Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity and its frequent coexistence with illness. OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus. METHODS: Participants were 4,735 community-dwelling adults 65 years and older. Frail, intermediate and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures. RESULTS: Of 4,735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2,147 (45.3%) as intermediate, and 2,289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13,790 +/- 4,480 vs 11,860 +/- 3,460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1,033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex and race. CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.
Arch Intern Med 2002 Nov 11;162(20):2333-41
Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with five-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a two-week crossover and 13 in a six-week study. After two weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-alphabeta-actin mRNA ratio was 1.4 +/- 0.5 on H-AGE and 0.9 +/- 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 +/- 429 and 698 +/- 347 ngml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-alpha rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.
Proc Natl Acad Sci U S A 2002 Nov 26;99(24):15596-601
Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina.
BACKGROUND: Proinflammatory cytokines play a role in acute coronary events. However, the potential role of antiinflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10, which is expressed in human atherosclerotic plaques, has potent deactivating properties in macrophages and T cells. The aim of this study was to assess whether serum concentrations of IL-10 differed between patients with unstable and stable angina pectoris. METHODS AND RESULTS: A total of 95 patients with angina pectoris and angiographically documented coronary artery disease were studied. Of these, 50 patients had chronic stable angina (with stable symptoms over three months), and 45 patients had Braunwald class IIIB unstable angina with ST-segment changes. Serum IL-10 and IL-6 concentrations were measured on admission using commercially available immunoassays. Serum IL-10 concentrations were lower in unstable angina patients compared with those who had chronic stable angina (28.4 versus 14.0 pg/mL; 95% CI, 9.8 to 19.0; P<0.0001), even after adjustment for variables that were significantly different on univariate analysis. IL-6 concentrations were higher in the unstable angina group (20.9 versus 11.4 pg/mL; 95% CI, 1.0 to 12.6; P=0.04). CONCLUSIONS: Patients with unstable angina had significantly lower serum IL-10 concentrations than did patients with chronic stable angina. This important finding is in keeping with previous data from animal model studies that suggest that IL-10 has a protective role in atherosclerosis.
Circulation 2001 Aug 14;104(7):746-9
CXC chemokine receptors expression during chronic relapsing experimental autoimmune encephalomyelitis.
Chemokines are small proinflammatory cytokines that possess the ability to stimulate migration of inflammatory cells towards the tissue site of inflammation. Previous reports showed that several chemokines may be involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune central nervous system (CNS) inflammation. Inflammatory cells respond to chemotactic chemokine gradient through the chemokine receptors (ChRs). The goal of this study was to analyze expression of ChRs belonging to CXC subfamily during different stages of chronic relapsing EAE. We found significantly increased expression of CXCR2 and CXCR4 in the spinal cord during the first and second disease attacks. The kinetics of this expression in CNS and blood suggests that CXCR2 is expressed by leukocytes migrating from the blood, but CXCR4 is expressed mainly by CNS parenchymal cells. Those results support the interpretation that chemokine-chemokine receptor interactions may play an important role in the development of CNS autoimmune inflammation.
Ann N Y Acad Sci 2000;917:135-44
C-reactive protein (CRP) in the cardiovascular system.
CRP (C-reactive protein) is an acute-phase reactant, the levels of which increase dramatically in response to severe bacterial infection, physical trauma and other inflammatory conditions. CRP is found in human atherosclerotic lesions. Atherosclerosis is clearly multifactorial in origin, and chronic inflammation is an important component in its pathogenesis. Focus on inflammation is critical in research on atherosclerosis. Elevated levels of CRP have been associated with increased risk of future coronary artery disease (CAD) events. I have summarized the recent literature on CRP studies in CAD. Both coronary heart disease and dilated cardiomyopathy(DCM) result in congestive heart failure due to myocardial damage. The inflammatory state produced by myocarditis of viral or other origin may induce advanced myocardial damage, resulting in heart failure with a poor prognosis. Routine CRP measurement proved to be valuable for identifying high-risk patients with DCM and lymphocytic myocarditis. I suggest that measurement of circulating CRP would be useful for the diagnosis of and for selecting therapeutic strategies for cardiovascular disorders.
Rinsho Byori 2001 Apr;49(4):395-401
Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness. OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus. METHODS: Participants were 4,735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures. RESULTS: Of 4,735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2,147 (45.3%) as intermediate, and 2,289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13,790 +/- 4,480 vs 11 860 +/- 3,460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1,033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex and race. CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.
Arch Intern Med 2002 Nov 11;162(20):2333-41
Effect of N-acetylcysteine on gentamicin-mediated nephropathy in rats.
