Priorities and rationing: pragmatism or principles?
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Advisory Committees↗
Biomedical subjects
R Klein
Publications and source records attributed to R Klein.
Developmental changes in NT3 signalling via TrkA and TrkB in embryonic neurons.
Neurotrophins promote neuronal survival by signalling through Trk receptor tyrosine kinases: nerve growth factor signals through TrkA, brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)4 through TrkB and NT3 through TrkC. Although studies in some, but not all, cell lines indicate that NT3 can also signal through TrkA and TrkB, it is not known if such signalling can occur in neurons. We show that NT3 can promote the in vitro survival of sensory and sympathetic neurons isolated from embryos that are homozygous for a null mutation in the trkC gene. During the mid-embryonic period, NT3 promoted the survival of as many trigeminal and nodose neurons as the preferred neurotrophins, NGF and BDNF. However, later in development, these neurons lost their ability to respond to NT3. NT3 also promoted the survival of almost all sympathetic neurons, but no decrease in effectiveness was observed during development. Trigeminal neurons from trkC-/- trkA-/- embryos did not respond to NT3 and nodose neurons from trkB-/- embryos likewise failed to respond to NT3. These results show that NT3 can signal through TrkA and TrkB in neurons at certain stages of development and may explain why the phenotype of NT3-/- mice is more severe than that of trkC-/- mice.
Age Factors↗
Labour's health policy.
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Health Care Reform↗
Membrane-bound LERK2 ligand can signal through three different Eph-related receptor tyrosine kinases.
The Eph-related family of receptor tyrosine kinases consists of at least 13 members, several of which display distinctive expression patterns in the developing and adult nervous system. Recently, a small family of ligands, structurally related to the B61 protein, was identified. Binding of these ligands to Eph-related receptors did not, however, elicit measurable biological signals in cultured cells. In order to study functional interactions between B61-related ligands and Eph-related receptors, we constructed chimeric receptors, containing an Eph-related ectodomain and the cytoplasmic domain of the TrkB neurotrophin receptor. Expression and activation of such chimeric receptors in NIH 3T3 cells induced transformation in focus formation assays. Membrane-bound LERK2 ligand is shown to signal through three different Eph-related receptors, namely Cek5, Cek10 and Elk. LERK2, however, fails to interact functionally with the Cek9 receptor. Quantitative analysis including binding assays indicates that Cek10 is the preferred LERK2 receptor. Preliminary mutagenesis of the LERK2 protein suggests a negative regulatory role for its cytoplasmic domain in LERK2 signaling.
3T3 Cells↗
The neurotrophin receptors TrkA and TrkB are inhibitory for neurite outgrowth.
To investigate the possibility that the neurotrophin tyrosine kinase receptors are also recognition molecules by virtue of their immunoglobulin-like domains, the ability of TrkA and TrkB to influence neurite outgrowth was tested in vitro. Cell monolayers of fibroblasts transfected to express either the TrkA or TrkB receptor reduced neurite outgrowth of phaeochromocytoma PC12 cells by 50-60% when compared to mock transfected fibroblasts or fibroblasts transfected with the epidermal growth factor receptor. Neurite outgrowth from cerebellar neurons was inhibited by 30-40% on these substrates. When a recombinantly expressed fragment of TrkA comprising the two immunoglobulin-like domains was coated as a substrate in combination with poly-L-lysine and laminin, neurite outgrowth was inhibited in a dose-dependent manner. This inhibition of neurite outgrowth was not mediated via an interaction with laminin as there is no specific binding of the TrkA fragment to laminin. The adhesion of cell bodies to this substrate was not affected by the immunoglobulin-like domains. These observations suggest that the mammalian neurotrophin receptors not only influence neurite outgrowth by neurotrophin triggered activation of the receptor, but also by cell surface recognition processes conveyed by the immunoglobulin-like domains.
Animals↗
A comparison of the study populations in the Diabetes Control and Complications Trial and the Wisconsin Epidemiologic Study of Diabetic Retinopathy.
