Genetic selection of a Plasmodium-refractory strain of the malaria vector Anopheles gambiae.

The anopheline mosquito is the target in most malaria control programs, primarily through the use of residual insecticides. A mosquito was studied that is refractory to most species of malaria through a genetically controlled mechanism. A strain of Anopheles gambiae, which was selected for complete refractoriness to the simian malaria parasite Plasmodium cynomolgi, also has varying degrees of refractoriness to most other malaria species examined, including the human parasites P. falciparum, P. ovale, and P. vivax for which this mosquito is the principal African vector. Furthermore, the refractoriness extends to other subhuman primate malarias, to rodent malaria, and to avian malaria. Refractoriness is manifested by encapsulation of the malaria ookinete after it completes its passage through the mosquito midgut, approximately 16 to 24 hours after ingestion of an infective blood meal. Fully encapsulated ookinetes show no abnormalities in parasite organelles, suggesting that refractoriness is due to an enhanced ability of the host to recognize the living parasite rather than to a passive encapsulation of a dead or dying parasite. Production of fully refractory and fully susceptible mosquito strains was achieved through a short series of selective breeding steps. This result indicates a relatively simple genetic basis for refractoriness. In addition to the value these strains may serve in general studies of insect immune mechanisms, this finding encourages consideration of genetic manipulation of natural vector populations as a malaria control strategy.

Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man.

The first half of this manuscript is devoted to a review of the methods used and the results obtained in the published measurements of the normal responses to tests of the three main types of hypothalamic-pituitary-adrenocortical (HPA) activity in man. These are, I, basal, unstressed activity leading to appropriate levels of total daily production of cortisol in the characteristic circadian pattern; II, responses to feedback stimulation of HPA activity by metyrapone administration; and III, responses to tests of the effects of stress on the HPA system including the effects of hypoglycemia, induced fever, vasopressin administration, and ACTH injections and infusions. The advantages and shortcomings of each type of procedure are discussed. The second half of this paper describes the authors' attempts to establish the limits of normality of standard and modified methods of evaluating the HPA system. The defined limits of normality have been used to assess the HPA function in 158 patients with known or suspected disorders of the HPA system. In normal controls, halfhourly plasma cortisol determinations established the normality of circadian and postprandial fluctuations and of mean plasma cortisol concentration, 6.2 +/- 0.3 (SEM) micrograms/dl, which were closely approximated by determinations every 6 h. Metyrapone, given in a dose of 500 mg every 2 h for 24 h increased urinary 17-OHCS excretion to 10.5-32.6 mg/day or to 1.7-7.8 times basal excretion rate. Increasing rates of insulin infusion disclosed significant relationships between resulting plasma glucose and cortisol concentrations. The slopes of the delta cortisol/delta glucose responses were similar after insulin infusions (0.46 +/- 0.05) and after insulin injections, 0.15 U/kg (0.43 +/- 0.09), and were always greater than 0.20 micrograms/mg. This index provides a useful objective measure of the normality of responses to hypoglycemic stress, 0.20-0.87 micrograms/mg. Adrenocortical responses to iv infusions of ACTH (cosyntropin 0.25 mg) may be equivocal at 2 h but are clear cut at 4, 6 and 8 h. Of 158 patients in whom hypopituitarism was known or suspected because of the presence of a pituitary tumor, acromegaly, hyperprolactinemia, or clinical features, HPA function was found to be entirely normal in 88 patients and partially or severely abnormal in the remaining 70 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Temperature dependence of kinetic interactions between progesterone and the uterine cytoplasmic receptor.

The temperature dependence of the rates of dissociation and association for progesterone-receptor interactions was measured over the temperature range of 0-20 degrees C. The dissociation process is biphasic indicating that either two forms of receptor are present or that the binding of progesterone to the receptor is a concatenated reaction. The enthalpy of activation for the dissociation of progesterone from the receptor is about 26-28 kcal/mol and the entropic energy of activation is about -5 kcal/mol. The enthalpy of activation for the association of these molecules is about 3 kcal/mol and the entropic energy of activation is about 6 kcal/mol. These data are consistent with a model of progesterone binding to the receptor that includes hydrogen bonds between each of the two ketone groups and hydrogen donors on the receptor protein and involves van der Waals' interactions, due to the close proximity of the receptor binding site to a large fraction of the progesterone surface.

