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Biomedical subjects

R J Brand

Publications and source records attributed to R J Brand.

At least 19 recordsLinked to original sources

A two-state recurrent stochastic model with time-dependent transition rates.

The two-state recurrent stochastic model with time-independent transition rates is generalized to a model with time-dependent transition rates. The rates can be any general function of external time, that is, any general function of the calendar time in which the process unfolds. Formulas for the state transition probabilities, the proportion of individuals in a particular state at time t, the distribution function, and the expectation of the number of individuals in a particular state at time t are derived.

Disease

Stromal acidosis affects corneal hydration control.

An estimate of overall corneal hydration control can be obtained by measuring the rate of thickness recovery following induced corneal swelling; it is expressed as the percent recovery per hour (PRPH). This recovery is nearly, but not exactly, exponential, because there appears to be an initial slower recovery phase lasting about 30-40 minutes. This 30-40 minute period of slower recovery corresponds to the time when corneal pH is reduced secondary to the contact lens-induced swelling, suggesting the possibility that stromal acidosis may retard the corneal deswelling process. In this study, we explored the effects of corneal acidosis on hydration control by monitoring corneal recovery under normal and reduced pH conditions. Corneal pH was controlled by having subjects were goggles and exposing their eyes to air (normal pH) or a gas mixture providing 21% O2 and 7% CO2 (low pH). Relative corneal pH levels were monitored by measuring fluorescence intensity (FI) ratios, which showed that the average (+/- standard deviation) FI ratio was significantly lower under 7% CO2 (0.838 +/- .024) vs air (0.985 +/- .025; P = 0.0001), corresponding to approximate pH values of 7.25 vs 7.50. Under these reduced pH conditions, open-eye steady-state (OESS) corneal thickness was not substantially affected. For 10 subjects, mean (+/- SD) corneal thickness decreased 0.93 +/- 3.7 microns vs 1.10 +/- 4.50 microns after exposures to 60 minutes of 7% CO2 and 40 minutes of air (P greater than or equal to 0.45), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis

Ammonia assimilation and glutamate incorporation in coenzyme F420 derivatives of Methanosarcina barkeri.

Methanosarcina barkeri was able to grow on L-alanine and L-glutamate as sole nitrogen sources. Cell yields were 0.5 g/l and 0.7 g/l (wet wt), respectively. The mechanism of ammonia assimilation in Methanosarcina barkeri strain MS was studied by analysis of enzyme activities. Activity levels of nitrogen-assimilating enzymes in extracts of cells grown on different nitrogen sources (ammonia, 0.05-100 mM; L-alanine, 10 mM; L-glutamate, 10 mM) were compared. Activities of glutamate dehydrogenase, glutamate synthase, glutamine synthetase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase could be measured in cells grown on these three nitrogen sources. Alanine dehydrogenase was not detected under the growth conditions used. None of the measured enzyme activities varied significantly in response to the NH4+ concentration. The length of the poly-gamma-glutamyl side chain of F420 derivatives turned out to be independent of the concentration of ammonia in the culture medium.

Alanine

Clinical assessment of corneal hydration control in Fuchs' dystrophy.

The diagnosis and monitoring of Fuchs' disease is typically based on information obtained from patient symptoms and a slitlamp examination. Although this clinical information provides a basis for diagnosis, it does not give a quantitative method for charting the progression of the disease systematically or a reliable basis for predicting the cornea's capacity to remain transparent after stress (e.g., cataract extraction). However, it is possible to quantify overall corneal hydration control by inducing corneal swelling and then monitoring the deswelling rate expressed as percent recovery per hour (PRPH). We have tested subjects with Fuchs' dystrophy and found that the PRPH provides a reasonable estimate of corneal hydration control. Unfortunately, the PRPH procedure involves considerable time and technical assistance and therefore is not convenient for clinical practice. In this report, we document the results of an initial effort to explore the relations between PRPH and six clinical measures consisting of five biomicroscopic indices and a subjective synthesis of clinical information called the probability of decompensation (POD) based on these indices. PRPH was significantly related to striae (p less than 0.001), stromal haze (p = 0.025), microcysts (p less than 0.001), and the POD (p less than 0.001) and not significantly related to guttae (p = 0.252) or Descemet's folds (p = 0.185). An empirically weighted predictor of PRPH was constructed from a statistical analysis of five slitlamp assessments and age. This approach for synthesizing clinical information produced a result at least as good as that obtained from the POD summary. These results show an important link between a quantitative laboratory assessment of corneal function and a clinical evaluation of corneal status and suggest that with continued refinement, clinical assessment may provide more quantitative information on Fuch's dystrophy and other diseases that affect corneal status.

