Alpha-1-acid glycoprotein and its potential impact on local anesthetic dose in neonates.

BACKGROUND: Alpha-1-acid glycoprotein is an acute-phase protein with a high affinity for amide local anesthetics. Compared to adults, neonates have lower concentrations of this glycoprotein in plasma, and are therefore at higher risk of developing local anesthetic toxicity. Alpha-1-acid glycoprotein concentrations rise in adults after surgery as a response to stress as well as in inflammatory conditions. Previous studies have shown that concentrations of alpha-1-acid-glycoprotein in neonates vary postpartum, influenced by gestational age and mode of delivery. AIM: This study aims to determine the concentrations of alpha-1-acid glycoprotein pre- and postoperatively in neonates undergoing major surgery. This information is important for determining safe and effective dosage of local anesthetic in this vulnerable group of patients. METHODS: In this prospective observational study, 25 neonates (median 3 days of age) undergoing major surgery were included. Blood sampling was performed preoperatively and at four occasions postoperatively. Alpha-1-acid-glycoprotein plasma concentrations were analyzed using an immunoturbidimetric assay. Mann-Whitney U test, Kruskal-Wallis and Spearman ranking correlation test were used for the statistical analysis. RESULTS: Higher plasma concentrations of alpha-1-acid-glycoprotein were found 48 h postoperatively compared to preoperatively [median (inter-quartile range) 0.815 g L-1 (0.663-0.983 g L-1 ) vs. 0.300 g L-1 (0.205-0.480 g L-1 p < 0.001)], respectively. It was not possible to detect any influence of sex, postnatal age, gestational age, or delivery mode on alpha-1-acid-glycoprotein concentrations in our data. CONCLUSIONS: Alpha-1-acid-glycoprotein concentrations increase in neonates as a response to surgery regardless of gestational age, sex, or mode of delivery.

Transcriptional derepression of the ERVWE1 locus following influenza A virus infection.

UNLABELLED: Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus of the W family (HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast layer of the placenta. This locus is transcriptionally repressed in adult tissues through promoter CpG methylation and suppressive histone modifications. Whereas syncytin-1 appears to be crucial for the development and functioning of the human placenta, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. We previously reported on the transactivation of HERV-W elements, including ERVWE1, during influenza A/WSN/33 virus infection in a range of human cell lines. Here we report the results of quantitative PCR analyses of transcripts encoding syncytin-1 in both cell lines and primary fibroblast cells. We observed that spliced ERVWE1 transcripts and those encoding the transcription factor glial cells missing 1 (GCM1), acting as an enhancer element upstream of ERVWE1, are prominently upregulated in response to influenza A/WSN/33 virus infection in nonplacental cells. Knockdown of GCM1 by small interfering RNA followed by infection suppressed the transactivation of ERVWE1. While the infection had no influence on CpG methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays detected decreased H3K9 trimethylation (H3K9me3) and histone methyltransferase SETDB1 levels along with influenza virus proteins associated with ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present findings suggest that an exogenous influenza virus infection can transactivate ERVWE1 by increasing transcription of GCM1 and reducing H3K9me3 in this region and in other regions harboring HERV-W elements. IMPORTANCE: Syncytin-1, a protein encoded by the env gene in the HERV-W locus ERVWE1, appears to be crucial for the development and functioning of the human placenta and is transcriptionally repressed in nonplacental tissues. Nevertheless, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. In the present paper, we report findings suggesting that an exogenous influenza A virus infection can transactivate ERVWE1 by increasing the transcription of GCM1 and reducing the repressive histone mark H3K9me3 in this region and in other regions harboring HERV-W elements. These observations have implications of potential relevance for viral pathogenesis and for conditions associated with the aberrant transcription of HERV-W loci.

Plasma concentrations of levobupivacaine associated with two different intermittent wound infusion regimens following surgical ductus ligation in preterm infants.

