In vitro conversion of 3H-pregnenolone by human testicular tissue from fetal age to senescence

The in vitro conversion of pregnenolone was studied in testicular tissue specimens from 6 fetuses, 3 prepubertal boys with undescended testes, 5 normal adult men, and 12 elderly males with prostatic carcinoma. Adult testicular tissue converted pregnenolone to testosterone mainly along the delta 5 metabolic pathway. Steroid intermediates that were converted from pregnenolone to delta 4 metabolites prior to the rate limiting C17-20 lyase step were "trapped" as 17 alpha-hydroxyprogesterone. The conversion patterns in testicular tissue from fetuses were similar to those in testicular tissue from adults and elderly men. In prepubertal testicular tissue, however, a significantly lower conversion was observed, mediated by the enzymes 3 beta-hydroxysteroid dehydrogenase/isomerase and 17 alpha-hydroxylase. The conversion mediated by 17 alpha-hydroxylase was significantly lower in testicular tissue from the elderly males than from younger adults, suggesting a relative steroidogenic insufficiency in the elderly males. Testicular tissue from an anencephalic fetus produced testosterone and steroid intermediates in vitro, although to a lesser extent than in testicular tissue from other fetuses. The enzymes 3 beta-hydroxysteroid dehydrogenase/isomerase and 17 alpha-hydroxylase appeared to be under gonadotropic control.     

Improving medical residents’ self-assessment of their diagnostic accuracy: does feedback help?

Advances in Health Sciences Education - When physicians do not estimate their diagnostic accuracy correctly, i.e. show inaccurate diagnostic calibration, diagnostic errors or overtesting can occur....     

In vivo primary induction of virus-specific CTL by immunization with 9-mer synthetic peptides.

A primary cytotoxic T lymphocyte (CTL) response in vivo requires antigen presentation by cytosolic processing and can not in general be obtained by vaccination with soluble proteins. In the present work we have found that vaccination of mice with pre-processed synthetic peptides, corresponding to endogenous 9-mers produced in influenza A virus-infected cells, resulted in strong primary CTL responses. The generated CTL efficiently killed virus-infected target cells with preference for viral strains having the identical amino acid sequences to the peptides used for immunization. The optimal conditions for a primary in vivo CTL response was obtained with 100 micrograms peptide dissolved in incomplete Freund's adjuvant and injected s.c. at the base of tail. Spleen cells which had been primed 7-10 days earlier were restimulated for 5 days in vitro, using an optimal low peptide concentration (0.05 microM) and tested against virus-infected and peptide-treated target cells. The peptide-induced CTL were major histocompatibility complex class I restricted and CD8 positive.     

Pharmacokinetics,cerebrospinal fluid penetration,and metabolism of piroxantrone in the Rhesus monkey

Summary Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activityin vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluatedin vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m² given over 60 minutes was biexponential with mean t_1/2 alpha of 1.0 minutes and a mean t_1/2 beta of 180 minutes. The mean area under the curve was 220 M·min and the clearance was 1420 ml/min/m². Piroxantrone was not detectable in the cerebrospinal fluid.Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cellsin vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite.The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.     

Mild measles and secondary vaccine failure during a sustained outbreak in a highly vaccinated population

A prolonged school-based outbreak of measles provided an opportunity to study "vaccine-modified" mild measles and secondary vaccine failure. Thirty-six (97%) of 37 unvaccinated patients had rash illnesses that met the Centers for Disease Control clinical case definition of measles, but 29 (15%) of 198 vaccinated patients did not, primarily because of low-grade or absent fever. Of 122 patients with seroconfirmed measles, 10 patients (all previously vaccinated) had no detectable measles-specific IgM and significantly milder illness than either vaccinated or unvaccinated patients with IgM-positive serum. Of 108 vaccinated patients with seroconfirmed measles, 17 patients (16%) had IgM-negative serology or rash illnesses that failed to meet the clinical case definition; their mean age (13 years), age at the time of vaccination, and time since vaccination did not differ from those of other vaccinated patients. The occurrence of secondary vaccine failure and vaccine-modified measles does not appear to be a major impediment to measles control in the United States but may lead to underreporting of measles cases and result in overestimation of vaccine efficacy in highly vaccinated populations.     