Adult

Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial.

In a prospective, randomised, controlled trial to determine whether comprehensive lifestyle changes affect coronary atherosclerosis after 1 year, 28 patients were assigned to an experimental group (low-fat vegetarian diet, stopping smoking, stress management training, and moderate exercise) and 20 to a usual-care control group. 195 coronary artery lesions were analysed by quantitative coronary angiography. The average percentage diameter stenosis regressed from 40.0 (SD 16.9)% to 37.8 (16.5)% in the experimental group yet progressed from 42.7 (15.5)% to 46.1 (18.5)% in the control group. When only lesions greater than 50% stenosed were analysed, the average percentage diameter stenosis regressed from 61.1 (8.8)% to 55.8 (11.0)% in the experimental group and progressed from 61.7 (9.5)% to 64.4 (16.3)% in the control group. Overall, 82% of experimental-group patients had an average change towards regression. Comprehensive lifestyle changes may be able to bring about regression of even severe coronary atherosclerosis after only 1 year, without use of lipid-lowering drugs.

Adult

The molecular cloning and nucleotide sequencing of the 3'-terminal region of Ornithogalum mosaic virus.

DNA complementary to the 3'-terminal 3684 nucleotides of the Ornithogalum mosaic potyvirus (OMV) genome was cloned and sequenced. The sequence consisted of a single large open reading frame which probably starts upstream of the cloned region. By comparison to other sequenced potyviruses, it was estimated that the clone contained the 3' non-coding (3'-NC) region, the coat protein (CP) gene and the large nuclear inclusion protein (NIb) gene, as well as approximately 85% of the small nuclear inclusion protein (NIa) gene. The 3'-NC region of 274 nucleotides showed 38% to 45% similarity to the corresponding regions of other potyviruses. The putative CP gene could encode a 253 amino acid coat protein with a calculated Mr of 28,807. Analysis of the amino acid sequences of OMV and other potyvirus proteins showed similarities of 66% to 77% for CP, 72% to 73% for NIb and 63% to 71% for NIa proteins. These data, as well as phylogenetic analysis of the CP sequences, suggested that OMV is a typical but taxonomically distinct potyvirus.

Amino Acid Sequence

Humidity effects on corneal hydration.

Overall corneal hydration control expressed as the percent recovery per hour (PRPH) can be assessed with an exponential model that uses data derived from two kinds of corneal thickness measurements; one from monitoring recovery after inducing corneal swelling, and the other from measurements made after the eye has been open long enough to reach its open-eye steady-state (OESS) corneal thickness. Up to now these thickness measurements have been made without controlling the ambient humidity. It is possible that changes in relative humidity may effect tear film osmolarity sufficiently to change the state of corneal hydration. To evaluate the effects of humidity on hydration control, the OESS and PRPH were determined under several humidity levels. For both the OESS and the PRPH, two substudies were conducted. For the OESS, substudy 1 consisted of measuring corneal thickness when humidity was changed from 30% (ambient) to 52 or 97% controlled humidity. This resulted in mean +/- standard deviation (SD) changes in OESS thickness amounting to -0.33 +/- 3.5 microns and 2.6 +/- 3.4 microns, respectively, with a differential change of 2.94 +/- 3.04 microns (95% confidence interval [CI] from 0.77 to 5.11 microns). Corresponding results for substudy 2 connected with changes from 43% (ambient) to 12 or 97% controlled humidity were -2.4 +/- 2.7 microns and -0.3 +/- 1.9 microns, respectively, with a differential change of 2.1 +/- 1.8 microns (95% CI from 0.9 to 3.4 microns).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Hypoxic effects on corneal morphology and function.

