The effect of poly (ADP-ribose) polymerase inhibition on aminoglycoside-induced acute tubular necrosis in rats.

INTRODUCTION: Aminoglycosides (AG) cause nephrotoxicity in 10 - 20% of patients. One of the mechanisms is by generating reactive oxygen species (ROS), leading to DNA destruction and activation of poly(ADPribose) polymerase (PARP) causing necrotic tubular cell death. PARP inhibition on gentamicin-induced nephrotoxicity was studied. METHODS: 19 female Wistar-Kyoto rats divided into 3 groups: control (3 rats receiving no treatment); gentamicin-treated group (8 rats); and 8 rats treated with gentamicin combined with 3-aminobenzamide (3 AB). Kidney functions, protein, and gentamicin levels as well as urinary trypsin inhibitory activity (TIA) were measured. Tissue microscopic examination and immunohistochemical study for proliferative cell nuclear antigen (PCNA) were determined. The effect of PARP inhibitor on the bactericidal activity of gentamicin was also assessed. RESULTS: The following results were statistically significant: urea (mg/dL) 39.9 ± 5.86, 88.3 ± 50.3, and 48.5 ± 12.7 (p = 0.048); serum creatinine (mg/dL): 0.6 ± 0.26, 1.05 ± 0.7, 0.6 ± 0.06 (p = 0.043); proteinuria (mg/24-hours): 7.27 ± 3.65, 41.2 ± 18.1, and 17.6 ± 13.9 (p = 0.050); the number of tubular macronuclei (per 10 mm2): 18.33 ± 16.07, 218 ± 101.8, 41.7 ± 36.2 (p = 0.012); the number of dilated tubes (per 10 mm2): 61.67 ± 12.58, 276.3 ± 112.7, 140.0 ± 90.9 (p = 0.04); and the number of PCNA positive nuclei (per 10 mm2): 223.3 ± 95.69, 3,585 ± 2,215.3, 626.7 ± 236.9 (p = 0.034) in the control, gentamicin, and gentamicin+3AB-treated groups, respectively. The following biochemical and histologic parameters were also examined, however, they showed no statistically significant difference: TIA (p = 0.055), mitoses (p = 0.14), mononuclear infiltrate (p = 0.188), and intratubular cast formation (p = 0.084). No effect on bactericidal activity was observed. CONCLUSION: This study illustrates that PARP inhibitor significantly attenuates gentamicin-induced nephrotoxicity in rats with no effect on the bactericidal activity.

Effect of atorvastatin on IgA nephropathy in the rat.

BACKGROUND: IgA nephropathy (IgAN) is the most common chronic glomerulonephritis in humans and is a major cause of end-stage kidney disease worldwide. There is no agreement on the exact underlying mechanism or therapeutic intervention for this disorder. Mesangial proliferation typifies the renal histopathology in IgAN. Statin drugs, as prenylationinhibitors, have been shown to have an antiproliferative effect on renal mesangial cells and to reduce IgAN-associated glomerulusclerosis and proteinuria. The aim of this study is to examine the effect of atorvastatin on kidney function, proteinuria and kidney histology changes in IgANinduced rats. METHODS: IgAN was induced in Wistar-Kyoto rats by bovine γ-globulin (BGG). Four groups of rats were treated in metabolic cages: 1) control; 2) atorvastatin (2 mg/kg body weight/day through nasogastric tube) - treated rats; 3) IgAN-rats; 4) IgAN-rats treated with atorvastatin. Urine volume, urine protein excretion, blood urea and creatinine concentrations in addition to creatinine clearance were examined every 14 days, throughout the duration of the study (56 days). All kidneys from sacrificed rats were examined for histology including glomerular cell nuclei count and immunofluorescence. RESULTS: There were no differences in blood creatinine concentrations between the groups. Creatinine clearance was lower on the 42nd day and proteinuria was higher on Days 14, 42 and 56, in rats in Group 3 compared to all others; additionally, histology examination revealed a higher glomerular cell nuclei count in this group. Immunofluorescence was equally positive for IgA in mesangial cells in the kidneys from rats of Groups 2, 3 and 4. CONCLUSIONS: Atorvastatin attenuates kidney-function impairment, proteinuria and mesangial cell proliferation in BGG model of IgANinduced rats.

Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering?

