Recombinant human-activated protein C inhibits cardiomyocyte apoptosis in a rat model of myocardial ischemia-reperfusion.

OBJECTIVES: Myocardial apoptosis is recognized as a major mechanism of cell death during ischemia-reperfusion. In this study, we assessed the hypothesis that activated protein C may have a cardioprotective effect via preventing apoptosis in a rat model of myocardial ischemia-reperfusion. METHODS: Thirty male Sprague-Dawley rats were anesthetized, instrumented for hemodynamic measurements and ventilated mechanically. Twenty rats were subjected to 20 min of left anterior descending coronary artery occlusion and 2 h of reperfusion. They were randomly assigned to receive intravenous Ringer lactate (vehicle) or activated protein C (2 mg/kg/h) 10 min after occlusion and during reperfusion. The other 10 rats were sham-operated. At the end of the reperfusion period, serum samples were obtained for evaluation of creatine kinase, C-reactive protein and tumor necrosis factor-alpha. Apoptosis was measured quantitatively by the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling method. RESULTS: Serum creatine kinase, C-reactive protein and tumor necrosis factor-alpha values and percentage of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling- positive myocyte nuclei demonstrated negligible myocardial injury in sham-operated controls. During reperfusion, mean arterial pressures were significantly higher in activated protein C-treated rats than in the control group (68.2+/-10.3 vs. 55.4+/-11.6 mmHg, P=0.01). Number of apoptotic cells was significantly reduced from 47.7 to 24.8% with activated protein C administration (P=0.008). No difference was seen between activated protein C-treated and untreated animals with respect to creatine kinase, C-reactive protein and tumor necrosis factor-alpha levels. CONCLUSIONS: Treatment with activated protein C significantly improved hemodynamics after ischemia-reperfusion and reduced ischemia-reperfusion-induced myocardial apoptosis in rats.

Pretreatment with simvastatin reduces lung injury related to intestinal ischemia-reperfusion in rats.

In this rat model study we evaluated whether pretreatment with simvastatin affects the severity of acute lung injury caused by intestinal ischemia-reperfusion (I/R). Twenty-four animals were randomly allocated to three equal groups (sham, control, simvastatin). The simvastatin group was pretreated with simvastatin 10 mg x kg(-1) x day(-1) for 3 days, whereas the other groups received placebo. The simvastatin and control groups underwent 60 min of superior mesenteric artery occlusion and 90 min of reperfusion. Compared with the simvastatin group, the control group exhibited significantly more severe intestinal I/R-induced acute lung injury, as indicated by lower Pao2 and oxygen saturation (P = 0.01 and P = 0.005, respectively) and higher mean values for neutrophil infiltration of the lungs (P = 0.003), total lung histopathologic injury score (P = 0.003), lung wet-to-dry weight ratio (P = 0.009), and lung-tissue malondialdehyde levels (P = 0.016). The control and simvastatin groups had similar serum levels and similar bronchoalveolar lavage fluid levels of cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) and P-selectin at all measurements, except for a significantly higher level of bronchoalveolar lavage fluid P-selectin in the control group (P = 0.006). Pretreatment with simvastatin reduces the severity of acute lung injury induced by intestinal I/R in rats.

Local and systemic interactions related to serum transforming growth factor-beta levels in burn wounds of various depths.

OBJECTIVES: This study aimed to investigate the interaction between serum levels of TGF-beta and active-immune cell infiltration in burn wounds of various depths. MATERIALS AND METHODS: Thirty female Sprague-Dawley rats were divided into three groups: full-thickness burns (F), partial-thickness burns (P), and no burns (S). After burn-induction, blood samples were obtained only once from shams and at postburn 1, 48 h, and 7 days in burn groups. Serum levels of TGF-beta were measured by means of the ELISA. The proportions of neutrophils, fibroblasts, vascular proliferation, CD68-macrophages, and CD3-lymphocytes were studied immunohistochemically and graded semiquantitatively. RESULTS: Serum TGF-beta levels in the F and P groups were lower than those in sham at 1h after burn (p<.05). No significant differences in TGF-beta were observed between groups F and P on days 2 and 7 after injury. No local accumulation of macrophages and fibroblasts was noted in either burn group, but the proportion of lymphocytes was higher in the P group at 1h after burn. Neutrophils were higher in the F group than the P on day 7 after burn. CONCLUSIONS: Prolonged neutrophil infiltration in full-thickness burn wounds and suppressed lymphocyte proliferation in partial-thickness burn wounds seem to be related to an increase in serum TGF-beta levels.

