Meta-analysis of drop-out rates in randomised clinical trials, comparing typical and atypical antipsychotics in the treatment of schizophrenia.

OBJECTIVE: To assess antipsychotic medication in the treatment of schizophrenia, based on trial drop-out rates. METHOD: The studies included were randomised controlled trials that compared any of the four clinically best-established atypical antipsychotics (quetiapine, olanzapine, risperidone or clozapine) against either of two typical antipsychotics regarded as the gold standard (haloperidol or chlorpromazine). RESULTS: Meta-analysis indicated less risk of all-cause patient withdrawal from atypical medication trials where dosage was flexible, in both the short, relative risk (RR) 0.70 (95% CI 0.64-0.76), P<0.00001, and long term, RR 0.72 (0.65-0.80), P<0.00001. Similar results were observed for withdrawal due to adverse events, RR: 0.54 (0.41-0.72), P<0.0001. Nevertheless, the favourable effects of atypical medication disappeared in trials relying on fixed dosage. CONCLUSIONS: We detected a significant positive effect in terms of the outcome of treatment discontinuation for atypical versus typical medication, though only where the use of flexible rather than fixed doses (closer to an experimental control situation) was possible.     

Non-invasive proportional assist and pressure support ventilation in patients with cystic fibrosis and chronic respiratory failure

BACKGROUND: Patients with advanced cystic fibrosis can benefit from non-invasive positive pressure ventilation (NPPV) for the treatment of acute decompensation as well as for the management of chronic respiratory failure. This study was undertaken to compare the physiological effects of non-invasive proportional assist ventilation (PAV) and pressure support ventilation (PSV) on ventilatory pattern, transcutaneous blood gas tensions, and diaphragmatic effort in stable patients with cystic fibrosis and chronic CO2 retention. METHODS: In 12 patients two periods of spontaneous breathing were followed randomly by PSV (12 (3) cm H2O) and PAV (flow assist 4.9 (1.3) cm H2O/l.s, volume assist 18.9 (5.1) cm H2O/l) set for the patient's comfort and administered for 40 minutes with 2 cm H2O continuous positive airway pressure. Ventilatory pattern, transcutaneous blood gas tensions, and surface diaphragmatic electromyography were measured in the last 10 minutes of each application. RESULTS: On average, both PSV and PAV improved ventilation (+30%), tidal volume (+30%), and transcutaneous CO2 (-7%) while reducing diaphragmatic activity (-30% with PSV, -20% with PAV). Mean inspiratory airway pressure was lower during PAV than during PSV (9.7 (1.9) and 12.9 (2.7) cm H2O, respectively; p<0.05). The mean coefficient of variation of tidal volume was about 20% (range 11-39%) during spontaneous breathing and did not change with either PAV or PSV. CONCLUSIONS: These results show that short term administration of nasal PAV and PSV to patients with stable cystic fibrosis with chronic respiratory insufficiency is well tolerated, improves ventilation and blood gas tensions, and unloads the diaphragm.     

Das Verhalten der Perspiratio Insensibilis und der Quaddelzeit bei Normalen Kindern Nach Verabreichung von Vitamin B1, B2 (Lactoflavin) und C

Zusammenfassung Nach Einspritzung einer einzigen Dose von Vitamin B₁, B₂ und C wurden folgende Ergebnisse erzielt: 1. Nach Verabreichung von Vitamin B₁ eine beständige Vermehrung der Perspiratio insensibilis und eine geringe Verminderung der Quaddelzeit; 2. nach Verabreichung von Vitamin B₂ in den meisten Fällen Vermehrung der Perspiratio insensibilis und Veränderungen in positivem und negativem Sinne der Quaddelzeit; 3. nach Verabreichung von Vitamin C in den meisten Fällen Vermehrung der Perspiratio insensibilis und in allen Fällen Verlängerung der Quaddelzeit.     

Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families.

Hirschsprung disease (HSCR) is considered a model for a complex inheritance disorder. Several genes, including the major HSCR-susceptibility RET proto-oncogene, play an aetiological role in the development of HSCR. Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis. Therefore, additional genetic alterations of RET are postulated in the aetiology or modification of the HSCR phenotype. In this study, the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, were investigated by direct DNA sequencing in a HSCR population. We genotyped the c.135 G/A polymorphism and resolved haplotypes comprising the mutation locus and the c.135 G/A polymorphism. Twenty different mutations were detected in 18 of 76 HSCR patients. In ten families the mutations were inherited from the parents, while only four patients had a positive family history for the disease. Moreover, in all ten families an incomplete penetrance of the HSCR phenotype was observed. We have investigated the effect of the non-mutated wild-type allele as well as the c.135 G/A polymorphism on the phenotype within the HSCR families. Our findings support the notion that both RET alleles are involved in the pathogenesis of a subgroup of HSCR patients in a dose-dependent fashion. Additionally, we have shown a modifying effect of the c.135 G/A polymorphism on the HSCR phenotype within HSCR families.     