BACKGROUND: Insulin resistance (IR) is the major driving force behind development and progression of atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). Therefore, correction of IR is a relevant therapeutic target.We performed the current trial to evaluate whether 12- month metformin therapy improves vascular stiffness in patients with NAFLD and to assess if this improvement is associated with change in glucose control, insulin resistance or circulating adiponectin. METHODS: In randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received placebo. Central aortic augmentation index (AI) was performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia) at baseline, at 4-and 12-month treatment period. Metabolic parameters, insulin resistance markers and serum adiponectin levels were determined. RESULTS: In placebo group: AI did not improve during the treatment period. Liver function and adiponectin levels did not change during the study.In multiple linear regression analysis, the independent predictors of arterial stiffness improvement were metformin treatment and increase in circulating adiponectin levels.Among metformin treated patients: AI decreased significantly during the study. ALP and ALT decreased during initial 4-month treatment period, however raised to the pretreatment levels after 12 months. Serum adiponectin level tended to increase during treatment period with metformin. CONCLUSIONS: Metformin treatment was associated with significant decrease in AI during one year treatment in NAFLD patients. These beneficial vascular effects was associated with exposure to metformin per se as well as change in adiponectin levels suggesting that metformin may mediate its vascular effects via glycemic control-independent mechanisms.

MEasuring Nutrition risk in hospitalized patients: MENU, a hospital-based prevalence survey.

BACKGROUND: Depending on the definition used, malnutrition is prevalent among 20-50% of hospitalized patients. Routine nutritional screening is necessary to identify patients with or at increased risk for malnutrition. The Nutrition Risk Screening (NRS 2002) has been recommended as an efficient tool to identify the risk of malnutrition in adult inpatients. OBJECTIVES: To utilize the NRS 2002 to estimate the prevalence of malnutrition among newly hospitalized adult patients, and to identify risk factors for malnutrition. METHODS: During a 5 week period, all adult patients newly admitted to all inpatient departments (except Maternity and Emergency) at Wolfson Medical Center, Holon, were screened using the NRS 2002. An answer of "yes" recorded for any of the Step 1 questions triggered the Step 2 screen on which an age-adjusted total score > or = 3 indicated high malnutrition risk. RESULTS: Data were obtained from 504 newly hospitalized adult patients, of whom 159 (31.5%) were identified as being at high risk for malnutrition. Malnutrition was more prevalent in internal medicine than surgical departments: 38.6% vs. 19.1% (P < 0.001). Body mass index was within the normal range among subjects at high risk for malnutrition: 23.9 +/- 5.6 kg/m2 but significantly lower than in subjects at low malnutrition risk: 27.9 +/- 5.3 kg/m2 (P < 0.001). Malnutrition risk did not differ by gender or smoking status, but subjects at high malnutrition risk were significantly older (73.3 +/- 16.2 vs. 63.4 +/- 18.4 years, P < 0.001). Total protein, albumin, total cholesterol, low density lipoprotein-cholesterol, hemoglobin and % lymphocytes were all significantly lower, whereas urea, creatinine and % neutrophils were significantly higher in patients at high malnutrition risk. CONCLUSIONS: Use of the NRS 2002 identified a large proportion of newly hospitalized adults as being at high risk for malnutrition. These findings indicate the need to intervene on a system-wide level during hospitalization.

Oxidative stress contributes to hemolysis in patients with hereditary spherocytosis and can be ameliorated by fermented papaya preparation.

In the present study, we questioned the role of oxidative stress in hereditary spherocytosis (HS), where red blood cells (RBC) have a shortened survival due to primary deficiency in membrane proteins. Using flow cytometry techniques, we showed that RBC derived from 17 HS patients of seven families generate more reactive oxygen species, membrane lipid peroxides, and less reduced glutathione than normal RBC. Following in vitro incubation of HS-RBC from seven patients with a fermentation bioproduct of Carica papaya (fermented papaya preparation (FPP)) with known antioxidative properties, oxidative stress markers were significantly reduced. Similar results were obtained following treatment with FPP for 3 months of 10 adult HS patients, as well as decreased tendency to undergo hemolysis. The hemoglobin levels increased by >1 g/dl, mean corpuscular hemoglobin concentration decreased by >1 g/dl, and the reticulocyte count decreased by 0.93%. Concomitantly, lactic dehydrogenase decreased by 17% and indirect bilirubin by 50%. A significant decrease in malonyldialdehyde was also detected. These data indicate that oxidative stress plays an important role in the pathophysiology of HS which can be ameliorated by an antioxidant such as FPP. Additional clinical trials with FPP and other antioxidants are warranted.

