Accumulation of poly(ADP-ribose) polymerase inhibitors in children with chronic renal failure

Nicotinamide, N-methyl-2-pyridone-5-carboxamide (Met2PY) and N-methyl-4-pyridone-3-carboxamide (Met4PY) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide (NAD) that can potentially inhibit poly(ADP-ribose) polymerase 1 (PARP-1; DNA repair enzyme). Our research was aimed at establishing whether chronic renal failure (CRF) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit PARP-1 activity. Nicotinamide, Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children. The effect of these NAD metabolites on PARP-1 activity was studied in vitro. We found that plasma concentration of all NAD metabolites (nicotinamide, Met2PY, Met4PY) in children with CRF could reach the concentration of 2, 30 and 10 μM as compared to 0.2, 1 and 0.5 μM, respectively, in healthy children. The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF. We found that Met2PY, Met4PY and nicotinamide inhibited in vitro PARP-1 activity with IC₅₀ values of 2.1, 0.18 and 0.12 mM, respectively. Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of PARP-1 activity. NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults.     

Low-dose angiotensin II receptor antagonists and angiotensin II-converting enzyme inhibitors alone or in combination for treatment of primary glomerulonephritis

OBJECTIVE: The renin-angiotensin system is thought to be involved in the progression of chronic renal diseases of both diabetic and non-diabetic origin. It has been confirmed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) reduce urinary protein excretion and attenuate the development of renal injury. Clinical data comparing the renal effects of ACEIs and ARBs, either singly or in combination, are scarce and usually concern the use of standard or high doses. MATERIAL AND METHODS: This was a prospective, randomized, 9-month study of the effects of low doses of losartan (25 mg; n = 18) versus enalapril (10 mg; n = 18) versus the combination of losartan (25 mg) and enalapril (10 mg) (n = 16) on proteinuria, kidney function and metabolic profile in 54 patients with biopsy-proven chronic glomerulonephritis, hypertension and normal or slightly impaired kidney function. The clinical evaluation and laboratory tests were performed before treatment (baseline) and after 3 and 9 months of therapy. RESULTS: After 3 months, significant decreases in proteinuria were observed in all groups: losartan, 22.6% (p = 0.02); enalapril, 43% (p = 0.012); and combined therapy, 63% (p = 0.001). This anti-proteinuric effect was even greater after 9 months of therapy: losartan, 44.2% (p = 0.02); enalapril, 49.6% (p = 0.02); and combined therapy, 51% (p = 0.003). There was no significant difference between losartan and enalapril with respect to their impact on proteinuria level. Proteinuria reduction was significantly greater in patients receiving combined therapy in comparison with losartan treatment after 3 months of therapy (p = 0.02). Creatinine clearance and serum creatinine were stable during the entire study period in all patients. No significant changes in lipids, serum uric acid or protein levels were observed. CONCLUSIONS: These results indicate that proteinuria is reduced by low doses of losartan or enalapril. The combination of these drugs seems to be beneficial and may offer an additional renoprotective effect. This needs to be confirmed in a study with a larger sample size.     

Familial vs sporadic ovarian tumors: characteristic genomic alterations analyzed by CGH

OBJECTIVE: Our purpose was to get an overview of the genetic events leading to the development of familial and sporadic ovarian tumors and to identify chromosomal regions that may contain genes important in tumor progression. METHODS: The comparative genomic hybridization (CGH) technique was employed in a total of 46 epithelial ovarian or peritoneal tumors: 27 sporadic tumors, 11 tumors disected from BRCA1 mutation (185delAG) carriers, and eight from BRCA2 mutation (6174delT) carriers (familial tumors). RESULTS: The average number of genetic alterations (deletions and amplifications) was significantly (alpha=0.0069) higher in familial tumors (9.17 +/- 4.25 alterations per tumor in the BRCA1 mutation carriers and 7.25 +/- 6.06 in the BRCA2 mutation carriers) compared to the sporadic group (4.26 +/- 3.61 alterations per tumor). The pattern of the chromosome amplifications resembled in the three groups and the most common amplifications detected were at chromosomes 8q, 3q, and 2q. The pattern of the chromosomal deletions varied between the groups. Among the BRCA1 group, the most common deletions were in chromosomes 9 and 19. The BRCA2 group showed a lower frequency of deletions. Deletion of chromosome 16 and 22 were the most frequent ones. No specific chromosomal deletion was significantly indicated in the sporadic group. CONCLUSIONS: Familial ovarian tumors exhibit a significantly higher number of chromosomal aberrations and genomic imbalances and nonrandom genetic changes were characterized in the BRCA1 and BRCA2 groups.     

