Susan R. Whittle

EFFECTS OF THE ANTICONVULSANT SODIUM VALPROATE ON γ‐AMINOBUTYRATE AND ALDEHYDE METABOLISM IN OX BRAIN

Succinic semialdehyde dehydrogenase and NADPH‐dependent aldehyde reductase have been purified from ox brain by affinity chromatography on 5′ AMP–Sepharose and 2′5′ ADP–Sepharose respectively. Aldehyde reductase has also been purified using chromatography on Procion Red HE3B–Sepharose. The effects of the anticonvulsant drug sodium valproate were examined on these enzymes, and also on GABA‐aminotransferase partially purified from ox brain. Aldehyde reductase was inhibited by valproate in an uncompetitive manner with respect to aldehyde substrates (Ki= 38–85 μM). The inhibitions of succinic semialdehyde dehydrogenase and GABA aminotransferase were approx 2 orders of magnitude weaker, suggesting that aldehyde reductase may be an important site of action of anticonvulsant drugs.

What Do Medical Students Understand By Research And Research Skills? Identifying Research Opportunities Within Undergraduate Projects

Background: Undergraduate research exposure leads to increased recruitment into academic medicine, enhanced employability and improved postgraduate research productivity. Uptake of undergraduate research opportunities is reported to be disappointing, and little is known about how students perceive research. Aim: To investigate opportunities for undergraduate participation in research, recognition of such opportunities, and associated skills development. Method: A mixed method approach, incorporating student focus and study groups, and documentary analysis at five UK medical schools. Results: Undergraduates recognised the benefits of acquiring research skills, but identified practical difficulties and disadvantages of participating. Analysis of 905 projects in four main research skill areas – (1) research methods; (2) information gathering; (3) critical analysis and review; (4) data processing – indicated 52% of projects provided opportunities for students to develop one or more skills, only 13% offered development in all areas. In 17%, project descriptions provided insufficient information to determine opportunities. Supplied with information from a representative sample of projects (n = 80), there was little consensus in identifying skills among students or between students and researchers. Consensus improved dramatically following guidance on how to identify skills. Conclusions: Undergraduates recognise the benefits of research experience but need a realistic understanding of the research process. Opportunities for research skill development may not be obvious. Undergraduates require training to recognise the skills required for research and enhanced transparency in potential project outcomes.

Generic skills in medical education: developing the tools for successful lifelong learning

Medical Education 2012: 46: 120–128

Differential effects of sedative and anticonvulsant barbiturates on specific [3H]GABA binding to membrane preparations from rat brain cortex

The sensitivity to barbiturates of [3H]GABA binding to synaptosomal membrane fractions from rat cortex has been examined. We show that a range of anaesthetic/sedative barbiturates enhance GABA binding in the presence of chloride or other ions that interact with the associated ionophore. Furthermore, picrotoxinin and the anticonvulsant barbiturate phenobarbital antagonise the enhancement produced by pentobarbital. These effects are therefore comparable to those observed at benzodiazepine receptors and may be mediated through the chloride ionophore component of the receptor complex. Other classes of anticonvulsants failed to antagonise pentobarbital activation, suggesting that these interactions may occur at a specific barbiturate site in the membrane.

Mapping Generic Skills Curricula: A Recommended Methodology.

Since the 1997 Dearing Report generic skills development has become an essential part of higher education in the UK. Generic skills programmes are, in the main, either run in parallel with existing curricula or ‘embedded’ within them. In 1993 the General Medical Council introduced student selected components (SSCs) into the UK medical curriculum with the intention of ‘embedding’ generic skills into undergraduate medical study. The SSC programme at Leeds School of Medicine was designed to develop specific generic skills in early focused projects and then allow students to practise these skills in clinical settings in later projects. In order to evaluate this programme, a methodology was devised to map the generic skills curriculum to an externally derived consensus on SSC outcomes. Englishs model, mapping ‘declared’, ‘delivered’ and ‘learned’ curricula, was used and a fourth, ‘assessed’ map added to check the ‘alignment’ of the curriculum through all its stages. Data for the maps were gathered from curriculum documentation, project supervisors and students using document scrutiny, questionnaires, interviews and focus groups. The methodology was run over a complete academic year for the entire programme. It proved valuable for mapping any ‘embedded’ generic skills programme to evaluate its success by collecting data from all stakeholders.

