In vivo activity and metabolic fate of 2-(2,3,3-triiodoallyl)tetrazole (ME1401), a novel antifungal agent

2-(2,3,3-Triiodoallyl)tetrazole (ME1401), a novel antifungal agent, showed therapeutic effectiveness in topical treatment of experimental dermal infections with Trichophyton mentagrophytes and Candida albicans in guinea-pigs. Addition of diethyl sebacate to the ME1401 preparations increased its in vivo antifungal activity and its penetration into the skin. When the estimation of efficacy of treatment with active formulations was made on the basis of skin lesion and the rate of negative skin cultures in comparison with those for infected, untreated or placebo-treated controls, the in vivo activity of 0.5% ethanol tincture or gel of ME1401 was comparable to that of reference antimycotic drugs such as clotrimazole, haloprogin and others. Pharmacokinetic studies in the experimental animals demonstrated that ME1401 was unstable in vivo, being readily converted to an active metabolite 2-(3-iodopropargyl)tetrazole (CN144) first and then to 2-propargyltetrazole (CN151). CN144 showed potent in vitro and in vivo antifungal activities, while the in vitro activity of CN151 was negligible.     

Change in apoptosis in the gastric surface epithelium and glands after eradication of Helicobacter pylori

BACKGROUND: Change in apoptosis in gastric glands after eradication of Helicobacter pylori has never been reported. AIMS: The purpose of this paper is to investigate the change in apoptosis in gastric glands after eradication of Heliobacter pylori. PATIENTS AND METHODS: We studied 23 Heliobacter pylori-positive patients with duodenal and gastric ulcers, who were monitored for 6-12 months after eradication, and eight controls. Biopsies were taken from the antrum and body. Apoptosis was evaluated immunohistochemically using anti-single stranded DNA antibody. Apoptotic index was calculated by counting immunostained cells in surface epithelial and glandular cells. RESULTS: In the surface epithelium, Apoptotic indexes were significantly higher in patients than in controls. In the upper portion of fundic glands, apoptotic indexes were significantly higher in patients with gastric ulcers (14.2% (9.3, 17.8)) (median (1st quartile, 3rd quartile)) than in controls (8.0% (2.0, 9.0), p < 0.01) and decreased significantly after eradication (3.4% (2.0, 5.3)), p < 0.01). In pyloric glands, apoptotic indexes were no different between patients and controls. In the lower portion of fundic glands, apoptotic indexes were very low, both in patients and in controls. CONCLUSIONS: Our results showed that apoptosis, not only of surface epithelial cells but also of glandular cells in the upper portion of fundic glands, increased in Heliobacter pylori-positive patients with gastric ulcers and decreased to normal levels after eradication of Heliobacter pylori.     

Ipsilateral atrophy in children with hemispheric cerebral tumors: CT findings

The CT findings of 19 children under 16 years of age with primary brain tumors in the cerebral hemisphere were investigated with special reference to the existence of cerebral hemiatrophy ipsilateral to the side of the tumor. "Ipsilateral cerebral hemiatrophy" was observed in four of 19 cases (21%). These included two cases with germinoma in the basal ganglia and two with low-grade astrocytoma in the frontal and occipital cortex. This peculiar CT finding was not specific to the location or histology of the tumor. The four cases were characterized by slow progression, which contrasted with the rapid progression of tumors shown in seven cases with a mass effect on CT.     

Expression of S-100 protein in intercalated duct cells of bovine pancreas

Although Mutoh et al. have found intercalated ducts in the pancreatic islets of avians, including the chicken, moorhen (Gallinula chloorpus), and Japanese quail (Coturnix coturnix japonica), and even demonstrated the functions of intercalated duct cells in pancreatic islets, to our knowledge, there have been only a few reports on the relationship between intercalated ducts and islets in mammalia. Accordingly, in this study, we investigated whether intercalated ducts are morphologically related to the islets of cattle, by using S-100 protein as a ductal cell marker for immunocytochemistry and examining the ultrastructure of intercalated ducts and islets electron-microscopically. The results revealed intercalated ducts that reacted positively for S-100 protein within and near islets, with approximately 12% of the islets having intercalated ducts in the vicinity and approximately 1.5% containing intercalated ducts within them. Ultrastructurally, intercalated ducts were also seem to be closely related to the islets. In conclusion, the results of the present study indicate that a close relationship exists between intercalated ducts and islets.     

