Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects.

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naïve genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.

Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir.

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C24), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C24 and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

Predictive value of HIV-1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment-experienced patients.

OBJECTIVES: The aim of the study was to determine the prognostic value of HIV replication capacity (RC) for subsequent antiretroviral (ARV) treatment response in ARV-experienced patients. METHODS: RC and phenotypic resistance testing were performed at baseline and week 12 on plasma samples from patients randomized to undergo a 12-week ARV drug-free period (ARDFP) or initiate immediate salvage therapy (no-ARDFP group) in the Options in Management with Antiretrovirals (OPTIMA) trial. Dichotomous and incremental phenotypic susceptibility scores (dPSSs and iPSSs, respectively) were calculated. The predictive value of RC and PSS for ARV therapy response and/or ARDFP was evaluated using multivariate regression analysis and Pearson correlations. RESULTS: In 146 no-ARDFP subjects, baseline RC (50.8%) did not change at week 12 and was not correlated with CD4 cell count or viral load changes at week 12 (P=0.33 and P=0.79, respectively) or at week 24 (P=0.96 and P=0.14, respectively). dPSS predicted virological but not CD4 cell count response to ARV therapy at weeks 12, 24 and 48 (P=0.002, P<0.001 and P=0.005, respectively). RC was significantly correlated with dPSS and iPSS at baseline, but did not increase their predictive value. In the 137 ARDFP patients, RC increased significantly (from 52.4 to 85.8%), but did not predict CD4 cell count and viral load changes during ARDFP (P=0.92 and P=0.26, respectively). RC after ARDFP did not predict subsequent CD4 cell count and viral load changes 12 weeks following ARV treatment reinitiation (P=0.90 and P=0.29, respectively). CONCLUSIONS: We found no additional predictive value of replication capacity for virological or immunological responses (above what PSS provides) in patients undergoing salvage ARV treatment.

Impact of overweight on the risk of developing common chronic diseases during a 10-year period.

BACKGROUND: Overweight adults are at an increased risk of developing numerous chronic diseases. METHODS: Ten-year follow-up (1986-1996) of middle-aged women in the Nurses' Health Study and men in the Health Professionals Follow-up Study to assess the health risks associated with overweight. RESULTS: The risk of developing diabetes, gallstones, hypertension, heart disease, and stroke increased with severity of overweight among both women and men. Compared with their same-sex peers with a body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) between 18.5 and 24.9, those with BMI of 35.0 or more were approximately 20 times more likely to develop diabetes (relative risk [RR], 17.0; 95% confidence interval [CI], 14.2-20.5 for women; RR, 23.4; 95% CI, 19.4-33.2 for men). Women who were overweight but not obese (ie, BMI between 25.0 and 29.9) were also significantly more likely than their leaner peers to develop gallstones (RR, 1.9), hypertension (RR, 1.7), high cholesterol level (RR, 1.1), and heart disease (RR, 1.4). The results were similar in men. CONCLUSIONS: During 10 years of follow-up, the incidence of diabetes, gallstones, hypertension, heart disease, colon cancer, and stroke (men only) increased with degree of overweight in both men and women. Adults who were overweight but not obese (ie, 25.0 < or = BMI < or = 29.9) were at significantly increased risk of developing numerous health conditions. Moreover, the dose-response relationship between BMI and the risk of developing chronic diseases was evident even among adults in the upper half of the healthy weight range (ie, BMI of 22.0-24.9), suggesting that adults should try to maintain a BMI between 18.5 and 21.9 to minimize their risk of disease.

Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine.

