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List of excluded full-text articles and the primary reason for exclusion. (DOCX 45 kb

CLIC-2 modulates cardiac ryanodine receptor Ca(2+) release channels

We have examined the biochemical and functional properties of the recently identified, uncharacterised CLIC-2 protein. Sequence alignments showed that CLIC-2 has a high degree of sequence similarity with CLIC-1 and some similarity to the omega class of glutathione transferases (GSTO). A homology model of CLIC-2 based on the crystal structure of CLIC-1 suggests that CLIC-2 belongs to the GST structural family but, unlike the GSTs, CLIC-2 exists as a monomer. It also has an unusual enzyme activity profile. While the CXXC active site motif is conserved between CLIC-2 and the glutaredoxins, no thiol transferase activity was detected. In contrast, low glutathione peroxidase activity was recorded. CLIC-2 was found to be widely distributed in tissues including heart and skeletal muscle. Functional studies showed that CLIC-2 inhibited cardiac ryanodine receptor Ca2+ release channels in lipid bilayers when added to the cytoplasmic side of the channels and inhibited Ca2+ release from cardiac sarcoplasmic reticulum vesicles. The inhibition of RyR channels was reversed by removing CLIC-2 from the solution or by adding an anti-CLIC-2 antibody. The results suggest that one function of CLIC-2 might be to limit Ca2+ release from internal stores in cells

Age and circadian influences on picolinic acid concentrations in human cerebrospinal fluid

It has been suggested that picolinic acid (PIC), an endogenous metabolite of l-tryptophan, possesses neuro-protective and anti-proliferative effects within the CNS. However, the literature surrounding PIC is limited, and its exact endogenous function is not known. Picolinic acid is produced via the kynurenine pathway which has been implicated in the pathogenesis of a range of neuro-inflammatory diseases. Although not extensively studied, there have been reports of altered PIC production alongside other kynurenine metabolites in inflammatory disorders. In order to investigate whether PIC concentrations are altered with disease in the CNS, we analysed PIC levels in the CSF of 241 patients who underwent lumbar puncture as part of their standard clinical evaluation. In patients with no apparent CNS disease, CSF PIC levels were 10-fold higher in samples taken between 20:00 and 16:00 h compared with those collected between 04:00 and 12:00 h. This result suggests a diurnal variation in PIC synthesis within the CNS. In addition, we observed a direct correlation between a patient's age and their PIC concentration. No significant correlations were observed between CSF PIC levels and any specific disease state.6 page(s

The kynurenine pathway and inflammation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P \u3c 0.0001), KYN (P \u3c 0.0001) and QUIN (P \u3c 0.05) and decreased levels of serum PIC (P \u3c 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P \u3c 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP

Adolescents' views on preventing self-harm: a large community study

Background: Deliberate self-harm (DSH) is a major problem in young people in the United Kingdom. The majority of young people who harm themselves do not seek help and therefore community based prevention strategies are important. However little is known about young peoples' views on the prevention of DSH. The aims of this study were to identify what adolescents believe can be done to prevent them from feeling like they want to harm themselves, and to investigate differences in the views held according to gender, ethnic group and previous experiences of self-harm. Method: Pupils is a representative sample of 41 secondary schools in England completed an anonymous, self-report questionnaire including the question "what do you think could be done to help prevent young people from feeling that they want to harm themselves?" Thematic analytic methods were used to categorise responses, which were then also analysed by gender, ethnicity, lifetime history of DSH and lifetime exposure to DSH among friends. Results: The written responses of 2,954 students aged 15-16 years were analysed. Eleven broad categories of responses were identified covering causes and possible ways of preventing suicidal behaviour in young people, including: the primacy of informal social networks over professional organisations, the importance of confiding stable relationships, the need for structured group activities, and the key role that schools play in young peoples lives. Mental illness was mentioned by only 3% of respondents, although concerns about stigma acted as a barrier to seeking help for some young people. Bullying and serious problems at home were highlighted as psychosocial stressors that need to be addressed. Conclusions: The adolescents in this study considered family, friends and school as the main sources of support in preventing suicidal behaviour, and more pertinent than external helping agencies. Enhancing the provision of school-based mental health programmes and increased youth-orientation in helping services are indicated

Carbohydrate oxidation and glucose utilisation under hyperglycaemia in aged and young males during exercise at the same relative exercise intensity

Purpose: The purpose of the present study was to investigate the age related carbohydrate oxidation and glucose utilisation rate response during exercise at the same relative intensity under hyperglycaemia in aged and young males Methods: 16 endurance trained aged (n = 8; 69.1 ± 5.2 yr) and young (n = 8; 22.4 ± 2.9 yr) males were studied during 40 minutes of cycling exercise (60% V̇O2max) under both hyperglycaemic and euglycaemic (control) conditions. Venous blood samples were collected at baseline, post infusion, mid and post exercise. Carbohydrate and fat oxidation rates were determined at both 15 and 35 mins during exercise and glucose utilisation rates were calculated. Results: The aged group displayed significantly lower rates of carbohydrate oxidation during exercise during maintained hyperglycemia (15 mins = 2.3 ± 0.4 vs. 1.6 ± 0.5 g.min-1; 35 mins = 2.3 ± 0.5 vs. 1.5 ± 0.5 g.min-1) and control (15 mins = 2.2 ± 0.4 vs. 1.6 ± 0.7 g.min-1; 35 mins = 1.9 ± 0.7 vs. 1.3 ± 0.7 g.min-1) conditions (P = 0.01). The rate of glucose utilisation during exercise was also significantly reduced (85.76 ± 23.95 vs 56.67 ± 15.09 uM.kg-1.min-1). There were no differences between age groups for anthropometric measures, fat oxidation, insulin, glucose, NEFA, glycerol and lactate (P > 0.05), although hyperglycemia resulted in elevated glucose and insulin, and attenuated fat metabolite levels. Conclusion: Our findings highlight that ageing results in a reduction in carbohydrate oxidation and utilisation rates during exercise at the same relative exercise intensity