The ventilatory threshold gives maximal lactate steady state

Summary The purpose of this study was to examine whether the ventilatory threshold (Th _v) would give the maximal lactate steady state ([1a]_{ss, max}), which was defined as the highest work rate (W) attained by a subject without a progressive increase in blood lactate concentration [1a]_b at constant intensity exercise. Firstly, 8 healthy men repeated ramp-work tests (20 W·min^–1) on an electrically braked cycle ergometer on different days. During the tests, alveolar gas exchange was measured breath-by-breath, and theW atTh _v (W _{Th v}) was determined. The results of two-way ANOVA showed that the coefficient of variation of a singleW _{Th v} determination was 2.6%. Secondly, 13 men performed 30-min exercise atW _{Th v} (Th _v trial) and at 4.9% aboveW _{Th v} (Th _v + trial), which corresponded to the 95% confidence interval of the single determination. The [1a]_b was measured at 15 and 30 min from the onset of exercise. The [1a]_b at 15 min (3.15 mmol·1^–1, SEM 0.14) and at 30 min (2.95 mmol·1^–1, SEM 0.18) were not significantly different inTh _v trial. However, the [1a]_b ofTh _v+ trial significantly increased (P<0.05) from 15 min (3.62 mmol·1^–1, SEM 0.36) to 30 min (3.91 mmol·1^–1, SEM 0.40). These results indicate thatTh _v gives the [1a]_ss,max, at which one can perform sustained exercise without continuous [1a]_b accumulation.     

Prevalence and characterization of leukotoxin-producing Staphylococcus intermedius in Isolates from dogs and pigeons

Staphylococcus intermedius isolates from dogs (n = 44) and pigeons (n = 62) were categorized into 12 types by intergenic ribosomal DNA spacer polymorphism analysis. All isolates from pigeons were lukS positive and all isolates from dogs were lukS and lukF positive by dot blot analysis. The mean leukotoxicity titer for dog isolates was at least 129-fold higher than that for pigeon isolates.     

Anti-arthritic properties of FK506 on collagen-induced arthritis in rats

Objective and design:To determine the effect of FK506 (tacrolimus) on paw inflammation, TNF- expression in joint, and bone and cartilage destruction in type II collagen-induced arthritis (CIA) model in rats.Methods:CIA was induced by immunization of female Lewis rats with an emulsion of bovine type II collagen and incomplete Freunds adjuvant. Paw inflammation was assessed by the increase in paw volume. Tumor necrosis factor (TNF) - expression in hind knee joint was assessed by immunohistochemical analysis. Lesions of bone and cartilage were assessed on the basis of histological change in knee joint, radiographic analysis in hind paw, bone mineral density in femora and proteoglycan contents in the cartilage of femoral heads. FK506 at doses of 1, 1.8 and 3.2 mg/kg or its placebo formulation was orally administered to rats for 28 days from the day after immunization (n = 10). Effect of FK506 was compared with that of vehicle (distilled water).Results:FK506 at a dose of 1.8 mg/kg significantly suppressed paw swelling (p < 0.01) and histological change in knee joint (p < 0.05). Tumor necrosis factor (TNF)- was mainly expressed in the region with a marked infiltration of inflammatory cells in the hind knee joint. FK506 (3.2 mg/kg) markedly reduced TNF- expression. FK506 at a dose of 1.8 mg/kg suppressed radiographic changes in hind paw (p < 0.05) and also recovered the decrease in bone mineral density in the femora (p < 0.05). Proteoglycan contents in the cartilage of femoral heads were determined to evaluate the cartilage destruction more quantitatively and found to significantly decrease in CIA rats. FK506 at a dose of 1.8 mg/kg recovered the loss of proteoglycan contents (p < 0.01).Conclusion:These results show that FK506 is effective in suppressing inflammation, TNF- expression in joint, and damage to bone and cartilage in rat CIA, and may be useful in the treatment of rheumatoid arthritis.     