The effect of single-dose orlistat on postprandial serum glucose, insulin and glucagon-like peptide-1 levels in nondiabetic obese patients.

OBJECTIVE: Glucagon-like peptide-1 is an insulin secretion-stimulating gut hormone that is produced in response to food intake. Orlistat (Xenical, F. Hoffman-La Roche, Basel, Switzerland), which decreases fat absorption and increases intestinal fat content, may therefore affect the secretion of glucagon-like peptide-1. In this study we examined the immediate effects of orlistat on postprandial serum glucose, insulin and glucagon-like peptide-1 levels prior to a change in body weight. DESIGN: Randomized, clinical study. PATIENTS: Sixteen nondiabetic obese patients (body mass index 35.7 +/- 3.8 kg/m(2), range 32.5-43.1) were enrolled in this study. The patients were randomly assigned to either the group treated with orlistat (120 mg, single dose) or the control group. There were eight patients in each of the two groups. Orlistat was given before a standard 600-kcal mixed meal containing 60% carbohydrates, 25% lipids and 15% protein. Blood samples were collected at baseline and at 30-min intervals for 180 min after the test meal. Graphical tendencies, peak value, time to reach the peak value, and area under the curve in the two groups were compared. MEASUREMENTS: Blood samples were obtained for the measurement of GLP-1, glucose, insulin, high density lipoprotein, total cholesterol and triglycerides. RESULTS: We found no difference in sex distribution, mean age, anthropometric measurements, or baseline glucose, insulin and glucagon-like peptide-1 levels between the orlistat and placebo groups. The peak insulin and glucagon-like peptide-1 levels were determined at 60 min in the control group. Hourly changes in serum glucose and insulin levels were similar between the groups, although the peak insulin and glucagon-like peptide-1 levels were reached at 120 min in the orlistat group. There were no statistically significant differences between the groups. CONCLUSIONS: A single dose of 120-mg orlistat caused no change in postprandial serum glucose, insulin or glucagon-like peptide-1 levels in nondiabetic obese patients. Although glucagon-like peptide-1 increases were delayed in the orlistat group, these changes were nonsignificant.

Postprandial lipemia as a risk factor for cardiovascular disease in patients with hypothyroidism.

Postprandial lipoprotein metabolism is suggested to play a role in the pathogenesis of atherosclerosis. In this study, we investigated postprandial lipemia and its relationship to cardiovascular risk factors in patients with overt and subclinical hypothyroidism. Twenty-nine female patients with TSH levels greater than 5 microIU/mL and 12 euthyroid control female subjects were included in the study. Fifteen patients had subclinical hypothyroidism and 14 had overt hypothyroidism. All subjects underwent an oral lipid tolerance test. If triglyceride levels increased by 80% or more, subjects were considered postprandial lipemia positive. Control, overt hypothyroid, and subclinical hypothyroid groups were not statistically different with respect to anthropometric measurements, fasting blood C-reactive protein, uric acid, homocysteine, glucose, insulin, lipoprotein (a), apolipoprotein B levels, and homeostasis model assessment index. Fasting triglyceride levels correlated positively with TSH levels. Postprandial lipemia frequency was higher in overt hypothyroid subjects than in the control group. The subclinical hypothyroid group did not differ from the hypothyroid group with respect to postprandial lipemia frequency. In subjects with TSH levels higher than 5 microIU/mL, PPL risk was increased sevenfold. The results of this study show that postprandial triglyceride metabolism is affected in hypothyroidism.

Interactions of systemic immune response and local wound healing in different burn depths: an experimental study on rats.

