The -87 (C----A) beta(+)-thalassemia mutation in a black family.
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Adolescent↗
Biomedical subjects
A M Walker
Publications and source records attributed to A M Walker.
50 kD prolactin binding protein in schizophrenics on neuroleptic medication.
Serum samples from 15 age-matched normal male subjects and 15 male schizophrenic patients on neuroleptic medication were subjected to immunoprecipitation with anti-human prolactin (PRL) and analysis of the immunoprecipitate by two-dimensional gel electrophoresis. We report the unexpected immunoprecipitation of large amounts of an approximately 50 kD protein in 12/15 of the schizophrenic patients. Preliminary analyses suggest that this 50 kD protein may be an IgG heavy chain. Since total levels of IgG and each of the IgG subclasses are the same in the normal and schizophrenic group, the increased amount of the 50 kD protein in the schizophrenics is clearly specific to anti PRL precipitation. Since the anti-PRL does not directly recognize either the 50 kD protein or any immunoglobulin light chains in the precipitate, we suggest that the 50 kD protein is precipitated because it is bound to PRL. Perhaps immunoglobulin binding of PRL is a mechanism used to compensate for chronically elevated PRL levels during neuroleptic treatment.
Adult↗
The impact of research quality and study design on epidemiologic estimates of the effect of nonsteroidal anti-inflammatory drugs on upper gastrointestinal tract disease.
BACKGROUND: Considerable differences in the estimates of the risk of upper gastrointestinal tract disease associated with treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed. We conducted a meta-analysis of epidemiologic studies of upper gastrointestinal tract disease related to NSAIDs to answer the following research questions: Are study characteristics (study design and quality) associated with different estimates of risk, for both aspirin and nonaspirin NSAIDs? Does the risk increase for particular groups of patients, such as women and the elderly? METHODS: Thirty-four studies addressing severe upper gastrointestinal tract disease associated with NSAIDs (including aspirin and nonaspirin NSAIDs) were examined and scored according to a quality checklist that we designed for this review. RESULTS: Only 44% of the studies controlled for major confounding variables (age and sex). While exposure was defined as current in 40% and 78% of the studies for nonaspirin NSAIDs and aspirin, respectively, few investigations checked for history of ulcer disease and concurrent diseases or other comedications known to be risk factors for upper gastrointestinal tract bleeding. The overall risk ratio, by means of a random-effects regression model, was 3.0 (95% confidence interval, 1.9 to 4.7). The individual estimates for aspirin and nonaspirin NSAIDs were similar. Both with and without control for quality, cohort studies provided a lower risk ratio estimate than did case-control studies. CONCLUSIONS: The design and quality of the studies appear to be strong independent predictors of the risk estimate; cohort studies were associated with lower risk estimates than case-control studies, and satisfactory studies were associated with lower risk estimates than unsatisfactory studies.
Aged↗
A case-control study of diet and cancer of the pancreas.
In a population-based case-control study carried out in Adelaide, South Australia, during the years 1984-1987, the diets of 104 cases of cancer of the pancreas 1 year prior to diagnosis were compared with the diets of 253 community controls. A quantitative food-frequency questionnaire was used to assess usual dietary intakes of 179 food items. Cases were compared with controls in terms of both the amounts of individual food items consumed and the estimated contributions of 48 nutrients to the diet. Food items consumed more by cases than controls included boiled eggs and omelettes as well as a number of items that could be collectively described as sweet and fatty. Food items consumed less by cases than controls included several vegetables and fruits. Conditional logistic regression analysis of nutrient intake adjusted for total energy and for alcohol and tobacco usage yielded an estimate of relative risk of 3.19, with a 95% confidence interval of 1.58-6.47 for the highest quartile of cholesterol intake (relative to the lowest quartile). For the top quartile of refined sugar intake, the estimated relative risk was 2.21 (95% confidence interval 1.07-4.55). Several nutrients derived principally from plant foods were statistically significantly associated with lower risks. Alcohol consumption was significantly lower among cases than controls. Current smokers had a relative risk of 1.76 (95% confidence interval 0.93-3.34) relative to those who had never smoked. There was no association of pancreatic cancer with coffee drinking.
Aged↗
Nutritional factors and pancreatic cancer: a case-control study from south-west Poland.
A population-based case-control study of diet and pancreatic cancer has been conducted in the Opole Voivodeship region in Poland, using 110 cases and 195 controls. A full diet history was used to estimate the daily intake of calories, fat, protein, carbohydrate, cholesterol, retinol, vitamin C, and fibre. There is a strong positive association with the intake of cholesterol with relative risks of 1.90, 3.77, and 4.31 for the 3 upper quartiles compared with the lowest (p, trend = less than 0.01). An inverse association was seen with vitamin C intake, with corresponding relative risks of 1.10, 0.30, and 0.37 (p, trend = less than 0.01). Weak inverse associations were seen with the intake of retinol and fibre. There is evidence of an inverse association with fat intake, particularly unsaturated fats, and of a positive association with the intake of carbohydrate and to a lesser extent, protein. These results further support the potential importance of dietary factors in the aetiology of cancer of the pancreas.