Temperature dependence of the dissociation rate constants for the nonactivated (molybdate-stabilized) and activated progesterone receptor-hormone complexes from the chick oviduct.

Both the nonactivated and activated forms of the chick oviduct cytosol progesterone receptor-hormone complexes displayed first-order dissociation kinetics at temperatures between 0 and 25 degrees C. The rate constant was always 2-3-times greater for the nonactivated than for the activated complex. The thermodynamic parameters calculated from the Eyring plot for the nonactivated and activated forms, respectively, were: delta H+ = 28.6 +/- 0.2 and 29.9 +/- 1.5 kcal/mol; -T delta S+ = 7.4 +/- 0.6 and 7.7 +/- 1.6 kcal/mol; and delta G+ = 21.3 +/- 0.5 and 22.1 +/- 0.1 kcal/mol. These values suggest that activation results in an increase in enthalpy of the ligand-receptor interaction, thus stabilizing the complex. The dissociation rate constants for the native complex obtained by two different experimental approaches, namely, isotope dilution ('chase') and dissociation against charcoal, indicated the absence of cooperativity in the receptor-ligand binding.

Estrogen replacement therapy. A survey of older women's attitudes.

OBJECTIVES: To understand the low prevalence of estrogen use among older women. To examine the reasons for the use and nonuse of estrogen replacement therapy. SUBJECTS AND METHODS: Nonblack women (n = 7667), aged 65 years or older, who participated in the Multicenter Study of Osteoporotic Fractures completed an estrogen questionnaire. RESULTS: Of the subjects, 1335 (17.4%) were currently using oral estrogens, 2084 (27.2%) were past users, and 4248 (55.4%) had never used oral estrogen therapy. The self-reported primary reasons for current users to have initiated therapy included hysterectomy (43.5%), menopausal symptoms (39.3%), prescribed by a physician (38.7%), or prevention or treatment of osteoporosis (33.6%). Of the 2084 former estrogen users (27.2%), the main reasons for starting therapy included prescribed by a physician (44.7%), menopausal symptoms (49.2%), and hysterectomy (28.5%). Approximately 30% of past estrogen users reported the primary reason for discontinuing therapy as "feeling that they didn't need it," whereas 16.4% reported undesirable side effects with bleeding as the most common (45.0%). The main reason women never started estrogen therapy (55.4%) was they feared that the medication was harmful (38.1%) or they felt they did not need it (29.5%). CONCLUSIONS: We conclude that older women in the United States remain skeptical about long-term estrogen use despite its potential for protection against 2 major chronic diseases, osteoporosis and cardiovascular disease. Greater understanding about the barriers to estrogen replacement therapy and improved knowledge of its risks and benefits may reduce the skepticism surrounding estrogen replacement therapy among older women.

Estrogen replacement therapy and mortality among older women. The study of osteoporotic fractures.

BACKGROUND: Most previous studies of estrogen replacement therapy (ERT) and mortality have focused on younger women. Recently, it has been suggested that the effect of ERT on mortality may represent a "healthy-user" effect, ie, those with healthier lifestyles having a greater likelihood of receiving ERT. METHODS: Nine thousand seven hundred four women, 65 years or older, participated; 1258 (14.1%) reported current use of ERT for at least 1 year at entry. During an average follow-up of 6.0 years, 1054 women (11.8%) died. RESULTS: After adjusting for multiple variables, mortality rate was lower among current (relative risk [RR], 0.69; 95% confidence interval [CI], 0.54-0.87) and past users (RR, 0.79; 95% CI, 0.66-0.95), mainly due to reductions in deaths due to cardiovascular disease. The protective effect of ERT was greatest among women younger than 75 years (RR, 0.55; 95% CI, 0.40-0.76) compared with women from 75 to 84 years of age (RR, 0.93; 95% CI, 0.62-1.41) and 85 years or older (RR, 1.33; 95% CI, 0.43-4.12). The RR for overall mortality was 0.95 (95% CI, 0.68-1.32) among short-term users (1-9 years) compared with 0.55 (95% CI, 0.40-0.75) among long-term users (> or = 10 years). Deaths considered unrelated to ERT tended also to be reduced in current users younger than 75 years (RR, 0.72; 95% CI, 0.49-1.06) and current long-term users (RR, 0.75; 95% CI, 0.51-1.10). CONCLUSIONS: Estrogen replacement therapy is associated with lower overall mortality rates and reduced deaths due to cardiovascular disease. Women using ERT had healthier lifestyles, and the risk for death thought to be unrelated to ERT also tended to be lower in ERT users, suggesting in part a healthy-user effect.

Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women? Study of Osteoporotic Fractures Research Group.

BACKGROUND: Muscle strength declines with advancing age; the causes of this are uncertain. In women, strength begins to decline around the time of menopause, suggesting that hormonal changes might influence strength. To determine the effect of postmenopausal estrogen use on muscle strength, neuromuscular function, and the risk of falling, we examined 9704 participants aged 65 years or more enrolled in the Study of Osteoporotic Fractures. METHODS: We measured hip abductor, triceps extensor, and hand-grip muscle strength, balance, gait speed, and self-reported functional disability. Falls during the first year of follow-up were determined from postcards that participants mailed every 4 months indicating whether they had fallen in the previous 4 months (> 99% complete follow-up). RESULTS: After adjusting for age, medications, medical history, and personal habits, current estrogen users did not differ in a clinically meaningful way from those who had never used estrogen on tests of hip abductor strength (mean difference, 0.15 kg; 95% confidence interval, -0.05 to 0.34 kg), triceps extensor strength (0.005 kg; -0.17 to 0.18 kg), or grip strength (0.30 kg; 0.00 to 0.59 kg). Gait speed, time to stand five times from a chair, balance, self-reported disability, and incidence of falls (odds ratio, 1.12; 95% confidence interval, 0.87 to 1.44) also did not differ between current users and never users. In addition, current users were similar to past users on all measures. CONCLUSION: We found no evidence that postmenopausal estrogen use has beneficial effects on muscle strength or neuromuscular function or that it reduces the risk of falling.

Predictors of ankle and foot fractures in older women. The Study of Osteoporotic Fractures Research Group.

To determine risk factors for ankle and foot fractures, data collected from 9704 women 65 years of age or older from four areas of the United States were analyzed. Self-reported baseline questionnaires covered areas such as lifestyle factors (physical activity, diet, and smoking habits) and functional impairment (history of fracture, falling, and other diseases). Bone mineral density (BMD) and performance on neuromuscular tests were also measured. During 5.9 years of follow-up, 191 women fractured an ankle and 204 women fractured a foot. Proportional hazard models were used to estimate relative risks. In multivariable models, factors associated with ankle fracture included one or more falls in the year prior to baseline (relative risk [RR] 1.5; 95% confidence interval [CI] 1.1-2.1), greater vigorous physical activity (RR per 2 times/week, 1.2; CI 1.1-1.3), weight gain since age 25 (RR per 20% gain, 1.4; CI 1.2-1.5), self-reported osteoarthritis (RR 0.5; CI 0.3-0.8), a sister's history of hip fracture after age 50 (RR 1.7; CI 1.0-3.0), out of house < or = 1 per week (RR 3.0; CI 1.4-6.6), and low distal radius BMD (RR per -0.1 g/cm2, 1.2; CI 1.0-1.4). Factors associated with foot fracture included insulin-dependent diabetes (RR 2.9; CI 1.2-7.2), use of seizure medications (RR 2.3; CI 1.0-5.7) or of benzodiazepines (RR 1.5; CI 1.1-2.2), history of hyperthyroidism (RR 0.5; CI 0.3-1.0), poor far depth perception (RR 0.7; CI 0.5-1.0), and low distal radius BMD (RR per -0.1 g/cm2, 1.3; CI 1.1-1.5). Ankle and foot fractures have different profiles of risk factors that are largely independent of low bone mass.

Characterization of the estrogen receptor extracted from hen oviduct nuclei with pyridoxal phosphate.

The estrogen receptor was extracted in high yield from nuclei of laying hen oviduct with 10 mM pyridoxal-5'-phosphate (PLP). The receptor extracted under these conditions, unlike that extracted with 0.4 M KCl, displayed no tendency to aggregate on sucrose gradients in low salt. The receptor was eluted as a single peak from DEAE-Sephacel at an ionic strength of 0.13 M KCl. The receptor after DEAE chromatography had approximately half the molecular weight of that in the nuclear extract. A larger form could be reconstituted by the addition of whole nuclear extract to the DEAE eluate. These data support the notion that the nuclear estrogen receptor is a dimer composed of similar subunits.

Effects of H2-antagonists on androgen imprinting of male hepatic functions.

