d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia

The N-methyl-d-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by d-amino acid oxidase. Both d-serine and its metabolizing enzymes are implicated in N-methyl-d-aspartate receptor hypofunction thought to occur in schizophrenia. We studied d-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. d-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, d-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or d-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and d-amino acid oxidase are expressed in human brain and provide some support for aberrant d-serine metabolism in schizophrenia. However, they raise further questions as to the roles of d-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain

Investigations of the role of d-amino acid oxidase and serine racemase in schizophrenia

D-serine metabolism is implicated in schizophrenia pathophysiology. This is based on reduced D-serine levels in the disorder, its ameliorative effects therapeutically and the potential genetic contributions of its metabolic enzymes, D-amino acid oxidase (DAO) and serine racemase (SRR). D-serine is a gliotransmitter and the N-methyl D-aspartate receptor (NMDAR) co-agonist. Thus, altered D-serine metabolism may contribute to NMDAR hypofunction in schizophrenia. The research in this thesis was designed to investigate D-serine metabolic enzymes further through studying their distribution, their expression in schizophrenia and their effect on NMDARs. The regional and cellular distribution of DAO and SRR in rodent and human brain were investigated using immunohistochemistry. Both enzymes were found within frontal cortex, hippocampus and cerebellum. In rodent frontal cortex, SRR expression was neuronal suggesting D-serine is not always glia-derived. In the human this was not the case, highlighting possible species differences. DAO in the rodent and human cortex was robustly detected, challenging previous views. In rodent cerebellum, both enzymes were neuronal and glial and in human, predominantly glial. In schizophrenia, DAO and SRR expression were investigated using western blotting and real-time PCR. DAO expression was elevated in the cerebellum in the disorder, without an accompanying change in SRR. In the dorso-lateral prefrontal cortex (DPFC), DAO and SRR mRNAs were unchanged in schizophrenia but SRR protein was significantly increased. The elevation in DPFC SRR protein was not replicated however in a second study. To investigate the effects of D-serine metabolic enzymes on NMDARs, an in vitro model of altered SRR expression was developed, but its use hindered through technical complications. The data detailed demonstrate new findings of DAO and SRR’s distributions in the brain and highlight novel potential roles for these enzymes. In addition, the data provide some paradoxical findings including DAO’s cortical expression. The investigations in schizophrenia lend to robust demonstrations of DAO’s elevated cerebellar expression in the disorder. However, its roles therein and that of DAO and SRR on NMDAR function remain unclear.</p

Investigations of the role of d-amino acid oxidase and serine racemase in schizophrenia

D-serine metabolism is implicated in schizophrenia pathophysiology. This is based on reduced D-serine levels in the disorder, its ameliorative effects therapeutically and the potential genetic contributions of its metabolic enzymes, D-amino acid oxidase (DAO) and serine racemase (SRR). D-serine is a gliotransmitter and the N-methyl D-aspartate receptor (NMDAR) co-agonist. Thus, altered D-serine metabolism may contribute to NMDAR hypofunction in schizophrenia. The research in this thesis was designed to investigate D-serine metabolic enzymes further through studying their distribution, their expression in schizophrenia and their effect on NMDARs. The regional and cellular distribution of DAO and SRR in rodent and human brain were investigated using immunohistochemistry. Both enzymes were found within frontal cortex, hippocampus and cerebellum. In rodent frontal cortex, SRR expression was neuronal suggesting D-serine is not always glia-derived. In the human this was not the case, highlighting possible species differences. DAO in the rodent and human cortex was robustly detected, challenging previous views. In rodent cerebellum, both enzymes were neuronal and glial and in human, predominantly glial. In schizophrenia, DAO and SRR expression were investigated using western blotting and real-time PCR. DAO expression was elevated in the cerebellum in the disorder, without an accompanying change in SRR. In the dorso-lateral prefrontal cortex (DPFC), DAO and SRR mRNAs were unchanged in schizophrenia but SRR protein was significantly increased. The elevation in DPFC SRR protein was not replicated however in a second study. To investigate the effects of D-serine metabolic enzymes on NMDARs, an in vitro model of altered SRR expression was developed, but its use hindered through technical complications. The data detailed demonstrate new findings of DAO and SRR’s distributions in the brain and highlight novel potential roles for these enzymes. In addition, the data provide some paradoxical findings including DAO’s cortical expression. The investigations in schizophrenia lend to robust demonstrations of DAO’s elevated cerebellar expression in the disorder. However, its roles therein and that of DAO and SRR on NMDAR function remain unclear.This thesis is not currently available in ORA. Some of this thesis has been published in European Journal of Neuroscience. Volume 26, Issue 6, pages 1657–1669, September 2007, DOI: 10.1111/j.1460-9568.2007.05769.

