Low-grade chronic inflammation and superoxide anion production by NADPH oxidase are the main determinants of physical frailty in older adults.

BACKGROUND: Physical performance measured by gait speed is being recognized as a major instrument for clinical evaluation in older adults, because it predicts physical frailty, loss of autonomy, hospitalization and decreased survival. Low-grade chronic inflammation and oxidative stress, mediated partly by the superoxide anion produced by NADPH oxidase, are closely linked and could be involved in age-related physical decline. OBJECTIVE: To determine whether slow gait speed is associated with superoxide anion overproduction by NADPH oxidase and low-grade chronic inflammation. DESIGN AND SETTING: Observational study among the 280 elderly of an ambulatory geriatric care unit (191 women, 89 men, 79.9 ± 6.1 years old). METHODS: Gait speed was evaluated by walking at self-chosen usual pace. Usual gait speed < 0.8 m/s was defined as slow gait speed. Superoxide anion production was evaluated using a lucigenin-based chemiluminescence method. Inflammation was evaluated by CRP, fibrinogen and leukocyte count. RESULTS: Among the 280 participants, 179 (63.9%) walked with a gait speed < 0.8 m/s (slow walkers) and 101 (36.1%) with a gait speed ≥ 0.8 m/s. Superoxide production and inflammation markers, such as fibrinogen, were more important in slow walkers (p = 0.004 and p = 0.006, respectively). In multivariate analysis, superoxide anion overproduction and fibrinogen were independently associated with physical frailty assessed by slow gait speed (p = 0.028 and p = 0.007, respectively). CONCLUSION: Physical frailty in older people is associated with superoxide anion overproduction by NADPH oxidase and low-grade chronic inflammation.

Homocysteine and inflammation as main determinants of oxidative stress in the elderly.

Oxidative stress is commonly observed in the elderly and could be involved in age-related diseases. However, the determinants of superoxide anion overproduction are not clearly understood. Superoxide anion production was evaluated using a lucigenin-based chemiluminescence method in 478 elderly subjects (304 women, 174 men; 79.5+/-7.1 years). Homocysteine (HCy) metabolism (homocysteinemia, vitamin B12, plasma, and erythrocyte folates), inflammation (CRP, fibrinogen, alpha-1 acid glycoprotein), lipid parameters (total cholesterol, triglycerides, HDL and LDL cholesterol), and nutritional parameters (albumin, transthyretin) were determined. The results show that HCy levels (p<0.001) and superoxide anion production (p=0.04) increase with aging, but CRP does not. Highest HCy (>20 microM) (OR 1.83 (1.09-3.07), p=0.02) and CRP over 5 mg/L (adjusted OR 2.01 (1.15-3.51), p=0.01) are the main determinants in superoxide anion production in the elderly. These clinical data are confirmed in an in vitro study using THP-1 monocyte-like cells. Incubation with HCy thiolactone (HTL) (0-200 microM) and LPS (0-20 ng/ml) dramatically enhances NADPH oxidase expression and activation. Moreover, a synergic action was evidenced for low concentrations of HTL (20 microM) and LPS (5 ng). Taken together, the clinical data and in vitro experiments support the hypothesis that moderate homocysteinemia and low-grade inflammation synergically enhance NADPH oxidase activity in the elderly.

Superoxide anion overproduction in sepsis: effects of vitamin e and simvastatin.

Oxidative stress during sepsis induces tissue damage, leading to organ dysfunction and high mortality. The antioxidant effects of vitamin E have been reported in several diseases, but not in sepsis. Statins have cholesterol-independent anti-inflammatory effects that are related to a decrease of isoprenoid proteins and oxidative stress. Therefore, we evaluated superoxide anion (O2- degree) production and ex vivo effects of vitamin E and simvastatin in sepsis. Fourteen healthy volunteers, 14 intensive care unit (ICU) nonseptic, and 14 ICU patients with sepsis were included in this prospective study. Plasma cholesterol, triglyceride, and vitamin E levels were determined by routine laboratory tests. Superoxide anion production was measured in the venous blood by chemiluminescence technique after phorbol myristate acetate stimulation. Effects of vitamin E and simvastatin on O2- degree production was investigated ex vivo. Luminescence was indexed to the leukocyte count. We also investigated the in vitro effect of simvastatin on translocation of NADPH oxidase p21 Rac2 subunit in THP-1 monocytic cell line. The ratio of vitamin E/cholesterol + triglycerides was significantly decreased in septic as compared with nonseptic patients and volunteers. The O2- degree production was significantly higher in the group of septic patients than in the others, regardless of the polymorphonuclear leukocyte count. Vitamin E and simvastatin induced ex vivo an inhibition of O2- degree production of 20% and 40% respectively. In vitro, simvastatin inhibited phorbol myristate acetate-induced- O2- degree production by monocytes through NADPH oxidase inactivation. We conclude that sepsis is associated with a significant decrease in vitamin E and an overproduction of O2- degree. Vitamin E and simvastatin lessen this phenomenon through NADPH oxidase inactivation.