Many of the sex-differentiated functions of the liver of adult male rats depend upon the occurrence of neonatal androgen imprinting, a brief surge of androgen early in life. We investigated whether androgen imprinting is necessary for the development and maintenance of levels of a microsomal enzyme, estrogen-2-hydroxylase (E-20Hase), and a male-specific cytosolic estrogen binder (MEB) which are higher in adult male than in adult female rats. Cimetidine, a weakly antiandrogenic H2 blocker, was administered to pregnant and lactating rats from day 12 of gestation through weaning on day 21. Livers of male progeny, 120-150 days of age, were assayed for E-2OHase and MEB activity; a maternal dose equivalent to 2.5 times the usual human dose inhibited MEB activity in the levels of the offspring by 40% but had no effect on E-2OHase. However, a higher dose (5 times the human dose) was effective in reducing the E-2OHase activity by 50%. Rats whose mothers had received either no drug or an equivalent dose of ranitidine, another H2 blocker without antiandrogenic activity, were used as controls. The groups were not different in hepatic cytosolic androgen receptor content, body weight, or serum testosterone. In other studies, the requirement of neonatal androgen imprinting for full expression of adult levels of MEB and E-2OHase was determined. Female rats, which have low levels of E-2OHase and undetectable levels of MEB, were given androgen on day 1, on day 60 after ovariectomy, or at both times. Levels of E-2OHase equivalent to those in adult males were induced in females receiving both androgen treatments, whereas either treatment alone induced E-2OHase to the level of that in males castrated at adulthood or neonatally, which is about 50% that in normal male controls. In addition, MEB levels were induced in females to 85% of that in normal males by both androgen treatments and to 50% by administration of androgen to adult females or to adult males castrated neonatally. Administration of androgen to females during the neonatal period only did not induce MEB. We conclude that both MEB and E-2OHase require androgen imprinting for full expression in adult male rats.

Inhibition of iron-sulfur protein-mediated reduction of cytochrome P-450SCC by specific antibodies.

The mechanism of inhibition of cholesterol side-chain cleavage by specific antibodies was studied systematically. The antibodies had no effect on substrate binding as determined by optical spectroscopy or on the heme environment of the cytochrome P-450 insofar as was detectable by electron paramagnetic resonance spectroscopy. They did not bind to either iron-sulfur protein or its reductase. The antibodies had no effect on chemical reduction of the P-450 or on P-450-CO complex formation. They did inhibit the NADPH-dependent reduction of P-450 and subsequent formation of the P-450-CO complex. This inhibitory effect was concentration dependent and was correlated with the inhibitory effect of the antibodies on enzymatic cholesterol side-chain cleavage. Similar results were obtained using Fab fragments. These results indicate that the antibodies inhibit side-chain cleavage by binding to a region close to the iron-sulfur protein-binding site, thereby preventing transfer of reducing electrons to the cytochrome P-450.

Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study.

BACKGROUND: Though among the most abundant human steroid hormones, the physiologic role of dehydroepiandrosterone and its sulfate (DHEAS) is not known. Our goal was to determine if DHEAS is associated with cognition and mood in older women, and if baseline DHEAS levels are predictive of cognitive decline. METHODS: In a prospective cohort, we studied 394 randomly selected community-dwelling women, aged 65 years or older, currently enrolled in the Study of Osteoporotic Fractures. Subjects were administered a modified Mini-Mental State Exam, Trials B, Digit Symbol, and the Geriatric Depression Scale-Shortened (GDSS), at study onset and 4-6 years later. Serum was obtained at study initiation for DHEAS analysis. RESULTS: DHEAS levels declined with age, as expected. There was no consistent association of DHEAS quartile or log DHEAS with any of the four outcomes, even after multivariate adjustment. Change in cognitive performance overtime was not associated with DHEAS levels. Analysis of the 32 women without any detectable DHEAS compared to those with detectable levels revealed higher measures on the GDSS (mean score 3.4 +/- 3.6 compared with 1.6 +/- 2.3, p = .028) and a higher percentage with depression (21.7% compared with 4.6%, p = .001). CONCLUSIONS: Serum DHEAS is not a sensitive predictor of cognitive performance or decline on a selected neuropsychological battery in elderly community women; however, nondetectable levels may be associated with depression.

Body size and hip fracture risk in older women: a prospective study. Study of Osteoporotic Fractures Research Group.