Normal corneal metabolism depends on a critical level of oxygen, below which a series of acute corneal responses occur, including an increase in stromal lactate, a reduction in intercellular pH, and an increase in corneal hydration. These acute responses are reversible when normal oxygen is restored; however, it has been shown that chronic exposure to low oxygen levels can result in permanent morphologic changes in the corneal endothelium. Clinicians have expressed concern that these observed structural changes may also be accompanied by alterations in corneal physiology. Whether such effects occur is not known, since it has been difficult to assess human corneal function accurately. Recently, we have developed an in vivo test, able to measure overall corneal hydration control, that can be used to study the effects of hypoxia on corneal function. This test provides information on several characteristics of hydration control, one of which is the percent corneal thickness recovery per hour (PRPH) after inducing corneal swelling. In this study, we assumed that corneal hypoxia accompanies both extended and polymethylmethacrylate (PMMA) contact lens wear and that the dose received is related to the years of past lens wear. Using this paradigm, we explored the relationship of hypoxic dose to an endothelial polymegethism index (EPI), endothelial cell density (ECD), and PRPH in 36 subjects with varying contact lens wearing histories. Based on multiple regression analysis, the relative change (expressed as percent per year) associated with hypoxic dose (adjusted for age and gender) was found to be dose-dependent and corresponded to estimated changes of 1.70%/yr, -0.25%/yr, and -1.26%/yr, with 95% confidence limits of (-0.3, 3.7), (-1.4, 0.9), and (-2.6, 0.06) for EPI, ECD, and PRPH, respectively. These preliminary data suggest that hypoxic exposure alters endothelial morphology and reduces corneal function; however, it is important to indicate that this was a exploratory investigation with several limitations, and that therefore these results should be viewed as preliminary until more definitive studies are completed.

Adolescent

Correlates of high density lipoprotein cholesterol in women studied by the method of co-twin control.

This study examines the relation between each of the following risk variables and high density lipoprotein (HDL) cholesterol: cigarette smoking, alcohol use, leisure exercise, postmenopausal estrogen use, and body mass, before and after adjustment for genetic and nongenetic variables shared by monozygous and dizygous co-twins. Subjects were 179 dizygous and 255 monozygous twin pairs from the Kaiser Permanente Twin Registry who participated in a special examination in 1978-1979 in Oakland, California. A multivariate co-twin analysis made it possible to adjust for measured covariables and also to adjust for unmeasured familial variables shared by co-twins. After adjustment for measured covariables, further adjustment for the unmeasured familial variables shared by monozygous co-twins reduced a positive association between alcohol and HDL cholesterol and eliminated a positive association between exercise and HDL cholesterol. On the other hand, adjustment for unmeasured familial variables shared by monozygous co-twins had little effect on significant associations between smoking and HDL cholesterol, postmenopausal estrogen use and HDL cholesterol, and body mass and HDL cholesterol. Although an important role for random error was not ruled out in the sample size available, findings are consistent with the following interpretations: 1) alcohol consumption and leisure exercise may have smaller effects on HDL cholesterol than predicted by studies unadjusted for familial factors because effects of these variables are confounded by familial factors; and 2) smoking, postmenopausal estrogen, and body mass have effects predicted by studies unadjusted for familial factors and may therefore be good targets for interventions to raise HDL cholesterol.

Adolescent

Corneal hydration control in Fuchs' dystrophy.

Corneal hydration control was tested in 22 patients with Fuchs' dystrophy, and eight subjects of similar age without the disease, by measuring the corneal thickness recovery from swelling induced by hypoxia or following overnight sleep. Measurement precision was enhanced by using a modified optical pachometer and conducting two test procedures which were analyzed by a coupled exponential model. We have identified three parameters of the recovery from corneal swelling which may be used to describe hydration control: percent recovery per hour (PRPH) (mean 25.4% for Fuchs' and 34.2% for normals), time for 95% of corneal thickness recovery (mean 10.2 hr for Fuchs' and 7.1 hr for normals), and the open-eye steady-state thickness (mean 562 microns for Fuchs' and 537 microns for normals.) A PRPH of 17.1%/hr was identified as the minimum below which the cornea could not regain its open-eye steady state during the entire day and approaches decompensation. Our test procedure quantifies the corneal hydration control mechanism and may provide a test of endothelial function which can be used to monitor the progression of Fuchs' disease and guide decisions related to corneal surgery.

