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.

Association of serum relaxin with striae gravidarum in pregnant women.

AIMS: The cause of striae gravidarum is still unclear. The study objective was to test the hypothesis that relaxin is involved in the process of striae gravidarum appearance during pregnancy. METHODS: A prospective observational study in 32 pregnant women. Participants were observed at 12th, 24th and 36th gestational week. During each session, striae scoring was assessed and blood for relaxin estimation was withdrawn. The striae assessment was done according to Davey score. Serum relaxin was estimated using Relaxin ELISA kit (Immunodiagnostic AG, Bensheim, Germany). RESULTS: Serum relaxin levels decreased as the pregnancy advanced (585.9 ± 295.1, 424.2 ± 253.8, 402.1 ± 221.2 pg/ml, respectively) but this decrease did not attain statistical significance. Pregnant women with striae gravidarum had lower serum relaxin levels compared to those without striae gravidarum at 36th gestational weeks, 330.8 ± 175.2 vs 493.8 ± 245.8 pg/ml (P = 0.037), respectively. The severity of striae gravidarum during pregnancy did not correlate with serum relaxin levels. CONCLUSION: Lower serum relaxin levels could contribute to the occurrence of striae gravidarum during pregnancy through decreased elasticity of the connective tissue.

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.

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.

PTHrP and insulin levels following oral glucose and calcium administration.

BACKGROUND: Parathyroid hormone-related peptide (PTHrP), identified as a tumor product, is responsible for humoral malignant hypercalcemia. Unlike PTH, PTHrP is found in almost every body tissue including pancreatic alpha, beta, delta, and pp cells, where it is processed into multiple secretory forms, co-packaged with insulin, and secreted in a regulated fashion in response to insulin secretagogues. Ionized calcium is a stimulator for the release of several peptide hormones. METHODS: In the present study, we examined the effect of an oral calcium (1 g elemental calcium) and glucose (75 g) load on insulin and PTHrP release in 16 healthy volunteers and of an oral calcium load in 16 non-insulin-dependent diabetes mellitus (NIDDM) patients. Serum calcium, glucose, insulin, and PTHrP levels were determined at 0, 5, 10, 15, 30, and 60 min. RESULTS: Our results indicate that, at each time point, type 2 diabetic patients exhibited greater basal values of PTHrP than controls (200.3+/-110.5 pg/ml vs. 82.0+/-22.3 pg/ml, respectively, p<0.0001). The PTHrP level was consistently higher in response to the glucose load than the calcium load at each time point observed (p<0.0001). NIDDM patients exhibited greater basal serum PTHrP levels than the control group. CONCLUSION: PTHrP was proven for the first time to be released from beta cells in parallel to insulin and in response to glucose stimulation.

BNP in septic patients without systolic myocardial dysfunction.

BACKGROUND: We tested our hypothesis that serum BNP levels rise in sepsis and septic shock patients as a result of an inflammatory state and not only because of left ventricular dysfunction. METHODS: Twenty-one patients with sepsis or septic shock were enrolled in the study. Echocardiography was performed in every patient on admission and at discharge. Laboratory data were evaluated on admission, during hospitalization, and at discharge. Serum IL-1beta, IL-6, TNFalpha, and BNP concentrations were determined. RESULTS: BNP values on admission (r=0.47, p=0.03), during hospitalization (r=0.64, p=0.014), and on the day of discharge (r=0.54, p=0.015) were all positively correlated with CRP values. Mean BNP (r=0.07, p=0.006) and BNP level at discharge (r=0.68, p=0.001) were also positively associated with IL-1 at discharge. Mean CRP (17.7 mg/dL+/-1.5 vs. 9.2 mg/dL+/-3.6, p=0.002), IL-6 (46.6 pg/mL+/-2.2 vs. 25.6 pg/mL+/-16.3, p=0.003), and SAPS II levels (41.3+/-4.7 vs. 33.9+/-6.5 p=0.01) were also higher in patients who died versus those who survived. No difference in BNP levels was recorded in subjects who died versus those who survived. There was no clinical or echocardiographic evidence of left ventricular systolic dysfunction (mean EF% on admission 55.1+/-21.7 vs. 61.3+/-8.6 on discharge, p=0.123). Serum BNP levels at discharge were inversely associated with EF values on admission (r=-0.475, p=0.046) and positively associated with E/A ratio on admission (r=0.565, p=0.028). No association was found between BNP values and death. CONCLUSION: BNP is positively correlated with CRP levels in septic patients without clinical or echocardiographic evidence of systolic dysfunction. No association was found between death and BNP values. It seems that, in septic patients, BNP is less accurate as a measure of ventricular dysfunction.

Low HDL levels and the risk of death, sepsis and malignancy.

