Depletion of hepatic 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated

Sulfation is considered a high-affinity but low-capacity conjugation mechanism that is limited by the availability of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the cosubstrate for sulfation. Salicylamide, phenol and 1-naphthol are all known substrates for the sulfation reaction. This study was conducted to determine whether the xenobiotics that are sulfated when administered to rats will lower hepatic PAPS and its precursor, sulfate. Urinary sulfate excretion was reduced 85% to 95% by these compounds. Hepatic PAPS was reduced 73%, 39%, and 87% by salicylamide, phenol and naphthol, respectively, 2 hr after administration of 2 mmol/kg. These compounds also decreased serum sulfate concentrations by 45% to 86% and lowered hepatic sulfate concentrations. In summary, these studies demonstrate that salicylamide, phenol and 1-naphthol lower hepatic PAPS and sulfate concentrations, as well as serum sulfate concentrations. These findings imply that increased sulfation, as a result of the sulfation of xenobiotics, results in depletion of hepatic PAPS concentrations, possibly because the utilization of PAPS by the sulfotransferases exceeds its generation via sulfate activation. Thus the capacity-limited sulfation of high dosages of xenobiotics appears to be due to the reduced availability of hepatic PAPS, which in turn is limited by the availability of sulfate.     

Effect of EGb 761, a ginkgo biloba extract, on early arrhythmia induced by coronary occlusion and reperfusion in dogs

EGb 761 is a preparation of Ginkgo biloba extract, which has complex biologic actions including free radical scavenging activity. To examine the anti-arrhythmic effect of EGb 761, a canine preparation of coronary artery occlusion-reperfusion was tested. Under intravenous anesthesia and open chest conditions, 32 dogs were subjected to 30 min of coronary occlusion, followed by reperfusion. Twelve received EGb 761 by intravenous injection, 1 mg/kg five minutes before coronary occlusion, followed by a continuous infusion of 0.1 mg/kg/min until five minutes after reperfusion. Immediately prior to reperfusion, an additional bolus dose of EGb 761 (1 mg/kg) was again injected (group A). The remaining 20 dogs received saline injection, and served as the control (group B). The electrocardiographic changes were recorded during the whole experimental course. The results showed that, during coronary occlusion, group A dogs had a lower count of ventricular premature beats than group B dogs. However, there was no difference in the incidence of ventricular tachycardia (VT) between the two groups. The duration of VT of the treated dogs was similar to that of the control dogs. The incidence of ventricular fibrillation (VF) was also similar. Upon reperfusion, the treated dogs were shown to be protected from VF. The duration of VT was also shorter in the treated group, although the incidence of VT was not different between the two groups. EGb 761 is effective in preventing early VF induced by coronary reperfusion while ineffective in protecting the ischemic VT and VF.     

The dorsal filament of the weakly electric Apteronotidae (Gymnotiformes; Teleostei) is specialized for electroreception

The Apteronotidae, a family of weakly electric fish from South America (Gymnotiformes), possess a structure called the dorsal filament with an unknown function and evolutionary origin. This study compared the gross anatomy of the dorsal filament of 13 species of apteronotids and used light microscopy to examine the filaments of Adontosternarchus balaenops, Apteronotus albifrons, and Apteronotus leptorhynchus. The dorsal filament is an unscaled, thin, tapering structure attached to a mid-dorsal groove on the posterior half of the fish's back. The interior of the filament is a gelatinous mucopolysaccharide matrix (connective tissue) containing blood vessels and a bilateral nerve in which nearly all the afferents are large (8-10 mu m) and heavily myelinated. The location of the anterior origin of the filament varies from 0.48 to 0.66 of the body length, posterior to the snout, in 13 species. The filament is covered with hundreds of large-type tuberous electroreceptors and some ampullary receptors, at approximately the same density and ratio as those on the nearby back. The morphology of the large-type tuberous receptors and their afferents suggests that they are phase-coding T-units. A double layer of epithelial cells separates the ventral side of the filament from the groove in the trunk of the fish, except at the anterior origin where the interior of the filament is continuous with the body. This specialized double epithelium could provide a high resistance barrier to electrical current. This study was unable to distinguish between two hypotheses: that the dorsal filament is a modified adipose fin (as suggested previously), retained only in this family of Gymnotiformes; or that it is a uniquely derived character of the Apteronotidae.     

