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Weak-acid, 31P-nuclear magnetic resonance (NMR) and microelectrode techniques for measuring intracellular pH (pHi) are compared by demonstration of their use in rat liver. The ultimate test of suitability of these methods is the confidence with which they can be used to clarify aspects of metabolic regulation, translocation of substances across biological membranes, and the control of cell pH itself. Though resting pHi in perfused liver is fairly similar with all three techniques, substantial quantitative differences between values obtained with 31P NMR and microelectrodes are revealed after addition of fructose to the perfused liver preparation. The use and limitations of weak-acid methods in determining the mechanism of inhibition of gluconeogenesis from lactate by acidosis and in determining the pH responsiveness of the lactate transporter in the hepatocyte plasma membrane are demonstrated. Microelectrode-derived values of pHi are probably referable to the bulk phase of the cytosol, whereas values from the other two methods are more complex in their interpretation. Microelectrode and NMR methods have the great advantage of being non-destructive, and continuous records may be obtained.

We studied the association between behavioral and demographic risk factors and 17-year mortality in members of the Alameda County (California) Study who were 60-94 years of age at baseline. In this age group, increased risk of death is associated with being male, smoking, having little leisure-time physical activity, deviating from moderate weight relative to height, and not regularly eating breakfast. These increased risks were independent of age, race, socioeconomic position (SEP), other behavioral risk factors, and baseline physical health status. Further examination of the group aged 70 or more revealed the same patterns of heightened risk.

1. A method for assessing cholecalciferol absorption in man is described. 2. The intestinal absorption of [3H]cholecalciferol was studied in 20 female geriatric patients, most of whom were vitamin D-depleted. 3. The plasma [3H]cholecalciferol response after oral ingestion was significantly lower than that of a group of younger female subjects. 4. The plasma response of labelled polar metabolites of cholecalciferol was also lower in the geriatric than in the younger group, suggesting that increased removal of label by conversion into more polar metabolites could not account for the reduced plasma [3H]cholecalciferol response. 5. There was no evidence that alteration in gastrointestinal motility could account for the different rate of appearance of the labelled vitamin in the plasma in the two groups. 6. It is suggested that there is a defect in intestinal absorption of cholecalciferol in the elderly.

The contribution of secular changes in the distribution of ischemic heart disease risk factors and medical care utilization to the decline in ischemic heart disease mortality was investigated using data collected on the nine-year ischemic heart disease mortality experience of two cohorts selected to be representative of Alameda County, California, in 1965 and 1974. With adjustment for age, sex, race, and baseline ischemic heart disease conditions and symptoms, there was a 45% decline in the nine-year odds of ischemic heart disease mortality between the two cohorts (1965/1974, odds ratio (OR) = 1.82, p = 0.0001). Further adjustment for cohort differences in the following ischemic heart disease risk factors did not explain the decline: smoking status, leisure-time physical activity, self-assessed physical activity, alcohol consumption, body mass index, or social network participation; neither did adjustment for measures of education, utilization of preventive medical care, availability of a regular physician or clinic, health insurance coverage, number of physician visits during the last 12 months, or occupation. There was no change in the estimated ischemic heart disease decline when all adjustment variables were included in a logistic model (1965/1974, OR = 1.81, p = 0.0002). These variables do not appear to explain the large decline in nine-year ischemic heart disease mortality between these two cohorts.

1. The rate of removal from the circulation of an intravenous lactic acid load has been studied in conscious rats, previously subjected either to bilateral nephrectomy or to a sham operation. 2. In rats with normal blood pH, the apparent contribution of the kidneys to removal of the lactic acid load is 30%; less than 12% of the renal contribution is attributable to urinary excretion. 3. In bilaterally nephrectomized rats made acidotic by administration of ammonium chloride, the rate of removal of a half-neutralized lacrtic acid load is progressively decreased with increasing severity of acidosis. No such effect is seen in sham-operated animals. 4. An increase in the ability of the kidney to remove lactate during acidosis compensates for approximately half of the simultaneous fall in the capacity of the remainder of the body for lactate assimilation. 5. Basal blood lactate concentrations fall in the presence of metabolic acidosis.

Studies were made of the mechanism whereby hepatic gluconeogenesis is increased in diabetic ketoacidosis (DKA) despite evidence in vitro of inhibition of gluconeogenesis by systemic acidosis. In perfused livers taken from normal rats, marked inhibition of lactate uptake and glucose output was achieved by simulation of metabolic acidosis in the perfusate. In perfused livers obtained from animals with DKA, lactate uptake and glucose output were greater than in normal perfused liver at all values of perfusate pH, and it was not possible to demonstrate significant inhibition of gluconeogenesis from lactate by perfusate acidosis. Varying severity of acidosis was induced in rats by (a) HCl infusion, (b) NH4Cl ingestion or (c) experimental DKA. Hepatic intracellular pH (pHi) was measured in vivo by 31P-n.m.r. spectroscopy. Whereas at the severer degrees of systemic acidosis marked falls in hepatic pHi were seen in the HCl- and NH4Cl-treated animals, little fall was seen in rats with DKA. The protection of hepatic pHi in rats with DKA was not due to differences in respiratory compensation compared with the other groups. It is suggested that this protection of hepatic pHi in DKA may be responsible for the failure of acidotic inhibition of gluconeogenesis from lactate. Possible reasons for pHi protection in DKA are considered. There is no difference in hepatic energy status as assessed in vivo by ATP/Pi ratios between control, DKA and NH4Cl-treated rats. DKA rats show a striking decrease in hepatic glycerophosphoethanolamine content.