BACKGROUND: Administration of local anesthetics by a surgically placed wound catheter has recently been shown to reduce the need for postoperative morphine administration in extremely preterm infants undergoing ductus ligation. The primary aim of this randomized safety study was to define the plasma levels of levobupivacaine (LB) following two different intermittent infusion regimens. METHODS: Eighteen preterm infants 23-27 gestational weeks, median birthweight 721 g scheduled for ductus ligation were included in the study. All patients were anesthetized according to a standardized protocol based on high-dose fentanyl (25-50 µg·kg(-1) ). Before skin closure, a subcutaneous catheter was inserted into the wound. The patients were randomized to receive one of the two intermittent infusion regimens: Group BII: Initial bolus plus early start of the intermittent infusion or Group DII: No bolus plus delayed start (8 h) of the intermittent infusion. Blood samples for determination of LB plasma concentrations were obtained on six occasions during the 24-h postoperative observation period, as well as hourly postoperative pain assessments using the Echelle Douleur Inconfort Noveau (EDIN) pain scale. RESULTS: Plasma concentrations of LB ranged from 0.094 to 1.682 µg·ml(-1) and 0 to 0.549 µg·ml(-1) in group BII and DII, respectively. Both regimens were associated with low postoperative EDIN pain scores (24 h median of 0 and 1 in group BII and DII, respectively). No signs of systemic local anesthetic toxicity were noted. CONCLUSIONS: The two studied intermittent infusion regimens were associated with plasma levels below potentially toxic levels and were both associated with adequate postoperative pain scores.

Plasma levels of levobupivacaine during continuous infusion via a wound catheter after major surgery in newborn infants: An observational study.

BACKGROUND: Epidurals may be challenging in neonatal patients due to technical difficulties relating to insertion and the risk of local anaesthesia toxicity. The use of wound catheters with an infusion of local anaesthetic has been shown to be well tolerated in adults and older children. There are few data concerning wound catheter techniques in neonatal patients. OBJECTIVES: The primary aim of this study was to analyse plasma levels of levobupivacaine associated with continuous wound infiltration via a catheter following neonatal surgical procedures. Secondary parameters, including the quality of postoperative analgesia and wound healing, were also noted. DESIGN: A prospective, observational study. SETTING: Paediatric ICU at the Karolinska University Hospital, Stockholm, Sweden, from March 2008 to December 2010. PATIENTS: Twenty newborn infants (median weight 3.48 kg) scheduled for major abdominal or thoracic surgery were included. Exclusion criteria were known or suspected hepatic dysfunction. Before skin closure, a subcutaneous catheter was inserted into the wound followed by a 0.5 mg kg(-1) bolus of levobupivacaine (0.125%, 0.4 ml kg(-1)) through the catheter. A continuous infusion was started 20 to 30 min later at a rate of 0.2 mg kg(-1)h(-1) (0.16 ml kg(-1) h(-1)). MAIN OUTCOME MEASURES: Plasma concentrations of levobupivacaine (total and unbound) at 12, 24, 48 and 72 h postoperatively. Morphine consumption, pain scores and wound healing were also analysed. RESULTS: Median concentrations of unbound and total levobupivacaine at 72 h were 0.018 and 1.305 µg ml(-1), respectively. In 18 out of 20 infants [90%; 95% confidence interval (CI) 68.3 to 98.8], the unbound plasma concentration of levobupivacaine remained relatively stable and below 0.05 µg ml(-1) throughout the 72 h observation period. Pain scores and morphine consumption levels were low. All wounds except one healed within 10 days. CONCLUSION: The studied infusion regimen was associated with plasma levels of levobupivacaine well below those associated with toxicity. Adequate wound healing, low pain scores and a reduced need for opioids were also noted.

Human cellular differences in cAMP--CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder.

Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.

Development and psychometric properties of the Swedish ALPS-Neo pain and stress assessment scale for newborn infants.

