A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis.

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.     

Dexamethasone suppression test as an aid for selection of specific antidepressant drugs in patients with endogenous depression

The dexamethasone suppression test (DST) and response to two different antidepressant drugs (maprotiline as a specific noradrenergic, and amitriptyline as a predominantly serotoninergic drug) were investigated in 44 endogenously depressed female inpatients. The more anxious and/or agitated patients were mostly treated with amtiriptyline, the non-anxious and retarded patients with maprotiline. It was found that among maprotiline responders (N = 15) there were significantly more abnormal DSTs and postdexamethasone serum cortisol levels were significantly higher than among amitriptyline responders (N = 16). On the other hand, DST abnormalities among amitriptyline non-responders (N = 10) were similar to those among maprotiline responders. The results confirm earlier reports by Brown et al. (1980), Ettigi et al. (1983) and Fraser (1983) and indicate that abnormal DST may identify the "noradrenergic" subtype of endogenous depression and that the DST represents a good way of selecting a specific antidepressant drug for the treatment of endogenously depressed patients.     

Experimental studies on guanosine 3',5'-cyclic monophosphate levels and airway responsiveness of the novel phosphodiesterase type 5 inhibitor SR 265579 in guinea-pigs.

The effect of 1-cyclopentyl-3-ethyl-6-(3-ethoxypyrid-4-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-one (SR 265579), a potent inhibitor of guanosine 3',5'-cyclic monophosphate (cyclic GMP) phosphodiesterase (PDE5), was examined regarding its specificity toward the other cyclic nucleotide phosphodiesterases, the effect on cyclic nucleotide levels and the bronchodilatory activity, both in vitro and in vivo in guinea-pigs. The effects were compared to those obtained with zaprinast (CAS 37762-06-4), a known PDE5 inhibitor. Anion-exchange chromatography of the soluble fraction of guinea-pig homogenates revealed 5 peaks which corresponded to PDE1, PDE2, PDE3, PDE4 and PDE5. SR 265579 produced a potent and competitive inhibition, with respect to cyclic GMP, of PDE5 with a Ki of 6.4 nmol/l. The compound was 25 fold more potent than zaprinast and demonstrated selectivity toward PDE5. The selectivity index was 14 and 33 with respect to PDE4 and 3, respectively. PDE1 and 2 were only inhibited at considerably higher concentrations. SR 265579 specifically increased the intracellular cyclic GMP levels in guinea-pig tracheal epithelial cells (EC50 = 117 nmol/l). Moreover, in the guinea pig, plasma cyclic GMP levels were significantly increased after the intravenous or oral administration of doses as low as 1 mg/kg. Isolated guinea-pig trachea were relaxed by the addition of SR 265579 as evaluated by measuring either spontaneous tone or relaxation of histamine and acetylcholine-precontracted preparations. PD2 values were of 7.64, 6.52 and 5.25, respectively. In vivo, after i.v. administration, bronchodilatory activity was demonstrated in an artificially-ventilated guinea-pig histamine-induced bronchospasm model with an ED50 of 0.63 mg/kg. In all experiments, SR-265579 was proved to be more active than zaprinast. These results demonstrate that SR 265579 is an orally active, potent and specific inhibitor of PDE5.     

Why laparoscopic cholecystectomy today?

Traditional open cholecystectomy became the gold standard of surgical treatment for symptomatic gallstone disease during the last century. In spite of its good results, clinicians have been trying to establish effective nonsurgical methods of eliminating gallstones. Although oral, percutaneous, or retrograde litholysis can be used effectively for cholesterol stones, these represent only 10% of all gallstones. Moreover, intracorporeal lithotripsy is an invasive method, and while extracorporeal shock wave lithotripsy is a promising procedure, even after careful selection, only 70%–80% of the patients become stone-free within 1 year. In fact, none of the methods which leave the gallbladder intact are free of complications, and they are followed by 50% stone recurrence within 5 years. Since 1987, laparoscopic cholecystectomy has become the procedure of choice as it is safe and only minimally invasive. We believe that the laparoscopic technique is a promising way to the surgery of the future.     