Aged

Type A behavior and mortality from coronary heart disease.

The relation of behavior (Type A or Type B) to the morbidity and mortality of coronary heart disease (CHD) is still debated. We studied the survival of 257 male patients with CHD from the initial, 8.5-year phase of the Western Collaborative Group Study to see whether behavior type--as assessed by a structured interview before the CHD event--was related to subsequent CHD mortality. Behavior type was not related to mortality in 26 patients who died within 24 hours of the coronary event. However, of the 231 patients who survived for 24 hours, the mortality rate associated with CHD among 160 Type A patients studied during an average 12.7 years was 19.1 per 1000 person-years. This was unexpectedly lower than the corresponding rate of 31.7 among 71 Type B patients who were followed for an average of 11.5 years (P = 0.04). In a proportional-hazards survival analysis, which controlled for variable follow-up time, the type of initial coronary event, and traditional risk variables, the relative CHD-associated mortality rate among Type A as compared with Type B patients was 0.58 (P = 0.03; 95 percent confidence interval, 0.35 to 0.96). The lower mortality among Type A subjects occurred in both younger and older subgroups but was more pronounced in patients whose initial diagnosis was symptomatic myocardial infarction rather than silent myocardial infarction or angina pectoris. This apparent advantage associated with Type A behavior is surprising and needs confirmation, but the results do indicate that patients with CHD and a Type A behavior pattern are not at increased risk for subsequent CHD mortality.

Adult

Coronary heart disease mortality in the Western Collaborative Group Study. Follow-up experience of 22 years.

In 1960-1961, 3,154 healthy, middle-aged men were entered into the Western Collaborative Group Study, a long-term study of coronary heart disease. A 22-year mortality follow-up of this cohort in 1982-1983 accounted for almost 99% of the cohort, and determined that 214 of the men had died of coronary heart disease. The risk of coronary heart disease mortality was studied for several variables measured at baseline, i.e., Type A/B behavior, systolic blood pressure, serum cholesterol level, cigarette smoking status, and age. Using a proportional hazards regression model, systolic blood pressure, serum cholesterol level, cigarette smoking status, and age were highly significant predictors (p less than 0.001) of 22-year coronary heart disease mortality. Type A/B behavior showed no association with 22-year coronary heart disease mortality (standardized relative hazard (SRH) = 0.98, 95% confidence interval (CI) = 0.85-1.12). Systolic blood pressure, serum cholesterol, and age showed relatively consistent positive associations with coronary heart disease mortality over four successive time intervals after the baseline examination. Cigarette smoking showed a significant positive association in the first and second intervals and a nonsignificant positive association in the third and fourth intervals. Type A/B behavior was positively but not significantly associated with coronary heart disease in the first and third intervals, significantly negatively associated (SRH = 0.70, 95% CI = 0.53-0.93) in the second interval and not associated in the fourth interval. The results confirm the importance of the traditional coronary heart disease risk factors, and raise a substantial question about the importance of Type A/B behavior as a risk factor for coronary heart disease mortality.

Adult

Social connections and mortality from all causes and from cardiovascular disease: prospective evidence from eastern Finland.

The association between an a priori measure of social connections and five-year mortality from all causes, cardiovascular diseases (International Classification of Diseases, Eighth Revision (ICD-8) codes 390-458), and ischemic heart disease (ICD-8 codes 410-414) was studied in 13,301 men and women from eastern Finland who were first interviewed in 1972 or 1977. For men, there was a graded association between extent of social connections and mortality. In multivariate models with adjustment for age, smoking, serum cholesterol, mean weighted blood pressure, measures of prevalent illness, and other possible confounders, men who were in the two lowest quintiles of the social connections scale were at increased risk compared with those in the highest quintile (odds ratio (OR)all cause = 1.54, 95% confidence interval (CI) = 1.21-1.95; ORcardiovascular disease = 1.54, 95% CI = 1.11-2.13; ORischemic heart disease = 1.34, 95% CI = 0.94-1.90). No strong or consistent association was found for women. The association for men was modified by levels of blood pressure with the effect of low social connections greater at higher levels of blood pressure. In three separate analyses, there was no evidence for confounding or effect modification due to prevalent illness at baseline.