[Drug prescriptions for the elderly. Results of a survey on 8,809 prescriptions obtained by coding in the North-East area of France]. / La prescription médicamenteuse chez la personne âgée. A propos d'une enquête sur 8,809 ordonnances obtenues par codage, dans la région Nord-Est de la France.

OBJECTIVES: To analyze the prescriptions in patients aged over 60 and more in the North-East area of France during a summer and a winter month, to analyze the impact of the seasonal factor and the number of prescriptions, and to classify in frequency the families and classes of medicinal products prescribed. METHODS: This study was conducted on two samples of prescriptions presented for reimbursement to the public health scheme of the Meurthe-et-Moselle, Vosges and Meuse areas, i.e. 4409 prescriptions (717 men, 1244 women) in July 1998 and 4400 prescriptions (772 men and 1335 women) in January 1999. The prescriptions concerned non-hospitalised persons aged over 60. Each prescription was identified according to the international medication classification codes, and classified according to the anatomical, therapeutic and chemical classification. RESULTS: The survey in July 1998 concerned 1961 patients and that of January 1999 2107 patients, representing respectively 4409 and 4400 prescriptions. The number of prescriptions of July and January were comparable (4409 vs 4400), but the number of prescription lines was greater in the winter month (3.51 +/- 2.3 vs 3.43 +/- 2.3; p<0.001). Among the prescriptions, 63% were for women and the number of prescription lines was greater than those for men (3.54 vs 3.24 in July, p<0.01; 3.59 vs 3.35 in January, p<0.01). Around 90% of the prescriptions were drawn-up by general practitioners. Ophthalmology was the specialty that prescribed the greatest number of prescriptions. The mean amount reimbursed for a prescription was higher in men with 32.10 in July (26.79 in women) and 32.28 in January (27.13 in women). Independently of age, gender and month, the most prescribed medication families in decreasing order were: cardio-vascular system (35%), central nervous system (15%), and digestive and metabolic system (14.5%). Prescriptions for the family of respiratory system treatments were greater in January than in July (9.4% vs 6.1%, p<0.01). CONCLUSION: In this study the women consumed more medicinal products than the men, but the mean cost of reimbursement per prescription was higher in the men. The most prescribed class of medication concerned the cardiovascular system. The seasonal factor was characterised by an increase in the number of lines per prescription and a greater prevalence of respiratory system products in January

Serum leptin level is a predictor of bone mineral density in postmenopausal women.

To assess whether leptin is an independent predictor of bone mineral density (BMD) in postmenopausal women, we studied the relationships of BMD to serum leptin, 25(OH)D, 1,25(OH)(2)D, PTH, E2, dehydroepiandrosterone sulfate, GH, IGF-I, creatinine clearance, calcium intake, fat mass, and lean mass in 107 women aged 50-90 yr. We also related serum leptin to markers of bone formation [serum bone alkaline phosphatase and osteocalcin (OC)] and resorption (urine C-telopeptide of type I collagen). In stepwise multiple linear regression, lean mass explained 28.5%, age 10.3%, and leptin 7.2% of the whole body BMD variance. Age explained 21.1%, lean mass 12.8%, and leptin 3.7% of the femoral neck BMD variance. After adjustment for fat mass and creatinine clearance, correlations between leptin and bone alkaline phosphatase (positive) and OC (negative) disappeared but, remained significant with urine C-telopeptide of type I collagen (r = -0.27, P < 0.01). Markers of bone formation and resorption were strongly intercorrelated. These data demonstrate that leptin is an independent predictor of whole body and femoral neck BMD in postmenopausal women. Although the relationships between leptin and markers of bone formation appear complex, leptin may exert a protective effect on bone by limiting the excessive bone resorption coupled to bone formation associated with bone loss after menopause.