Effects of chlomipramine and fluoxetine on subcutaneous carrageenin-induced inflammation in the rat

We have previously shown that, after acute administration, antidepressant drugs exert anti-inflammatory actions in rats. In this study we evaluated the effects of 3 different doses of chlomipramine (10, 20, and 40 mg/kg i.p), and fluoxetine (5.0, 10, and 20 mg/kg i.p.) on subcutaneous carrageenin-induced inflammation. Both drugs dose-dependently reduced the inflammatory exudate, as well as the PGE2-like bio- and immunoactivity in the exudate. Chlomipramine dose-dependently reduced substance P concentrations in the exudate, whereas fluoxetine was effective only at the highest dose. Our results confirm that antidepressant drugs are able to reduce the development of inflammation in the rat and suggest that the inhibition of substance P production might play a role in mediating the anti-inflammatory effects of chlomipramine.     

Seroepidemiology of hepatitis E virus in the Egyptian Nile Delta

The seroendemicity of hepatitis E virus (HEV) in an entire village population located in the Egyptain Nile Delta is described. Serum specimens were obtained from 68% of the total population of 1,850 villagers. The lack of serum specimen was greatest in the youngest age group (< 5). Commercially available enzyme immunoassays (EIA) for antibody to hepatitis A virus (anti-HAV), to hepatitis B virus core antigen (anti-HBc), to second-generation hepatitis C virus (anti-HCV) core and nonstructural antigen, and to hepatitis E virus (HEV) were used. Only repeated reactive sera were coded as positive. Stool specimens were examined for Schistosoma mansoni by the Kato method and standard methods for the examination of the liver and spleen by ultrasonography were used. Unadjusted for nonrespone, the seroprevalence of anti-HEV was 17.2% (SE +/- 1.1). Anti-HEV seroprevalence increased by age and was not associated statistically with any of the other viral markers including HCV. Anti-HAV seroprevalence was consistently > 95%, even in the youngest age group (< 5). The overall sero-endemicity of HEV was higher than reported elsewhere and appears not to have been introduced into the village population recently.     

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients

BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.     

Sensorineural hearing loss in patients reaching chronic renal failure in childhood

An analysis of 25 patients with carcinoids of the colon (1,94% of the amount of patients with cancer of the colon) was made. In the recent decade this disease has become 2 times more frequent. Sixteen patients had carcinoids of the rectum, 9 patients had carcinoids of the right half of the colon. Malignant carcinoids were diagnosed in 16 cases, 8 of them being located in the right half. Radical operations are recommended for all carcinoids of the right half of the colon and for tumors of the rectum if more than 2 cm.     

Detection and typing of hepatitis C RNA in liver biopsies and its relation to histopathology

The role of kainic acid (KA) (an agonist of non-NMDA receptors) in the control of GH secretion and the modulation of KA action by gonadal secretion were analysed in male rats. In the first experiment 4, 8, 12, 16, 20 and 30-day old males were sacrificed 15 min after injecting with vehicle or KA (2.5 mg/kg BW). In the second experiment, the effects of KA, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and MK-801 were analysed in monolayer cultures of dispersed adenohypophyseal cells. In the third experiment, adult males were sham-operated or orchiectomized and decapitated seven days later, 15 min after injecting with vehicle or KA (2.5 or 15 mg/kg BW). In the fourth experiment, males neonatally injected with estradiol benzoate or vehicle were sacrificed on days 45, 60 or 90, 15 min after administration of vehicle or KA (2.5 or 15 mg/kg BW). We found that: (i) KA is a powerful secretagogue for GH in neonatal and postpubertal males but its releasing effectiveness decreases in adulthood; (ii) GH secretion by cultured pituitary cells remains unaffected in the presence of KA (1,10 or 100 mumol/l); (iii) the KA-stimulated GH secretion is increased after orchiectomy and abolished in males neonatally estrogenized. These results indicate that in male rats activation of non-NMDA receptors, probably those located in hypothalamus, increases GH secretion. The releasing properties of KA increases in orchiectomized males and completely disappears in males neonatally estrogenized.     

Effect of a leukotriene antagonist, ONO-1078, on electric stimulation of vagus (ESV)-induced bronchoconstriction and microvascular leakage in guinea pigs

In atropine-pretreated guinea pigs, electric stimulation of vagus (ESV, 10 Hz, 5 ms, 2 V or 10 V, for 90 s) increased intrapulmonary pressure (IPP), and Evans blue extravasation in trachea, main bronchi, peripheral and distal intrapulmonary airways in a voltage-dependent manner. ONO-1078, a noval leukotriene antagonist, (0.03 and 0.1 mg.kg-1, iv) showed no remarkable inhibiting effect on ESV-induced increase of IPP. However, the agent significantly inhibited ESV-induced increase of Evans blue extravasation in the airways, especially in lower potency of stimulation (2 V). The results suggest that leukotrienes may be involved in airway microvascular leakage in response to neurogenic inflammation.     

An inactivated avian polyomavirus vaccine is safe and immunogenic in various Psittaciformes

The safety and immunogenicity of adjuvanted and nonadjuvanted inactivated avian polyomavirus vaccines, administered either intramuscularly or subcutaneously (s.c.), were evaluated in a group of mixed species Psittaciformes. In 233 vaccinates representing species of macaws, cockatoos, conures, and parrots, gross reactions were limited to small scab formation at the s.c. injection site in three African grey parrots. Both vaccines stimulated a virus neutralizing (VN) antibody response, particularly in birds that were seronegative prior to vaccination. Ninety-three percent of the birds that were seronegative at the beginning of the study seroconverted (greater than fourfold increase in VN antibody titer) by 2 weeks after the second vaccination. Seventy-six percent of all the vaccinates had at least a fourfold increase in VN antibody titer at this time. There was no significant difference in seroconversion between the birds vaccinated with adjuvanted or nonadjuvanted vaccines. This study indicates that an inactivated avian polyomavirus vaccine can be used to safely immunize various species of psittacine birds in a field setting.     

Efficient signal transduction by a chimeric yeast-mammalian G protein alpha subunit Gpa1-Gsalpha covalently fused to the yeast receptor Ste2

Saccharomyces cerevisiae uses G protein-coupled receptors for signal transduction. We show that a fusion protein between the alpha-factor receptor (Ste2) and the Galpha subunit (Gpa1) transduces the signal efficiently in yeast cells devoid of the endogeneous STE2 and GPA1 genes. To evaluate the function of different domains of Galpha, a chimera between the N-terminal region of yeast Gpa1 and the C-terminal region of rat Gsalpha has been constructed. This chimeric Gpa1-Gsalpha is capable of restoring viability to haploid gpa1Delta cells, but signal transduction is prevented. This is consistent with evidence showing that the C-terminus of the homologous Galpha is required for receptor-G protein recognition. Surprisingly, a fusion protein between Ste2 and Gpa1-Gsalpha is able to transduce the signal efficiently. It appears, therefore, that the C-terminus of Galpha is mainly responsible for bringing the G protein into the close proximity of the receptor's intracellular domains, thus ensuring efficient coupling, rather than having a particular role in transmitting the signal. To confirm this conclusion, we show that two proteins interacting with each other (such as Snf1 and Snf4, or Ras and Raf), each of them fused either to the receptor or to the chimeric Galpha, allow efficient signal transduction.     

The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague-Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.