Bloody Good! The Impact of eLearning on Medical and Nursing Practice

Blood transfusion is a commonly-performed medical procedure that improves and saves the lives of patients. However, this procedure also has significant risks, is sometimes used inappropriately and has substantial costs associated with the collection, testing, processing and distribution of blood and blood products.BloodSafe eLearning Australia (BEA) (www.bloodsafelearning.org.au) is an education program for Australian doctors, nurses and midwives, designed to improve the safety and quality of clinical transfusion practice. Courses are interactive and include case studies, videos, and best-practice tips. Successful completion of a multiple-choice assessment provides learners with a certificate of completion. To date there are more than 400,000 registered learners, from more than 1500 organisations, who have completed more than 765,000 courses.Stakeholder feedback shows that the program: provides credible, consistent education across Australia; is cost effective; reduces duplication; is ‘best-practice’ elearning that is readily accessible; allows institutions to focus on practical aspects of transfusion education; results in change to clinical practice; and supports the broader implementation of a blood management strategy in Australia.User evaluation shows that the courses have a positive impact, with 89% of respondents stating they had gained additional knowledge of transfusion practice, processes and/or policy and more than 87% reporting they will make, or have made, changes to their work practices which will improve patient safety and outcomes.The BloodSafe eLearning Australia program provides education to a large number of health professionals across Australia. Evaluation demonstrates that these courses provide users with a consistent and reliable knowledge base that translates into changes to practice and improved patient outcomes

Federated Governance: A successful model for e-learning

An innovative and sustainable approach to clinical e-learning is described. The approach is based on a national federation to provide funding, clinical and educational expertise, IT solutions and program oversight; to develop, curate and champion a resource with multiple courses for healthcare professionals. The approach has resulted in formal recognition by nearly all Australian healthcare organizations and a high course completion rate by individuals. Crucially the approach has succeeded in increasing learner motivation to complete the course and delivered unexpected benefits in process and cost efficiency

Impact of Conventional and Integrated Management Systems on the Water-Soluble Vitamin Content in Potatoes, Field Beans, and Cereals

The reduction of the environmental footprint of crop production without compromising crop yield and their nutritional value is a key goal for improving the sustainability of agriculture. In 2009, the Balruddery Farm Platform was established at The James Hutton Institute as a long-term experimental platform for cross-disciplinary research of crops using two agricultural ecosystems. Crops representative of UK agriculture were grown under conventional and integrated management systems and analyzed for their water-soluble vitamin content. Integrated management, when compared with the conventional system, had only minor effects on water-soluble vitamin content, where significantly higher differences were seen for the conventional management practice on the levels of thiamine in field beans (<i>p</i> < 0.01), Spring barley (<i>p</i> < 0.05), and Winter wheat (<i>p</i> < 0.05), and for nicotinic acid in Spring barley (<i>p</i> < 0.05). However, for all crops, variety and year differences were of greater importance. These results indicate that the integrated management system described in this study does not significantly affect the water-soluble vitamin content of the crops analyzed here