Biogenic aldehyde metabolism in rat brain: Differential sensitivity of aldehyde reductase isoenzymes to sodium valproate

The effects of inhibitors of aldehyde reductase (alcohol:NADP+ oxidoreductase, EC 1.1.1.2) on the formation of 3-methoxy-4-hydroxyphenethylene glycol from normetanephrine have been studied in rat brain homogenates. The reaction pathway was shown to be unaffected by several inhibitors of the major (high Km) form of aldehyde reductase such as sodium valproate. Two isoenzymes of aldehyde reductase have been separated and characterized from rat brain. The minor (low Km) isoenzyme is shown to be relatively insensitive to sodium valproate and exhibits a similar inhibitor-sensitivity profile to that obtained for methoxyhydroxyphenethylene glycol formation. The low Km isoenzyme is therefore implicated in catecholamine metabolism. The metabolism of succinic semialdehyde and xylose by rat brain cytosol has also been examined. Aldose metabolism may also be attributed to the action of the low Km reductase, but the existence of a separate succinic semialdehyde reductase is postulated. The possible roles of aldehyde reductases in brain metabolism and the relationship between these enzymes and aldose reductase (alditol:NADP+ 1-oxidoreductase, EC 1.1.1.21) are discussed.

Mapping generic skills curricula: outcomes and discussion

Generic skills development is increasingly being embedded into UK higher education curricula to improve the employability and lifelong learning skills of graduates. At the same time universities are being required to benchmark their curricular outcomes against national and employer standards. This paper presents and discusses the results of a study mapping the outcomes, delivery, learning and assessment of an embedded generic skills curriculum and benchmarking these against externally agreed standards. By collecting data from students, supervisors and curriculum documentation across the whole five year course in a UK medical school it evaluates the success of the generic skills programme in achieving its objectives. It goes on to discuss how data from the maps might also be used to encourage student learning. It recommends the adoption of this methodology to map embedded skills curricula with the aim of highlighting skills delivery for curriculum designers and skills development for students.

Student-selected components in the undergraduate medical curriculum: a multi-institutional consensus on purpose.

Student-selected components (SSCs) are an established part of undergraduate medical curricula in the UK. Implementation has been against a background of differing educational approaches to curricular change, together with a lack of clarity about their purpose, relationship with the core curriculum and contribution to overall assessment. This has resulted in a diversity of programmes with perceived differing importance between medical schools. This paper documents the approach used by a consortium of medical schools with diverse curricula to develop consensus on the educational purpose and learning outcomes of SSCs. Agreement on common purposes and outcomes was achieved, and consensus documents are reported. These may be valuable for other medical schools implementing any form of student-selected project work. This work will now be the starting point for further work on producing recommendations for assessment of SSCs, which will be applicable across different medical schools.

Sodium valproate, GABA and epilepsy

Abstract Sodium valproate, a branched chain fatty acid, is an effective anti-convulsant drug both in clinical and experimental epilepsies. There is substantial evidence that valproate modifies the metabolism and action of the inhibitory neurotransmitter GABA. Whether this relates to the anti-convulsant action of this drug is still unclear. Possible modes of action of valproate are considered in this article.

Anti-convulsants and brain aldehyde metabolism: Inhibitory characteristics of ox brain aldehyde reductase

Abstract The major isoenzyme of aldehyde reductase has been purified from ox brain by affinity chromatography. Carbamazepine ( K i = 7.3 × 10 −4 M) and phenacemide ( K i = 2.5 × 10 −4 M), in common with all other established anti-convulsant drugs tested, have been shown to inhibit the activity of this enzyme. A selection of structural analogues of the anti-convulsant sodium valproate were found to be potent inhibitors of the reductase ( K i values in the range 10 −3 M −5 × 10 −5 M) and these analogues also showed anti-convulsant activity in the mouse maximal electroshock test. A third group of compounds, the flavonoids, constitute the most potent group of aldehyde reductase inhibitors yet reported. Quercetin and morin exhibited K i values less than 1 μM. The possible relationship between aldehyde metabolism and anti-convulsant action is discussed and structural characteristics pre-disposing to potent inhibition of aldehyde reductase are described.