PURPOSE: To determine the relationship between measures of body size and the risk of hip fracture in elderly women. PARTICIPANTS AND METHODS: The association between measures of body size and hip fracture risk was assessed in 8,011 ambulatory, nonblack women 65 years of age or older enrolled in the Study of Osteoporotic Fractures with measurements of total body weight, percent weight change since age 25, hip girth, lean mass, fat mass, percent body fat, body mass index, modified body mass index, and femoral neck bone mineral density (BMD) at the second examination. These 8,011 women were followed prospectively for incident hip fractures occurring after the second examination, which were confirmed by review of x-ray films. RESULTS: During an average of 5.2 years after the second examination, 236 (2.9%) women experienced hip fractures. Similar associations were observed between hip fracture risk and all measures of body size including total body weight, percent weight change since age 25, hip girth, lean mass, fat mass, percent body fat, body mass index, and modified body mass index. Women with smaller body size had a higher risk of subsequent hip fracture compared with those with larger body size, while women with average and larger body sizes shared similarly lower risks of subsequent hip fracture. For example, the incidence rate of hip fracture was 9.35 per 1000 woman-years in women in the lowest quartile of total weight compared with 4.63 per 1000 woman-years in women in the highest quartile of total weight (age-adjusted relative risk 1.93, 95% confidence interval (CI) 1.34 to 2.80), while rates of hip fracture among women in the second and third quartiles of total weight (5.22 and 4.32 per 1000 woman-years, respectively) were not significantly different from the rate among women in the highest quartile (P > 0.64). The increased risk of hip fracture among women of smaller body size remained after further adjustment for additional potential confounding factors including height at age 25, smoking status, physical activity, health status, estrogen use, and diuretic use. After further adjustment for femoral neck BMD, women with smaller body size were no longer at significantly increased risk of hip fracture compared with those with larger body size. For example, after adjustment for height at age 25, smoking status, physical activity, health status, estrogen use, and diuretic use, thin women had a 2.5-fold increase in the risk of hip fracture (multivariate relative risk 2.51, 95% CI 1.69 to 3.73) compared with the referent group composed of the heaviest women. After further adjustment for femoral neck BMD, the multivariate relative risk of hip fracture among thin women compared to heaviest women was 0.98 (95% CI, 0.64 to 1.50). CONCLUSION: Older women with smaller body size are at increased risk of hip fracture. This effect is because of lower hip BMD in women with smaller body size. Assessment of body size for prediction of hip fracture risk can be accomplished by measuring total body weight.

Circadian variation in ventricular arrhythmias in hypertensive men.

Circadian patterns have been observed for various cardiovascular functions and events including sudden cardiac death. This study examined whether ventricular arrhythmias could be a pathophysiologic explanation for the increase in prevalence of sudden cardiac death observed between 6 A.M. and noon. Hypertensive men 35 to 70 years of age and without a history of symptomatic cardiac disease were withdrawn from diuretic treatment and received 1 month of oral electrolyte repletion with both 40 mmol of potassium chloride and 400 mg of magnesium oxide daily. Then continuous 24-hour Holter monitoring was performed and ventricular arrhythmias were classified by 6-hour time intervals. The interval from 6 A.M. to noon revealed a higher prevalence of complex or frequent ventricular arrhythmias than the interval from midnight to 6 A.M., as well as a higher mean number of ventricular premature complexes per hour. The differences were statistically significant (p less than 0.01) and amounted to increases of about one third. Ventricular arrhythmias during the other two 6-hour periods were intermediary in frequency. It is concluded that the increase in sudden cardiac death noted in the morning might be related, at least in part, to an increase in frequency of ventricular arrhythmias; the implications of this observation for preventive cardiology deserve further investigation.

Risk of ventricular arrhythmias in hypertensive men with left ventricular hypertrophy.