OBJECTIVE: To evaluate the phenotypic susceptibilities and genotypic resistance patterns to both didanosine and stavudine of baseline and follow-up HIV-1 isolate pairs, derived from antiretroviral naive subjects treated with this dual nucleoside combination. DESIGN AND METHODS: Phenotypic drug susceptibility testing was performed in peripheral blood mononuclear cells on 34 viral isolate pairs derived from patients participating in the BMS AI-460 trial. Sequencing of the complete reverse transcriptase of 36 study isolate pairs, baseline and follow-up, was performed using standard dideoxy techniques. RESULTS: The mean fold change in susceptibilities to didanosine was 1.6 (P= 0.278) and to stavudine 1.9 (P= 0.002, Wilcoxon's signed rank test). Mutations classically associated with zidovudine resistance were observed to emerge in 7 out of 36 isolates, T215Y/F (four), M41L +T215Y/F (two) and D67N (one). Other mutations observed included the A62V, V751, F77L, F116Y, Q151 M multinucleoside resistance complex (one), the Q151M mutation (two) and the rare V75T mutation (two). No mutations classically associated with didanosine exposure and resistance were observed. No relationship was evident between the emergence of zidovudine associated mutations and the level of phenotypic resistance to either stavudine or didanosine or between the emergence of zidovudine associated mutations and changes in plasma HIV RNA levels. CONCLUSION: These comprehensive data demonstrate modest (< twofold) mean reductions in didanosine and stavudine susceptibilities at follow-up. The emergence of zidovudine associated mutations in this retroviral-naive population treated with combination didanosine and stavudine therapy is notable. Furthermore, the emergence of these mutations and of the Q151 M multinucleoside resistance complex raise concerns for potential nucleoside analog cross-resistance. The potential mechanisms driving the selection of the zidovudine associated mutations in the setting of didanosine and stavudine therapy and the relevance of these findings to current three and four drug regimens merit further evaluation.

Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV.

OBJECTIVE: To determine the efficacy of recombinant human growth hormone (rhGH) in the treatment of the fat redistribution syndrome (FRS) in patients with HIV. DESIGN: A prospective, open-label study. SETTING: An urban, university-affiliated Infectious Disease Clinic. PATIENTS: Ten HIV-infected patients (seven men, three women) with FRS. INTERVENTIONS: Treatment with 6 mg of rhGH a day, subcutaneously for 12 weeks. MAIN OUTCOME MEASURES: Body mass index (BMI), body composition by bioelectrical impedance analysis (BIA), body composition by anthropometrics (including waist/hip ratio), buffalo hump. RESULTS: The mean age was 41.7 years, the CD4 cell count was 247, and the HIV RNA was 95 735 copies/ml; 50% had undetectable viral RNA. The BMI was significantly increased from baseline to the end of treatment with growth hormone (25.3-26.9 kg/m2; P < 0.04); the waist/hip ratio significantly decreased from baseline levels, after treatment with growth hormone (1.03-0.9; P < 0.04); mid-thigh circumference increased significantly when baseline was compared with measures after treatment (49.1-51.8 cm; P < 0.03). One patient had to discontinue therapy because of hyperglycemia. CONCLUSION: Short-term treatment with rhGH improved the alterations in body shape that occur with FRS in HIV-infected patients. Waist/hip ratios and mid-thigh circumference are useful measures to follow alterations in body shape in FRS.

The values of quantitative serum HIV-1 RNA levels and CD4 cell counts for predicting survival time among HIV-positive individuals with CD4 counts of < or = 50 x 10(6) cells/l.

OBJECTIVE: To evaluate the HIV-1 RNA level as a predictor of survival time among individuals with advanced AIDS. METHODS: The serum HIV-1 RNA level, the CD4 cell count, and other clinical variables were evaluated at baseline, as predictors of survival time, among 56 retrospectively identified HIV-1 positive individuals with < or = 50 x 10(6) CD4 cells/l who attended the Beth Israel Deaconess Medical Center, Division of Infectious Diseases, between 1 July 1989 and 30 September 1993. RESULTS: During follow-up, 55 of these 56 patients died. The median survival time was 20.5 months. In univariate Cox proportional hazard modeling neither the baseline HIV-1 RNA level nor the CD4 cell count were predictive of survival time. However, in multivariate models longer survival time was associated with the use of trimethoprim-sulphamethoxazole at entry [hazard ratio (HR), 0.42; P = 0.007], whereas shorter survival time was associated with a history of an AIDS-defining illness other than Pneumocystis carinii pneumonia (HR, 2.87; P = 0.007). Correlative analysis revealed a modest correlation of the baseline CD4 cell count with survival time (Spearman p = 0.41; P = 0.002). However, no correlation was found between HIV RNA levels and survival time (P = 0.5). CONCLUSIONS: In this population with very advanced disease, the HIV-1 RNA level was a poor discriminator of survival time, being inferior to the CD4 cell count and to specific clinical variables such as the nature of the prior AIDS-defining illness and the type of Pneumocystis carinii pneumonia prophylaxis employed. Among individuals with advanced AIDS, these data emphasize the relative importance of the CD4 cell count and of specific clinical factors, over the HIV-1 RNA level in predicting survival time.