Case-Control Studies↗
[Pancreatic cancer and ABO blood types: a study of cases and controls].
BACKGROUND: A hospital-based case-control study (controls were matched to cases by age, sex and hospital) has been carried out to analyze the relation between pancreatic cancer and blood type. METHODS: This study is based on data collected by the Boston Collaborative Drug Surveillance Programme. This large hospital-based study has been collecting hospital admissions occurred in six different countries. To estimate relative risk (RR) associated with blood type, odds ratios were calculated by multiple logistic regression using conditional maximum likelihood estimation based on the matching factors (age, sex and hospital). The final analysis is based in 108 matched sets (108 cases and 374 controls). RESULTS: The results indicate a modest excess risk among persons with blood type A (RR = 1.52, 95% confidence interval: 0.87-2.67). Smoking was also a positive predictor of disease. CONCLUSIONS: In accordance with previous reports, this study shows some evidence of a positive association between blood type A and risk of pancreatic cancer.
ABO Blood-Group System↗
Exposure to phenothiazine drugs and risk of cataract.
Clinical reports have indicated an increased risk of ocular opacities in users of phenothiazine drugs, and some recent epidemiologic studies have found an association between cataract and a history of tranquilizer use. To examine the effects of major tranquilizers (phenothiazines and haloperidol) on the risk of cataract extraction, while controlling for suspected risk factors such as diabetes and steroid use, a matched cohort study was performed using information from a large health maintenance organization in Seattle, Wash. The use of either antipsychotic or other phenothiazine drugs increased the risk of cataract extraction by roughly 3.5 times in individuals who were both current users and were exposed some time in the 2 to 5 years prior to their extraction. Risk was also increased in individuals with prior use of antidiabetic agents, systemic steroids, and benzodiazepines. Contrary to some prior reports, there was no elevated risk associated with use of antihypertensives, and there was no protective effect for aspirin, acetaminophen, or ibuprofen.
Aged↗
Misclassification of covariates.
In the context of reported data on asthma mortality, we examine two types of covariate misclassification. The first type is non-differential misclassification, in which the proportion of subjects misclassified is invariant over exposure and disease status. Building on work by Cox and Elwood and by Blettner and Wahrendorf, we find that the range of admissible values for misclassification proportions is bounded by the observed data, and may not include any values that account for observed heterogeneity of effect estimates. The second type is differential misclassification, in which the classification error differs according to the disease or exposure classes to which study subjects belong. If the relation between exposure and the confounding variable or between the confounding variable and disease is strong, differential misclassification can produce large variations in the stratum-specific odds ratio estimates.
Asthma↗
Electromyographic changes in the isolated rat diaphragm during the development of fatigue.
To investigate whether the power spectrum of the electromyogram of a fatiguing muscle can be used to infer the degree to which the muscle is fatigued, we recorded isometric tension and two monopolar electromyograms from eight isolated rat diaphragm preparations suspended in an organ bath containing a balanced salt solution. Each preparation was excited with a fixed phrenic nerve impulse pattern made up of a 70-Hz train of impulses of supramaximal voltage delivered for 170 ms with a 500-ms recovery period. Tension fell rapidly over the first 60 s of the fatigue run and more slowly for the remaining 60 s analysed. The duration of extracellular action potentials increased and their amplitude decreased as the tension developed by the diaphragm decreased; conduction velocity along muscle fibres also decreased. The centroid frequency (fcen) of the power spectrum of the first action potential elicited by each train of stimuli decreased rapidly until tension fell to approximately 70% of the initial value; thereafter little change in fcen occurred, although tension continued to fall to 33% of its initial value. Our results demonstrated that under controlled conditions, fcen provided a sensitive index of fatigue in its early stages, but provided no information once fatigue was pronounced.
Animals↗
Reconstitution of single calcium channels from secretory granules of rat adenohypophysis in planar lipid membranes.
