Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors.

In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg.

Video-based computer-assisted learning.

As a relevant exemplar of MPEG-1 and MPEG-2 digital video use, a multimedia computer-assisted learning (CAL) application dealing with Critical Communication Issues in medicine was developed. The application allowed the student to navigate through a series of high-quality digital video and audio clips that were delivered in near real-time from an Intranet server. This paper gives a brief background to the MPEG-2 video compression system and discusses the use of digital video in a CAL environment.

Teaching undergraduates about familial breast cancer: comparison of a computer assisted learning (CAL) package with a traditional tutorial approach.

We have developed a computer assisted learning package for teaching clinical medical students about familial breast cancer. It explains the principles of genetic predisposition to breast cancer, the association with other cancers, the principles of family history taking and confirmation, risk assessment and possible interventions. Clinical medical students were randomised to either conventional teaching or CAL, 48 students attended the evaluation session. Students randomised to conventional teaching received a 20 min mini-lecture, those randomised to CAL completed the package with technical, but not academic support available. At the end of the intervention both groups of students completed a short written assessment of acceptability and knowledge and understanding of breast cancer genetics. There was no significant difference between the CAL and mini-lecture groups in terms of marks or acceptability. Thus CAL appears to be an acceptable and effective method of teaching clinical medical students about familial breast cancer. Although time consuming to develop, CAL can be used in a variety of settings to increase curriculum flexibility. Methods of motivating students to complete the CAL, and of providing educational support are being explored.

Conformationally constrained anesthetic steroids that modulate GABA(A) receptors.

Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.

Identification and characterization of a transcriptional silencer upstream of the human BRCA2 gene.

Expression of the breast cancer susceptibility tumor-suppressor protein BRCA2, a protein potentially involved in DNA recombination repair, is tightly regulated throughout development. We have identified a transcriptional silencer at the distal end of the human BRCA2 gene promoter. This silencer is involved in the negative regulation of the expression of this gene in breast cell lines tested but not in HeLa or HepG2 cells. The 221-base-pair silencer region is characterized by a full-length Alu-repeat. Presence of specific BRCA2 silencer-binding proteins in the breast cell extracts indicates the potential regulation of BRCA2 gene expression by these proteins.

Development and integration of CAL: a case study in medicine.

CONTEXT: The Faculty of Medicine and Medical Sciences at the University of Aberdeen viewed the use of Computer Assisted Leaning (CAL) and other IT based learning resources as a possible way of coping with an increase in student numbers whilst maintaining or increasing the quality of medical teaching. OBJECTIVES: Our primary objective was to develop and integrate Computer Assisted Learning (CAL) applications into the undergraduate medical curriculum. SUBJECTS/MATERIALS: A wide spectrum of CAL applications were developed dealing with many topics in the curriculum. METHODS: We formulated a structured approach to CAL development by establishing a team of professionals (forming a CAL Unit), using existing expertise and by implementing a process to ensure that the CAL had a maximum impact upon the curriculum. The CAL included multimedia tutorials, learning guides, computer aided assessment (CAA) and Model Patients. RESULTS: There are now over 150 IT based learning resources in our curriculum and course evaluation has showed that these have been well received by students. CONCLUSIONS: We conclude that with the wise use of the many skills and facilities usually available within an institution and by promoting collaborative projects with others, the production of high quality CAL is possible within most institutions.

Anesthetic activity of novel water-soluble 2 beta-morpholinyl steroids and their modulatory effects at GABAA receptors.

(3 alpha,5 alpha)-3-Hydroxypregnan-20-ones and (3 alpha,5 alpha)-3-hydroxypregnane-11,20-diones bearing a 2 beta-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2 beta,3 alpha,5 alpha)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2 beta,3 alpha,5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABAA receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABAA receptors.

Medical teaching at a peripheral site by videoconferencing.

The departments of Child Health and Mental Health of Aberdeen University's Medical Faculty recently took part in a 3 month trial assessing the potential of videoconferencing as a medium for teaching students on peripheral hospital attachments. The equipment used was British Telecom's VC7000 Videoconferencing System and an ISDN2 (integrated services digital network) connection, which was installed between two sites. The locations used were a teaching room in the Royal Aberdeen Children's Hospital and the Paediatric Unit at Raigmore Hospital in Inverness. This paper describes the resources required to support the trial, the methods used to run it and the results of staff and student evaluation of the trial. Evaluation forms were completed and returned by eight members of staff and by 30 fourth- and fifth-year medical students. The results indicated that, although after this particular trial both staff and students rated the overall usefulness as low, they attributed this to technical problems and limitations specific to the type of equipment used rather than to the method itself. The overall impression was that videoconferencing with ISDN has potential as a teaching tool in the medical undergraduate course but that further improvements in image quality and voice switching are required.

Digital video for networked CAL delivery.

Digital moving images (AVI format), were integrated into a specific computer-assisted learning (CAL) application, providing a highly visual and interactive self-learning tool in an area of the medical curriculum which is difficult to teach by traditional methods. This paper outlines the process used to obtain the digital video using relatively inexpensive equipment and the subsequent delivery over a university network without resorting to major upgrading of the network specifications.

Protein synthesis in a fish heart: responses to increased power output.

The effects of exercise on the rates of protein synthesis in the chambers of the trout heart were investigated in vitro and in vivo. An in vitro rainbow trout heart preparation was developed which permitted perfusion of the coronary supply to the compact region of the ventricular muscle. This preparation was used to examine the mechanical responses to preload pressures, the oxygen consumption at different power outputs and the rates of protein synthesis in the various heart components. By increasing preload pressure it was possible to double cardiac output, oxygen consumption and power output without changing heart rate. Mechanical efficiency of the hearts was approximately 20%. Perfusion of the coronary vessels improved cardiac output. Protein synthesis was measured in isolated hearts by the incorporation of [3H]phenylalanine added at high concentration (1.35 mmol l-1) to the perfusion medium. The various chambers of the heart showed marked differences in their rates of protein synthesis. Increasing cardiac output and power output in vitro by twofold over 20 min increased the fractional rate of protein synthesis by approximately 2.5-fold in the atrium and ventricle but did not affect the rates in the bulbus arteriosus. Perfusion of the coronary vessels significantly increased the rates of protein synthesis of the compact layer of the ventricle. In vivo there were no significant differences in the fractional protein synthesis rates between the atrium and ventricle; slow-speed continuous swimming over 40 min (1.5 body lengths s-1) caused an increase in the rates of protein synthesis in all the chambers except the bulbus arteriosus. The stimulation in the fractional rates of protein synthesis by approximately 32% was not as great as in vitro. Both in vivo and in vitro the increased rates of protein synthesis occurred without any change in RNA to protein ratios, indicating an improved activity of protein synthesis per unit of RNA. It is concluded that short-term increases in cardiac contractility, possibly acting through the mechanical stretch on the cardiac muscle, stimulated protein synthesis, particularly in the ventricle, through increased ribosomal activity.