Kynurenines in neurological disorders

The kynurenine pathway is thought to be involved in neurological disorders but its precise role and the mechanisms involved have yet to be established. Tryptophan can be metabolised via this pathway to produce the neurotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN), and the direct generators of reactive oxygen species, 3-hydroxykynurenine (3HKYN) and 3-hydroxyanthranilic acid (3HANA), as well as the neuroprotective NMDA receptor antagonist, kynurenic acid (KYNA). High performance liquid chromatography (HPLC) methods were successfully developed and validated for measuring tryptophan, kynurenine, KYNA, 3HANA and anthranilic acid (ANA) in blood samples, using absorbance and fluorescence detection. The method for determining 3HKYN using electrochemical detection was more problematic and was only used for tryptophan loaded samples and their respective baseline samples. Using HPLC, the concentrations of tryptophan, kynurenine, KYNA, 3HKYN and 3HANA were measured in the blood of Huntington's disease (HD) patients and patients with chronic brain injury, where the injury had occurred at least one year previously. QUIN was also determined for these patients using gas chromatography-mass spectrometry (GC-MS). In addition, the dynamics of the kynurenine pathway were investigated following oral tryptophan depletion and loading. In contrast to these chronic conditions, patients with acute stroke were also studied. The concentrations of tryptophan, kynurenine, KYNA, ANA and 3HANA were determined in the blood of the stroke patients, examining any changes in these concentrations during the two weeks after the stroke. The extent of inflammation and oxidative stress were also assessed for all patients, by measuring the levels of neopterin and the lipid peroxidation products, malondialdehyde and 4-hydroxynonenal. Patients with late stage HD showed abnormal tryptophan metabolism via the kynurenine pathway, together with increased inflammation and oxidative stress. Increased levels of kynurenine together with increased kynurenine: tryptophan (K:T) ratios, indicating greater indoleamine 2,3-dioxygenase (IDO) activity, were observed in blood samples from HD patients in comparison with healthy control subjects. In conjunction with this increased IDO activity, there was a decrease in the ratios of KYNA: kynurenine, suggesting decreased kynurenine aminotransferase (KAT) activity. Inflammation, which may be stimulating IDO activity, could also be decreasing KAT activity, suggested by negativecorrelations between the KYNA: kynurenine ratios and the inflammatory marker, neopterin. The inactivity of KAT suggests a small deficiency in KYNA over a long period of time which could cause a reduction in NMDA receptor antagonism, resulting in slow progressive excitotoxicity contributing to the neurodegeneration in HD. Low KYNA: kynurenine ratios were observed in baseline and tryptophan depleted samples, but after tryptophan loading, HD patients showed similar ratios compared with control subjects. This suggests that loading may be beneficial for HD patients, as more of the neuroprotectant, KYNA can potentially be produced. However, the results suggest that concentrations of the neurotoxin, QUIN, may also be increasing after tryptophan loading. Low concentrations of 3HKYN and 3HANA, with no change in QUIN levels, were also observed in the blood of HD patients. 3HANA levels continued to be decreased for the HD patients after loading. This may suggest degradation of 3HKYN and 3HANA by autoxidation producing reactive oxygen species which could contribute to the high levels of oxidative stress found in these patients. Tryptophan loading in healthy control subjects showed significant increases in the inflammatory marker, neopterin, and in the lipid peroxidation products. These results should be considered when tryptophan loading is used in psychiatric practice and in diets high in tryptophan, such as the Atkins diet. Patients with severe chronic brain injury showed similar alterations in kynurenine pathway metabolism as HD patients, at baseline and throughout the loading and depletion protocols. Although the brain injury had occurred at least one year previously, these patients showed persistent inflammation and oxidative stress, demonstrated by their increased levels of neopterin and lipid peroxidation products compared with healthy controls. In baseline blood samples, there were increased K:T ratios indicating greater IDO activity in the patients. Patients with chronic brain injury showed decreased concentrations of the neuroprotectant, KYNA, as well as low KAT activity, indicated by the decreased KYNA: kynurenine ratios. After tryptophan loading, K:T ratios decreased and the KYNA: kynurenine ratios increased in patients in comparison with controls, suggesting a reversal in the activities of the enzymes IDO and KAT. Similar levels of the inflammatory marker, neopterin, were observed in patients and controls after tryptophan loading. This suggests that these changes in IDO and KAT activities may be related to inflammation. As for the HD patients, patients with chronic brain injury showed lower levels of 3HKYN and 3HANA in their blood, with no change in QUIN levels. These metabolites may be undergoing autoxidation, producing reactive oxygen species which contribute to the ongoing oxidative stress in these patients.The kynurenine pathway was activated following an acute stroke, as indicated by the increased K:T ratios, suggesting greater IDO activity. Stroke patients also had raised levels of neopterin and lipid peroxidation products, indicating inflammation and oxidative stress. There were no changes in the blood concentrations of kynurenines, neopterin or lipid peroxidation products during the fourteen days after a stroke. Stroke patients had reduced levels of 3HANA in their blood, as observed for the HD and chronic brain injury patients. There were negative correlations between the concentration of 3HANA and the volume of the brain lesion, measured by computed tomography (CT) scan, demonstrating the importance of the decreased concentrations of 3HANA. In addition, there were increased levels of ANA in the blood of the stroke patients and the ratios of 3HANA: ANA also correlated with brain lesion volume. Another measurement which correlated with lesion volume was lipid peroxidation, suggesting that oxidative stress contributes to the extent of the brain damage after a stroke. This may suggest that the role of 3HANA in stroke is related to its autoxidation and the generation of reactive oxygen species. Increased concentrations of KYNA were observed in patients who died within three weeks of having a stroke. These high levels of KYNA may have been produced following excitotoxicity and the generation of free radicals, and may cause excessive NMDA receptor blockade or reduced mitochondrial adenosine triphosphate (ATP) synthesis, thus contributing to cell death. The kynurenine pathway was activated and showed abnormal metabolism in all the patient groups, suggesting a potential role for these metabolites in neuronal dysfunction in HD, chronic brain injury and acute stroke. Further work is required to elucidate the role of tryptophan metabolites and whether they may have a direct contribution to neuronal damage in neurological disorders

