6R-Tetrahydrobiopterin induces dopamine synthesis in a human neuroblastoma cell line,LA-N-1. A cellular model of DOPA-responsive dystonia

Dopa-responsive dystonia (DRD) is an extrapyramidal disorder caused by deficit of 5,6,7,8-tetrahydrobiopterin (BH4), cofactor for tyrosine hydroxylase (TH). In these patients the nigrostriatal dopaminergic neurons normally express TH and the cellular machinery for the dopamine uptake. LA-N-1 is a human neuroblastoma cell line expressing tyrosine hydroxylase. Here we show that LA-N-1 cells are able to take up exogenous dopamine (DA) by an high-affinity mechanism; significant amounts of serotonin and its metabolite 5HIAA, but neither DA nor its metabolites, DOPAC and HVA, could be measured in the cell culture homogenate. 5,6,7,8-Tetrahydrobiopterin, cofactor for both tyrosine and tryptophan hydroxylases, is able to activate dopamine synthesis and also decreases the content of 5HIAA by 50%, indicating that LA-N-1 might be a useful model for studying dopamine-serotonin interaction in cultured cells and the neuronal mechanism of DRD.     

δ13CO2 Excretion and Expression of Dyspeptic Symptoms in Patients Evaluated for Helicobacter pylori Infection by [13C] Urea Breath Test

Previous studies showed that either the urease activity possessed by H. pylori and the bacterial load may influence the results of the [¹³C] urea breath test. However, the correlation between urease activity and dyspepsia is unclear. The aim of our study was to evaluate whether the urease activity of the gastroduodenal tract may influence the severity of dyspeptic symptoms. In all, 2520 dyspeptic patients (1109 men, 1411 women; mean age 47 ± 16 years) without gastroesophageal reflux disease, diabetes, vascular disorders, liver and biliary tract diseases, and tumors of the gastrointestinal tract and with a normal appearing abdominal ultrasonography were enrolled. All these patients underwent a [¹³C] urea breath test and filled out a questionnaire on dyspeptic symptoms. Subjects were divided in five different groups according to delta over baseline (DOB) values (group 1 < 3.5, group 2 = 3.5–6; group 3 = 6.1–11, group 4 = 11.1–23, group 5 > 23.1). The prevalence and intensity of dyspeptic symptoms were compared among groups. In all, 1688 patients (67%, 928 females and 760 males; mean age 48 ± 15 years) were H. pylori-positive. The chi-squared test and analysis of variance showed increase of frequency and intensity of each dyspeptic symptom according to DOB values. In conclusion, Dyspepsia may parallel gastric urease activity. However, whether higher DOB values are related to higher bacterial load or, alternatively, to the presence of particular H. pylori strains able to produce larger amounts of urease is uncertain.     

Laparoscopic reoperation following unsuccessful antireflux surgery in childhood

We determine the feasibility of laparoscopic revision surgery in children following previous open and laparoscopic antireflux operations. To give an objective overview about this topic, we analyzed the outcome of 15 children (8 girls and 7 boys) who had undergone attempted laparoscopic revision between 4 and 72 months (median 16 months) after a previous antireflux operation. Seven patients had previously undergone an open antireflux procedure (4 Nissen fundoplication; 3 Thal procedure) and 8 a laparoscopic procedure (5 Nissen; 3 Toupet's procedure). Two of these children were mentally handicapped. The indications for revision were: recurrent reflux, 5; valve migration, 5; valve dismount, 5. Eight procedures comprised construction of a new Nissen fundoplication and in 7 cases a Toupet's procedure was performed. Revision was successfully completed laparoscopically in 10 cases, 7 of 8 patients following a previous laparoscopic procedure and in 3 of 7 following a previous open operation. Operating time ranged between 70 and 140 minutes (median 90 minutes). No perioperative complications occurred in either group. All patients were discharged within 3 to 4 days after the redo procedure. Follow-up time varied between 6 months and 7 yrs. Preoperative symptoms were relieved in all patients and all antireflux medication has been discontinued, except in two cases that still had rare symptoms. Although technically challenging, laparoscopic reoperation for recurrent gastroesophageal reflux disease can be performed safely and with good results, in the hands of experienced endoscopic surgeons. Reoperation is likely to be more difficult following failure of an open procedure than after failure of a laparoscopic one. Concerning the type of procedure, redo surgery is more difficult to perform after Nissen's than after Toupet's or Thal's procedure.     

