Ronenn Roubenoff
Novartis
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Featured researches published by Ronenn Roubenoff.
Journal of the American Geriatrics Society | 2004
Ian Janssen; Donald S. Shepard; Peter T. Katzmarzyk; Ronenn Roubenoff
Objectives: To estimate the healthcare costs of sarcopenia in the United States and to examine the effect that a reduced sarcopenia prevalence would have on healthcare expenditures.
Nature Genetics | 2007
Robert M. Plenge; Chris Cotsapas; Leela Davies; Alkes L. Price; Paul I. W. de Bakker; Julian Maller; Itsik Pe'er; Noël P. Burtt; Brendan Blumenstiel; Matt DeFelice; Melissa Parkin; Rachel Barry; Wendy Winslow; Claire Healy; Robert R. Graham; Benjamin M. Neale; Elena Izmailova; Ronenn Roubenoff; Alex Parker; Roberta Glass; Elizabeth W. Karlson; Nancy E. Maher; David A. Hafler; David M. Lee; Michael F. Seldin; Elaine F. Remmers; Annette Lee; Leonid Padyukov; Lars Alfredsson; Jonathan S. Coblyn
To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, ∼150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10−3, GWA scan; P < 10−6, replication; P = 10−9, combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 × 10−6 in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.
Circulation | 2003
Lisa M. Sullivan; Ronenn Roubenoff; Charles A. Dinarello; Tamara B. Harris; Emelia J. Benjamin; Douglas B. Sawyer; Daniel Levy; Peter W.F. Wilson; Ralph B. D’Agostino
Background—Experimental studies support a key role for cytokines in left ventricular remodeling. In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with worse functional status and adverse prognosis. It is unclear whether cytokine levels can predict the incidence of CHF in asymptomatic individuals. Methods and Results—We investigated the relations of serum interleukin-6 (IL-6), C-reactive protein (CRP), and spontaneous production of tumor necrosis factor-&agr; (TNF&agr;) by peripheral blood mononuclear cell (PBMC) to CHF incidence among 732 elderly Framingham Study subjects (mean age 78 years, 67% women) free of prior myocardial infarction and CHF. On follow-up (mean 5.2 years), 56 subjects (35 women) developed CHF. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was a 60 (PBMC TNF&agr;) to 68% (serum IL-6) increase in risk of CHF per tertile increment in cytokine concentration (P =0.04, and 0.03, respectively, for trend). A serum CRP level ≥5 mg/dL was associated with a 2.8-fold increased risk of CHF (P =0.02). Subjects with elevated levels of all 3 biomarkers (serum IL-6 and PBMC TNF&agr; >median values, CRP≥5 mg/dL) had a markedly increased risk of CHF (hazards ratio 4.07 [95% CI 1.34 to 12.37], P =0.01) compared with the other subjects. Conclusions—In our elderly, community-based sample, a single determination of serum inflammatory markers, particularly elevated IL-6, was associated with increased risk of CHF in people without prior myocardial infarction. Additional epidemiological investigations are warranted to confirm the contribution of inflammation to the pathogenesis of CHF in the general population.
Journal of Clinical Investigation | 1994
Ronenn Roubenoff; Rebecca A. Roubenoff; Joseph G. Cannon; Joseph J. Kehayias; Hong Zhuang; Bess Dawson-Hughes; Charles A. Dinarello; Irwin H. Rosenberg
The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.
JAMA | 2009
Wolfgang Lieb; Alexa Beiser; Zaldy S. Tan; Rhoda Au; Tamara B. Harris; Ronenn Roubenoff; Sanford Auerbach; Charles DeCarli; Philip A. Wolf; Sudha Seshadri
CONTEXT The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). OBJECTIVE To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. DESIGN, SETTING, AND PARTICIPANTS Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. MAIN OUTCOME MEASURE Incidence of dementia and AD during follow-up until December 31, 2007. RESULTS During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. CONCLUSION Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.