Part-time residency training in internal medicine: analysis of a ten-year experience.

PURPOSE: To evaluate a ten-year experience (1983-1993) with a part-time residency curriculum. METHOD: In 1994, the authors analyzed the curriculum through interviews with graduates of a part-time residency track, surveys of faculty and graduates of a full-time residency program, and a quantitative comparison of faculty evaluations of those part-time and full-time residents. RESULTS: Both participants and full-time residents supported the part-time track and reported no adverse effect on the residency program as a whole. Analysis of faculty evaluations found that part-time residents scored significantly higher with respect to clinical skills (p = .0005) and humanistic skills (p = .0001), while there was no difference between the groups in leadership or teaching skills. CONCLUSIONS: This part-time residency curriculum provided a highly useful program track for a group of internal medicine residents with concomitant obligations, allowing them to complete their training in an uninterrupted fashion. The part-time structure did not adversely affect clinical competence and may have fostered humanistic attributes. The authors believe that this form of curriculum deserves wider consideration in residency training.

The fat redistribution syndrome in patients infected with HIV: measurements of body shape abnormalities.

OBJECTIVE: To describe the body shape changes in the syndrome of fat redistribution or lipodystrophy seen in patients infected with HIV. DESIGN: An objective description of patients with HIV with fat redistribution syndrome. Body-height, weight, shape, and composition were measured by anthropometrics and biolectrical impedance analysis by a single observer. Clinical data were collected by chart review. SUBJECTS/SETTING: Thirty-nine patients with HIV receiving primary HIV care at a university hospital-affiliated infectious disease clinic who presented with complaints of body shape changes or who were referred by their primary care providers for body shape changes. ANALYSIS: Descriptive statistics were performed. RESULTS: Four of the 39 patients (10%) had not used protease inhibitor therapy. HIV status (by clinical presentation, CD4 and VL) varied widely. Laboratory abnormalities were moderate. Percent body fat differed widely when measured by bioelectrical impedance analysis and anthropometry (23% vs 13%). The mean body mass index was 25.6 kg/m2 for men and 25.8 kg/m2 for women. The mean waist/hip ratio was above normal, at 1.02. The mean mid-arm circumference and triceps skinfolds were below national standards for both men (30.4 cm and 8.1 mm, respectively) and women (26.7 cm and 7.5 mm, respectively). Nine patients (23%) had an increased dorso-cervical pad. Seventeen patients returned for follow-up measurements at 3 months; no significant differences were found between baseline and follow-up measurements. CONCLUSIONS: The waist/hip ratio, mid-arm and mid-thigh circumference, and triceps skinfolds were useful measures to define and follow the fat redistribution syndrome in patients with HIV. These body composition changes were not transitory in this short follow-up period.

Relationship of job strain and iso-strain to health status in a cohort of women in the United States.

OBJECTIVE: This study examined the relationships of job strain and iso-strain psychosocial work-environment exposures to health status in a cohort of working women in the United States. METHODS: In a cross-sectional survey, 33689 women responded to the Karasek job content and the MOS SF-36 health status questionnaires. The psychosocial work-environment exposures were characterized using the job strain and iso-strain frameworks. Health status was assessed with the following 6 scales: physical functioning, vitality, freedom from pain, mental health, role limitations due to physical health, and role limitations due to emotional health. RESULTS: When compared with active work, high-strain work (high job demands and low job control) was associated with lower vitality, mental health, higher pain, and increased risks of both physical and emotional role limitations. Iso-strain work (high strain and low work-related social support) increased the risks further. Job insecurity was also associated with lower health status. CONCLUSIONS: The analyses supported the hypothesis that the psychosocial work environment is an important determinant of health status among working women. The findings suggest that incorporating social conditions at work into the measurement of psychosocial work-environment exposure improves the identification of high-risk work arrangements.

Association between psychosocial work characteristics and health functioning in American women: prospective study.