Incorporating the nursing and midwifery Aboriginal and Torres Strait Islander health curriculum framework into a BN program

When considering Aboriginal and Torres Strait Islander people\u27s culture, the appropriate approach with students should be to explore and reflect upon cultural safety initially followed by context, with an overlay of Aboriginal and Torres Strait Islander health throughout. * Learning outcomes should be reflective of this process throughout a curriculum - novice, intermediate and entry to practice, developing complexity throughout a degree to increase understanding and application. * Using the CATSINaM Nursing and Midwifery Aboriginal and Torres Strait Islander Health Curriculum Framework will facilitate progression and integration into curriculum. * How can I develop Aboriginal and non-Aboriginal partnerships to cocreate curriculum content

Health screening, cardiometabolic disease and adverse health outcomes in individuals with severe mental illness

Background: Poor physical health in severe mental illness (SMI) remains a major issue for clinical practice. Aims: To use electronic health records of routinely collected clinical data to determine levels of screening for cardiometabolic disease and adverse health outcomes in a large sample (n = 7718) of patients with SMI, predominantly schizophrenia and bipolar disorder. Method: We linked data from the Glasgow Psychosis Clinical Information System (PsyCIS) to morbidity records, routine blood results and prescribing data. Results: There was no record of routine blood monitoring during the preceding 2 years for 16.9% of the cohort. However, monitoring was poorer for male patients, younger patients aged 16–44, those with schizophrenia, and for tests of cholesterol, triglyceride and glycosylated haemoglobin. We estimated that 8.0% of participants had diabetes and that lipids levels, and use of lipid-lowering medication, was generally high. Conclusions: Electronic record linkage identified poor health screening and adverse health outcomes in this vulnerable patient group. This approach can inform the design of future interventions and health policy

Determination of quantitative trait loci (QTL) for early maturation in rainbow trout (Oncorhynchus mykiss)

To identify quantitative trait loci (QTL) influencing early maturation (EM) in rainbow trout (Oncorhynchus mykiss), a genome scan was performed using 100 microsatellite loci across 29 linkage groups. Six inter-strain paternal half-sib families using three inter-strain F(1) brothers (approximately 50 progeny in each family) derived from two strains that differ in the propensity for EM were used in the study. Alleles derived from both parental sources were observed to contribute to the expression of EM in the progeny of the brothers. Four genome-wide significant QTL regions (i.e., RT-8, -17, -24, and -30) were observed. EM QTL detected on RT-8 and -24 demonstrated significant and suggestive QTL effects in both male and female progeny. Furthermore, within both male and female full-sib groupings, QTL on RT-8 and -24 were detected in two or more of the five parents used. Significant genome-wide and several strong chromosome-wide QTL for EM localized to different regions in males and females, suggesting some sex-specific control. Namely, QTL detected on RT-13, -15, -21, and -30 were associated with EM only in females, and those on RT-3, -17, and -19 were associated with EM only in males. Within the QTL regions identified, a comparison of syntenic EST markers from the rainbow trout linkage map with the zebrafish (Danio rerio) genome identified several putative candidate genes that may influence EM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10126-008-9098-5) contains supplementary material, which is available to authorized users