Annals of Internal Medicine | 2003
Lisa M. Sullivan; Ralph B. D'Agostino; Ronenn Roubenoff; Tamara B. Harris; Douglas B. Sawyer; Daniel Levy; Peter W.F. Wilson
Context Biological research and retrospective clinical studies show that insulin-like growth factor I (IGF-I) promotes salutary left ventricular modeling. Contribution This community-based study followed 717 elderly people without known myocardial infarction or heart failure for 5 to 9 years. Participants with higher levels of IGF-I developed heart failure less often than did those with lower levels. Implications High IGF-I levels are associated with decreased risks for heart failure. Cautions High IGF-I levels are also associated with increased risks for cancer. Future research should confirm these associations and explore mechanisms to increase IGF-I levels in people at risk for heart failure without increasing the risk for cancer. The Editors Considerable experimental and clinical evidence supports a key role of insulin-like growth factor I (IGF-I) in the pathogenesis of left ventricular remodeling and heart failure (1). In basic science studies, IGF-I promotes myocardial hypertrophy, increases cardiac contractility, and attenuates myocyte necrosis and apoptosis in models of ischemic, hemodynamic, and toxic cardiac injury (2-7). In clinical reports, patients with congestive heart failure have lower levels of serum IGF-I that correlate with the degree of left ventricular systolic dysfunction, presence of cachexia and skeletal muscle weakness, and indices of neurohormonal and cytokine activation (8, 9). Furthermore, administering IGF-I has been reported to improve left ventricular contractility indices in small clinical case series (10) and experimental models of heart failure (4). Epidemiologic investigations have shown an increasing incidence of congestive heart failure with age (11). Serum IGF-I levels have been reported to decrease with age in community-based investigations (12, 13). These parallel observations suggest that a decrease in serum IGF-I level with age may increase the incidence of heart failure in the elderly (14). However, no previous investigation has prospectively examined the relationship of serum IGF-I level to the incidence of heart failure. We hypothesized, on the basis of the body of scientific evidence noted, that a low serum IGF-I level may be associated with an increased risk for congestive heart failure. Accordingly, we examined the relationship of serum IGF-I levels to the risk for congestive heart failure in an elderly, community-based sample. Methods Study Sample The Framingham Heart Study began in 1948 as a prospective longitudinal epidemiologic investigation of 5209 women and men who are examined every 2 years (15). The 1167 participants who were alive at the time of the 22nd biennial examination cycle (between 1992 and 1994) were eligible for the present investigation. We excluded 450 participants (39%) for the following reasons: prevalent congestive heart failure (84 participants) or myocardial infarction (106 participants) and insufficient blood specimen for IGF-I analyses (260 participants). Participants with a myocardial infarction were excluded because low serum IGF-I level is a risk factor for myocardial infarction (16), which in turn is a powerful risk factor for heart failure (11). After the exclusions, 717 participants (mean age, 78.4 years; 479 women) were eligible. At the baseline examination, all participants underwent a medical history, routine physical examination (including anthropometry and blood pressure measurement), 12-lead electrocardiography, and laboratory assessment of cardiovascular disease risk factors. The institutional review board at Boston Medical Center approved the study, and all participants gave written informed consent. Measurement of Serum IGF-I At the baseline examination, 3 mL of serum from each participant was obtained in the early afternoon (with the participant in a supine position and a nonfasting state). Specimens were immediately transported by courier from Framingham, Massachusetts, to the U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, and stored at 80 C. Serum on dry ice was then shipped to Endocrine Sciences, Inc. (Calabasas Hills, California). Serum IGF-I was measured by radioimmunoassay after acid ethanol extraction (17) in 3 batches; the intrassay coefficient of variation was less than 4%. Insulin-like growth factorbinding proteins were not measured. Outcome All participants were under continuous surveillance for the development of cardiovascular disease events, including congestive heart failure. Three experienced investigators reviewed all suspected congestive heart failure events by examining hospital records, information from physicians, and pathology reports by using previously described methods (18). Congestive heart failure was diagnosed on the basis of the previously detailed Framingham Heart Study criteria (19); these criteria, which require the simultaneous presence of at least 2 major criteria or 1 major criterion in conjunction with 2 minor criteria to diagnose heart failure, have been validated previously (20). Major criteria included paroxysmal nocturnal dyspnea or orthopnea, jugular venous distention, pulmonary rales, radiographic cardiomegaly, acute pulmonary edema, third heart sound, central venous pressure greater than 16 cm H2O, hepatojugular reflux, and weight loss of at least 4.5 kg in 5 days in response to treatment of heart failure. Minor criteria included bilateral ankle edema, nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, and heart rate of 120 beats/min or greater. Minor criteria were acceptable only if they were