Placental transfer of the insulin analog glargine in the ex vivo perfused placental cotyledon model.

OBJECTIVE: The aim was to characterize the transfer of the insulin analog glargine across the placenta using the placental perfusion model. METHODS: Placentas were obtained and selected cotyledons were cannulated and dually perfused. Glargine, 50 mU/L (n = 2) and 200 mU/L (n = 1), and a reference marker, antipyrine (50 µg/mL), were added to the maternal circulation. Samples were taken from the maternal and fetal compartments. RESULTS: Glargine was not detected in the fetal compartment. In the maternal compartment, the steady state concentration was 50% lower than the starting concentration. CONCLUSIONS: Glargine probably does not cross the human placenta. Reduced maternal steady state concentrations may suggest insulin uptake by the placenta.

Effect of Long-Term L-Arginine Supplementation on Arterial Compliance and Metabolic Parameters in Patients with Multiple Cardiovascular risk Factors: Randomized, Placebo-Controlled Study.

OBJECTIVES:: This study was designed to determine the effect of long-term L-arginine supplementation on arterial compliance, inflammatory and metabolic parameters in patients with multiple cardiovascular risk factors. METHODS:: In this randomized, placebo-controlled trial, 90 patients were randomly assigned to two groups: Group 1 received daily oral L-arginine, Group 2 received matching placebo capsules. Patients were evaluated for lipid profile, glucose, HbA1C, insulin, hs-CRP, renin and aldosterone .Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota). RESULTS:: Although large artery elasticity index (LAEI) did not differ significantly between the groups at baseline (10.64.3 vs.11.64.5 ml/mm HgX100, p=0.346), at the end of the study LAEI was significantly greater in patients treated with L-arginine than in the placebo group (12.73.4 vs. 8.02.8 ml/mm HgX10, p<0.0001). Systemic vascular resistance was significantly lower in patients treated with L-arginine than in the placebo group after 6 months. Small artery elasticity index (SAEI) did not differ significantly between the groups at baseline or at the end of the study. Serum aldosterone decreased significantly in Group 1 from 10.76.3 to 8.45.0 ng/ml (p=0.008), but did not change in the placebo group. CONCLUSION:: L-arginine supplementation improves LAEI in patients with multiple cardiovascular risk factors. This improvement was associated with a decrease in systolic blood pressure, peripheral vascular resistance as well as a decrease in aldosterone levels. The results suggest that long term L-arginine supplementation has beneficial vascular effects in pathologic disease states associated with endothelial dysfunction.

Inhibition of immune-mediated concanavalin a-induced liver damage by free-radical scavengers.

BACKGROUND/AIMS: The aims of the present study were to elucidate whether oxidative stress has a role in Con A-induced hepatitis and to examine if antioxidants may protect against liver damage in this model. METHODS: Hepatitis was induced in Balb/c mice by administration of Con A (18 mg/kg) to the tail vein. Liver enzymes and histology were determined 24 h after Con A injection. Tumor necrosis factor alpha (TNFalpha) and interleukin-10 (IL-10) levels were assayed 2 h after Con A injection. Hepatic malondialdehyde levels were measured at 1, 3, 8, 12, 18, and 24 h after Con A injection in order to examine the timing of free-radicals formation. Nuclear factor kappa B (NF-kappabeta) activation was determined by electrophoresis mobility shift assay (EMSA) 1 and 2 h after Con A injection. In separate experiments, mice were pretreated with either dimethylsulfoxide or dimethylthiourea before Con A inoculation. The antioxidant and NF-kappabeta inhibitor pyrrolidine dithiocarbamate (PDTC) was used as positive control. RESULTS: Hepatic malondialdehyde levels increased 12, 18, and 24 h after Con A inoculation but not earlier. Serum levels of liver enzymes and TNFalpha, hepatic malondialdehyde, and protein carbonyls and the histologic necroinflammatory score were significantly reduced in the antioxidants-treated mice, while IL-10 levels were increased. Dimethylsulfoxide, dimethylthiourea, and PDTC inhibited oxidative stress, but only PDTC inhibited Con A-induced NF-kappaB activation. CONCLUSIONS: Reactive oxygen species play a role in immune-mediated Con A-induced hepatitis probably secondary to immune-mediated liver damage. Scavenging of reactive oxygen species by antioxidants prevents hepatitis independently of NF-kappaB inhibition and may be a new therapeutic target in this experimental model.