Stellenwert von Computertomographie und Magnetresonanztomographie bei der Diagnostik von Malignomen der Mundh?hle und des Oropharynx

Problem: There is a lack of clear criteria for the use of MR and CT in the diagnosis of head and neck cancer – some of it is even contradictory. The results of this study should lead to the establishment of more clear criteria. Patients: 165 patients suffering from head and neck tumors were subjected to a total of 463 CT and 197 MRI examinations. Results: The CT and MRI staging corresponded in 67% and 60% of the oropharynx tumors, respectively, with the clinical findings. In the case of oral cavity tumors, the clinical TNM stages were identical with CT and MRI results in 50% and 43% of cases, respectively. In the case of lymphatic node staging, the frequency of error was slightly higher using MRI, at 27%, compared with the CT rate of 22%. In the evaluation of cervical lymphatic nodes, CT proved to be more sensitive attaining 78% compared to the MRI rate of 69%. Conclusion: The results provide clear indications as to the MRI and CT examinations. Primary preoperative screening and post-therapeutic aftercare should be assessed using CT, as should lymphatic node diagnosis in the neck area. In the case of special problems such as, for example, the relevant bone and periostium infiltration, MR should be considered as a supplementary examination at a second stage.      

Signalling pathways in bradykinin- and nitric oxide-induced hypotension in the normotensive rat; role of K+-channels

1. Bradykinin and nitric oxide (NO) are potent hypotensive agents. In the present study, the role of K⁺-channels in the signalling pathways responsible for their hypotensive action was investigated in normotensive, anaesthetized rats. The rats were treated with ion-channel inhibitors before administration of bradykinin (2.8, 5.6, 28 and 56 nmol kg⁻¹, i.v.) followed in some of the protocols by nitroprusside (1.1, 3.5, 7, 14, and 28 nmol kg⁻¹, i.v.).
2. No attenuation of the hypotensive response to bradykinin was detected for inhibitors of the Na-K-Cl-cotransporter (30 μmol kg⁻¹ furosemide), the ATP-sensitive K⁺-channel (40 μmol kg⁻¹ glibenclamide), high conductance Ca²⁺-activated K⁺-channel (180 μmol kg⁻¹ tetraethylammonium, 54 μmol kg⁻¹ tetrabutylammonium, 35 nmol kg⁻¹ iberiotoxin, 35 nmol kg⁻¹ charybdotoxin) or the low conductance Ca²⁺-activated K⁺-channel (74 nmol kg⁻¹ apamin).
3. However, the voltage-sensitive K⁺-channel (I_A) inhibitor 4-aminopyridine (4.05–40.5 μmol kg⁻¹) induced a concentration-dependent (P<0.0001) attenuation of the hypotensive response (P<0.0001). Bradykinin had no effect on heart rate in anaesthetized rats and this observation was not altered by pretreatment with 4-aminopyridine.
4. 4-Aminopyridine (53 μmol kg⁻¹) also significantly attenuated the hypotensive response to nitroprusside (P<0.0003) without altering the heart rate concentration-response curve. Of the two Ca²⁺-activated K⁺-channel inhibitors tested on nitroprusside-induced hypotension, tetrabutylammonium induced a slight attenuation (P<0.0101), whereas iberiotoxin had no effect.
5. We therefore concluded that, although the acute hypotensive response to bradykinin in the normotensive rat is not mediated through nitric oxide synthesis, the hypotensive response to both agents was mediated through opening of voltage-sensitive K⁺-channels (I_A), resulting in a decrease in peripheral vascular resistance.

     

Stabilizing seizure disorders

Scientific understanding of seizures and epilepsy is rapidly evolving. Recent advances in diagnosis, classification, and medical and surgical treatment have significantly altered our approach to patients with these conditions.     

Estimates of the annual number of clinically recognized pregnancies in the United States, 1981-1991.

The authors estimated the number of clinically recognized pregnancies that occurred annually from 1981 to 1991 in the United States by type of outcome and by race. Estimates of the numbers of livebirths, induced abortions, ectopic pregnancies, and fetal deaths were obtained by using data from the Centers for Disease Control and Prevention in Atlanta, Georgia. The number of spontaneous abortions was estimated by using previously published, age-specific rates. More than 67 million pregnancies occurred during the study period. Overall, 62.5% of these pregnancies resulted in livebirths, 21.9% in legal induced abortions, 13.8% in spontaneous abortions, 1.3% in ectopic pregnancies, and 0.5% in fetal deaths. These data can be used to provide denominators for the calculation of a variety of pregnancy outcome-specific rates.