OBJECTIVE: To examine prospectively the relation between psychosocial work characteristics and changes in health related quality of life over four years in a cohort of working women in the United States. DESIGN: Longitudinal cohort study. SETTING: United States. PARTICIPANTS: 21 290 female registered nurses who completed the Karasek's job content questionnaire and a modified version of the short form 36 questionnaire (SF-36) as used for a survey of health status by the medical outcomes study. MAIN OUTCOME MEASURES: Seven dimensions of health status: physical functioning, role limitations due to physical health problems, bodily pain, vitality, social functioning, role limitations due to emotional problems, and mental health. RESULTS: Examined separately low job control, high job demands, and low work related social support were associated with poor health status at baseline as well as greater functional declines over the four year follow up period. Examined in combination, women with low job control, high job demands, and low work related social support ("iso-strain" jobs) had the greatest functional declines. These associations could not be explained by age, body mass index, comorbid disease status, alcohol consumption, smoking status, education level, exercise level, employment status, marital status, or presence of a confidant. CONCLUSIONS: Adverse psychosocial work conditions are important predictors of poor functional status and its decline over time.

Weight, weight gain, activity, and major illnesses: the Nurses' Health Study.

The Nurses' Health Study was initiated in 1976 to study the relation between oral contraceptives and breast cancer. Subsequent funding was available to follow the cohort to address relations between cigarette smoking, postmenopausal hormones, hair dyes, and a range of cancers including breast, endometrial, ovarian, and lung cancer. The 121,700 participating nurses are followed up every 2 years via mail questionnaire to update exposure information to identify incident cancers and other illnesses. Follow-up through 1994 has achieved 90% response from living cohort members. Over the course of the study, additional exposures have been added and refined, including weight at age 18, current weight, height, waist and hip measurements and history of major voluntary weight loss among others. Our focus has been on the health effects of weight gain during middle age. The results relating to diabetes, coronary heart disease, certain types of cancer and total mortality are reviewed. Our primary analytic tools have been multiple logistic regression and Cox proportional hazards models. These methods allow for flexibility in defining the exposures of interest as well as determining their relative importance while controlling for key risk factors. Our models show that even moderate weight gain after age 18 increases risk of each condition. The benefits of physical activity include reduced risk of disease. Issues in the measurement and validation of weight and activity highlight the complexities that are inherent in observational studies addressing the health consequences of lifestyles and anthropometric variables. Our experience of working with repeated measures of body weight and recreational activity are described. Recreational activity has been ascertained in various ways on several questionnaires and may be subject to misclassification. For both weight and activity it may be the pattern of these values that is of importance (e.g. "weight cycling") for some outcomes or conditions. Our research in this area is ongoing. These issues regarding longitudinal measurement will never be completely resolved because weight and activity are intrinsically complex concepts. For these and other such variables, the primary solution is to minimize the problems associated with longitudinal studies. This is best accomplished by developing and maintaining a very strong study design/protocol, including: careful consideration of the sample frame and sample size; maintenance of a high response rate; and continuous monitoring and improvement of the survey/interview instrument(s).

Racial discrimination and skin color in the CARDIA study: implications for public health research. Coronary Artery Risk Development in Young Adults.

OBJECTIVES: This study assessed whether skin color and ways of handling anger can serve as markers for experiences of racial discrimination and responses to unfair treatment in public health research. METHODS: Survey data on 1844 Black women and Black men (24 to 42 years old), collected in the year 5 (1990-1991) and year 7 (1992-1993) examinations of the Coronary Artery Risk Development in Young Adults (CARDIA) study, were examined. RESULTS: Skin color was not associated with self-reported experiences of racial discrimination in 5 of 7 specified situations (getting a job, at work, getting housing, getting medical care, in a public setting). Only moderate associations existed between darker skin color and being working class, having low income or low education, and being male (risk ratios under 2). Comparably moderate associations existed between internalizing anger and typically responding to unfair treatment as a fact of life or keeping such treatment to oneself. CONCLUSIONS: Self-reported experiences of racial discrimination and responses to unfair treatment should be measured directly in public health research; data on skin color and ways of handling anger are not sufficient.

Determinants of expenditures and use of services among elderly HMO enrollees.