Studies were performed on the mechanisms of the protective effects of free-radical scavengers against gentamicin-mediated nephropathy. Administration of gentamicin, 100 mg/kg s.c., for five days to rats induced marked renal failure, characterized by a significantly decreased creatinine clearance and increased blood creatinine levels, fractional excretion of sodium Na(+), lithium Li(+), urine gamma glutamyl transferase and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was observed in gentamicin-treated rats. Immunohistochemical localization demonstrated nitrotyrosine formation and poly(ADP-ribose)synthase activation in the proximal tubule from gentamicin-treated rats. Renal histology examination confirmed the tubular necrosis. N-acetylcysteine (10 mg/kg i.p. for five days) caused normalization of the above biochemical parameters. In addition, N-acetylcysteine treatment significantly prevents the gentamicin-induced tubular necrosis. These results suggest that (1) N-acetylcysteine has protective effects on gentamicin-mediated nephropathy and (2) the mechanisms of the protective effects can be, at least in part, related to interference with peroxynitrite-related pathways.
Eur J Pharmacol 2001 Jul 13;424(1):75-83
We assayed levels of lipid peroxidation, protein carbonyl formation, glutamine synthetase (GS) activity and oxidized and reduced glutathione to study the link between oxidative damage, aging and beta-amyloid (Abeta) in the canine brain. The aged canine brain, a model of human brain aging, naturally develops extensive diffuse deposits of human-type Abeta. Abeta was measured in immunostained prefrontal cortex from 19 beagle dogs (4 to 15 years). Increased malondialdehyde (MDA), which indicates increased lipid peroxidation, was observed in the prefrontal cortex and serum but not in cerebrospinal fluid (CSF). Oxidative damage to proteins (carbonyl formation) also increased in brain. An age-dependent decline in GS activity, an enzyme vulnerable to oxidative damage, and in the level of glutathione (GSH) was observed in the prefrontal cortex. MDA level in serum correlated with MDA accumulation in the prefrontal cortex. Although 11/19 animals exhibited Abeta, the extent of deposition did not correlate with any of the oxidative damage measures, suggesting that each form of neuropathology accumulates in parallel with age. This evidence of widespread oxidative damage and Abeta deposition is further justification for using the canine model for studying human brain aging and neurodegenerative diseases.
J Neurochem 2002 Jul;82(2):375-81
Oxidative stress participates in the breakdown of neuronal phenotype in experimental diabetic neuropathy.
AIMS/HYPOTHESIS: This study compared the effects of streptozotocin-induced diabetes in rats with those of two pro-oxidant interventions; a diet deficient in vitamin E and treatment with primaquine. METHODS: Measurements were made by the classic motor and sensory conduction velocity deficits and by indicators of the breakdown of small fibre phenotype i.e., sciatic nerve content of nerve growth factor and the neuropeptides, substance P and neuropeptide Y. RESULTS: As with diabetes, the pro-oxidant interventions decreased conduction velocities (though the effect of vitamin E deficiency was not significant), the sciatic nerve content of nerve growth factor and the neuropeptides (all percentages refer to the mean value for the appropriate control groups). In diabetes, nerve growth factor was depleted to 50% in the control rats (p < 0.05); oxidative stress depleted nerve growth factor to 64% (primaquine; p < 0.05) and 81% (vitamin E deficient; not significant) of controls. Substance P was depleted to 51% in the control rats (p < 0.01) with depletions to 74% and 72% (both p < 0.01) by oxidative stress; equivalent depletions for neuropeptide Y were 38% controls in diabetes (p < 0.001) and 67% (primaquine; p < 0.001) and 74% (vitamin E deficient; p < 0.05) for oxidative stress. CONCLUSION/INTERPRETATION: The relative magnitudes of these changes suggest an effect in diabetes of oxidative stress, coupled with some other cellular event(s). This is supported by the effects of a diester of gamma-linolenic acid and alpha-lipoic acid, which completely prevented the effects on the pro-oxidant interventions on conduction velocity, nerve growth factor and neuropeptide contents, but was only partially preventative in diabetes.
Diabetologia 2001 Apr;44(4):424-8
Assessment of dietary therapies in a canine model of Batten disease.
The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that occur in a number of animal species, including dogs. A study was conducted to determine whether the resupply of nutrients lost in NCL English Setter dogs would modify the course of the disease. Carnitine and polyunsaturated fatty acids have been reported to be reduced in NCL English Setters. Therefore, the normal laboratory diets of NCL dogs were supplemented with carnitine, fish oil and corn oil and the disease progression was compared with that of an untreated litter mate. The following specific prognostic indicators of NCL were monitored: cognitive function, brain atrophy, brain glucose metabolism and lifespan. Carnitine, with or without lipid supplements, dramatically delayed the progression of cognitive decline in NCL dogs. When fish oil and corn oil only were supplied, brain atrophy was reduced. A combination of all three supplements preserved cognitive function and increased lifespan by 10%. However, brain glucose hypometabolism and cerebral atrophy were not reduced. The results in this study indicated that the effectiveness of therapeutic interventions can be assessed by non-invasive methods at a relatively early stage of the disease process. Our study suggests that dietary supplementation with carnitine is a promising new approach for delaying or preventing the cognitive decline in dogs, and perhaps, with human NCL patients.
