Biomedical subjects
Publications and source records attributed to R Roubenoff.
At this time, there are no commonly accepted definitions for either the "failure to thrive" syndrome or for the newly described syndrome of sarcopenia. This lack of a common definition makes it difficult to contrast study results and understand the etiology of these syndromes. This article reviews the current state of understanding of these conditions and suggests potential mechanisms that may be further investigated.
BACKGROUND: The aim of this study was to assess whether plasma homocysteine is a risk factor for stroke and other thrombotic events in patients with systemic lupus erythematosus (SLE)--a condition known to be associated with premature atherothrombotic complications. METHODS: In this prospective study, we investigated the association between homocysteine and risk of stroke and thrombotic events in 337 SLE patients in the Hopkins Lupus Cohort Study, with follow-up of 1619 person-years (mean 4.8 [SD 1.7] years). Each patient had four follow-up assessments per year to obtain information about established risk factors for thrombosis and coronary artery disease. The prospectively defined endpoints were occurrence of stroke and arterial or venous thrombotic events between 1987 and 1995. Blood samples were taken at study entry from fasting patients. Plasma homocysteine, folate, vitamin B12, and pyridoxal 5'-phosphate (PLP) concentrations were measured. Raised homocysteine concentrations were defined as more than 14.1 mumol/L. FINDINGS: 93% of the study population were women, 54% African American, and 45% white. The mean age of participants was 34.9 (SD 11.7) years. During follow-up there were 29 cases of stroke and 31 arterial thrombotic events. Raised homocysteine concentrations were found in 51 (15%) SLE patients. The log-transformed total homocysteine concentrations correlated with serum folate (r = 0.31, p = 0.0001). In univariate analyses, raised homocysteine concentrations were significantly associated with stroke (odds ratio 2.24 [95% CI 1.22-4.13], p = 0.01) and arterial thrombotic events (3.74 [1.96-7.13], p = 0.0001). After adjustment for established risk factors, total plasma homocysteine concentrations remained an independent risk factor for stroke (2.44 [1.04-5.75], p = 0.04) and arterial thromboses (3.49 [0.97-12.54], p = 0.05). INTERPRETATION: Homocysteine is a potentially modifiable, independent risk factor for stroke and thrombotic events in patients with SLE.
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OBJECTIVE: To demonstrate the feasibility of high-intensity progressive resistance training in rheumatoid arthritis (RA) patients compared with healthy control subjects. METHODS: Eight subjects with RA, 8 healthy young subjects, and 8 healthy elderly subjects underwent 12 weeks of high-intensity progressive resistance training, while 6 elderly subjects performed warm-up exercises only. Fitness, body composition, energy expenditure, function, disease activity, pain, and fatigue were measured at baseline and followup. RESULTS: All 3 training groups demonstrated similar improvements in strength compared with the change among control subjects (RA group 57% [P < 0.0005], young exercise group 44% [P < 0.01], elderly exercise group 36% [P < 0.05]). Subjects with RA had no change in the number of painful or swollen joints but had significant reductions in self-reported pain score (21% [P < 0.05]) and fatigue score (38% [P = 0.06]), improved 50-foot walking times (mean +/- SD 10.4 +/- 2.2 seconds versus 8.3 +/- 1.5 seconds [P < 0.005]), and improved balance and gait scores (48.9 +/- 3.8 versus 50.4+/- 2.0 [P = 0.07]). CONCLUSION: High-intensity strength training is feasible and safe in selected patients with well-controlled RA and leads to significant improvements in strength, pain, and fatigue without exacerbating disease activity or joint pain.
OBJECTIVE: To determine the effects of rheumatoid arthritis (RA) on whole-body protein metabolism. METHODS: We examined protein metabolism and its hormonal and cytokine mediators before and 12 weeks after progressive resistance muscle strength training in 8 healthy young (mean +/- SD age 25 +/- 2 years) and 8 healthy elderly (70 +/- 5 years) men and women, and in 8 adults with RA (42 +/- 13 years). An additional 6 healthy elderly subjects (69 +/- 3 years) served as a swimming-only control group. RESULTS: Subjects with RA had higher rates of protein breakdown than did young or elderly healthy subjects (79.9 +/- 17.2 versus 60.3 +/- 5.8 and 63.7 +/- 12.4 mumoles/gm total body potassium/hour, respectively, P < 0.05), while there was no effect of age per se. Patients treated with methotrexate had normal rates of protein breakdown (P < 0.01 versus RA without methotrexate; P not significant versus healthy young subjects). Increased protein catabolism in RA was no longer evident after strength training. In multiple regression analysis, levels of tumor necrosis factor alpha (TNF alpha) (r = 0.47, P = 0.01) and growth hormone (r = -0.51, P = 0.006) were associated with protein breakdown, and plasma glucagon levels were inversely correlated with protein synthesis (r = -0.45, P = 0.02). Growth hormone (r = -0.56, P = 0.002) and glucagon (r = 0.45, P = 0.04, levels were associated with protein oxidation. CONCLUSION: Adults with RA have increased whole-body protein breakdown, which correlates with growth hormone, glucagon, and TNF alpha production.
