Prenatal diagnosis of bilateral fetal renal polycystosis

Congenital abnormalities of the renal and urinary tract (CARUT) of the foetus constitute about 20-30% of all abnormalities. The frequency of infant mortality of genito-uretral malformations is about 10 to 100,000 lye-burts. The early and opportune antenatal diagnosis of these abnormalities by ultrasound examination of the foetus improves considerably the prognosis of children having such divergences in their renal and urinary tract. The authors represent a clinical case of antenatal diagnosis of a foetus with congenital bilateral renal polycystosis in the first half of the period of pregnancy and emphasize the importance of systematic ultrasonographic screening of the pregnant patients. A bibliographical survey of the CARUT is made together a review of the potentialities of ultrasonographic screening for diagnosing in time for due action in the presence of any abnormalities of the renal and urinary tract.     

LDL and HDL subclass distribution in patients with end-stage renal diseases

OBJECTIVES: To examine the alterations in LDL and HDL subclass distribution in ESRD patients compared with a control group and to investigate the relationship of LDL particle size to the other plasma lipoproteins levels. DESIGN AND METHODS: Plasma lipids, LDL and HDL subclasses were determined in 63 hemodialysis patients (HD), 42 predialysis patients and 345 control subjects. Lipoprotein subclasses were separated by polyacrylamide 3 to 31% gradient gel electrophoresis. RESULTS: In predialysis group, 88% subjects had small LDL particles compared with 58.5% of hemodialysis patients and 16.5% of control subjects. Mean LDL size particle diameter was significantly smaller in HD and predialysis patients in comparison with controls (p < 0,0005, p < 0,0001; respectively). Significant inverse correlation between LDL particle size and triglyceride level was observed for both patient groups. Decreased levels of the largest HDL2b subclass was found in both predialysis (16.5%) and in HD patients (30%) as compared with controls (50%), and increased levels of the small HDL3a subclass was found only in predialysis group (21%) in comparison with controls (4.5%). CONCLUSIONS: Alterations in LDL and HDL subclass distribution toward smaller particles is the main lipid abnormality associated with atherogensis found in ESRD. ESRD is associated with reduced levels of HDL2b subclass and increased levels of HDL3c subclass, which occurs in coronary artery disease (CAD) as well.     

Identification of a novel HLA-C*02 allele, HLA-C*02:02:09

We report HLA-C*02:02:09 as a novel allele with a transition C->T at position 354.     

Characterization of the potency of epidermal growth factor (EGFR)-DNA targeting combi-molecules containing a hydrolabile carbamate at the 3-position of the triazene chain

Previous strategies for stabilizing combi-triazenes were based on masking the 1,2,3-triazene chain with a 3-acetoxymethylene group. The half-lives of the latter molecules were only ca 5 min longer than those of their parent 1,2,3-triazenes. The novel combi-molecules described herein contain a hydrolysable carbamate group that modulates their kinetics of degradation. Their half-lives were prolonged by ca 20–55 min when compared with their acetoxymethyltriazene counterparts. While they decomposed slowly in serum-containing medium, their intracellular decomposition was extremely rapid. They blocked EGFR tyrosine kinase in an isolated enzyme assay and in MDA-MB-468 breast cancer cells. Similarly, they all induced a dose-dependent DNA damage and G2/M cell cycle arrest in MDA-MB-468 cells, except the most stable compound ZRL2 (a 3-vinyl carbamate). ZRL4 (a chloromethyl carbamate) was the most potent and ZRL2 was the least active of the series against MDA-MB-468 cells. In selectivity assay with NIH-3T3 and NIH-3T3/HER-14, all compounds selectively blocked proliferation of NIH-3T3/HER-14. ZRS1 exerted the strongest growth inhibitory potency of the series. The results in toto suggest that ZRL2, despite being the most stable compound, could not hydrolyze at a rate that permitted the generation of DNA damaging species, thereby behaving primarily as an EGFR inhibitor. Thus the study permitted the definition of an optimized combi-molecule as one that decomposes at a rate that is slower than that of acetoxymethyltriazenes, but rapid enough to generate strong EGFR-DNA targeting potential and growth inhibition. Based on the latter criteria, ZRS1 and ZRL4 were tested in vivo and ZRS1 has proven the more effective.     