This study examined determinants of expenditures and use of services by a group of elderly HMO enrollees. Study subjects were 895 elderly members of the Fallon Community Health Plan who enrolled between January 1, 1980 and December 31, 1983. We explored whether the determinants of expenditures and utilization varied across different types of services, specifically inpatient hospital care and ambulatory care. Having a heart problem, a mobility/disability, and arthritis were consistent predictors of high resource use. Having a mental health problem and a history of past hospitalization were also significant predictors across most models. The health policy implications of these data and their implications for quality assurance within the HMO setting are discussed.

Can physical activity minimize weight gain in women after smoking cessation?

OBJECTIVES: The purpose of this study was to examine prospectively whether exercise can modify weight gain after smoking cessation in women. METHODS: Data were analyzed from a 2-year follow-up period (1986-1988) in the Nurses' Health Study, an ongoing cohort of 121,700 US women aged 40 to 75 in 1986. RESULTS: The average weight gain over 2 years was 3.0 kg in the 1474 women who stopped smoking, and 0.6 kg among the 7832 women who continued smoking. Among women smoking 1 to 24 cigarettes per day, those who quit without changing their levels of exercise gained an average of 2.3 kg more (95% confidence interval [CI] = 1.9, 2.6) than women who continued smoking. Women who quit and increased exercise by between 8 to 16 MET-hours (the work metabolic rate divided by the resting metabolic rate) per week gained 1.8 kg (95% CI = 1.0, 2.5), and the excess weight gain was only 1.3 kg (95% CI = 0.7, 1.9) in women who increased exercise by more than 16 MET-hours per week. CONCLUSIONS: Smoking cessation is associated with a net excess weight gain of about 2.4 kg in middle-aged women. However, this weight gain is minimized if smoking cessation is accompanied by a moderate increase in the level of physical activity.

Predictors of weight change in men: results from the Health Professionals Follow-up Study.

OBJECTIVE: Since the prevalence of adult obesity is increasing in the United States, we examined the effect of changing common habits (exercise, TV viewing, smoking and eating habits) on four year change in body weight. DESIGN: A prospective cohort study of US male health professionals with follow-up from 1988-1992. Participants were 19478 men aged 40-75 in 1986, who were free of cancer, coronary heart disease, stroke and diabetes. METHODS: Multiple regression was used to determine the association between four year change in body weight (from 1988-1992) and common habits, after adjusting for baseline age, hypertension and hypercholesterolemia. RESULTS: For middle aged men, vigorous activity was associated with weight reduction and TV/VCR viewing and eating between meals with weight gain. Quitting smoking and a history of voluntary weight loss prior to the study period were consistently related to weight increase. Recently being on a diet was more strongly associated with weight loss among older men. Over the four year follow-up period, middle-aged men who increased their exercise, decreased TV viewing and stopped eating between meals, lost an average weight of -1.4 kg (95% confidence interval (CI) -1.6 - -1.1 kg), compared to a weight gain of 1.4 kg among the overall population. The prevalence of obesity among middle-aged men was lowest among those who maintained a relatively high level of vigorous physical activity, compared to those who were relatively sedentary. CONCLUSION: These data suggest that improvement in the mix of health habits, particularly increasing vigorous activity, as well as decreasing TV use and changing eating habits, results in weight maintenance or a modest weight loss over four years.

Social networks, stress and health-related quality of life.

Although evidence suggests that social networks reduce the risk of mortality and are negatively associated with severe mental disability, little is known about their relationship to everyday functioning and health-related quality of life (HRQoL). In addition, the importance of social networks in the presence of chronic stress remains unclear. We examined the association between social networks and aspects of mental functioning (mental health, vitality and role-emotional functioning) and the relationship between social networks and mental functioning in the presence of stressors. Multiple linear and logistic regression models were used to examine data in 47,912 middle-aged and older healthy women. The Medical Outcomes Study Shortform Health Survey measured dimensions of quality of life. We observed strong associations between levels of social networks and multivariate-adjusted quality of life scores, particularly in potentially high stress situations. Compared to the most socially integrated, women who were socially isolated had reductions in mental health and vitality scores of 6.5 and 7.4 points, respectively and a 60% increased risk of limitation in role-emotional functioning. Social networks are positively associated with mental functioning in women. This association is strongest for women reporting high levels of home and work stressors.

Health behaviors, social networks, and healthy aging: cross-sectional evidence from the Nurses' Health Study.