Small Cytoplasmic Antigens from Pseudomonas aeruginosa Stimulate γδ T Lymphocytes

γδ T lymphocytes respond to different bacterial antigens and transformed cells. The antigenic molecules responsible for this activity have been studied extensively in antigenic preparations from Mycobacterium . We describe here the in vitro effect of Pseudomonas aeruginosa on γδ T lymphocytes and the properties of the implicated compounds. We found a preferential γδ T-cell expansion when we used heat-treated P. aeruginosa preparations and a dose-dependent inhibition of proliferation of peripheral blood mononuclear cells (PBMC) when non-heat-treated antigens were studied. This expansion corresponded to a Vγ9-positive subpopulation. In contrast to αβ T lymphocytes, the highest stimulatory activity was restricted to very small cytosolic compounds. This activity was protease resistant and phosphatase sensitive and always dependent on interleukin (IL)-2 or αβ T-cell activation. We concluded that the antigenic molecules from P. aeruginosa that activated γδ T lymphocytes were small, non-peptidic, phosphorylated compounds, similar to those previously described from Mycobacterium .     

Stable preference for high ethanol concentrations after ethanol deprivation in Sardinian alcohol-preferring (sP) rats.

Results of a recent study have demonstrated that exposure to multiple ethanol concentrations and repeated ethanol deprivation periods in Indiana ethanol-preferring (P) rats resulted in the development of an alcohol deprivation effect (ADE; the temporary increase in voluntary ethanol intake after a period of deprivation from ethanol) characterized by consumption of intoxicating amounts of ethanol. The current study was designed to possibly extend these results to Sardinian alcohol-preferring (sP) rats, generated with the same selective program previously used for P rats. To this aim, ethanol-naive sP rats were exposed initially to the home cage four-bottle choice [10%, 20%, and 30% (vol./vol.) ethanol solutions and water] for eight consecutive weeks. Subsequently, rats were divided into two groups: The first group had continuous access to the four-bottle regimen (nondeprived rats), and the second group was exposed to five cycles of 14-day periods of deprivation from ethanol and 14-day periods of reexposure to the four-bottle regimen. An ADE developed after each deprivation period. However, the extra intake of ethanol was limited to the first hour of each reaccess period. Magnitude of ADE did not change with repeated periods of deprivation. However, a shift in preference toward the two highest concentrations of ethanol solutions was evident from the first reexposure to ethanol and was maintained throughout the study. These results provide further evidence on the heterogeneity of ethanol-drinking behavior among rat lines selectively bred for high ethanol preference and consumption.     

High affinity neurotrophin receptors in the human pre-term newborn, infant, and adult cerebellum

The immunohistochemical occurrence of the high affinity neurotrophin (NT) receptors trkA, trkB, and trkC is shown in the pre-term newborn, infant, and adult human post-mortem cerebellum. Immunoreactive neuronal perikarya and processes were observed in all specimens examined, where they appeared unevenly distributed in the cerebellar cortical layers and deep nuclei, and showed regional differences among cerebellar lobules and folia. The trk receptor-antibodies, tested by Western blot on human cerebellum homogenates, revealed multiple immunoreactive bands for trkA and single bands for trkB and trkC. The results obtained show the tissue localization of the trk receptor-like immunoreactivity in the human cerebellum from prenatal to adult age. The analysis for codistribution of the receptors with the relevant ligand and among the receptors in discrete cortical and deep nuclei tissue fields shows a wide variety of conditions, from a good similarity in terms of type and density of labeled structures, to a lack of correspondence, and suggests the possibility of colocalization of trk receptors with the relevant neurotrophin and among them in the cerebellar cortex. These results sustain the concept that the neurotrophin trophic system participates in the development, differentiation, and maintenance of the human cerebellar connectivity and support the possibility of a multifactorial trophic support for the neurotrophins through target-derived and local mechanisms.     

Immunohistochemical and in situ hybridization detection of growth-hormone-producing cells in human thymoma.

We have studied 25 thymomas by both immunohistochemistry and in situ hybridization for the presence of growth hormone (GH)-producing cells. Our results indicate that 1) GH-immunoreactive cells were present in 13 of 17 thymomas of cortical and predominantly cortical type but not in medullary (spindled) thymomas (n = 3) or low- to high-grade thymic carcinomas (n = 5), 2) GH-positive cells were mainly located at the periphery of the neoplastic lobules, at the periphery of the perivascular spaces and in the areas of medullary differentiation, 3) cells containing GH mRNA appeared at locations similar to those of GH-immunoreactive cells, and 4) GH-immunoreactive material was present only in the epithelial cell component as revealed by immunoelectron microscopy. In conclusion, this paper demonstrates the occurrence of GH-producing cells in noncarcinoid thymic tumors. The relevance of GH in thymoma cell biology requires additional investigations.     

Effect of aspirin and indomethacin on epidermal growth factor secretion in duodenal tissue fragments cultivated in vitro.

The aim of the present study was to determine the effect of aspirin and indomethacin on epidermal growth factor (EGF) secretion in duodenal tissue fragments cultivated in vitro. The fragments were obtained from healthy subjects by gastroscopy, cultured in McCoy's medium and gassed with 95% O2 and 5% CO2 at 37 degrees C. After an incubation of 30 min, the culture medium was decanted, and the quantity of hormone determined by radioimmunoassay. The mean EGF level detected in the medium was 10.94 ng/mg protein tissue. The addition of aspirin (final concentration 10(-7) M) to the medium reduced mean EGF levels to 7.5 ng/mg (p less than 0.05), whereas aspirin 10(-8) M did not produce such a modification. The addition of indomethacin (final concentration 10(-8) M) decreased mean EGF levels to 5.37 ng/mg (p less than 0.001). In all experimental conditions, the addition of anti-somatostatin (SRIF) antibodies determined a remarkable increase in EGF (p less than 0.01). The results of this study show aspirin and indomethacin to be direct, not SRIF-mediated inhibitors of EGF release.