Adult

Type A behavior pattern and health status after 22 years of follow-up in the Western Collaborative Group Study.

Type A/B behavior has been studied extensively as a risk factor for coronary heart disease. This study tests the hypothesis that Type A/B behavior is associated with ill health in general. All-cause mortality was examined in the original cohort of 3,154 men aged 39-59 years at baseline in the Western Collaborative Group Study in 1960-1961. Morbidity was examined in a group of 2,365 men aged 61-81 years who were surviving members of the cohort in 1982-1983 and who agreed to fill out a self-administered health status questionnaire. On the basis of these data, a three-level general morbidity index was constructed that included coronary heart disease and a number of other chronic conditions. Type A/B behavior was not significantly associated with all-cause mortality over the 22-year follow-up. However, among men 61-71 years of age, behavior type assessed at the baseline examination 22 years earlier (1960-1961) was positively associated with the morbidity index (p less than 0.001). Furthermore, behavior type and the morbidity index showed a dose-response association; extreme Type A personalities had the highest level of morbidity, while those with the fewest Type A characteristics had the lowest level of morbidity. This general pattern of association was not due to the presence of coronary heart disease or to any other particular disease condition in the morbidity index and did not change when an ordinal logistic regression model was used to control for other baseline risk variables. For the older men (aged 72-81 years), the pattern of association was similar but did not reach statistical significance. Thus, in a group of men over 60, a positive association was found between general morbidity status and Type A/B behavior measured over two decades earlier.

Aged

Compliance to treatment for hypertension in elderly patients: the SHEP pilot study. Systolic Hypertension in the Elderly Program.

Assessing the compliance of people over 60 years of age and older with an antihypertensive treatment regimen was a major objective of the Systolic Hypertension in the Elderly Program (SHEP) pilot study. The study randomized 551 men and women over the age of 60 (mean age = 72 years) to a stepped care treatment that included chlorthalidone or placebo in a double-blind trial. Three measures of compliance to treatment protocol--pill count, self-report, and a urine chlorthalidone assay--all indicated high levels of compliance in 80 to 90% of participants at 3 months and 1 year after randomization. Pill-taking compliance was similar in the active and placebo groups, although the rate of discontinuance from study medications at 1 year was higher in the placebo than in the active group. Compliance was high in all age categories, including those over age 80. These data suggest that elderly patients can achieve high levels of compliance with antihypertensive medications.

Age Factors

Type A behavior and cancer mortality. Theoretical considerations and preliminary data.

If stress and cancer are related by coping failure, that connection presumably involves the immune system. This involvement has already been shown in animals. It can be hypothesized that Type A personalities (driving, impatient, sometimes hostile) go through states of repeated frustration because of unachieved goals. From that point of view, Type A individuals are alternately able to cope and unable to cope. Such a pattern would theoretically tend toward repeated episodes of suppression and recovery of the immune system, with increased probability of growth of transformed cells. An opposing hypothesis, derived from human survival studies, suggests that a subgroup of Type B individuals (termed "Type C"--accepting, giving-up) are more likely to suffer a poor prognosis. A preliminary study relating Type A/B behavior pattern to cancer mortality was done in a cohort of 3154 men from the Western Collaborative Group Study (WCGS). The cancer mortality rate for the period 1960-1977 was 0.037 for Type A subjects (58 cancer deaths/1589 Type A subjects), and 0.025 for Type B subjects, yielding an odds ratio of 1.55. The odds ratio dropped to 1.29 (95% confidence interval = 0.84-1.96) when controlled for age, cigarette smoking, serum cholesterol, systolic blood pressure, and education. Preliminary analysis from a follow-up to mid-1983 shows a similar association. The findings suggest that, if anything, Type A subjects are more likely to die of cancer than Type B subjects. Although the finding is not strongly suggestive of a clinically or theoretically significant association between Type A/B behavior pattern and cancer mortality, it is sufficiently interesting to warrant further investigation.

Adult