Long-term effects of peroxisome proliferator-activated receptor ligand bezafibrate on N-terminal pro-B type natriuretic peptide in patients with advanced functional capacity impairment.

BACKGROUND: The effects of pan-peroxisome proliferator-activated receptor (PPAR) ligand bezafibrate on N-terminal pro-B type natriuretic peptide (ProBNP) level in patients with coronary artery disease (CAD) is unknown. The current study aimed to investigate the long-term effects of bezafibrate on ProBNP level in patients with pre-existing CAD and advanced functional capacity impairment. METHODS: Metabolic and inflammatory parameters were analyzed from stored frozen serum samples obtained from 108 patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. They presented with New York Heart Association (NYHA) functional class III, comprising 58 patients in the bezafibrate group and 50 in the placebo groups, and completed a 2-year prospective, double-blind, placebo-controlled follow-up. RESULTS: During follow-up ProBNP level did not change significantly in the placebo group, whereas it increased slightly in the bezafibrate group, which was older and with lower baseline ProBNP values. No significant differences between the groups were found for ProBNP levels after 2 year of follow-up. Analysis-of-covariance (ANCOVA) -taking into account age and baseline ProBNP level- showed that bezafibrate was not associated with longitudinal ProBNP changes during the follow-up period (p = 0.3). CONCLUSION: Long-term treatment by bezafibrate was not associated with longitudinal ProBNP changes in patients with pre-existing CAD and advanced functional capacity impairment.

Reducing blood transfusion requirements in preterm infants by a new device: a pilot study.

OBJECTIVE: To test a new device designed to salvage red blood cells (RBCs) from blood samples drawn from preterm infants, with the intent of decreasing blood loss and lowering the requirements for RBC transfusions. DESIGN: A case-controlled pilot study was conducted in two Israeli neonatal intensive care units in large municipal hospitals. Twenty low-birthweight preterm infants were randomly and equally divided into the ErythroSave group or a control group. All blood tests in the study group (except for complete blood count and coagulation parameters) were obtained during the first week of life by the new device in the study group and by ordinary syringes in the control group. The main outcome measure was the total number of units of blood needed. RESULTS: The average volume of blood obtained for laboratory analyses from each infant was 27 mL in the ErythroSave group and 24 mL in controls (not significant). The average volume of transfused packed cells was 6.4 mL for the ErythroSave group and 21.3 mL for the controls (p = 0.008). CONCLUSION: The use of ErythroSave for sampling blood significantly reduced blood transfusion requirements in premature infants compared to sampling by conventional syringes.

Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level.

OBJECTIVE: Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. METHODS AND RESULTS: Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARalpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi. CONCLUSIONS: Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Insulin resistance is associated with increased risk of major cardiovascular events in patients with preexisting coronary artery disease.

BACKGROUND: Over the past years it has been recognized that insulin resistance (IR) is an independent risk factor for the development of diabetes, whereas its association with cardiovascular events remains controversial. The aim of our study was to explore the association between IR per se and cardiovascular events among patients with preexisting coronary artery disease. METHODS: The mean follow-up period of this prospective study was 6.2 years. Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained at baseline from 2938 patients aged 45 to 74 years. The homeostatic index of IR (HOMA-IR) was calculated according to the homeostasis model assessment. RESULTS: New major cardiovascular events (fatal and nonfatal myocardial infarction and sudden death) were recorded in 108 (11.1%) patients from the lowest IR tertile, in 147 (14.7%) from the intermediate tertile, and in 166 (17.2%) from the highest tertile (P = .0002). The linear trend for total and cardiac death across the tertiles of HOMA-IR was significant as well (P = .02 and P = .009, respectively). The highest age-adjusted rates for major cardiovascular events and new diabetes were found among patients within the top tertile of HOMA-IR (57% and 130% higher rates, respectively, tertile 3 vs tertile 1, P < .0001 for both). Multivariable analysis identified HOMA-IR (tertile 3 vs tertile 1) as an independent predictor of increased risk of major cardiovascular events and new diabetes with hazard ratios (95% CI) of 1.4 (1.1-1.8) and 1.5 (1.1-2.0), respectively. CONCLUSIONS: Insulin resistance per se is an independent risk factor for cardiovascular events and new diabetes in patients with preexisting coronary artery disease.