The prospective effects of smoking status and body mass on change in leisure-time physical activity from 1965 to 1974 were examined in a cohort of 4,622 persons 20-94 years of age from the Alameda County Study. With adjustment for age and baseline physical activity, current smokers showed a greater nine-year decline in leisure-time physical activity than those who had never smoked. The coefficient for current smokers from a multivariate linear regression model was of a similar magnitude among women and men (coefficient = -0.27, 95% confidence interval [CI] = -0.50 to -0.05 for women; coefficient = -0.26, 95% CI = -0.54 to 0.02 for men). Larger declines in physical activity were seen with increasing number of current pack-years exposure among both women and men. Compared with women of average body mass index, women of heaviest body mass index had larger declines (coefficient = -0.70, 95% CI = -1.04 to -0.36) while women of the lightest body mass index had larger increases (or smaller declines) in physical activity (coefficient = 0.33, 95% CI = 0.00 to 0.66). Although body mass index did not initially appear to be associated with a change in physical activity among men, age-specific analyses indicated that the effect of body mass index on physical activity varied with age such that younger (20-39 years of age), thinner men increased their activity, while older (60 years of age and over), thinner men decreased their physical activity more than men of the same age with average body mass index.

Pulmonary function, chest radiographic appearances, and the cellular composition of bronchoalveolar lavage fluid were assessed in 13 patients who were receiving amiodarone treatment. Eight of the patients had developed clinical and radiological evidence of lung disease and five were symptom free. The proportions of lymphocytes (mean 8.6 (SD 6.9)) and neutrophils (mean 3.4 (3.3)) obtained by bronchoalveolar lavage were similar in patients with and without lung complications. Electron microscopic examination of alveolar macrophages showed intralysosomal inclusion bodies in all subjects, regardless of clinical state. There was no significant difference in the mean number of inclusion bodies per macrophage transection between those with and those without lung disease. The differential cell count in bronchoalveolar lavage fluid and the presence of macrophage inclusion bodies were therefore not useful as markers of disease activity. Among those who developed clinical and radiological evidence of lung disease, the cumulative drug dose per kilogram of body weight and the duration of treatment (mean 16.5 (SD 9.0) months) were significantly correlated with the degree of lung restriction as measured by total lung capacity and forced vital capacity. It is concluded that, while the severity of the restrictive pulmonary defect that is induced by amiodarone is largely dose related, the development of lung toxicity is to some extent idiosyncratic.

1. The isolated perfused kidneys of fed rats in normal acid-base status showed a constant rate of lactate removal from the perfusate between 5 and 90 min of perfusion at a perfusate pH of 7-4-7-5. 2. Lactate removal by kidneys of rats in normal acid-base status was stimulated within 30 min by a reduction in perfusate pH to 7-1-7-2, but depressed when perfusate pH was reduced further. 3. Kidneys taken from rats previously made acidotic and perfused with media of various pH values showed a progressive fall in the rate of lactate removal during the perfusion. 4. Glucose output by the kidneys of rats in normal acid-base status perfused with lactate as substrate was not affected by an alteration in perfusate pH. The kidneys of acidotic rats generally showed an increased rate of glucose output compared with those of control rats.

We report on a large branchiogenic cyst in a neonate. The etiology of these cysts is assumed to be of branchial origin because of their communication with the pharynx and their intimate association with the thyroid and thymus glands. This report documents an additional occurrence of this rare lesion. Physicians are alerted to the fact that, should massive enlargements and compromise of the respiration be present, external decompression of these cysts is feasible.

Many studies indicate that women live longer than men but report more physical illness. This report is the first prospective study of sex ratios for morbidity and mortality due to a variety of causes in a single cohort: a random sample of 5,239 adults, aged 30 years or older in 1965, who have been followed through 1983 (19 years) by cause and age. For both cancer incidence and mortality there was a female excess before age 50 years, followed by a male excess peaking between ages 60 and 69 years. Sex ratios for ischemic heart disease mortality, on the other hand, indicated a male excess at virtually all ages, and that these sex ratios declined with age. However, three measures of heart disease morbidity (self-reported chest pain, heart trouble, and high blood pressure) demonstrated a female excess that did not vary by age. All four measures of functional disability (impaired self-care, impaired mobility, cessation of work, and reduction of work) demonstrated a female excess that did not vary by age (with the exception of a male excess in impaired self-care in adults aged 30 to 39 years). Further analyses of sex differences in health need to acknowledge the heterogeneity of the relation of sex to disease, and the complex age-sex interaction that varies remarkably with both cause and manifestation of outcome (morbidity vs. mortality).

The overnight urinary calcium/creatinine ratio is higher in the early years after the menopause than before it. However, the increment of urinary calcium/creatinine after a late evening calcium supplement is less in early postmenopausal than in premenopausal women. It is suggested that calcium therapy in postmenopausal osteoporosis may be best administered as a single late evening dose rather than in divided doses throughout the day.