This study aimed to clarify the local and systemic immune responses at different burn depths. Thirty female Sprague-Dawley rats were divided into three groups: full-thickness (F), partial-thickness (P), and Sham (S). Burns were induced on three separate areas on the dorsums of rats. Serum levels of interferon (IFN)-gamma; tumor necrosis factor-alpha; interleukin (IL)-1, IL-6, and IL-10 were measured once in controls and 1 hour after burn, 48 hours after burn, and 7 days after burn in F and P groups. Neutrophils, CD68-positive macrophages, HLA-DR-positive cells, and CD3-positive lymphocytes were graded semiquantitatively, and the wounds were examined once in shams and at 1 hour after burn, 48 hours after burn, and 7 days after burn in F and P groups. IL-6 levels were highest in F group, followed by P group 1 hour after burn. IFN-gamma levels were higher in the F group; IL-1 levels were higher in F and P groups at 1 hour after burn. Local accumulation of macrophages was similar in F and P groups. Lymphocytes were denser in P group at 1 hour after burn, and neutrophils were denser in F group at 7 days after burn. We suggest that early elevations of IL-6 and IFN-gamma prolong inflammation in full-thickness burns. Modulation of proinflammatory cytokines may improve burn wound treatment.

Effects of metoprolol therapy on cardiac troponin-I levels after elective percutaneous coronary interventions.

AIMS: Beta-blockers (BBs) have been shown to improve survival and reduce the risk of re-infarction in patients following myocardial infarction. There are conflicting data about the effects of BB therapy on cardiac biomarkers after percutaneous coronary interventions (PCIs). The aim of the study was to investigate the effects of BB use on cardiac troponin-I (cTnI) levels in patients who had undergone elective PCI. METHODS AND RESULTS: In this prospective study, 287 patients with coronary artery disease were included. Patients were randomized either to BB or control groups prior to the intervention. Blood samples for cTnI were obtained before and at 6, 24, and 36 h after the procedure. Of the 287 patients included, 143 received metoprolol succinate 100 mg/day, and 144 received no BB and served as the control group. Baseline clinical characteristics of both groups, except for history of coronary artery bypass graft surgery, were similar. We observed no significant difference in the elevation of cTnI levels between the two groups after PCI (BB group, 17 patients, 11.9%; control group, 10 patients, 6.9%; P=0.2). CONCLUSION: Metoprolol succinate therapy seems to have no cardioprotective effect in limiting troponin-I rise after PCI.

Effects of raloxifene on platelet functions in patients with postmenopausal osteoporosis.

Many studies have addressed the effects of estrogenic compounds on platelet function. Raloxifene is a selective estrogen receptor modulator (SERM), which is currently used for the treatment of postmenopausal osteoporosis. At present, there are no clinical data about the effects of raloxifene on platelet function. The purpose of this study was to determine if raloxifene at therapeutic doses affects platelet function in patients with postmenopausal osteoporosis. The effects of raloxifene on platelet function were investigated using a commercial platelet function analyzer (PFA-100) with collagen epinephrine and collagen adenosine 5'-diphosphate (ADP) cartridges. We studied platelet function of 30 patients with postmenopausal osteoporosis before and 15 days after initiation of raloxifene 60 mg/daily. Closure times did not differ significantly between samples obtained before (117.8 +/- 20.5 s) and after raloxifene therapy (106.5 +/- 25.4 s) in collagen/epinephrine cartridges (P > 0.05). There was also no statistically significant difference in mean closure times with collagen/ADP cartridges at baseline (86.2 +/- 18.5 s) and after raloxifene therapy (84.4 +/- 13.8 s) (P > 0.05). Platelet counts (278.3 +/- 72.9 vs. 262.4 +/- 56.7 109/L, P > 0.05) and mean platelet volumes (8.9 +/- 1 vs. 9.1 +/- 1 fL, P > 0.05) were not different before and after raloxifene therapy. Although estrogen related compounds do affect platelet function, there is suggestive data in our study that raloxifene in therapeutic dose exhibit no effect on platelet function in patients with postmenopausal osteoporosis.