Polymorphism of vitamin D receptor gene start codon in patients with calcium kidney stones

BACKGROUND: A linkage has been detected between vitamin D receptor (VDR) locus and calcium kidney stone disease. In order to assess the eventual role of VDR gene start codon polymorphisms in stone production, we analyzed the genotype-phenotype association in a group of patients with calcium kidney stones. METHODS: One hundred and fifty-five patients were studied. VDR genotypes were characterized at the translation start site by restriction fragment length polymorphism analysis, using endonuclease FokI. Phenotypes of calcium-phosphate metabolism were compared in patients with different genotypes: strontium enteral absorption (used as a surrogate marker for calcium absorption), bone mineral density (BMD), calcium and phosphate excretion were measured. RESULTS: Genotype distribution was not different in hypercalciuric and normocalciuric stone formers. Enteral strontium absorption, calcium excretion and BMD did not vary with the patient's genotype. Serum concentrations of phosphate (p=0.022) and renal threshold for phosphate excretion (p=0.026) were lower in patients with genotype FF (homozygous for the absence of the FokI site) than in those with genotype ff (homozygous for the presence of the FokI site). The lower phosphatemia was confirmed in FF hypercalciuric patients, but not in normocalciuric ones. Serum concentrations of phosphate and calcitriol in the group of hypercalciuric patients were inversely correlated with the genotype FF. CONCLUSIONS: The FokI genotype does not appear to be involved in the causes of idiopathic hypercalciuria and kidney stones. Hypercalciuric patients with FF genotype may be a subgroup with low plasma concentrations of phosphate, predisposed to tubular leakage of phosphate.     

Elevated impulsivity and impaired decision-making in abstinent Ecstasy (MDMA) users compared to polydrug and drug-na?ve controls.

Ecstasy (MDMA; 3,4-methylenedioxymethamphetamine) has a well-recognized neurotoxic effect on central serotonergic (5-HT) systems in animals, and there is some evidence of persistent serotonergic dysregulation in human ecstasy users. Serotonin is believed to mediate impulsive behavior and effective decision-making. Thus, the aim of the present study was to investigate impulsive behavior and decision-making in abstinent regular ecstasy users. Three groups were compared: 'ecstasy users' (recreational ecstasy users who reported modest use of illicit drugs other than cannabis), 'polydrug controls' (ecstasy na?ve illicit drug users), and 'drug-na?ve controls'. All participants completed personal details and general drug history questionnaires, the National Adult Reading Test, Matching Familiar Figures Test (MFF20), a risky decision-making task (RDMT), and the Card Arranging Reward Responsivity Objective Test (CARROT). The groups did not differ on the CARROT measure of responsiveness to financial incentive; however, the ecstasy group displayed significantly elevated MFF20 impulsivity, and showed reduced discrimination between magnitudes of prospective gains and losses when making risky decisions, compared to the 'polydrug' and 'drug-na?ve' control groups. These findings may reflect a vulnerability of 5-HT systems in the orbital prefrontal cortex and interconnected corticolimbic circuitry to the cumulative neurotoxic effects of ecstasy and have clinical significance for regular ecstasy users. The combination of elevated impulsivity and impaired use of reinforcement cues in uncertain decision-making may comprise risk factors for continued drug abuse and everyday functioning.     

NEPHROBLASTOMA. DNA CHARACTERISTICS AND THEIR MODIFICATIONS INDUCED BY PRENEPHRECTOMY CHEMOTHERAPY: A CYTOFLUORIMETRIC STUDY

Treatment of nephroblastoma (Wilms' tumor) has presently achieved a 90% survival rate. Stage and grade are considered the most reliable prognostic parameters, but other biological factors are under study in order to improve patient stratification. Deoxyribonucleic acid (DNA) ploidy has been suggested to be useful in this setting. We retrospectively studied 79 patients with nephroblastoma (58 pretreated with chemotherapy and 21 not pretreated) by means of flow cytometry. DNA content and synthetic phase values were correlated with pathologic features and outcome. DNA modifications induced by chemotherapy were investigated. Sixty-nine tumors were diploid and 10 aneuploid. DNA content did not correlate with clinical course and was not modified by pretreatment. Aneuploid tumors were restricted to lower stages. Mean S-phase rate was lower and did not vary according to histology in pretreated tumors, while it was higher and increased with grade (p = 0.007) in previously untreated tumors. The fraction of cells in synthetic activity was related to outcome: Patients whose tumors displayed higher S-phase rates had a more favorable clinical course. Ploidy did not appear to be of prognostic significance. S-phase rate decreased after chemotherapy (p = 0.0002) and was related to survival. The worse outcome of pretreated patients might be attributed to a minor sensitivity to postoperative treatment: Preoperative chemotherapy would decrease the cell proliferation and might select resistant cellular clones of (possible) neoplastic residues.     

Effect of montelukast on exhaled NO in asthmatic children exposed to relevant allergens

The level of exhaled nitric oxide (FENO) is increased in house dust mite (HDM)-sensitized asthmatic children after exposure to HDM antigen, and inhaled steroids can prevent this increase. The aim of this study was to evaluate whether montelukast could prevent an increase in FENO levels in allergic asthmatic children after a brief period of exposure to relevant allergens. Sixteen children were evaluated at the residential house 'Istituto Pio XII' (Misurina, Bellunio, Italy) in the Italian Alps, a dust mite-free environment. FENO levels were evaluated before ( t ₀) and immediately after ( t ₁) the children were exposed to HDM allergens for 2 weeks in their homes at sea level. No significant difference in FENO was observed in the fluticasone-treated group of children after 2 weeks at sea level. In the group treated with montelukast, an increase in FENO was observed between t ₀ and t ₁, which failed to reach statistical significance. These preliminary data suggest that oral montelukast could be effective in preventing the relapse in airway inflammation in allergic asthmatic children who are occasionally exposed to relevant allergens for a short period of time.