Multiunit activity from the A9 and A10 areas in rats following chronic treatment with different neuroleptic drugs

Effects of repeated twice daily i.p. administration of haloperidol (0.5 mg/kg), clozapine (3.0 mg/kg) and prothipendyl (1.0 mg/kg) on spontaneous A9 and A10 cell activity were studied using extracellular multiunit recording in rats, which offers relatively rapid access to neural activity in a large number of cells. Two cell types were identified, which probably represent the putative dopaminergic and non-dopaminergic neurons. Repeated neuroleptic treatment reduced the number of spontaneously active type 1 A10 cells per track. The effect of haloperidol was more pronounced than that of clozapine or prothipendyl. A9 cells were affected by haloperidol only. The frequency and amplitude of A9 and A10 active cells remained quite stable, except for a clozapine-induced increase of their values for type 1 A10 cells. Stability of spontaneously active type 1 A10 cells was significantly reduced by the chronic neuroleptic treatment. Collectively the activity of type 2 cells was not altered. Prothipendyl was classified as an atypical neuroleptic drug with potency comparable to clozapine.     

Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A

The amount of residual F8 (FVIII:C) determines the clinical severity of hemophilia A. Recently, we showed that the mutation detection rate in severely affected male patients (FVIII:C<1% of normal) is virtually 100% when testing for the common intron 22-/intron 1- inversions and big deletions, followed by genomic sequencing of the F8 gene. Here we report on the spectrum of mutations and their distribution throughout the F8 gene sequence in 135 patients with moderate (n=23) or mild (n=112) hemophilia A. In contrast to the severe form of the disorder, analysis on the genomic level failed to detect the molecular defect in approximately 4% of the moderately and in approximately 12% of the mildly affected patients. A total of 36 of the mutations identified in this study are novel. The vast majority of the detected changes were missense. The newly detected amino acid substitutions were scored for potential distant or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling. Two molecular changes in the promoter region of the factor VIII gene (c.-112G>A and -219C>T), affecting the core segment (minimal promoter) were detected in two patients with mild hemophilia A. To our knowledge this is the first report on promoter mutations in the F8 gene.     

Effect of tibolone on sexual function in late postmenopausal women

BACKGROUND: Sexual dysfunction may significantly affect quality of life and marital relations in the postmenopausal period. The aim of the study was to assess the effect of tibolone on climacteric symptoms and sexuality in late postmenopausal but still symptomatic women. PATIENTS AND METHODS: A six-month prospective study was conducted of two groups of clinically healthy postmenopausal women: a control group (n = 18; mean age 57.8 +/- 4.1 yrs; menopause at 49.7 +/- 2.5; years of amenorrhea 8.1 +/- 4.0 yrs) and a tibolone group (n = 22; mean age 57 +/- 4.5 yrs; menopause at 47.7 +/- 3.9; years of amenorrhea 9.2 +/- 4.6 yrs), who received 2.5 mg tibolone daily for six months. The Kupperman menopausal index (KI) was calculated for both groups at baseline and at six months. Sexual function was assessed by the Female Sexual Function Index (FSFI) questionnaire at the beginning and at the end of the study. The FSFI comprised five main domains: desire, arousal, lubrication, orgasm and pain. Satisfaction and a total score were also recorded. RESULTS: The results showed that during the observation period KI decreased significantly in the tibolone group (15.7 +/- 9.2 vs 11.3 +/- 6.8, p < 0.001), while in the control group no difference was observed. There was a significant improvement of sexual function in the tibolone group in all domains: desire -- from 2.6 +/- 1.0 to 3.1 +/- 1.0 (p < 0.001); arousal -- from 2.3 +/- 1.8 to 3.4 +/- 1.1 (p < 0.001); lubrication - 2.6 +/- 2.1 and 3.5 +/- 1.4 (p < 0.05). The ability to reach orgasm increased (p < 0.001) and pain and discomfort during and after sexual intercourse significantly decreased (p < 0.01). The overall satisfaction and the total score in the treated group changed favourably in a statistically significant manner, while these parameters did not change in the control group. CONCLUSIONS: Treatment with tibolone had a beneficial effect on the climacteric symptoms and sexual function of late postmenopausal women. Moreover, tibolone seems to have an advantage over conventional hormone replacement therapy (HRT) in improving desire and arousal.     