Does eradication of Helicobacter pylori infection help normalize serum lipid and CRP levels?

It is still unclear whether Helicobacter pylori infection is associated with risk factors for coronary artery disease. The aim of this study was to determine whether eradication of H. pylori infection affects serum lipid levels and C-reactive protein (CRP) levels. Seventy-eight patients who had H. pylori antigen positivity in their stools were enrolled. Clarithromycin, 1 g/day, amoxicillin, 2 g/day, and omeprazole, 40 mg/day, were given for 14 days. Serum total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and CRP were measured at baseline and 8 weeks after therapy. According to H. pylori stool antigen study after 8 weeks, individuals in whom H. pylori was eradicated were recruited as group A and those in whom H. pylori was not eradicated formed group B. Group A comprised 57 patients, and group B 21 patients. Patients in group A comprised 32 women and 25 men and their ages ranged from 35 to 59 years. Patients in group B included 13 women and 8 men, aged 32-61 years. No significant difference in LDL, TC, or TG serum levels were found between group A and group B. Although CRP and HDL serum levels were found to be the same before and after treatment in group B, CRP levels were found to decrease and HDL levels to increase significantly in group A (P < 0.05). We conclude that H. pylori infection may affect lipid metabolism in a way that could increase the risk of atherosclerosis. Thus H. pylori infection is an independent risk factor for coronary artery disease.

Correlations among serum leptin levels, complete blood count parameters and peripheral CD34(+) cell count in prepubertal obese children.

Leptin is a hormone produced by adipocytes that helps reduce body weight by depressing appetite and increasing metabolic activity. Leptin also promotes early hematopoiesis. The main aim of this study was to compare complete blood count (CBC) parameters and peripheral blood CD34(+) cell counts in prepubertal obese and nonobese children. Relationships between leptin levels and CBC parameters and peripheral CD34(+) progenitor cell counts in the obese group were also investigated. Thirty one healthy, prepubertal, obese children and 30 nonobese, age-matched prepubertal controls were included in the study. A fasting blood sample was collected from each subject, and CBC findings, serum leptin level, and peripheral blood CD34(+) progenitor cell count were recorded. In the obese group, the mean results for body mass index (BMI), BMI standard deviation score (BMI SDS), and serum leptin level were significantly higher than the corresponding control findings. There were no significant differences between the groups with respect to CBC parameters and CD34(+) cell percentage. In both the obese and control groups, the girls' serum leptin levels were significantly higher than the boys'. In the obese group, serum leptin level was strongly correlated with BMI and with BMI SDS (Pearson correlation coefficients r=0.70, p<0.001, and r=0.59, p<0.001, respectively) in both girls and boys. None of the CBC parameters nor CD34(+) progenitor cell percentage was correlated with leptin, BMI, or BMI SDS. The results indicate that serum leptin levels in obese children are positively correlated with BMI. However, in contrast to adults, high leptin level in childhood obesity does not seem to be associated with altered CBC parameters or increased peripheral CD34(+) progenitor cell count.

Helicobacter pylori seroprevalence in patients with coronary artery disease.

Recent studies have suggested that chronic infections such as Helicobacter pylori may be a risk factor for coronary artery disease (CAD). The aim of thIS study was to investigate the seroprevalence of H. pylori in patients with CAD. We enrolled 151 patients with CAD (93 men and 58 women, aged 48.1 +/- 17.3 years [mean +/- SD]) and 149 control subjects matched by age and sex (90 men and 59 women, aged 51.4 +/- 13.9 years). An enzyme-linked immunosorbent assay immunoglobulin (Ig) G test for H. pylori diagnosis was performed on all enrolled subjects (CAD patients and controls). Ninety-one of 151 patients with CAD (60.2%) and 86 of the 149 subjects in the control group (57.7%) were H. pylori positive (P > 0.05). H. pylori infection rates were similar in patients with CAD and control groups. The main conclusion of this study is that H. pylori infection is not a risk factor for developing CAD. Further studies should be undertaken to confirm our results.