young-old (mean age, 70 years), 15 middle-old (mean age, 81 years), and 20 oldest-old (mean age, 87 years) subjects. Regions of interest included CSF spaces, lobar regions, and limbic-subcortical regions. RESULTS: There were significant differences between groups in intracranial, total brain, left hemisphere, right hemisphere, temporal lobe, basilar-subcortical region, and hippocampus volumes, with oldest-old subjects showing the smallest volumes, followed by middle-old and young-old subjects. Oldest-old subjects had significantly greater subarachnoid volumes than the younger groups. There were no significant differences in rates of change of regions of interest across age groups. CONCLUSIONS: After age 65 there is minimal brain volume loss observed over time in healthy elderly. Brain volume differences seen cross-sectionally, at any age, likely reflect small, constant rates of volume loss with healthy aging. Healthy oldest-old subjects do not show greater rates of brain loss compared with younger elderly, suggesting that large changes seen in cross-sectional studies reflect the presence of preclinical dementia in older groups.
Aged↗
Recognition of neurologic diseases in geriatric inpatients.
OBJECTIVES: To determine the prevalence of neurologic disease and the diagnostic impact of neurologic consultation on a geriatric inpatient unit. MATERIAL AND METHODS: Consecutively admitted patients were prospectively assessed by a neurologist and by medical house staff on a geriatrics unit over a 4-month period. Neurologic diagnoses were compared. RESULTS: Fifty-eight men, aged 76.4+/-8.7 years old (mean+/-SD), had 1.4+/-1.1 new or revised neurologic diagnoses made by the neurologist. The prevalence of neurologic disorder was: gait or balance disorder (90%); cognitive disorders (71%); neuromuscular disorder (59%); cerebrovascular disorder (38%); and extrapyramidal disorders (22%). New diagnoses were made by the neurologist among the cognitive (40%), neuromuscular (36%) and cerebrovascular disorders (19%). CONCLUSIONS: Neurologic disease is highly prevalent in geriatric inpatients. A neurologist's assessment resulted in altered diagnoses suggesting that neurologists should play a role in geriatric assessment and in education of health professionals caring for the elderly.
Activities of Daily Living↗
Oldest-old healthy brain function. The genomic potential.
There will be a remarkable increase in the number of people older than 85 years--the oldest-old--in the next 50 years. This age group is especially vulnerable to increasing disabilities, many of which are the result of the aging nervous system. Among these aging changes, the most devastating and likely to have the greatest impact on our society is the development of dementia. Since dementia is present in the majority of those who live to the current maximum of the human life span, this suggests that dementia is a normal aging event. Although the exact causes of this common cognitive failure in the oldest-old are not known, there is recent evidence from genetic studies of aging and Alzheimer disease to suggest that there are a number of susceptibility genes that may modify or delay the onset of late-life brain failure. These gene families form a natural target for devising strategies for significantly delaying the onset of late-life dementia.
Aged↗