AIM: To validate and evaluate the psychometric properties of the ALPS-Neo, a new pain assessment scale created for the continuous evaluation of pain and stress in preterm and sick term infants. METHODS: A unidimensional scale for continuous pain, Astrid Lindgren Children's Hospital Pain Scale (ALPS 1), was developed further to assess continuous pain and stress in infants treated in the neonatal intensive care unit (NICU). The pain scale includes observations of five behaviours. A manual was created, clarifying the scoring criteria. An internal and an external panel assessed face validity. Psychometric properties were evaluated in three different steps. Inter-rater reliability was estimated from video-based assessments (n = 625) using weighted kappa statistics (test I). Inter-rater reliability was further evaluated in test II (n = 125) and test III (n = 96) by real-time assessments using the intraclass correlation coefficient (ICC) and Cronbach's alpha. RESULTS: The final inter-rater reliability (test III) was assessed as good with ICC 0.91 for the total score and 0.62-0.81 for the five items. Cronbach's alpha showed 0.95 for the total score. CONCLUSION: ALPS-Neo is a new assessment tool for optimising the management of pain and stress in newborn infants in the NICU. It has proved easy to implement and user-friendly, permitting fast, reliable observations with high inter-rater reliability.

New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio.

Altered function of kynurenine pathway has emerged recently as one of the factors contributing to the pathogenesis of depression. Neuroprotective kynurenic acid (KYNA) and neurotoxic 3-hydroxykynurenine (3-HK) are two immediate metabolites of L: -kynurenine. Here, we aimed to assess the hypothesis that antidepressant drugs that may change brain KYNA/3-HK ratio. In primary astroglial cultures, fluoxetine, citalopram, amitriptyline and imipramine (1-10 µM) increased de novo production of KYNA and diminished 3-HK synthesis (24 and 48, but not 2 h). RT-PCR studies revealed that Kat1, Kat2 and kynurenine-3-monooxygenase (Kmo) gene expressions were not altered after 2 h. At 24 h, the expression of Kat1 and Kat2 genes was enhanced by all studied drugs, whereas Kmo expression was diminished by citalopram, fluoxetine and amitriptyline, but not imipramine. After 48 h, the expression of Kat1 and Kat2 was further up-regulated, and Kmo expression was down-regulated by all antidepressants. The ratio KYNA/3-HK was increased by fluoxetine, citalopram, amitriptyline and imipramine in a time-dependent manner-the effect was not observed after 2 h, modest after 24 h and robust after 48 h incubation time. Our findings indicate that the action of antidepressants may involve re-establishing of the beneficial ratio between KYNA and 3-HK. Shift in the kynurenine pathway, observed after prolonged exposure to antidepressant drugs, may partly explain their delayed therapeutic effectiveness.

beta-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling.

The central levels of endogenous tryptophan metabolite kynurenic acid (KYNA), an antagonist of N-methyl-d-aspartate (NMDA) and alpha7-nicotinic receptors, affect glutamatergic and dopaminergic neurotransmission. Here, we demonstrate that selective agonists of beta(1)-receptors (xamoterol and denopamine), beta(2)-receptors (formoterol and albuterol), alpha- and beta-receptors (epinephrine), 8pCPT-cAMP and 8-Br-cAMP (analogues of cAMP) increase the production of KYNA in rat brain cortical slices and in mixed glial cultures. Neither betaxolol, beta(1)-adrenergic antagonist, nor timolol, a non-selective beta(1,2)-adrenergic antagonist has influenced synthesis of KYNA in both paradigms. In contrast, KT5720, a selective inhibitor of protein kinase A (PKA), strongly reduced KYNA formation in cortical slices (2-10 microM) and in glial cultures (100 nM). beta-adrenergic antagonists and KT5720 prevented the beta-adrenoceptor agonists-induced increases of KYNA synthesis. In vivo, beta-adrenergic agonist clenbuterol (0.1-1.0 mg/kg) increased the cortical endogenous level of KYNA; the effect was blocked with propranolol (10 mg/kg). beta-adrenoceptors agonists, cAMP analogues and KT5720 did not affect directly the activity of KAT I or KAT II measured in partially purified cortical homogenate. In contrast, the exposure of intact cultured glial cells to pCPT-cAMP, 8-Br-cAMP and formoterol has lead to an enhanced action of KATs. These findings demonstrate that beta-adrenoceptor-mediated enhancement of KYNA production is a cAMP- and PKA-dependent event. PKA activity appears to be an essential signal affecting KYNA formation. Described here novel mechanism regulating KYNA availability may be of a potential importance, considering that various stimuli, among them clinically used drugs, activate cAMP/PKA pathway, and thus could counteract the central deficits of KYNA.