Eur J Paediatr Neurol 2001;5 Suppl A:151-6
Dermatosis associated with feeding generic dog food: 13 cases (1981 to 1982).
The records of 13 dogs with a crusting dermatosis of the mucocutaneous junctions, pressure points and trunk were evaluated. All of the dogs had been fed corn- and wheat-based commercial dry dog foods that failed to meet the National Research Council's recommendations for balanced nutrition. The dermatosis in all 13 dogs resolved completely after the diet was changed to one that met the National Research Council's recommendations. The disease was similar to that which has previously been called canine dry pyoderma, but is now known to be a zinc-responsive dermatosis.
J Am Vet Med Assoc 1988 Mar 1;192(5):676-80
Dietary beta-carotene absorption by blood plasma and leukocytes in domestic cats.
Three experiments were conducted to study the uptake of oral beta-carotene by blood plasma and leukocytes in domestic cats. In Experiment 1, mature female Tabby cats (12 month old) were given once orally 0, 10, 20 or 50 mg of beta-carotene and blood taken at 0, 12, 24, 30, 36, 42, 48 and 72 hour after dosing. Concentrations of plasma beta-carotene increased in a dose-dependent manner. Peak concentrations were observed at 12-24 hour and declined gradually thereafter. The half-life of plasma beta-carotene was 12-30 hour. In Experiment 2, cats were dosed daily for six consecutive days with 0, 1, 2, 5 or 10 mg beta-carotene. Blood was sampled once daily at 12 hour after each feeding. Daily dosing of cats with beta-carotene for six days resulted in a dose-dependent increase in circulating beta-carotene. Experiment 3 was designed to study the uptake of beta-carotene by blood leukocytes. Cats were fed 0, 5 or 10 mg of beta-carotene daily for 14 days. Blood leukocytes were obtained on day seven and 14 to determine beta-carotene content in whole lymphocytes and in subcellular fractions. Blood lymphocytes took up large amounts of beta-carotene by day seven of feeding. Furthermore, beta-carotene accumulated mainly in the mitochondria (40% to 52%), with lower amounts accumulating in the microsomes (20 to 35%), cytosol (15% to 34%), and nuclei (1.5% to 6%). Therefore, domestic cats readily absorb beta-carotene across the intestinal mucosa and transfer the beta-carotene into peripheral blood leukocytes and their subcellular organelles. Beta-carotene uptake kinetics show that some aspects of beta-carotene absorption and metabolism in cats are similar to those of humans.
J Nutr 2000 Sep;130(9):2322-5
Evaluation of the components of a commercial probiotic in gnotobiotic mice experimentally challenged with Salmonella enterica subsp. enterica ser. Typhimurium.
Vitacanis((R)), a probiotic preparation containing a Lactobacillus acidophilus, an Enterococcus faecium and a Saccharomyces cerevisiae, has been developed for the prevention of intestinal disorders in dogs and cats. In the present study, these microorganisms were tested jointly or singly during experimental infection of gnotobiotic mice with Salmonella typhimurium. Four experimental groups consisting of animals given probiotics jointly or singly and a control group consisting of germfree mice were used. The groups were treated with one or three of the microorganisms (experimental) or PBS (control) 10 days before intragastric challenge with a suspension containing about 10(2) cells of the bacterial pathogen. A higher survival (P<0.05) was observed in gnotobiotic mice given E. faecium (82%). All the animals in the other groups died after the challenge but the survival time was longer (P<0.05) for groups given all three of the microorganisms (7.4+/-2.4 days) or given only L. acidophilus (7.2+/-2.9 days) than for the control mice (4.4+/-1.1 days) and the mice that received S. cerevisiae (4.9+/-1.6 days) mice. The survival data agreed with the histopathological findings which showed more severe liver and intestinal lesions in control mice and in mice given Saccharomyces. In vitro antagonistic assays showed inhibition growth of E. faecium and S. Typhimurium around the colonies of L. acidophilus and for S. Typhimurium around the colonies of E. faecium. However, in vivo, S. Typhimurium became similarly established in the digestive tract of gnotobiotic mice at levels ranging from 10(8) to 10(10)CFU/g of feces and remained at these high levels until the animals died or were sacrificed. Among the three probiotic components of the commercial product Vitacanis((R)), E. faecium was the only one that provided protection against challenge with S. Typhimurium. Protection was not due to the reduction of the intestinal populations of the pathogenic bacteria.
Vet Microbiol 2001 Mar 20;79(2):183-9