C-reactive protein, bezafibrate, and recurrent coronary events in patients with chronic coronary heart disease.

BACKGROUND: Elevated C-reactive protein (CRP) levels are related to increased coronary risk in healthy subjects and in patients with acute coronary syndromes. The aims of the present study were to assess the following: (1) the association between CRP and subsequent coronary risk in patients with chronic coronary heart disease (CHD), (2) the effect of long-term bezafibrate treatment on CRP levels, and (3) to evaluate the consequences of change in CRP level over time on subsequent risk. METHODS: Patients with chronic CHD (n = 3122) were recruited to a secondary prevention study that assessed the efficacy of bezafibrate versus placebo. C-reactive protein was measured in plasma samples collected at prerandomization and after 2 years of follow-up. Mean follow-up time was 6.2 years. Primary end point was fatal and nonfatal myocardial infarction and sudden cardiac death. RESULTS: Increased baseline CRP levels were associated with increased risk (hazard ratios [HRs] per unit of log-transformed CRP level change) of myocardial infarction (HR 1.17, 95% CI 1.03-1.33), the primary end point (HR 1.19, 95% CI 1.06-1.34), total death (HR 1.19, 95% CI 1.02-1.40) and cardiac death (HR 1.28, 95% CI 1.04-1.59). After 2 years, CRP levels increased by 3.0% (from a mean level of 3.44 mg/L) in the bezafibrate group and by 3.7% (from 3.49 mg/L) in the placebo group. C-reactive protein levels after 2 years were associated with increased subsequent cardiovascular risk. CONCLUSIONS: Baseline CRP and 2-year CRP levels were associated with subsequent risk of myocardial infarction and death in patients with chronic CHD. Bezafibrate did not reduce CRP levels as compared with placebo.

Relation of haptoglobin phenotype to early vascular changes in patients with diabetes mellitus.

Haptoglobin (Hp) is an antioxidant protein and the major susceptibility gene for atherosclerosis in diabetic patients. The effect of Hp phenotype on arterial compliance and metabolic and inflammatory parameters was investigated. Patients were divided into 3 groups according to Hp phenotype of Hp 2-2, Hp 2-1, and Hp 1-1. Arterial elasticity of large and small arteries was evaluated using the pulse-wave contour analysis method. The large-artery elasticity index (LAEI) was lower in patients with Hp 2-2 compared with Hp 1-1 (8.4 +/- 2.3 vs 12.6 +/- 4.1 ml/mm Hg x 100; p <0.0001). The difference in LAEIs between the Hp 2-1 and Hp 1-1 groups was also significant (9.9 +/- 2.6 vs 12.6 +/- 4.1 ml/mm Hg x 100; p = 0.025). The Hp 2-2 and Hp 2-1 groups did not differ from one another. The small-artery elasticity index (SAEI) was significantly lower in patients with Hp 2-2 compared with Hp 1-1 (2.8 +/- 1.0 vs 4.4 +/- 1.9 ml/mm Hg x 100; p = 0.004). Differences in SAEIs between patients with Hp 2-1 and Hp 1-1, as well as those with Hp 2-1 and Hp 2-2, were not detected. Systemic vascular resistance differed significantly across groups, driven by the difference between patients with Hp 2-2 and Hp 1-1. In conclusion, LAEI and SAEI were significantly lower and systemic vascular resistance was higher in homozygotes for the 2 allele (Hp 2-2) compared with patients with Hp 2-1 or Hp 1-1 phenotypes. Differences in arterial elasticity were detected despite the lack of by-phenotype differences in glycemic control, blood pressure, or presence of cardiovascular risk factors.

Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy.