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This study investigated whether methotrexate, by interrupting the methyl transfer function of folate, can induce genomic DNA hypomethylation in patients with inflammatory arthritis. Consecutive subjects with inflammatory arthritis (rheumatoid or psoriatic), who were taking methotrexate (n = 7) or other medications (n = 6), and control subjects, either healthy or with osteoarthritis and taking nonsteroidal anti-inflammatory agents only (n = 9) were recruited. The methylation status of genomic DNA from peripheral blood mononuclear cells was determined. Plasma levels of folate, B12, and pyridoxal-5'-phosphate (PLP), all of which are involved in biologic methylation, were also examined. The extent of genomic DNA methylation was lowest in subjects with inflammatory arthritis who were not taking methotrexate, highest in subjects with inflammatory arthritis who were taking methotrexate, and intermediate in control subjects (p < 0.05). Plasma levels of folate and B12 were similar among the three groups. The mean plasma PLP level in subjects with inflammatory arthritis was 33% lower than that in control subjects (p = 0.04). No significant correlation between genomic DNA methylation and folate, B12, and PLP levels was observed. These data do not support the hypothesis that methotrexate induces genomic DNA hypomethylation. However, these data indicate that inflammatory arthritis is associated with genomic DNA hypomethylation that is reversed with methotrexate. Future studies using a larger number of subjects are warranted to confirm these findings.
Bioelectrical impedance analysis (BIA) is a promising tool in the evaluation of body composition in large population studies because it is fast, is inexpensive, and does not require extensive operator training or cross-validation. The empiric nature of the relation between resistance and reactance measured by BIA and body composition has led to the development of equations that translate the raw data into liters of body water or kilograms of fat-free mass (FFM) or fat mass. These equations may not be easily transferred from one population to another if the populations differ significantly in important determinants of body composition such as age, obesity, and illness. I review two recent studies from the Framingham Heart Study in which BIA was first compared with dual-energy X-ray absorptiometry (DXA) as a validation technique, and then compared with the body mass index (BMI, in kg/m2) as an alternative estimate of body fat. BIA was a good predictor of DXA-derived FFM (r = 0.85-0.88, P < 0.001) and was superior to BMI as an estimator of body fat.
The effects of 12 wk of progressive resistance strength training on in vivo and in vitro immune parameters were evaluated in a controlled study of eight subjects with rheumatoid arthritis (RA), eight healthy young (22-30 yr), and eight healthy elderly (65-80 yr) individuals. Six healthy elderly (65-80 yr) nontraining control subjects were also evaluated to account for seasonal and psychosocial effects. Training subjects exercised at 80% of their one-repetition maximum and performed eight repetitions per set, three sets per session on a twice weekly basis. Peripheral blood mononuclear cell (PBMC) subpopulations, cytokine and prostaglandin (PG) E2 production, proliferative response, and delayed type hypersensitivity (DTH) skin response were measured before and after 12 wk of training. Training did not induce changes in PBMC subsets, interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF), IL-6, IL-2, or PGE2 production, lymphocyte proliferation, or DTH response in any of the training groups, compared with control subjects. These data suggest that 12 wk of high-intensity progressive resistance strength training does not affect immune function in young or elderly healthy individuals or subjects with RA.
Elderly LTCF residents pose a challenging problem in terms of nutrition assessment at all three levels: intake, macronutrient, and micronutrient. In terms of macronutrient status, the focus of this work, newer techniques such as BIA and indirect calorimetry offer the promise of more accurate and widespread assessment in LTCFs. Future work will need to focus on the cost-effectiveness of this approach and on demonstrating that improved nutrition assessment can lead to better nutrition therapy and improved outcome.
OBJECTIVE: To compare vitamin B6 levels in rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: We measured levels of vitamin B6 in 23 adults with well-controlled RA, and in 23 healthy control subjects matched for age, sex, race, and weight. RESULTS: Although plasma folate and vitamin B12 concentrations and erythrocyte B6 activity coefficients were similar in the patients and controls, plasma levels of pyridoxal-5'-phosphate (PLP) were lower in the RA patient group (mean +/- SD 46.1 +/- 48.1 versus 69.3 +/- 58.4 nmoles/liter; P < 0.004). In multivariate analyses, PLP was inversely associated with tumor necrosis factor alpha (TNF alpha) production by peripheral blood mononuclear cells (PBMC) (P < 0.001), after adjustment for age, pain score, erythrocyte sedimentation rate, and use of nonsteroidal antiinflammatory drugs. CONCLUSION: PLP levels are reduced in patients with RA. This reduction is associated with TNF alpha production by PBMC.
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The body mass index (weight in kilograms/height in square meters) is a common surrogate for fatness. With the advent of bioelectrical impedance analysis, more precise measurement of fatness in populations is now possible. We measured height, weight, and percentage that is fat by bioelectrical impedance analysis in 2032 adults, ages 31 to 92, participating in the Framingham studies. Body mass index was a poor predictor of fatness in women (R2 = 0.55) and men (R2 = 0.38), and was imprecise (standard error of estimate = 5 percentage points). The relationship between percentage fat and body mass index was quadratic in both sexes, and was altered by age in women (P < .0001) and, to a lesser extent, in men (P < .027). These data suggest that body mass index is an imprecise measurement of fatness compared with bioelectrical impedance.
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Weight loss is a frequent sequela in patients with congestive heart failure and is commonly referred to as cardiac cachexia. This weight loss is unlike that seen in simple starvation because it preferentially involves the depletion of lean body mass. In addition, the presence of cardiac cachexia can have profound clinical implications for patients in terms of complications, clinical outcome, and overall cost. The mechanism for the alterations in body composition is multifactorial, but a major cause may be the cytokine-mediated host response to the underlying disease. This article reviews the syndrome of cardiac cachexia in light of recent evidence regarding the role of cytokines, as well as potential therapies.
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.