The echocardiographic predictors of ventricular arrhythmias are reported for the Hypertension Arrhythmia Reduction Trial. Men with mild hypertension were withdrawn from their diuretic therapy and repleted with 40 mEq/day of oral potassium and 20 mEq/day of oral magnesium for 1 month. M-mode echocardiography and 24-hour continuous ambulatory electrocardiography were performed on 123 men, mean age 62 years. Forty-eight men (39%) had echocardiographic evidence of left ventricular (LV) hypertrophy defined as an LV mass index greater than 134 g/m2 and this finding was not related to the presence of LV hypertrophy on electrocardiogram or to age. Men who had echocardiographic LV hypertrophy were more likely than men without echocardiographic LV hypertrophy to have greater than or equal to 30 ventricular premature complexes (VPCs)/hr (odds ratio = 2.7; 95% confidence interval = 0.9, 8.0), multiform extrasystoles (odds ratio = 1.7; confidence interval = 0.8, 3.7), episodes of ventricular tachycardia (odds ratio = 2.3; confidence interval = 0.7, 7.1) and the combination of frequent (greater than or equal to 30 VPCs/hr) or complex (ventricular couplets, multiform extrasystoles or episodes of ventricular tachycardia) ventricular arrhythmia (odds ratio = 1.7; confidence interval = 0.8, 3.5). Similar associations between echocardiographic LV hypertrophy and ventricular arrhythmias were observed on 24-hour tracings obtained on entry to the study (before electrolyte repletion) in the 96 men who were taking diuretics at this time. The combination of a frequent or complex arrhythmia was also more common in men aged 60 to 70 compared to men aged 35 to 59 (odds ratio = 3.4; confidence interval = 1.4, 8.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Silent myocardial ischemia in men with systemic hypertension and without clinical evidence of coronary artery disease.

The prevalence, characteristics and circadian pattern of silent myocardial ischemia, and its association with ventricular arrhythmias was studied in hypertensive men aged 35 to 70 years (mean 61) without clinical cardiac disease. Participants were withdrawn from diuretic treatment and received 1 month of oral electrolyte repletion with 40 mmol of potassium chloride, and 400 mg of magnesium oxide daily. Twenty-four-hour Holter monitoring was then performed. Episodes of silent myocardial ischemia occurred in 50 of 186 men (27%) and lasted from 2 to 289 minutes (mean 30 and median 18). Statistical analysis comparing the interval from midnight to 6 A.M. with each of the other three 6-hour time intervals revealed that participants were less likely to have silent myocardial ischemia in this period (p less than 0.01 for each comparison) than at other times of the day. There was little difference in the proportion of men with a frequent or complex ventricular arrhythmia during the entire day or within 1 hour of the silent myocardial ischemic episode (or during a comparable time period) comparing those with to those without silent myocardial ischemia. These findings indicate that silent myocardial ischemia occurs in approximately 25% of an older population of hypertensive men without history of symptomatic cardiac disease. The circadian pattern of frequency of silent ischemic events in men free of clinical cardiac disease is similar to that reported for patients with cardiac disease and coincides with that reported for sudden death. There was no significant association between silent myocardial ischemia and ventricular arrhythmias.

Transformation of a rabbit progesterone receptor from an 8S form to 5.5S and 4S forms.

The 8S form of the rabbit uterine progesterone receptor transforms slowly at 0 degree C to a 4S form with an intermediate 5.5S form. The transformation is accelerated by either heat, increased ionic strength and dilution of cytosol. The transformation, which is reversibly inhibited by sodium molybdate, is unrelated to total cytosolic alkaline phosphatase activity. The transformation is accompanied by a positive change in receptor surface charge and a decrease in the rate of progesterone dissociation. The stability of the 8S progesterone-receptor complex is reduced and the sedimentation coefficient increased by acidic conditions; acid does not affect the 4S receptor as drastically.

Correlates of impaired function in older women.

OBJECTIVE: To determine the factors associated with impaired function in older women. DESIGN: Cross-sectional analysis of baseline data collected for a multicenter, prospective study of risk factors for osteoporotic fractures. SETTING: Four clinical centers in Portland, Oregon, Minneapolis, Minnesota, Baltimore, Maryland, and the Monongahela Valley, Pennsylvania. PARTICIPANTS: A total of 9,704 ambulatory, non-black women, aged 65 years and older, recruited from population-based listings. MEASUREMENTS: Independent variables, including demographic and historical information (medical conditions, health habits, and medications) and physiologic measures (anthropometry, blood pressure, mental status, vision, and neuromuscular performance) were obtained from a baseline questionnaire, interview, and examination. Measurement of function was assessed by self-reported ability to perform six physical and instrumental activities of daily living (ADL) and impaired function (dependent variable) was defined as difficulty performing three or more physical and instrumental ADLs. RESULTS: In order of decreasing strength of association, hip fracture, osteoarthritis, parkinsonism, slower walking speed, lower hip abduction force, back pain, greater Quetelet index, osteoporosis, former alcohol use, stroke, never drinking alcohol, lower mental status, use of anxiolytics and/or sleeping medications, inability to hold the tandem position, postural dizziness, cataracts, greater waist to hip ratio, lower physical activity in the past year, greater lifetime cigarette consumption, and lower grip strength were independently associated with impaired function in multivariate analyses. Age, low educational level, diabetes, current heavy alcohol use, postural hypotension, depth perception, and contrast sensitivity were not independent predictors. A combination of neuromuscular performance measures, including decreased muscle strength and impaired balance and gait, appeared to account for the effect of age on disability. CONCLUSION: A combination of many factors, including medical conditions, health habits such as obesity, smoking, alcohol abstinence, and physical inactivity, and direct measures of neuromuscular performance are associated with impaired function in older women.