BACKGROUND: High density lipoprotein (HDL) plays an important role as an anti-atherogenic molecule, but also possesses anti-inflammatory and anti-angiogenic properties. The effect of extremely low levels of HDL on the risk of sepsis and malignancy were therefore examined. METHODS: A retrospective analysis of patients hospitalized at the Edith Wolfson Medical center was conducted. Patients were divided into Group 1: 108 patients with serum HDL levels < or =20 mg/dl. Group 2: 96 patients with serum HDL levels > or =65 mg/dl. Medical history and laboratory data was recorded. RESULTS: The mean HDL levels in Group 1 were 16.1 +/- 33 mg/dl compared to 74.9 +/- 12.6 mg/dl in Group 2. Using a multivariate logistic regression analysis, low HDL was inversely associated with death (OR 0.96, 95% 0.93-0.99, P = 0.02), 3.98 fold increase in odds of fever (OR 3.98, 95% CI 1.3-11.8, P = 0.01), and 6.7-fold increase in the risk of cancer (OR 6.68, 95% CI 1.8-24.5, P = 0.004). HDL serum levels were inversely associated with sepsis. For each 1 mg/dl increase in HDL, a relative 11% decrease in odds of sepsis was observed (OR 0.886, 95% CI 0.8-0.976, P = 0.01). CONCLUSIONS: Extremely low serum HDL levels (< or =20 mg/dl) are associated with an increased risk of death, sepsis and malignancy.

Reduced pseudocholinesterase activity in patients with HELLP syndrome.

The authors previously reported a case of decreased pseudocholinesterase activity in a patient with HELLP syndrome. It was assumed that the reduced pseudocholinesterase activity in HELLP syndrome is associated with impaired liver function. The present study assesses the prevalence of low pseudocholinesterase in patients with HELLP syndrome. Serum pseudocholinesterase activity was determined with spectrophotometer in 15 patients with HELLP syndrome. Two control groups matched for gestational age were recruited: 15 healthy women with uncomplicated pregnancy and 15 women with severe preeclampsia without HELLP. The prevalence of reduced pseudocholinesterase activity lower than normal limit was 60.0% (9/15) in patients with HELLP syndrome, 33.3% (5/15) in patients with severe preeclampsia, and 6.6% (1/15) in women with normal pregnancy, respectively (P =.009). The pseudocholinesterase activity was found to correlate with serum alanine aminotransferase levels (r = 0.417, P = .006) and with serum aspartate aminotransferase levels (r = 0.462, P = .002). Considering the increased prevalence of reduced pseudocholinesterase activity in patients with HELLP syndrome, the authors suggest that whenever general anesthesia is applied in these patients, the anesthesiologist should be aware that the patient may show slow metabolic degradation of choline-ester drugs.

Different degrees of fetal oxidative stress in elective and emergent cesarean section.

BACKGROUND: Several studies have addressed the influence of labor and mode of delivery on oxidative stress. Still it is unclear whether oxidative stress is related to delivery itself or whether it reflects a pre-existing fetal oxidative status. OBJECTIVE: To investigate whether the degree of fetal oxidative stress is different between distressed fetuses that were delivered by emergent cesarean section and non-distressed fetuses that were delivered by elective cesarean section. METHODS: The protocol of this prospective study was approved by the Institutional Review Board Committee. Amniotic fluid and umbilical artery blood were prospectively collected from 21 parturients who were delivered by an emergent cesarean section for non-reassuring fetal heart rate pattern and from 21 parturients who were delivered by an elective cesarean section in a tertiary care center. Oxidative stress was evaluated in amniotic fluid, umbilical cord plasma and erythrocytes by determining malondialdehyde concentration and glutathione peroxidase (GPX) activity. RESULTS: Malondialdehyde concentration was higher in amniotic fluid (mean +/- SEM) (2.2 +/- 0.7 nmol/l vs. 0.6 +/- 0.02 nmol/l, p < 0.05), in umbilical cord plasma (1.2 +/- 0.2 nmol/l vs. 0.7 +/- 0.3 nmol/l, p < 0.05) and in umbilical cord erythrocytes (159.6 +/- 48.6 nmol/g Hb vs. 85.8 +/- 5.2 nmol/g Hb, p < 0.05) in women delivering by emergent cesarean compared to those delivering by elective cesarean. GPX activity was enhanced in amniotic fluid (12.4 +/- 2.2 U/l vs. 5.1 +/- 0.6 U/l, p < 0.05) and GPX activity/hemoglobin ratio was higher in cord blood (22.0 +/- 0.8 U/g Hb vs. 18.7 +/- 0.9 U/g Hb, p < 0.05) in women delivering by emergent cesarean compared to those delivering by elective cesarean. CONCLUSION: Distressed fetuses delivered by emergency cesarean exhibited increased malondialdehyde concentrations, an indicative parameter for oxidative damage, and enhanced GPX activity an antioxidant enzyme, in amniotic fluid and umbilical cord blood compared to non-distressed fetuses delivered by elective cesarean section. This is probably an indication of higher fetal oxidative stress.