Lipid lowering therapy of serum LDL cholesterol (LDL) has proved beneficial in reducing cardiovascular morbidity and mortality. Lately the recommended target LDL level in very high risk patients was reduced to <70 mg/dl, raising the question of what the price of such a low level will be. To elucidate this concern, we investigated the associations of low serum LDL cholesterol levels (< or = 70 mg/dl) and the incidences of fever, sepsis, and malignancy. Retrospective analysis of 203 patients' charts was carried out. Patients were divided into 2 groups: Group 1 (n = 79) had serum LDL levels < or = 70 mg/dl, while Group 2 (n = 124) had levels >70 mg/dl. The first group demonstrated increased odds of hematological cancer by more than 15-fold (OR 15.7, 95% CI 1.78-138.4, p = 0.01). Each 1 mg/dl increase in LDL was associated with a relative reduction of 2.4% in the odds of hematological cancer (OR 0.976, 95% CI 0.956-0.997, p = 0.026). Low LDL levels also increased the odds of fever and sepsis between the groups (OR 5.3, 95% CI 1.8-15.7, p = 0.02). In summary, low serum LDL cholesterol level was associated with increased risks of hematological cancer, fever, and sepsis.

Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate.

BACKGROUND: Development of insulin resistance (IR) may be important in the pathogenesis of both metabolic syndrome and type 2 diabetes mellitus. Few data are available regarding the short-term efficacy of the peroxisome proliferator-activated receptor ligand bezafibrate on IR, and its long-term effect is unknown. The present analysis aimed to investigate the effect of bezafibrate on IR in patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention Study. METHODS: Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from patients who completed a 2-year, randomized, double-blind, placebo-controlled study. The homeostatic indexes of IR (HOMA-IRs) were calculated according to the homeostasis model of assessment. RESULTS: Both the patients taking bezafibrate (n = 1262) and those taking placebo (n = 1242) displayed similar baseline characteristics. The HOMA-IRs significantly correlated at baseline and during follow-up with glucose (r = 0.35 and 0.31, respectively) and triglycerides (r = 0.16 and 0.19, respectively). In a subgroup of 351 patients with diabetes, HOMA-IR at baseline was 88% higher than in their counterparts with normal glucose levels (P<.001). In the placebo group, during follow-up there was a significant 34.4% rise in HOMA-IR. In contrast, in the bezafibrate group there was only a nonsignificant 6.6% change in HOMA-IR. The intergroup differences in percentage changes of HOMA-IR were in favor of bezafibrate (P<.001). CONCLUSIONS: In patients with coronary artery disease enrolled in our study, as represented by the placebo group, HOMA-IR increased over time. During the 2 years of the follow-up, bezafibrate significantly attenuated this process.

C-reactive protein as a predictor of incident ischemic stroke among patients with preexisting cardiovascular disease.

BACKGROUND AND PURPOSE: C-reactive protein (CRP) has emerged as an important predictor of cardiovascular disease, but there are few prospective data on its association with risk of ischemic stroke in patients at high risk. METHODS: We examined the association between CRP levels and subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease included in a controlled clinical trial (Bezafibrate Infarction Prevention) that assessed the efficacy of bezafibrate, a fibric acid derivative, versus placebo for secondary prevention. CRP was measured by a high-sensitivity assay in plasma samples collected before randomization and again at the second follow-up year of an overall mean follow-up of 6.2 years. RESULTS: Risk of ischemic stroke per 1000 person-years increased from 4.1% for baseline CRP in the lowest tertile (<2.3 mg/L; n=982) to 5.9% for levels at the middle tertile (2.3 to 5.4 mg/L; n=1013) and 10.5% for CRP levels at the upper tertile (>5.4 mg/L; n=984; P<0.001). With adjustment for potential confounders, baseline CRP levels in the top versus bottom tertile were associated with a 2.16-fold increased hazard (95% CI, 1.32 to 3.53) for ischemic stroke, and CRP levels measured after 2 years were associated with a hazard ratio of 2.43 (95% CI, 1.30 to 4.57). The risk of an incident ischemic stroke did not differ between the bezafibrate group compared with the placebo group regardless of baseline CRP levels. CONCLUSIONS: These findings, based on a large prospective study, demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients at high risk.

Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction.