Modifiable risk factors predict functional decline among older women: a prospectively validated clinical prediction tool. The Study of Osteoporotic Fractures Research Group.

OBJECTIVE: To identify modifiable predictors of functional decline among community-residing older women and to derive and validate a clinical prediction tool for functional decline based only on modifiable predictors. DESIGN: A prospective cohort study. SETTING: Four geographic areas of the United States. PARTICIPANTS: Community-residing women older than age 65 recruited from population-based listings between 1986 and 1988 (n = 6632). MEASUREMENTS: Modifiable predictors were considered to be those that a clinician seeing an older patient for the first time could reasonably expect to change over a 4-year period: benzodiazepine use, depression, low exercise level, low social functioning, body-mass index, poor visual acuity, low bone mineral density, slow gait, and weak grip. Known predictors of functional decline unlikely to be amenable to intervention included age, education, medical comorbidity, cognitive function, smoking history, and presence of previous spine fracture. All variables were measured at baseline; only modifiable predictors were candidates for the prediction tool. Functional decline was defined as loss of ability over the 4-year interval to perform one or more of five vigorous or eight basic daily activities. RESULTS: Slow gait, short-acting benzodiazepine use, depression, low exercise level, and obesity were significant modifiable predictors of functional decline in both vigorous and basic activities. Weak grip predicted functional decline in vigorous activities, whereas long-acting benzodiazepine use and poor visual acuity predicted functional decline in basic activities. A prediction rule based on these eight modifiable predictors classified women in the derivation set into three risk groups for decline in vigorous activities (12%, 25%, and 39% risk) and two risk groups for decline in basic activities (2% and 10% risk). In the validation set, the probabilities of functional decline were nearly identical. CONCLUSIONS: A substantial portion of the variation of functional decline can be attributed to risk factors amenable to intervention over the short term. Using eight modifiable predictors that can be identified in a single office visit, clinicians can identify older women at risk for functional decline.

Urinary incontinence in older women: who is at risk? Study of Osteoporotic Fractures Research Group.

OBJECTIVE: To estimate the prevalence of and identify factors associated with urinary incontinence in older women. METHODS: A cross-sectional study involved 7949 community-dwelling women, with a mean (+/- standard deviation) age of 76.9 +/- 5.0 years, recruited from population-based listings to participate in the Study of Osteoporotic Fractures. The prevalence and severity of urinary incontinence during the previous 12 months were assessed by questionnaire. Factors potentially associated with urinary incontinence were assessed by questionnaire, interview, and physical examination. Multivariate logistic regression analysis was used to determine the independent associations between these factors and the primary outcome of daily incontinence. RESULTS: Forty-one percent (3285) of the women reported urinary incontinence, with 14% (1130) reporting daily incontinence. In multivariate analysis, the prevalence of daily urinary incontinence increased significantly with age (odds ratio [OR] 1.3 per 5 years, 95% confidence interval [CI] 1.2-1.5), prior hysterectomy (OR 1.4, 95% CI 1.1-1.6), higher body mass index (OR 1.6 per 5 units, 95% CI 1.4-1.7), history of stroke (OR 1.9, 95% CI 1.3-2.7), diabetes (OR 1.7, 95% CI 1.2-2.4), chronic obstructive pulmonary disease (OR 1.7, 95% CI 1.1-1.9), and poor overall health (OR 1.6, 95% CI 1.3-2.1). Faster gait speed (OR 0.8 per 0.2 units, 95% CI 0.6-1.0) was associated with decreased incontinence. CONCLUSION: Urinary incontinence is a common problem in older women, more common than most chronic medical conditions. Of the associated factors that are preventable or modifiable, obesity and hysterectomy may have the greatest impact on the prevalence of daily incontinence.