Effects of bicarbonate ingestion on the respiratory compensation threshold and maximal exercise performance

Six males performed cycle ergometer exercise on two occasions in random order. Each exercise was preceded by a 2-h period in which matched capsules were administered orally, containing either starch (C) or NaHCO3 (E) in a dose of a 0.2 g.kg-1 body wt; pre-exercise blood pH and [HCO3-] were 7.34 +/- 0.01 and 23.7 +/- 0.5 mM (mean +/- S.E.) for the C study, and 7.41 +/- 0.01 and 28.6 +/- 1.3 mM for the E study (p less than 0.001 and p less than 0.01, respectively). Exercise was continuous and maintained for 10 min at 40% of maximal oxygen uptake (40% VO2max), followed by 15 min at 12 W above the respiratory compensation threshold ([+RCT]) which was determined by the increase of the ventilatory equivalent for carbon dioxide (VE.VCO2(-1)), and for as long as possible at 95% VO2max. Endurance time at 95% VO2max was significantly longer in E than in C (2.98 +/- 0.64 min vs. 2.00 +/- 0.44 min, p less than 0.05). The rate of increase in arterialized venous lactate (LA) was higher in E than in C from rest to exercise at [+RCT], while there was no significant difference in the hydrogen ions ([H+]). Consequently, [H+].LA-1 (nM.mM-1) was significantly lower in E than in C. The change of VE.VCO2(-1) was shifted downward in E compared to C during exercise with the lowest value being observed at the same exercise stage. These results suggest that the respiratory responses to exercise are not affected by the higher level of [HCO3-] induced by NaHCO3 ingestion, and appear to reflect the net change of plasma [HCO3-] or [H+]. Also, induced metabolic acidosis has little effect on [H+] appearance in blood.     

Inflammatory cytokine levels in paw tissues during development of rat collagen-induced arthritis: Effect of FK506, an inhibitor of T cell activation

Objective and design: To characterize rat collagen-induced arthritis (CIA) on the basis of levels of inflammatory cytokines, tumor necrosis factor (TNF)-, interleukin (IL)-1 and IL-6 in paw tissues, and further investigate the effect of FK506 (tacrolimus), a potent inhibitor of T cell activation, on cytokine levels.Methods: CIA was induced in female Lewis rats. The volume of hindpaws was measured before and after collagen immunization. TNF-, IL-1 and IL-6 levels in paw tissue extracts were determined by ELISA. Proteoglycan contents of cartilage in femoral heads was measured as an indication of cartilage destruction. To assess the effect of FK506 on inflammatory cytokine levels, rats were orally treated with 5 mg/kg of FK506 from days 14–21.Results: TNF- a level in paw tissues did not significantly change compared to levels found before collagen immunization, throughout development of CIA. In contrast, IL-1 and IL-6 levels in paw tissues significantly increased between day 14 and day 28 after collagen imuninization, when the arthritis was at a developed stage. Therapeutic treatment with FK506 reduced the elevated level of IL-6, but not IL-1, in paw tissue. FK506 treatment was effective in suppressing paw swelling and also recovering the loss of proteoglycan contents in the cartilage.Conclusions: Levels of IL-1 and IL-6, but not TNF- , in paw tissue were upregulated in association with the development of arthritis in rat CIA. These results suggest that IL-1 and IL-6, rather than TNF- , may play important roles at local inflammatory sites in producing joint destruction in rat CIA. FK506 may improve arthritis in established stages of CIA, by reducing the elevated level of IL-6.Received 4 March 2004; returned for revision 2 April 2004; accepted by M. J. Parnham 9 April 2004