BACKGROUND: We compared the Diabetes Control and Complications Trial (DCCT) cohort with patients who had insulin-dependent diabetes mellitus (IDDM) in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) to determine whether the DCCT cohort was similar to the patients with IDDM in the general population and whether the DCCT results are generalizable to a nonresearch population. METHODS: Demographic and clinical characteristics were compared between the DCCT study cohort and the WESDR cohort of patients with IDDM with age at onset of diabetes at younger than 30 years and followed up from 1980 to 1986. The DCCT eligibility criteria were applied to the WESDR cohort, and patients were identified who fulfilled the major criteria of the DCCT primary prevention and secondary intervention cohorts. Conventionally treated subjects in the DCCT primary prevention and secondary intervention cohorts were compared with their respective WESDR groups with regard to clinical characteristics, progression of retinopathy, and development of gross proteinuria. RESULTS: Comparison of the DCCT primary prevention and secondary intervention cohorts at baseline with the respective WESDR groups revealed an older age and an older age at diagnosis, a lower hemoglobin A1c (HbA1c) level, and more frequent injections and monitoring in the DCCT cohorts, but there were few other substantive differences. The progression of retinopathy and the association with baseline HbA1c level were similar for the conventionally treated DCCT and WESDR cohorts, except for a lower rate of progression in the DCCT secondary intervention cohort compared with that of the WESDR cohort, perhaps because of the lower HbA1c level. CONCLUSIONS: At baseline, patients in the DCCT cohort were generally similar to patients with IDDM in the population-based WESDR cohort, except for differences in the levels of HbA1c that diminished over time as the HbA1c levels in the WESDR cohort decreased. The demographic similarities between the DCCT and WESDR cohorts, the similar rates of progression of retinopathy in conventionally treated patients, and the similar associations between the HbA1c levels and progression of retinopathy in the DCCT and WESDR cohorts support the validity of generalizing the DCCT results to patients with IDDM in the general population.
Adolescent↗
Diet and nuclear lens opacities.
Relations between diet and nuclear opacities in the lens of the eye were investigated in a population-based cohort of middle-aged and older adults who lived in Beaver Dam, Wisconsin. Nuclear sclerosis was assessed from photographs of the lens taken during 1988-1990 in 1,919 persons in the Beaver Dam Eye Study. Diets in the past (1978-1980) were assessed retrospectively with the use of a food frequency questionnaire in home interviews. Relations with intake of foods and nutrients were evaluated using logistic regression analyses. In men, after controlling for age, smoking, and heavy drinking, intakes of numerous nutrients in the highest versus lowest quintile were associated with 40-50 percent reduced odds of more severe nuclear sclerosis. Relations with some nutrients (vitamins A, C, and E, riboflavin, thiamin, niacin) were at least partly explained by previously identified inverse associations with multivitamin use. Relations with other nutrients (folate, alpha-carotene, and dietary fiber) appeared to reflect associations with intake of foods, particularly vegetables. Inverse associations with individual nutrients and foods were often weaker or nonexistent in women. These data indicate that the intake of vitamin supplements (in men and women) and certain foods (particularly in men) may explain associations of several nutrients with risk for nuclear sclerosis.
Adult↗
Factors associated with having eye examinations in persons with diabetes.
OBJECTIVES: To estimate compliance with guidelines on ocular examinations for diabetic persons, to examine factors that affect compliance, and to determine reasons for noncompliance. DESIGN: Cross-sectional population study. SETTING: Primary care setting. PATIENTS: The population is 765 diabetic persons with younger onset and 533 with older onset who participated in the 1990 to 1992 follow-up examination of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. MEASUREMENTS: A medical history was taken in which subjects were asked about eye examinations by ophthalmologists and optometrists. RESULTS: Sixty-four percent of the younger-onset group and 62% of the older-onset group had had a dilated eye examination in the previous year. Persons in both groups were more likely to have had a dilated examination if they had a longer duration of diabetes, more severe retinopathy, a history of glaucoma or cataract, and health insurance that covered eye examinations. Persons with younger-onset diabetes were more likely to have had an examination if they were older, were visually impaired, and had more education or higher income. Persons in the older-onset group were more likely to have had an examination if they were female or taking insulin. In those not having an eye examination, 79% and 71% of the younger- and older-onset groups, respectively, reported not having had one because they had no problems with their eyes, and 31% and 35% reported not having been told they needed one. Thirty-two percent and 11% said they were too busy, and 30% and 12% said they could not afford an examination. CONCLUSIONS: Diabetic persons should be educated as to the need for eye care; the results show that barriers to eye care exist in the form of affordability and lack of time.
Adolescent↗
Age-related eye disease and survival. The Beaver Dam Eye Study.
OBJECTIVE: To investigate the relationship of cataract, age-related maculopathy, glaucoma, and visual impairment to survival in the population-based Beaver Dam Eye Study. DESIGN: In this population-based study, visual acuity was measured with use of standardized protocols. At baseline, stereoscopic color fundus photographs and color slit-lamp and retroillumination photographs were graded in a masked fashion to determine the presence of age-related maculopathy and cataract, respectively. Deaths were ascertained by contacting family members, daily review of obituaries, and use of vital status records. PARTICIPANTS: Subjects aged 43 through 84 years who lived in Beaver Dam, Wis, were identified and examined between 1988 and 1990. RESULTS: From the time of the baseline examination until a median of 4 years later, 9.5% (467/4926) of the population had died. After correcting for age and sex, poorer survival was associated with more severe nuclear sclerosis (5-year survival of 88.9% for the most severe compared with 94.1% for the least severe stage) and visual impairment (5-year survival of 87.5% for impaired compared with 91.8% for unimpaired vision). However, after controlling for systemic factors, only more severe nuclear sclerosis in people without diabetes was significantly associated with poorer survival (hazard ratio per level of severity, 1.19; 95% confidence interval, 1.00 to 1.40). CONCLUSIONS: These data suggest that after controlling for age and sex, nuclear sclerotic cataract severity, cataract surgery, and visual impairment are risk indicators for poorer survival. Cortical cataract, posterior subcapsular cataract, glaucoma, and age-related maculopathy were unrelated to poorer survival.
