Animal model for the study of methanol toxicity: comparison of folate-reduced rat responses with published monkey data

The postpartum period is an ideal time to begin contraception, as women are more highly motivated to adopt contraception at this time and it is convenient for both patients and service providers. For intrauterine device (IUD) contraception, this period offers other advantages, such as ease of insertion and minimal adverse impacts on breastfeeding. Among early studies, most postpartum insertions were performed anywhere from a few hours to seven days or more after delivery, and retention of the IUD in the uterus was poor. Since the 1970s, immediate postplacental insertion (IPPI), i.e., IUD insertion performed within 10 minutes after placental delivery, has been advocated, and fairly, low expulsion rates have been reported. Up to now, IPPI has not been widely accepted in clinics because its expulsion rate still appears to be higher than that of interval insertion. In order to further study IPPI and perfect this contraceptive technique, it is essential to comprehensively review IPPI results and compare the Chinese experience with that of the rest of the world.     

Methotrexate and 6-mercaptopurine maintenance therapy for childhood acute lymphoblastic leukemia: dose adjustments by white cell counts or by pharmacokinetic parameters?

In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were > or = 1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therapy was analyzed in relation to the erythrocyte concentration of MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respective major cytotoxic metabolites of MTX and 6MP). For each patient, E-MTX and E-6TGN levels were measured 2-15 (median, 6) and 2-17 (median, 7) times, respectively. From these measurements, arithmetic means of E-MTX and E-6TGN were calculated (mE-MTX and mE-6TGN, respectively). Since MTX and 6MP probably work synergistically, the product of mE-MTX and mE-6TGN was calculated for each patient (mE-MTX x 6TGN). The degree of myelosuppression was registered as the mean WBC determined following cessation of the therapy minus the mean WBC measured during the therapy (mWBCshift). The mean WBCs measured on therapy (mWBC(on)) and off therapy were highly correlated (r = 0.48, P = 0.009). The median mWBCshift was 2.7 x 10(9)/l (range, 1.4-4.8 x 10(9)/l). In a multivariate regression analysis, the best-fit model to predict the mWBCshift included mE-MTX x 6TGN, age at drug withdrawal, and mWBC in the order given [mWBCshift = 4.3 + 0.00089 x (mE-MTX x 6TGN) - 0.097 x age - 0.41 x mWBC(on); global rs = 0.66, P = 0.0002]. Thus, the patients with higher mE-MTX x 6TGN values, the younger patients, and the patients with the lowest WBC during therapy had the most pronounced degree of myelosuppression as measured by mWBCshift. These results indicate that E-MTX and E-6TGN may give a better reflection of the treatment intensity than do the WBCs alone.     

Combined use of laparoscopic cholecystectomy and endoscopic retrograde cholangiography (ERC) and papillotomy (ERCP) in management of cholecysto-choledocholithiasis

In a review of 328 cases the combination of laparoscopic cholecystectomy with specific use of endoscopic retrograde cholangiography (pre- and postoperatively) proved to be a riskless, secure and time-saving procedure. In our opinion this is a minimal invasive method of treatment for patients with cholecysto-/choledocholithiasis.     

A histopathologic study of direct pulp-capping with adhesive resins

The concentration of heat-shock proteins of 70 kD (HSP70) in heart tissue has been shown to increase during transient myocardial ischaemia and to persist during several hours of reperfusion. In this study the relationship between the local myocardial HSP70 concentration and blood flow was addressed for control physiological conditions and acute myocardial ischaemia. A specific aim of this study was to address the question of whether low flow areas under control physiological conditions have undergone a transient ischaemia during the preceding hours and thus may be in a state of hibernation or stunning. In 12 anaesthetized, open-chest beagle dogs (6 control and 6 with 60-min coronary artery stenosis) heart rate, mean aortic pressure, mean arterial partial pressure of O2 and partial pressure of CO2 averaged 85+/-16 beats/min, 94+/-14 mmHg, 102+/-17 mmHg and 39+/-6 mmHg, respectively. Regional HSP70 and myocardial blood flow (RMBF) were measured using an HSP70-enzyme-linked immunosorbent assay and the tracer microsphere technique, respectively, in samples of 250 mg wet mass. In the control group the mean RMBF was 1.06+/-0.59 ml.min-1.g-1 and the local HSP70 concentration was 7.08+/-1.03 microg/mg cytosolic protein. Myocardial HSP70 showed a blood flow-independent regional biological heterogeneity, equivalent to a coefficient of variation of 0.31. Local HSP70 concentrations did not differ (P>0.05) between control low and high flow samples, 6.16+/-1.0 vs 6.08+/-0.75 microg/mg cytosolic protein, respectively. However, after 60 min of coronary artery occlusion the local HSP70 concentration increased from 7.08 +/-1.03 to 13.43+/-3.19 microg/mg cytosolic protein (P<0. 001). There was a significant inverse relationship between the percent reduction of local blood flow and HSP70 (r=-0.56, P<0.001). From these results it is concluded that: (1) low flow samples under control physiological conditions are unlikely to be in a state of hibernation or stunning since their HSP70 concentration is normal and (2) the increase in the local HSP70 concentration during myocardial ischaemia reflects the degree of impairment of O2 delivery.     

Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial

BACKGROUND: Although intravenous heparin is commonly used after thrombolytic therapy, few reports have addressed the relationship between the degree of anticoagulation and clinical outcomes. We examined the activated partial thromboplastin time (aPTT) in 29,656 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial and analyzed the relationship between the aPTT and both baseline patient characteristics and clinical outcomes. METHODS AND RESULTS: Intravenous heparin was administered as a 5000-U bolus followed by an initial infusion of 1000 U/h, with dose adjustment to achieve a target aPTT of 60 to 85 seconds. aPTTs were collected 6, 12, and 24 hours after thrombolytic administration. Higher aPTT at 24 hours was strongly related to lower patient weight (P < .00001) as well as older age, female sex, and lack of cigarette smoking (all PT< .0001). At 12 hours, the aPTT associated with the lowest 30-day mortality, stroke, and bleeding rates was 50 to 70 seconds. There was an unexpected direct relationship between the aPTT and the risk of subsequent reinfarction. There was a clustering of reinfarction in the first 10 hours after discontinuation of intravenous heparin. CONCLUSIONS: Although the relationship between aPTT and clinical outcome was confounded to some degree by the influence of baseline prognostic characteristics, aPTTs higher than 70 seconds were found to be associated with higher likelihood of mortality, stroke, bleeding, and reinfarction. These findings suggest that until proven otherwise, we should consider the aPTT range of 50 to 70 seconds as optimal with intravenous heparin after thrombolytic therapy.     

Incidence of neoplasms in ages 0-19 y in parts of Sweden with high 137Cs fallout after the Chernobyl accident

An experiment was conducted to elucidate the origin of tetraploids (2n = 4x = 44) of Paragonimus westermani that occur together with diploid (2n = 2x = 22) and triploid (2n = 3x = 33) types in Liaoning Province, the People's Republic of China. Metacercariae of the diploid type, obtained from Hyogo Prefecture, Japan, and those of the triploid type from Tsushima, Nagasaki Prefecture, Japan, were mixed and inoculated into dogs and cats. The following results were obtained. The flukes were found in pairs within cysts in random combinations of 2x + 2x, 2x + 3x, and 3x + 3x (7:15:7). Oocytes in the oviduct were at stages from diplotene to metaphase. In a triploid fluke encysted with a diploid fluke, the primary oocytes were intruded by sperms from the diploid fluke. In the primary oocytes of diploid as well as triploid flukes, from diplotene to diakinesis, the homologues of the nucleolar chromosomes were heteromorphic as far as the size of the short arm was concerned. This implies that the triploid is an autotriploid generated in an ancestral diploid population that was polymorphic for the nucleolar chromosome.     

A convenient method to discriminate between cytochrome P450 enzymes and flavin-containing monooxygenases in human liver microsomes

Liver microsomes are a frequently used probe to investigate the phase I metabolism of xenobiotics in vitro. Structures containing nucleophilic hetero-atoms are possible substrates for cytochrome P450 enzymes (P450) and flavin-containing monooxygenases (FMO). Both enzymes are located in the endoplasmatic reticulum of hepatocytes and both need oxygen and NADPH as cofactors. The common method to distinguish between the two enzyme systems is to use the thermal inactivation of FMO and to inhibit P450 completely with carbon monoxide, N-octylamine or N-benzylimidazole. In the literature no indication could be found that the heat inactivation of FMO does not affect any of the human P450 enzymes or that the overall P450 inhibitors inhibit the different human P450 enzymes sufficiently and do not affect the FMO. The effect of N-benzylimidazole and heat inactivation was tested on specific activities of seven P450 enzymes in human liver microsomes, 1A2, 2A6, 2C9, 2C19, 2D6, 3A4/5, and 2E1, using methoxyresorufin O-demethylation, coumarin 7-hydroxylation, (S)-warfarin 4-hydroxylation, (S)-(+)-mephenytoin 4-hydroxylation, dextrometorphan O-demethylation, oxidation of denitronifedipine, and chlorzoxazone 6-hydroxylation respectively. The sulfoxidation of methimazole (MMI) was used as a specific probe for the determination of FMO activity. Methimazole sulfoxidation was compared with the well known assay for FMO metabolism, the formation of N,N-dimethylaniline (DMA) N-oxide, to be confirmed as an exclusively FMO mediated reaction. The participation of P450 and FMO in the sulfoxidation of four sulfur containing peptides, ametryne; terbutryne, prometryne and methiocarb was investigated using human liver microsomes. All four reactions were demonstrated to be catalysed predominantly by cytochrome P450.     

Effects of combined nimodipine and metrifonate on rat cognition and cortical EEG

The present study investigated if short-term treatment with an L-type Ca2+-channel inhibitor, nimodipine, can stimulate cognitive functioning and cortical electroencephalograph (EEG) arousal, and potentiate the effect of a cholinesterase inhibitor, metrifonate. Pretraining administration of nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on water maze and passive avoidance behavior of young neurologically intact controls, or water maze and passive avoidance performance failure induced by scopolamine pretreatment (i.p.; 0.4 mg/kg during the water maze and 2.0 mg/kg during the passive avoidance study), medial septal lesioning, or aging. Furthermore, nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on the improvement by metrifonate (10 mg/kg, p.o.) of the water maze and passive avoidance failure induced by scopolamine pretreatment or medial septal lesioning, nor did it affect the potential of metrifonate (30 mg/kg. p.o.) to improve the water maze or passive avoidance behavior of aged rats. Finally, nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on spontaneously occurring thalamically generated neocortical high-voltage spindles or spectral EEG activity of young controls, nor did it alleviate the spectral EEG abnormality induced by scopolamine (0.2 mg/kg, i.p.) administration. Also, the combination of nimodipine 3 or 10 mg/kg and a subthreshold dose of metrifonate 10 mg/kg could not suppress high-voltage spindles or scopolamine treatment-induced spectral EEG activity abnormalities. According to the present results, short-term treatment with nimodipine does not stimulate cognitive functions or increase cortical EEG arousal, and does not block or potentiate the propensity of metrifonate to improve cognitive performance of rats.