Tortuosity of terminal arterioles in the basal ganglia is increased in status lacunaris

The goal of this study was to evaluate the participation of small (diameter between 26 microns and 90 microns) and terminal (diameter between 10 microns and 25 microns) arterioles in the status lacunaris of the basal ganglia and to classify tortuous vascular profiles based on morphometry. Paraffin sections, 40 microns thick, of the basal ganglia from autopsied patients over the age of 45, were stained with PAS. A three-dimensional microscope, R400 (edge) was used to evaluate the structure of the blood vessels. Six patterns of the tortuous profiles were identified: simple kink, loop, knot, tangle, coil, and wave, and well as their combinations. Tortuous arterioles in the basal ganglia were present both in control group and status lacunaris cases. However, statistical Student's t-test analysis revealed a significant increment in the number of microfields containing tortuous terminal arterioles in the status lacunaris group (mean 7.50 +/- 4.62) versus the control group (mean 2.92 +/- 1.38) (p = 0.001). A risk for status lacunaris was associated with the increased frequency of tortuous terminal arterioles (Odd ratio = 1.94, 95%-Confidence Interval = 1.17-3.22) (p = 0.008) but not small arterioles (Odd ratio = 1.64, 95%-Confidence Interval = 0.62-4.38) (p = 0.39). Our findings suggest than an increased number of tortuous terminal arterioles is associated with status lacunaris. Six characteristic patterns of the tortuous profiles as well as their combinations were identified.     

Extrarenal Angiomyolipoma with Melanocytic and Hibernoma-like Features

Angiomyolipoma is a tumor commonly occurring in the kidney, but occasionally found in extrarenal sites. Retroperitoneal angiomyolipoma with unusual features presenting in a 39 year old woman with hypertension is reported in this paper. Tumor fat was inconspicuous, and present largely as hibernoma-like microvesicular lipid. Tumor cells also demonstrated positivity for HMB-45 and S-100 protein, and by electron microscopy showed occasional cytoplasmic striated granules indistinguishable from stage II premelanosomes. However, electron microscopy and immunocytochemistry also confirmed the presence of a substantial myogenous component in the tumor, establishing the diagnosis of angiomyolipoma. The implications of these findings, and the role of immunocytochemistry and electron microscopy in the diagnosis of this tumor are discussed.     

Isolated splenic infarction following left cardiac catheterization: Case report and a review of the literature

A cardiac catheterization was performed in a 57-year-old man for post-infarction angina. A severe left flank pain developed following the angiography. Ultrasonography, computed tomography, and radionuclear scanning of the abdomen showed splenic infarction. An isolated cholesterol atheroembolism of spleen from disrupted atheromatous plaques so far has not been reported. © 1996 Wiley-Liss, Inc.     

Humoral and cellular immune responses in asthmatic isocyanate workers: Report of two cases

Two workers (23 and 28 years old) developed rhinitis and bronchial asthma after occupational contact with the isocyanate MDI. Positive skin prick test results for MDI-HSA and IgE antibodies to all isocyanate-HSA conjugates were obtained in both cases, and the inhalation challenge test with MDI produced immediate and late asthmatic reactions. In the patch test and the stimulation assay of peripheral mononuclear blood cells, a specific sensitization to the diamine MDA (in both cases) and to further amines (in one case), as well as to hydrolysates of the respective diisocyanates, was seen, which appears to be independent of the IgE response to isocyanate-HSA conjugates. Our results offer evidence of IgE-mediated, as well as lymphocyte, responses induced by exposures to isocyanate products over several months or years. © 1996 Wiley-Liss, Inc.     

Methylenetetrahydrofolate reductase gene polymorphisms in essential hypertension relation: with the development of hypertensive end-stage renal disease

BACKGROUND: The pathogenesis of hypertensive nephropathy is multifactoral and in addition to BP, other factors contribute to the development of this renal pathology and its progression to end-stage renal disease. These include genetic predisposition and increased pleasure level of homocysteine-intermediate protein catabolism product known to induce kidney injury. The 677C --> T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated homocysteine level in the general population, and therefore it has been hypothesized to be a risk factor for the development of renal failure in the course of essential hypertension. METHODS: In this case-control, cross-sectional study the frequency of the MTHFR 677C --> T and the 1298A --> C polymorphism was compared between patients with hypertension-related chronic renal failure (n = 90), patients with essential hypertension without kidney injury (n = 90), and healthy individuals (n = 90) who were matched for age and gender. In addition, the influence of these polymorphisms on homocysteine concentration in individuals with essential hypertension was examined. RESULTS: The frequency of the MTHFR 677 TT genotype did not differ between groups (4.5%, 12.3%, and 11.1%, respectively). Patients with hypertension and the 677TT genotype showed significantly higher homocysteine levels as compared to individuals having CC and CT. In the multivariate correlation analysis the MTHFR 677TT genotype (P < .01; beta = 0.27), age (P < .001; beta = 0.33), and body mass index (P < .01; beta = 0.3) were independent predictors for total homocysteine level. CONCLUSIONS: Plasma homocysteine levels in individuals with essential hypertension is affected by the MTHFR 677C --> T polymorphism. However, we did not prove the hypothesis that MTHFR 677C --> T influences the risk of development of renal failure in the course of hypertension.