The aim of this study was to evaluate the prognostic value of interleukin-6 (IL-6) for myocardial infarction (MI) and mortality in a population with stable coronary artery disease (CAD) during a mean period of 6.3 years. IL-6 is a major proinflammatory cytokine of acute phase response; elevated levels are associated with worse prognosis in unstable angina and after acute MI. However, data regarding its long-term prognostic value in stable CAD are limited and controversial. A nested case-control study design was used. Of 3,090 patients with stable CAD, 129 with an adequate blood sample for IL-6 and who reached the end points (MI or sudden death) were randomly selected. Each case was 1:1 matched with 129 controls (alive at the end of the study and free of cardiovascular events) according to age, gender, and treatment. Of the 129 cases, 113 had a MI as the initial event, and for the other 16 the initial event was sudden death. There were 8 patients who first had a MI and later died suddenly. IL-6 was significantly higher in cases (2.34 pg/ml) than in controls (1.65 pg/ml) (p = 0.0004). IL-6 was significantly correlated with C-reactive protein (r = 0.2, p = 0.002); a borderline significance was also found for fibrinogen (r = 0.11, p = 0.07). Each increase of 1 pg/ml in IL-6 was associated with a 1.70 (range 1.23 to 2.45) increased relative odds of subsequent MI or sudden death. Events rate per 1,000 patients-years for the 5 quintiles of IL-6 were 72.26, 89.61, 79.76, 142.53, and 181.08, respectively (p <0.0001). A significantly higher risk in the upper quintile was found (odds ratio, 3.44; 95% confidence interval 1.57 to 8.13). In conclusion, elevated IL-6 levels are strongly associated with future cardiac events and mortality in a population with stable CAD during a long-term follow-up.

Adiponectin and the development of diabetes in patients with coronary artery disease and impaired fasting glucose.

OBJECTIVES: Adiponectin has insulin-sensitizing properties, and high adiponectin levels have been shown to be associated with reduced risk of developing diabetes. Patients with coronary artery disease (CAD) have relatively low adiponectin levels and high prevalence of glucose intolerance. The role of adiponectin in predicting the development of diabetes in this high-risk group has not been determined. The study aimed to determine whether baseline adiponectin levels predict the development of diabetes in a group of patients with CAD and impaired fasting glucose (IFG). METHODS: A total of 588 patients who participated in the Bezafibrate Infarction Prevention (BIP) study and who had at baseline fasting glucose of 100-125 mg/dl were included and followed for 6.2+/-1.3 years. Adiponectin was determined in frozen plasma samples taken at baseline. RESULTS: Of the patients with IFG at baseline, 256 (44%) developed diabetes during follow-up. The patients who developed diabetes had at baseline higher body-mass index, fasting glucose, C-reactive protein, triglycerides, homeostatic assessment of insulin resistance (HOMA-IR) and diastolic blood pressure than patients who did not develop diabetes. Adiponectin levels at baseline were significantly lower in patients who developed diabetes than in patients who did not develop diabetes (P = 0.009, nonparametric Kruskall-Wallis test). An increase of 1 unit of natural logarithm of adiponectin level was associated with a hazard ratio of 0.77 (95% CI, 0.61-0.96) for diabetes development. CONCLUSION: Patients with CAD and IFG have a very high rate of conversion to type 2 diabetes. Even in this high-risk group, high adiponectin levels are associated with reduced risk of developing diabetes.

Severe hypophosphatemia in sepsis as a mortality predictor.

Hypophosphatemia has long been reported to be associated with sepsis and has been correlated with sepsis severity. This retrospective study was undertaken at a university hospital to determine whether severe hypophosphatemia could serve as a mortality predictor in septic patients. Charts of 6,190 septic patients who were hospitalized during one year (2001-02) were examined. Fifty-five patients were selected and were divided into 2 groups: group 1 comprised 26 patients with severe hypophosphatemia (serum inorganic phosphate (Pi) <1 mg/dl); group 2 comprised 29 patients without severe hypophosphatemia (Pi >1 mg/dl. The patients' charts were reviewed and information was collected regarding medical anamnesis, physical examination, hematological and biochemical analyses, chest x-ray, and cultures of blood and urine. The results demonstrated that 80.8% of the patients with severe hypophosphatemia died, vs 34.5% of the patients without severe hypophosphatemia (p = 0.001). Being in the severe hypophosphatemic group increased the risk of death by nearly 8-fold (odds ratio = 7.98; 95% CI = 2.3 to 27.6). These findings indicate that severe hypophosphatemia can serve as an independent mortality predictor in sepsis.