Comparison of pH-stat and alpha-stat cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets

Melagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at > or = 1.0 micromol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (< 0.5 micromol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.     

Specificity of the T-cell responses in covalently linked peptides each comprising of a T helper epitope

The selection of T-cell specificities in chimeric peptides comprising of two T helper epitopes (288-302 and 240-252) from the fusion protein of measles virus was investigated. The resulting chimeric peptides (288-P-240 and 240-P-288) were shown to be immunogenic by inducing proliferative responses in both B10.s and C57BL/6 strains of mice. In B10.s mice immunization with the chimeric peptides resulted in proliferative T-cell responses only to the constituent 288-302 peptide, whereas in C57BL/6 mice no proliferative responses to the constituent 288-302 or 240-252 peptides were detected. In vivo competition studies between the 288-302 and 240-252 peptides for binding to the I-As molecule have shown that the peptide 288-302 was dominant in B10.s mice and competed with the non-dominant 240-252 peptide for the induction of an in vivo response. The absence of any proliferative T-cell response to the constituent 288-302 and 240-252 peptides after immunization of C57BL/6 mice with the 288-P-240 or 240-P-288 chimeric peptides, suggests that the dominant T-cell responses might have shifted to newly formed T cell epitope(s) as a result of the covalent linkage of the two peptides. In conclusion, these results indicate that the selection of Th epitopes within chimeric peptides is dependent not only on the amino acid composition of the epitope but also on the context of the epitope within the chimera and the haplotype of the mouse strain used.     

Right and left ventricular dysfunction in patients with severe pulmonary disease

AIM OF STUDY: To measure the effect of specific preoperative information on postoperative anxiety, satisfaction with information, and demand for analgesia, of Chinese males having transurethral resection of the prostate (TURP). DESIGN: A controlled experimental design. The researchers allocated all patients (n = 30) undergoing TURP in a general hospital in Hong Kong, during a 3-month period, to one of two groups. The experimental group (n = 15) received a specific information pamphlet and a general preoperative counselling video. The control group (n = 15) received a video alone. PROCEDURE AND MEASURES: Following ethical approval, a researcher took baseline measures of state and trait anxiety using the Chinese State-Trait Anxiety Inventory (C -STAI). Five days after surgery the researcher administered the C-STAI (A-State), a patients' satisfaction questionnaire, and, recorded requests for analgesia during the first 5 postoperative days. RESULTS: Experimental subjects reported significantly lower anxiety levels post-operatively and a significantly higher level of satisfaction with the preoperative information, than controls. Postoperative demand for analgesia did not significantly differ between groups. CONCLUSIONS: The findings support the importance of providing patients with specific, written preoperative information about their surgery and its effects to minimize their postoperative anxiety levels, and improve their satisfaction with the care provided.     

Antibody responses measured by various serologic tests in pigs orally inoculated with low numbers of Toxoplasma gondii oocysts

OBJECTIVE: To follow antibody responses measured by various serologic tests in pigs orally inoculated with low (< or = 10 oocysts) numbers of Toxoplasma gondii oocysts. ANIMALS: 24, 2- to 3-month-old pigs. PROCEDURE: Pigs (n = 42) were inoculated orally with 10 (14 pigs) or 1 (28 pigs) infective oocysts, and 6 pigs served as uninoculated controls. Blood (serum) samples were obtained at 1- to 3-week intervals until euthanasia. At necropsy, the brain, heart, and tongue of pigs were bioassayed in mice and cats for isolation of T gondii. Modified agglutination test (MAT), using whole, fixed tachyzoites and mercaptoethanol; latex agglutination test (LAT); indirect hemagglutination test (IHAT); Sabin-Feldman dye test (DT); and ELISA were used to evaluate serologic responses to T gondii. RESULTS: T gondii was isolated from tissues of 13 of 14 pigs each fed 10 oocysts, 17 of 28 pigs each fed 1 oocyst, and 0 of 6 control pigs. 29 of 30 T gondii-infected pigs developed antibodies when measured by MAT, DT, and ELISA; the 1 seronegative-infected pig had been fed 10 oocysts and was euthanatized 69 days after inoculation. LAT detected antibodies in 26 of 30 T gondii-infected pigs. IHAT detected antibodies in 11 T gondii-infected pigs. CONCLUSION: MAT, DT, and ELISA were more sensitive serologic assays than LAT and IHAT for detecting antibodies induced by low numbers of T gondii in pigs.