Adult↗
A cohort study of the relationship of diabetic retinopathy to blood pressure.
OBJECTIVE: To determine whether blood pressure at baseline was associated with incidence or progression of diabetic retinopathy during a 10-year interval in a population-based cohort. PARTICIPANTS: A probability sample of all persons receiving primary care for diabetes in an 11-county area of southern Wisconsin were invited to participate in the study examinations in 1980 to 1982, 1984 to 1986, and 1990 to 1992. PROCEDURES: Blood pressure measurements, height, weight, ocular photographs, and glycosylated hemoglobin measurements were obtained and ocular examinations and a medical history interview were performed at each evaluation. MAIN OUTCOME MEASURES: Fundus photographs of seven standard photographic fields were obtained and graded according to the modified Airlie House Classification scheme. End points were incidence, any progression, or progression to proliferative diabetic retinopathy. RESULTS: At the baseline examination, 996 subjects were determined to have younger-onset diabetes and 1370 subjects had older-onset diabetes compared with 891 and 987, respectively, at the 4-year follow-up examination and 765 and 533, respectively, at the 10-year follow-up examination. In discrete linear logistic analyses, a 10-mm Hg increase in systolic blood pressure was significantly associated with incidence of retinopathy in subjects with younger-onset diabetes 10 years after the baseline examination (odds ratio, 1.27; 95% confidence interval, 1.03 to 1.57). No consistent association of blood pressure and retinopathy in subjects with older-onset diabetes was observed. Mortality did not affect the relationship of blood pressure and retinopathy. CONCLUSION: Increased systolic blood pressure at baseline was associated with a modest subsequent increased risk of incidence of diabetic retinopathy in subjects with younger-onset diabetes.
Adult↗
Dietary fat and age-related maculopathy.
OBJECTIVE: To describe the relationship between type and level of fat in the diet and the prevalence of age-related maculopathy. DESIGN: Retrospective population-based study. SETTING AND PARTICIPANTS: Residents of Beaver Dam, Wis, between the ages of 45 and 84 years, participating in the Beaver Dam Eye Study and Nutritional Factors in Eye Disease Study. DATA COLLECTION: Presence and severity of age-related maculopathy were determined from masked grading of fundus photographs taken from 1988 through 1990. Diets in the past (1978 through 1980) were assessed retrospectively using a food frequency questionnaire during in-person home interviews. RESULTS: Persons with intake of saturated fat and cholesterol in the highest compared with the lowest quintile had 80% and 60% increased odds for early age-related maculopathy, respectively, after adjusting for age and intake of beer. These relationships were not influenced by adjusting for several other potential confounding variables (carotenoid intake, intake of vitamins C or E in supplements, smoking, body mass index, time spent outdoors in the summer, gender, and history of diabetes, hypertension, or cardiovascular disease). Odds ratios for late age-related maculopathy were in similar directions but were not statistically significant. CONCLUSIONS: High intake of saturated fat and cholesterol is associated with increased risk for early age-related maculopathy in the Beaver Dam population. This supports the hypothesis that atherosclerosis or its risk factors are related to age-related maculopathy. Confirmation of this finding in other populations and in prospective studies is needed.
Aged↗
Retinal microaneurysm counts and 10-year progression of diabetic retinopathy.
OBJECTIVE: To determine the relationship of change in the number of retinal microaneurysms to the 10-year progression to significant retinopathy, proliferative retinopathy, and clinically significant macular edema. DESIGN: Population-based study of persons with younger- and older-onset diabetes with 10 years of follow-up. SETTING AND PATIENTS: Eleven-county area in southern Wisconsin, where 189 patients with diabetes who had only retinal microaneurysms in photographs at baseline participated in 4- and 10-year follow-up examinations. OUTCOME MEASURES: Ten-year incidence of moderate nonproliferative diabetic retinopathy or worse, proliferative retinopathy, or clinically significant macular edema as determined by masked grading of stereoscopic color fundus photographs of seven standard fields. RESULTS: The increase in the number of retinal microaneurysms and the ratio of the number of retinal microaneurysms at the 4-year follow-up to the number at baseline were positively associated with incidence of proliferative retinopathy or clinically significant macular edema at the 10-year follow-up. Proliferative retinopathy was approximately 4.6 times and clinically significant macular edema was approximately 9.1 times more likely to develop at 10-year follow-up in eyes in which the number of microaneurysms increased by 16 or more from baseline to the 4-year follow-up than in eyes with no increase. Proliferative retinopathy was 3.4 times and clinically significant macular edema was 6.7 times more likely to develop at 10-year follow-up in eyes that had ratios of 3 or greater of the number of retinal microaneurysms at the 4-year follow-up to the number at baseline than in eyes in which the ratios were smaller. These relationships remained after controlling for the level of glycosylated hemoglobin and type of diabetes. CONCLUSIONS: Microaneurysm counts using stereoscopic color fundus photographs are an early important measure of progression of retinopathy and may serve as a surrogate end point for severe change in some clinical trials.