not attributed to another medical condition (such as chronic lung disease, cirrhosis, ascites, or nephrotic syndrome). Statistical Methods We used multivariable Cox proportional-hazards regression models (21) to examine the association of serum IGF-I with the incidence of congestive heart failure. Since there was no effect modification by sex, all analyses were performed for pooled sexes, with sex as a covariate. The distribution of serum IGF-I was slightly skewed positively, and raw values were log-transformed to reduce excessive influence of high values at the upper end of the distribution. Other investigators have used a similar approach (12, 22). Serum IGF-I was treated both as a continuous variable (raw value and with natural logarithmic transformation) and as a categorical variable (values below versus at or above the median value of 140 g/L). Age- and sex-adjusted probabilities of developing congestive heart failure on follow-up were estimated for individuals with serum IGF-I values below versus at or above the median value of 140 g/L from Cox regression models incorporating age and sex as covariates. In multivariable analyses, we adjusted for the following covariates (defined at the baseline examination): age, sex, ratio of serum total cholesterol to high-density lipoprotein (HDL) cholesterol, diabetes mellitus, systolic and diastolic blood pressure, antihypertensive treatment, smoking status, body mass index, clinical valve disease, prevalent atrial fibrillation, electrocardiographic left ventricular hypertrophy, and prevalent cardiovascular disease other than myocardial infarction (individuals with myocardial infarction were excluded, as noted). All 717 participants had complete information on these covariates. Criteria for these covariates have been described previously (18). We examined the following statistical models in hierarchical fashion: multivariable models with all covariates defined at baseline, as detailed, ignoring the occurrence of myocardial infarction on follow-up (model A); models adjusting for covariates at baseline and the occurrence of a myocardial infarction on follow-up (model B) (the latter adjustment is important because low serum IGF-I levels can predispose to the development of congestive heart failure by promoting myocardial infarction [16]); and models in which participants who experienced a myocardial infarction on follow-up were censored at the time of myocardial infarction (model C). Hazard ratios and their 95% CIs were estimated for each SD increase in the log IGF-I and raw IGF-I, and for levels at or above 140 g/L versus below (separately for each statistical model). Additional Analyses In the statistical models adjusting for covariates defined at the baseline examination and occurrence of an interim myocardial infarction (model B), we performed analyses incorporating several interaction terms (serum IGF-I level covariate) to examine for any variation in the effect of serum IGF-I on congestive heart failure hazard (effect modification) according to age, sex, body mass index, presence or absence of diabetes, and total cholesterolHDL cholesterol ratio. High IGF-I levels in conditions such as acromegaly may be associated with cardiac systolic and diastolic dysfunction (23). We therefore evaluated for any nonlinearity (U shape) in the relationship of serum IGF-I level to risk for congestive heart failure. Furthermore, since serum interleukin-6 has been reported to lower IGF-I levels (24) and cytokines have been implicated in the pathogenesis of congestive heart failure (25), we performed supplementary analyses adjusting for serum interleukin-6 in a subgroup of 525 individuals who had both serum interleukin-6 (enzyme-linked immunosorbent assay, R&D Systems, Minneapolis, Minnesota) and IGF-I measurements available. We performed secondary analyses in which death was modeled as a competing outcome to congestive heart failure (26), given the high mortality rate in our elderly cohort. Although left ventricular systolic function was not assessed at the baseline examination, routine echocardiography was done at examination cycle 20, approximately 4 years from the baseline examination. Additional analyses were performed on a subgroup of individuals who attended examination cycle 20 and had normal left ventricular systolic function at that examination. A 2-sided P
Current Opinion in Clinical Nutrition and Metabolic Care | 2003
Ronenn Roubenoff
&NA; Aging causes loss of many of the anabolic signals to muscle that are present in young adulthood. Recent research suggests that there is also an increase in catabolic signals with age. Purpose of review Research in the field of sarcopenia is evolving rapidly, and the process is now recognized as an important cause of frailty and morbidity in the elderly. This review focuses on recent developments in the field, especially regarding the role of catabolic stimuli in causing sarcopenia. Recent findings There is now an impressive body of literature implicating increased interleukin‐6 levels in successfully aging adults. New data indicate that high interleukin‐6 levels carry a poor prognosis, although it is not clear if the cytokine has primarily a causal or counter‐regulatory function. Interleukin‐6 and other cytokines could function through direct catabolic effects, or by causing reduced dietary energy intake (the anorexia of aging), or by inducing insulin resistance or lowering growth hormoneinsulin‐like growth factor‐I concentrations. Furthermore, apoptosis has now been linked to sarcopenia, suggesting that an inflammatory signal could trigger loss of muscle cells in the elderly even in the absence of overt inflammatory disease.