Making the links between illness experience and person-centred care through concept mapping

poster presentation

A creation story of leadership development

Background: This article focuses on key reflection and learning by team members of a project that evaluated the development of leadership skills in senior staff from a rural local health district in New South Wales, Australia. The project evaluated the outcomes of learning and teaching strategies used in the delivery of the Effective Leadership Program, together with the impact that empowerment had on enabling individuals to flourish in their growth and development as leaders. Aims: This article aims to demonstrate how the creative research methodology empowered participants to be active in the evaluation process while challenging them through innovation. Conclusions: Through creative approaches to evaluation of the Effective Leadership Program, it became evident that participants gained heightened awareness and appreciation of their own leadership skills and knowledge. In addition, critical creativity was shown to facilitate healthcare practitioners\u27 readiness for and receptiveness to change and challenging processes, bringing a more critical approach to decisions. Relevance to practice development: Creativity forms a key component of practice development and can stimulate new thought and action in individuals to work in person-centred ways. The processes outlined in the project used practice development methods to facilitate learning in participants at a deep level

What is the lived experience of Advanced Nurse Practitioners of managing risk and patient safety in acute settings? A phenomenological perspective

Background: Managing clinical risk and patient safety is high on clinical and political agendas. Advanced Nurse Practitioners (ANPs) are frontline practitioners making critical decisions regarding risk and patient safety. Whilst research around nurse decision-making has been conducted, the extent to which ANPs manage and navigate patient safety and risk is under-researched. Research question: What is the lived experience of Advanced Nurse Practitioners of managing risk and patient safety in acute settings? A phenomenological perspective.Method: Ten ANPs across three acute settings were recruited and iterative data collected over ten months on experiences of managing risk and safety (reflective interviews, written reflections, researcher journal). Data analysis was based on Van Manen’s approach, assisted by NVivo 11 to facilitate circles of interpretation with each data source.Findings: In an environment driven by time pressures, how practitioners cope with managing risk and patient safety is dependent on the presenting situation, breadth of knowledge-base, application of evidence, degree of perceived management support, and channelling of emotive moods. In situations of uncertainty, insufficient knowledge, and/or lack of information, practitioners were guided by care, concern, worry, feeling happy or comfortable and, in critical times, fuelled by fear. These were illuminated to be both drivers and barriers to practitioners’ capabilities in grasping patient presentations. Snapshot judgements were individualized and negotiated dependent on practitioners’ and patients’ capacity to cope with risk. Experiences of risk often identified a learning need or knowledge deficit, revealing an opportunity to develop and advance ANP practice.Implications: These findings have implications for the preparation, training, and ongoing educational and emotional support of ANPs within their practice. Recognising the emotional toll of managing risk and providing the necessary support will ultimately positively impact recruitment and retention of these crucial health care professionals

A creation story of leadership development

Background: This article focuses on key reflection and learning by team members of a project that evaluated the development of leadership skills in senior staff from a rural local health district in New South Wales, Australia. The project evaluated the outcomes of learning and teaching strategies used in the delivery of the Effective Leadership Program, together with the impact that empowerment had on enabling individuals to flourish in their growth and development as leaders. Aims: This article aims to demonstrate how the creative research methodology empowered participants to be active in the evaluation process while challenging them through innovation. Conclusions: Through creative approaches to evaluation of the Effective Leadership Program, it became evident that participants gained heightened awareness and appreciation of their own leadership skills and knowledge. In addition, critical creativity was shown to facilitate healthcare practitioners’ readiness for and receptiveness to change and challenging processes, bringing a more critical approach to decisions. Relevance to practice development: Creativity forms a key component of practice development and can stimulate new thought and action in individuals to work in person-centred ways. The processes outlined in the project used practice development methods to facilitate learning in participants at a deep level