Free cytosolic Ca2+ ([Ca2+]i) has been demonstrated to play a crucial role in the prolactin secretory pathway. It regulates events as apparently diverse as prolactin gene transcription and the fusion of secretory granules with the plasma membrane. It is therefore important to understand the mechanisms which regulate the level of [Ca2+]i. Because prolactin secretory granule membranes have been shown to contain large amounts of Ca2+ and there is evidence that this calcium can be released independently of the granule hormone content, we have investigated the possibility that prolactin secretory granule membranes contain Ca2+ channels. When purified prolactin secretory granules were fused with an artificial phospholipid bilayer, we found a Ca2+ channel with a linear current-voltage relationship (conductance -45 pS) in symmetrical 50 mM CaCl2 solutions. Said channel had an open probability that was weakly dependent on the transmembrane potential, and a very good selectivity for calcium over chloride ions. The channel opened and closed very rapidly, when the majority of events lasting well below 25 ms. This channel could be important for the provision of high [Ca2+]i levels necessary for granule-plasma membrane fusion and could also be involved in the modulation of Ca2+ fluxes across the plasma membrane after the exocytotic release of prolactin.
Animals↗
Arousal responses to hypertension in lambs: effect of sinoaortic denervation.
Newborn lambs were subjected to hypertensive stimuli of 1-min duration to examine features of hypertension-induced arousal from sleep. Reflex mechanisms involved were studied by performing the same tests after sinoaortic denervation (SAD). In intact lambs, hypertension increased the probability of arousal from both quiet sleep (QS) and rapid-eye-movement (REM) sleep. Hypertension resulted in arousal in 51% (QS) and 50% (REM) of tests. Arousal time was significantly longer in REM (29.3 +/- 0.9 s, mean +/- SE) than in QS (22.6 +/- 0.6 s, P less than 0.01). Arterial oxygen saturation (So2) and partial pressure of oxygen (Po2) measured at the point of arousal, or after 60 s if arousal failed to occur, were unchanged from control values. After SAD hypertension did not increase the probability of arousal. Arousals significantly decreased (P less than 0.001) to 31% (QS) and 10% (REM). These findings indicate that acute hypertension, mediated via arterial baroreceptors, is a potent stimulus for arousal. In intact lambs, the arousal probability increased and arousal time decreased with increasing stimulus strength (1-30 mmHg), but the arousal time difference between QS and REM remained constant. Consideration of these findings in terms of a simple baroreflex threshold model suggests that the slower response in REM sleep is explained by slower neural processes after the achievement of a critical arousal input rather than by a higher threshold for baroreceptor input in this state.
Aging↗
Prolactin (PRL) processing by kallikrein: production of the 21-23.5K PRL-like molecules and inferences about PRL storage in mature secretory granules.
We have previously described a series of C-terminally-clipped forms of PRL, the 21-23.5K PRL-like molecules (PLMs). Because we noted estrogen (E2) induction of PLMs and E2 also induces a pituitary glandular kallikrein, we have investigated the possibility that processing of PRL by kallikrein is responsible for the production of the PLMs. Subcellular fractionation of pituitaries from control or E2-treated female rats showed total kallikrein to be concentrated 1- to 4-fold and 6- to 20-fold in the granules (vs. original homogenate) from control and E2-treated animals, respectively. Cleavage of purified PRL by kallikrein resulted in the formation of large quantities of a number of the PLMs. Incubation of secretory granules derived from control or E2-treated animals under the same conditions showed no cleavage of PRL in the absence of a limiting granule membrane and a small production of the PLMs in the presence of a granule membrane. Production in the latter instance was slightly greater in granules derived from E2-treated animals. Addition of purified kallikrein to secretory granules from control or E2-treated animals in the presence or absence of granule membranes, resulted in the additional production of large amounts of only the smallest PLM (PLM 9), indicating a lack of cleavage of the two most C-terminal sites for the enzyme. Increasing the concentration of beta-mercaptoethanol to 0.64 M, to ensure monomerization of the granule PRL, had no effect on endogenous kallikrein activity of the number of products resulting from the addition of exogenous kallikrein to granules. In summary: 1) purified kallikrein can cleave purified PRL to form products which run with the same isoelectric point and mol wt values as the PLMs; 2) kallikrein is present in PRL secretory granules; 3) some PLM production occurs in a membrane-bound secretory granule fraction, but none occurs after removal of the membrane; this intragranular production, like cleavage of purified PRL with purified kallikrein, is dependent on the presence of a detergent and a reducing agent; 4) cleavage of granular PRL by exogenous kallikrein is limited to a single site and the more C-terminal sites are protected; and 5) protection of the C-terminus is not removed by intermolecular and intramolecular disulfide bond reduction. We conclude: 1) that pituitary glandular kallikrein is a strong candidate for the enzyme responsible for the production of the PLMs, and 2) that there is some element of PRL storage, other than intermolecular disulfide bonds, which involves the C-terminus of the molecule.
Animals↗
Mortality from cancer of the colon or rectum among workers exposed to ethyl acrylate and methyl methacrylate.
