1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis

Kynurenine Pathway (KP) is the dominant metabolic route of tryptophan which is catalyzed by indoleamine-2,3-dioxygenase (IDO). This pathway is upregulated in liver disease where the level of KP metabolites correlates with the severity of disease. Cirrhosis is associated with cardiac dysfunction, which manifests itself during severe physiological challenges such as liver transplantation. Cardiac dysfunction in cirrhosis is linked to systemic inflammation and impaired cardiac beta-adrenergic signaling pathways. The KP pathway is involved in modulation of cardiac signaling and is upregulated by systemic inflammation. Therefore, this study aimed to evaluate the effect of IDO inhibition on development of cardiac dysfunction in an experimental model of cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Experimental groups were given either 1-methyl tryptophan (1-MT, 1, 3, 9 mg/kg), or saline. 28 days after BDL, cardiac chronotropic response to epinephrine was assessed ex vivo. HPLC was employed to measure hepatic and cardiac levels of tryptophan, kynurenine and kynurenic acid. Cirrhosis in rats was associated with impaired cardiac chronotropic responsiveness to adrenergic stimulation. 1-MT dose-dependently improved cirrhosis-induced chronotropic dysfunction as well as elevated serum levels of CRP and IL-6 in BDL rats. Hepatic and cardiac kynurenine/tryptophan ratio were elevated in cirrhotic rats and were reduced following 1-MT administration. Chronic administration of 1-MT could also reduce hepatic inflammation, fibrosis and ductular proliferation. 1-MT attenuates cardiac dysfunction in rats with biliary cirrhosis. This protective effect is not limited to the cardiac function as liver histopathologic changes were also improved following chronic 1-MT administration

Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. RESULTS: A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aβ and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. CONCLUSIONS: The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential

Correction to Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? [Journal of Neuroinflammation (2013) 10, 34] 10.1186/1742-2094-10-34

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Prevalence of pathological internet use among adolescents in Europe: demographic and social factors.

AIMS: To investigate the prevalence of pathological internet use (PIU) and maladaptive internet use (MIU) among adolescents in 11 European countries in relation to demographic, social factors and internet accessibility. DESIGN: Cross-sectional survey. SETTING: The 7th Framework European Union (EU) funded project, Saving and Empowering Young Lives in Europe (SEYLE), is a randomized controlled trial (RCT) evaluating interventions for risk behaviours among adolescents in Austria, Estonia, France, Germany, Hungary, Ireland, Israel, Italy, Romania, Slovenia and Spain, with Sweden serving as the coordinating centre. PARTICIPANTS: A total of 11 956 adolescents (female/male: 6731/5225; mean age: 14.9 ± 0.89) recruited from randomly selected schools within the 11 study sites. MEASUREMENTS: Internet users were classified by gender into three categories: adaptive, maladaptive and pathological, based on their score in the Young Diagnostic Questionnaire for Internet Addiction (YDQ). FINDINGS: The overall prevalence of PIU was 4.4%; it was higher among males than females (5.2% versus 3.8%) and differed between countries (χ(2)  = 309.98; d.f. = 20; P < 0.001). PIU correlated significantly with mean hours online and male gender. The highest-ranked online activities were watching videos, frequenting chatrooms and social networking; significantly higher rates of playing single-user games were found in males and social networking in females. Living in metropolitan areas was associated with PIU. Students not living with a biological parent, low parental involvement and parental unemployment showed the highest relative risks of both MIU and PIU. CONCLUSIONS: Across a range of countries in Europe, using the Young Diagnostic Questionnaire for Internet Addiction yields a prevalence of 'pathological internet use' of 4.4% among adolescents, but varies by country and gender; adolescents lacking emotional and psychological support are at highest risk

Validation and cultural adaptation of a German version of the Physicians' Reactions to Uncertainty scales

Contains fulltext : 51656.pdf ( ) (Open Access)BACKGROUND: The aim of the study was to examine the validity of a translated and culturally adapted version of the Physicians' Reaction to Uncertainty scales (PRU) in primary care physicians. METHODS: In a structured process, the original questionnaire was translated, culturally adapted and assessed after administering it to 93 GPs. Test-retest reliability was tested by sending the questionnaire to the GPs again after two weeks. RESULTS: The principal factor analysis confirmed the postulated four-factor structure underlying the 15 items. In contrast to the original version, item 5 achieved a higher loading on the 'concern about bad outcomes' scale. Consequently, we rearranged the scales. Good item-scale correlations were obtained, with Pearson's correlation coefficient ranging from 0.56-0.84. As regards the item-discriminant validity between the scales 'anxiety due to uncertainty' and 'concern about bad outcomes', partially high correlations (Pearson's correlation coefficient 0.02-0.69; p < 0.001) were found, indicating an overlap between both constructs. The assessment of internal consistency revealed satisfactory values; Cronbach's alpha of the rearranged version was 0.86 or higher for all scales. Test-retest-reliability, assessed by means of the intraclass-correlation-coefficient (ICC), exceeded 0.84, except for the 'reluctance to disclose mistakes to physicians' scale (ICC = 0.66). In this scale, some substantial floor effects occurred, with 29.3% of answers showing the lowest possible value. CONCLUSION: Dealing with uncertainty is an important issue in daily practice. The psychometric properties of the rearranged German version of the PRU are satisfying. The revealed floor effects do not limit the significance of the questionnaire. Thus, the German version of the PRU could contribute to the further evaluation of the impact of uncertainty in primary care physicians