Arthritis & Rheumatism | 2009
Chenchen Wang; Christopher H. Schmid; Patricia L. Hibberd; Robert A. Kalish; Ronenn Roubenoff; Ramel Rones; Timothy E. McAlindon
OBJECTIVE To evaluate the effectiveness of Tai Chi in the treatment of knee osteoarthritis (OA) symptoms. METHODS We conducted a prospective, single-blind, randomized controlled trial of 40 individuals with symptomatic tibiofemoral OA. Patients were randomly assigned to 60 minutes of Tai Chi (10 modified forms from classic Yang style) or attention control (wellness education and stretching) twice weekly for 12 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 12 weeks. Secondary outcomes included WOMAC function, patient and physician global assessments, timed chair stand, depression index, self-efficacy scale, and quality of life. We repeated these assessments at 24 and 48 weeks. Analyses were compared by intent-to-treat principles. RESULTS The 40 patients had a mean age of 65 years and a mean body mass index of 30.0 kg/m(2). Compared with the controls, patients assigned to Tai Chi exhibited significantly greater improvement in WOMAC pain (mean difference at 12 weeks -118.80 mm [95% confidence interval (95% CI) -183.66, -53.94; P = 0.0005]), WOMAC physical function (-324.60 mm [95% CI -513.98, -135.22; P = 0.001]), patient global visual analog scale (VAS; -2.15 cm [95% CI -3.82, -0.49; P = 0.01]), physician global VAS (-1.71 cm [95% CI -2.75, -0.66; P = 0.002]), chair stand time (-10.88 seconds [95% CI -15.91, -5.84; P = 0.00005]), Center for Epidemiologic Studies Depression Scale (-6.70 [95% CI -11.63, -1.77; P = 0.009]), self-efficacy score (0.71 [95% CI 0.03, 1.39; P = 0.04]), and Short Form 36 physical component summary (7.43 [95% CI 2.50, 12.36; P = 0.004]). No severe adverse events were observed. CONCLUSION Tai Chi reduces pain and improves physical function, self-efficacy, depression, and health-related quality of life for knee OA.
Journal of Applied Physiology | 2008
Walter R. Frontera; Kieran F. Reid; Edward M. Phillips; Lisa S. Krivickas; Virginia A. Hughes; Ronenn Roubenoff; Roger A. Fielding
Cross-sectional studies are likely to underestimate age-related changes in skeletal muscle strength and mass. The purpose of this longitudinal study was to assess whole muscle and single muscle fiber alterations in the same cohort of 12 older (mean age: start of study 71.1+/-5.4 yr and end of study 80+/-5.3 yr) volunteers (5 men) evaluated 8.9 yr apart. No significant changes were noted at follow-up in body weight, body mass index, and physical activity. Muscle strength, evaluated using isokinetic dynamometry, and whole muscle specific force of the knee extensors were significantly lower at follow-up. This was accompanied by a significant reduction (5.7%) in cross-sectional area of the total anterior muscle compartment of the thigh as evaluated by computed tomography. Muscle histochemistry showed no significant changes in fiber type distribution or fiber area. Experiments with chemically skinned single muscle fibers (n=411) demonstrated no change in type I fiber size but an increase in IIA fiber diameter. A trend toward an increase in maximal force in both fiber types was observed. Maximum unloaded shortening velocity did not change. In conclusion, single muscle fiber contractile function may be preserved in older humans in the presence of significant alterations at the whole muscle level. This suggests that surviving fibers compensate to partially correct muscle size deficits in an attempt to maintain optimal force-generating capacity.
AIDS | 2005
Michael P. Dubé; Robert A. Parker; Pablo Tebas; Steven Grinspoon; Robert Zackin; Gregory K. Robbins; Ronenn Roubenoff; Robert W. Shafer; David A Wininger; William A. Meyer; Sally Snyder; Kathleen Mulligan
Objective:To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. Methods:Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. Results:Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (−16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (−13.1%) compared with efavirenz (+1.8%; P = 0.003). Conclusions:Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.