LE Magazine May 2003
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
Inflammatory mediators are induced
by dietary glycotoxins, a major risk factor for diabetic
angiopathy.
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
Pet health
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
Oxidative damage increases with
age in a canine model of human brain aging.
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
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