Physical function is a significant component of health-related quality of life among older adults. Potential correlates of healthy aging, including health behaviors and social network characteristics, were examined among 56,436 US women aged 55-72 in 1992. Healthy aging was assessed by maintenance of physical function measured by four subscales of the Medical Outcomes Study Short Form (SF)-36 Health Survey: physical functioning; role limitations; freedom from bodily pain; and vitality. Individual health behaviors, defined as current smoking, alcohol consumption, sedentary behavior, and being overweight each contributed to significant decrements in functioning across all age-groups. After controlling for these health behaviors and other confounders (age, race, education, and co-morbid conditions), elements of a woman's social network were significantly correlated with functional status. Strong predictors of high functioning among older women were having close friends and relatives and presence of a confidant. For example, the absence of a confidant was associated with a 4.44 point reduction in physical functioning (95% CI: -7.0, -1.9), and a 5.68 point reduction in vitality (95% CI: -7.9, -3.4). These effects were comparable in magnitude to those observed among heavy smokers, or women in the highest category of body mass index.

Diversity of domain V of 23S rRNA gene sequence in different Enterococcus species.

The highly conserved central loop of domain V of 23S RNA (nucleotides 2042 to 2628; Escherichia coli numbering) is implicated in peptidyltransferase activity and represents one of the target sites for macrolide, lincosamide, and streptogramin B antibiotics. DNA encoding domain V (590 bp) of several species of Enterococcus was amplified by PCR. Twenty enterococcal isolates were tested, including Enterococcus faecium (six isolates), Enterococcus faecalis, Enterococcus avium, Enterococcus durans, Enterococcus gallinarum, Enterococcus casseliflavus (two isolates of each), and Enterococcus raffinosus, Enterococcus mundtii, Enterococcus malodoratus, and Enterococcus hirae (one isolate of each). For all isolates, species identification by biochemical testing was corroborated by 16S rRNA gene sequencing. The sequence of domain V of the 23S rRNA gene from E. faecium and E. faecalis differed from those of all other enterococci. The domain V sequences of E. durans and E. hirae were identical. This was also true for E. gallinarum and E. casseliflavus. E. avium differed from E. casseliflavus by 23 bases, from E. durans by 16 bases, and from E. malodoratus by 2 bases. E. avium differed from E. raffinosus by one base. Despite the fact that domain V is considered to be highly conserved, substantial differences were identified between several enterococcal species.

Long-term weight patterns and risk for cholecystectomy in women.

BACKGROUND: Obesity and rapid weight loss in obese persons are known risk factors for gallstones. However, the effect of intentional, long-term, moderate weight changes on the risk for gallstones is unclear. OBJECTIVE: To study long-term weight patterns in a cohort of women and to examine the relation between weight pattern and risk for cholecystectomy. DESIGN: Prospective cohort study. SETTING: 11 U.S. states. PARTICIPANTS: 47,153 female registered nurses who did not undergo cholecystectomy before 1988. MEASUREMENTS: Cholecystectomy between 1988 and 1994 (ascertained by patient self-report). RESULTS: During the exposure period (1972 to 1988), there was evidence of substantial variation in weight due to intentional weight loss during adulthood. Among cohort patients, 54.9% reported weight cycling with at least one episode of intentional weight loss associated with regain. Of the total cohort, 20.1% were light cyclers (5 to 9 lb of weight loss and gain), 18.8% were moderate cyclers (10 to 19 lb of weight loss and gain), and 16.0% were severe cyclers (> or = 20 lb of weight loss and gain). Net weight gain without cycling occurred in 29.3% of women; net weight loss without cycling was the least common pattern (4.6%). Only 11.1% of the cohort maintained weight within 5 lb over the 16-year period. In the study, 1751 women had undergone cholecystectomy between 1988 and 1994. Compared with weight maintainers, the relative risk for cholecystectomy (adjusted for body mass index, age, alcohol intake, fat intake, and smoking) was 1.20 (95% CI, 0.96 to 1.50) among light cyclers, 1.31 among moderate cyclers (CI, 1.05 to 1.64), and 1.68 among severe cyclers (CI, 1.34 to 2.10). CONCLUSION: Weight cycling was highly prevalent in this large cohort of middle-aged women. The risk for cholecystectomy associated with weight cycling was substantial, independent of attained relative body weight.