Adult↗
Serum antioxidants and age-related macular degeneration in a population-based case-control study.
OBJECTIVE: To investigate relationships between levels of tocopherols and carotenoids in the serum and age-related macular degeneration (ARMD). DESIGN: A nested case-control study within a population-based cohort. PARTICIPANTS: Cases included a sample of subjects with retinal pigment abnormalities with the presence of soft drusen (n = 127) or with late ARMD (geographic atrophy [n = 9]) or neovascular and exudative macular degeneration (n = 31). An equal number of controls (167 pairs) were selected from among participants in the Beaver Dam Eye Study. The controls had no photographic evidence of soft drusen, retinal pigment abnormalities, or late ARMD and were matched with cases for age, sex, and current smoking status. DATA COLLECTION: Presence and severity of ARMD were determined from masked grading of fundus photographs obtained from 1988 to 1990. Levels of individual carotenoids and tocopherols were determined in serum collected at the same time. RESULTS: Average levels of individual carotenoids were similar in cases and controls. Average levels of vitamin E (alpha-tocopherol) were lower in people with exudative macular degeneration (P = .03). However, the difference was no longer statistically significant after controlling for levels of cholesterol in the serum. Persons with levels of lycopene, the most abundant carotenoid in the serum, in the lowest quintile were twice as likely to have ARMD. Levels of the carotenoids that compose macular pigment (lutein with zeaxanthin) in the serum were unrelated to ARMD. CONCLUSIONS: Very low levels of one (lycopene) but not other dietary carotenoids or tocopherols were related to ARMD. Lower levels of vitamin E in subjects with exudative macular degeneration compared with controls may be explained by lower levels of serum lipids.
Adult↗
Telling axons where to grow: a role for Eph receptor tyrosine kinases in guidance.
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Animals↗
Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM complications study.
We present the methodology for 45 degrees retinal photography and detail the development, application and validation of a new system of 45 degrees field grading standards for the assessment of diabetic retinopathy. The systems were developed for the EURODIAB IDDM Complications Study, part of a European Community funded Concerted Action Programme into the epidemiology and prevention of diabetes (EURODIAB). Assessment of diabetic retinopathy was carried out centrally by a trained reader of colour retinal photographs using the newly-developed system. The system proved to be acceptably accurate, repeatable repeatable and relatively simple to apply. It compared well with the recognised 'gold standard' 7-field 30 degrees stereo photography (assessed using a modified Airlie House classification scheme), against which the new system was validated in a series of 48 eyes. Selection was as a stratified random sample based on clinical retinopathy status: 5, no retinopathy; 25, non-proliferative retinopathy; 16, proliferative or photocoagulated; plus 2, eyes with potentially confounding lesions (vein occlusion). Simple presence of retinal lesions was correctly detected by both systems in 43 of the 48 eyes, giving 100% agreement on detection. Both systems correctly identified the two known cases of confounding vein occlusion. In eyes with diabetic retinopathy (n = 41), when severity was expressed in three groups: mild background, moderate/severe background and proliferative/photocoagulated, at least one grader (out of five) using the new system matched the verified results in 38 out of 31 (93%) eyes and three or more graders matched in 31 (76%) eyes.(ABSTRACT TRUNCATED AT 250 WORDS)
Aneurysm↗
Mycobacteria--related to the aetiopathogenesis of primary biliary cirrhosis?
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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Accreditation: what can we learn from the Anglophone model?
There is growing interest in the development and application of standards for the health care to both promote quality assurance but also to improve the processes by which health services are held accountable to the public. This paper maps the development of organisational accreditation systems in the USA, Canada, Australia and the United Kingdom. In the USA, accreditation, which began as a means of ensuring the correct environment for clinical practice has developed into a form of public regulation. In the United Kingdom, many different approaches to the setting of standards and their assessment has created a variety of accreditation systems. The case studies demonstrate that as the concept of accreditation diffuses into the health care systems of different countries, it is being adapted to meet the wider policy needs of different national circumstances.
Accreditation↗