Mortality from colon and rectum cancer has been reviewed in three cohorts working in 1933-1982 in two plants manufacturing and polymerizing acrylate monomers. The two cohorts with later dates of hire showed no excess mortality. In the earliest cohort, excess colon cancer seemed restricted to men employed extensively in the early 1940s in jobs entailing the highest exposures to vapor-phase ethyl acrylate (EA) and methyl methacrylate (MMA) monomer and volatile by-products of the EA/MMA polymerization process. The excess mortality appeared only some two decades after the equivalent of three years' employment in jobs with the most intense exposures. A smaller elevation in colon cancer mortality also appeared in a low-exposure group in the early cohort. Rectal cancer mortality was elevated in the same categories that showed excess rates of colon cancer death. Because of the lower rates, the rectal cancer results are more imprecise.
Acrylates↗
Preterm birth in lambs: sleep patterns and cardio-respiratory changes.
Cardio-respiratory physiology in sleep was examined in eight preterm lambs born at 133-135 (134 +/- 1, mean SEM) days of gestation after 3-5 days of pulsatile ACTH/TRH infusion, and contrasted with eight lambs born at term (147 +/- 1 days). Lambs were instrumented with electrodes for recording electrocorticogram, electro-oculogram and nuchal electromyogram to define behavioural states, as well as carotid arterial catheters for determination of arterial pressure, heart rate and arterial blood gases. Compared to full-term lambs, the preterm lambs exhibited extended active sleep times, elevated PaCO2 and faster heart rate in all behavioural states than full-term lambs; with increasing postnatal age, sleep times and heart rate declined. As similar differences are found in preterm human infants, the preterm lamb will be a useful model to study the underlying physiology of these cardio-respiratory alterations.
Animals↗
Breathing at birth and the associated blood gas and pH changes in the lamb.
We examined the relationship between the initiation of breathing at birth and the timing of delivery of the chest in a group of 13 lambs undergoing spontaneous unassisted delivery at term. In 8 of 11 lambs with a diaphragm electromyogram or intrapleural pressure signal the first breath occurred before chest delivery. The first breath was always followed by a period of irregular and often powerful inspiratory efforts. Some of these inspirations were followed by a forceful expiration. A regular respiratory rhythm never developed until the chest had delivered, suggesting that chest expansion is essential for the establishment of rhythm. Although PaO2 increased rapidly after birth, pHa declined and reached its lowest level approximately 20 minutes postnatally suggesting that considerable anaerobic metabolism occurs in the face of adequate arterial oxygenation. The level of respiratory activity in the first 30 min following birth did not appear to be related to arterial PO2, PCO2 or pH. Neither the appearance of the EMG activity of the first breath, nor blood samples taken from 2 lambs simultaneously with the first breath, suggested that the first breath was a gasp initiated by asphyxial blood gases. Our results therefore do not support the current hypothesis that the first breath is a gasp initiated by asphyxia accompanying delivery.
Animals↗
Use of replacement estrogens and the risk of myocardial infarction.
We evaluated the relation between postmenopausal estrogen use and the risk of first-time myocardial infarction using both cohort and nested case-control analyses for data derived from a large health maintenance organization. The study population comprised all women aged 50 to 64 years who were members of the Group Health Cooperative of Puget Sound during the years 1978-1984. In the cohort analysis of 120 cases of first-time myocardial infarction that occurred during 17,513 woman-years at risk among current users and 110,971 woman-years at risk among nonusers of replacement estrogens, the relative incidence of myocardial infarction among current users compared with nonusers, adjusted for age and calendar year, was 0.7 (95% confidence interval 0.4-1.3). This small inverse relation between myocardial infarction and current use of replacement estrogens remained unchanged after adjustment in the case-control study for previous prescription of diuretics and antiarhythmic, antihypertensive, and antidiabetic drugs. These data are consistent with previous observations that estrogen replacement therapy causes a small reduction in the risk of hospitalization for myocardial infarction, and incompatible with any large increase in the risk of myocardial infarction in users of replacement estrogen.
Case-Control Studies↗
Replacement estrogen use and body mass index.
Peripheral fat is a major source of endogenous estrogens in menopausal women. To investigate whether obesity affects use of replacement estrogens in postmenopausal women, we examined the relation between body mass index and use of replacement estrogens in data from Group Health Cooperative of Puget Sound, the German Cardiovascular Prevention Study, and the Cancer and Steroid Hormone (CASH) study. In each data set, there was a major decline in replacement estrogen use with higher body mass index. All data sets showed hysterectomy to be a strong predictor of replacement estrogen use. Smoking, past use of oral contraceptives and other estrogens, and ages at menarche and menopause did not appear to influence the body mass-estrogen relation. The strong and consistent association between body mass index and use of replacement estrogens in data collected at different times and in different places by different methodologies strongly suggests a common underlying biologic mechanism.
Adult↗