Treatment of resistant ventricular tachycardia with endocavitary fulguration and antiarrhythmic therapy, compared to antiarrhythmic therapy alone: experience in 111 consecutive cases with a mean follow-up of 18 months

Endocavitary fulguration was performed in 31 cases of high-risk ventricular tachycardia (VT) for which antiarrhythmics, including Amiodarone and Class-I antiarrhythmic agents, given alone or in combination, proved ineffective. Permanent VT was incessant in nine patients at the time of fulguration: five of these were moribund, and two were unconscious. Included in the series were ten cases of arrhythmogenic right ventricular dysplasia, 13 cases of chronic VT after myocardial infarction, five cases of idiopathic dilated cardiomyopathy, two cases of idiopathic VT, and one case that involved a congenital anomaly. Combined fulguration and antiarrhythmic therapy succeeded in preventing VT in the 27 patients who survived the initial period of treatment. Thirteen patients needed two or more sessions, however, before their VT was brought under control. Three of the four early deaths were probably related to an imperfect technique. Four late deaths were due to spontaneous evolution of the disease. One patient without cardiac failure died suddenly. The follow-up period ranged from a minimum of 13 to a maximum of 34 months, with an average follow-up of nearly 2 years. The success rate for fulguration alone or for antiarrhythmic drugs is about 90%. This group of patients is compared with a group that involved 73 less severe cases treated with drugs. Fulguration appears to be the better form of treatment.     

FoxP3 demethylation is increased in human colorectal cancer and rat cholangiocarcinoma tissue

Objectives

FoxP3 expression is a marker for Tregs which are known to be involved in tumor immunity. We aimed to evaluate FoxP3 promoter demethylation in human colorectal cancer (CRC) and rat intrahepatic cholangiocarcinoma (ICC).

Design and methods

Bisulfite-treated genomic DNA templates of shock frozen paired samples were studied from 13 anonymous CRC patients and from 10 male rats (n = 6 ICC induced by thioacetamide and n = 4 age-matched controls). Real-time PCR was carried out using a LightCycler 480 system. Human FoxP3 and CD3 promoter demethylations were estimated using previously described assays; and rat FoxP3 promoter demethylation using a newly developed assay.

Results

A significant 3.5-fold increase of the demethylation in FoxP3 promoter region was found in human CRC and rat ICC (P < 0.05). The average frequency of cells with FoxP3 demethylation in patients suffering from CRC was 0.26% in normal tissue and 0.92% in tumor tissue (n = 11 paired samples). Although, no significant difference was found between the mean frequency of CD3 demethylation in normal tissue (4.80%, n = 6) and in tumor tissue (4.14%, n = 6) from CRC patients, the ratio of demethylated CD3/FoxP3 promoter areas was significantly lower in tumor specimens (P < 0.05). Using our novel assay, we found a significant increase in mean frequencies of cells with FoxP3 demethylation in rats with ICC (7.42%, n = 6) in comparison to controls (2.14%, n = 4).

Conclusion

FoxP3 seems to be an interesting biomarker for immune response to epithelial tumors. Functional consequences from the increase of Tregs remain to be demonstrated. Further studies with outcome data are necessary.