Ammonium chloride metabolic acidosis and the activity of renin-angiotensin-aldosterone system in children

The present study was undertaken to assess the effects of acute metabolic acidosis on the activity of the renin-angiotensin-aldosterone system in 12 children with a mean age of 8.9 years who underwent NH₄Cl loading test. Ammonium chloride was given in a dose of 0.15 g/kg per day for 3 consecutive days to evaluate renal acidification. Prior to and following NH₄Cl administration blood acid-base parameters, plasma and urine electrolytes, creatinine and aldosterone concentrations as well as plasma renin activity (PRA), urine flow rate and net H⁺ excretion were measured. Ammonium chloride administration significantly depressed blood pH (P<0.05), bicarbonate (P<0.01) and base excess (P<0.01) and resulted in a slight, but significant elevation of plasma potassium concentration (P<0.05). Furthermore, NH₄Cl ingestion induced a marked increase in urine flow rate (P<0.01) and urinary sodium, potassium and chloride excretion (P<0.01). In response to NH₄Cl metabolic acidosis, PRA doubled (4.72±1.18 vs 8.13±1.02 ng/ml per hour,P0.05) and there was a nearly fourfold increase in plasma aldosterone level (0.49±0.12 vs 1.52±0.24 ng/ml,P<0.01) and in urinary aldosterone excretion (19.2±4.3 vs 71.8±13.8 g/day,P<0.01). The elevated aldosterone production observed in this study is assumed to be mediated by the combined effect of sodium and water diuresis-related increased PRA, hyperkalaemia and the direct stimulation of adrenal steroidogenesis by metabolic acidosis.     

Zona pellucida thickness variation and occurrence of visible mononucleated blastomeres in preembryos are associated with a high pregnancy rate in IVF treatment

Purpose: The ability of six morphological criteria (embryo development rate, fragmentation, regularity of blastomere shape, equality of blastomere size, zona pellucida thickness variation [ZPTV], and visible mononucleated blastomeres [VMBs]) to predict pregnancy in IVF treatment cycles was evaluated. Methods: In order to select a homogeneous study group, 85 consecutive nulliparous couples with single tubal infertility undergoing their first IVF treatment and receiving three preembryos at embryo replacement 2 days after ovum pickup were included. Results: A total of 255 preembryos was replaced two days after ovum pickup and resulted in 34 clinical pregnancies (40%). By logistic regression analysis, ZPTV and VMBs showed highly significant and strong predictive values, whereas none of the other parameters was a significant predictor of pregnancy. In the treatments in which all replaced preembryos had a ZPTV of less than 15%, the pregnancy rate was extremely low (1/22). If the maximum ZPTV of any of the replaced preembryos was in the interval between 15 and 20%, the pregnancy rate was 24.1% (7/29). In the treatments in which at least one preembryo had a ZPTV of more than 20%, the pregnancy rate was 76.5% (26/34). When VMBs were added to the results of the ZPTV analysis, the pregnancy rate was as high as 92.3% (24/26). Conclusions: ZPTV and VMBs seem to be strong predictors of pregnancy in IVF treatment and thus important indicators of good embryo quality.     

Propylene oxide in blood and soluble nonprotein thiols in nasal mucosa and other tissues of male Fischer 344/N rats exposed to propylene oxide vapors--relevance of glutathione depletion for propylene oxide-induced rat nasal tumors.

High concentrations of propylene oxide (PO) induced inflammation in the respiratory nasal mucosa (RNM) of rodents. Concentrations > or =300 ppm caused nasal tumors. In order to investigate if glutathione depletion could be relevant for these effects, we determined in PO exposed male Fischer 344/N rats PO in blood and soluble nonprotein SH-groups (NPSH) in RNM and other tissues. Rats were exposed once (6 h) to PO concentrations between 0 and 750 ppm, and repeatedly for up to 20 days (6 h, 5 days/week) to concentrations between 0 and 500 ppm. At the end of the exposures, PO in blood and NPSH in tissues were determined. PO in blood was dependent on concentration and duration of exposure. After the 1-day exposures, NPSH depletion was most distinctive (RNM > liver > lung). Compared to controls, NPSH levels were 43% at 50 ppm PO in RNM and 16% at > or =300 ppm in both RNM and liver. Lung NPSH fell linearly to 20% at 750 ppm. After repeated exposures over 3 and 20 days to 5, 25, 50, 300, and 500 ppm, NPSH losses were less pronounced. At both time points, NPSH were 90%, 70%, 50%, 30%, and 30% of the control values in RNM. Liver NPSH decreased to 80% and 50% at 300 and 500 ppm, respectively. After 20 days, lung NPSH declined to 70% (300 ppm) and 50% (500 ppm). We conclude that continuous, severe perturbation of GSH in RNM following repeated high PO exposures may lead to inflammatory lesions and cell proliferation, critical steps on the path towards tumorigenicity.