Attitudes of patients and family members towards implantable psychiatric medication.

INTRODUCTION: Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term implantable medication delivery system. METHODS: The current study assesses attitudes towards implantable medication in psychiatric patients and their family members. Patients included in the study had diagnoses of Schizophrenia, Schizoaffective Disorder, Mood or Anxiety related disorders. RESULTS: 49.62% of patients and 74.47% of family members endorse support for implantable medication. CONCLUSIONS: This study demonstrates that implants may be an acceptable alternative to oral and injectable medication for a subset of psychiatric patients and their families.

Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism.

We describe a novel aspect of action of memantine ex vivo, in the brain cortical slices and in vitro, in mixed glial cultures. The drug potently increased the production of kynurenic acid, an endogenous tryptophan metabolite blocking N-methyl-D-aspartate (NMDA) and nicotinic alpha7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 microM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 microM) nor raclopride, D2 receptor antagonist (10 microM) changed the memantine-induced effects. Propranolol (100 microM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 microM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 microM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 microM) enhanced the production of kynurenic acid. Memantine (up to 0.5 mM) has not affected the activity of kynurenic acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of kynurenic acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.

Survival after PICU admission: The impact of multiple admissions and complex chronic conditions.

OBJECTIVE: Factors predicting survival over time after pediatric intensive care unit (PICU) admissions are not fully understood. The primary aim of the current study was to investigate whether multiple admissions (MADM) compared to single PICU admissions (SADM) were associated with poor survival over time after being admitted to PICU facilities. Our secondary aim was to investigate if the presence of a complex chronic condition (CCC) would further impair prognosis. DESIGN: A closed cohort of all children up to 16 years of age admitted to the three PICUs in Sweden between 2008 and 2010 was prospectively collected and followed until 2012, providing survival data for at least one but up to four years of follow-up. SETTING: Three Swedish tertiary referral centers for pediatric intensive care and extracorporeal membrane oxygenation (ECMO) care were used. PATIENTS: In total, 3,688 Swedish children with 5,019 PICU admissions were included. INTERVENTIONS: No interventions were conducted. MEASUREMENTS: An extensive data set was recorded, including up to four-year survival information following first PICU admission. The patients were assigned to seven admission diagnostic groups, which were then divided into SADM or MADM groups. The difference in survival over time and mortality rates (MR) and mortality rate ratios (MRR) were calculated. SADM and MADM groups with and without an existing CCC were formed. The difference in survival over time between groups was calculated. MAIN RESULTS: A highly significant difference in survival over time was noted between SADM and MADM patients (p<0.0001), which was intensified by the presence of a CCC. MADM patients with a CCC had the worst outcome, while SADM patients without a CCC had the best outcome. MADM patients with no CCC demonstrated decreased survival over time compared to SADM patients with a CCC. Survival over time was statistically worsened for patients with MADM compared to SADM for the following admission diagnostic groups: Cardiovascular, Gastrointestinal/Renal, Respiratory, Neurological, and Miscellaneous. The mortality rate (deaths/patient year of follow-up) during the time of follow-up was 0.023 for SADM and 0.062 for MADM patients. The mortality rate ratio (MRR) between these groups was 2.69. CONCLUSION: Compared to single admissions, multiple admissions to PICU were associated with a significant decrease in survival over time in some but not all diagnostic groups. Regarding our secondary aim, we found that when the presence of a CCC is factored into the survival analysis, survival over time is further impaired.

Prolonged therapy with antidepressants increases hippocampal level of kynurenic acid and expression of Kat1 and Kat2 genes.

BACKGROUND: Accumulating data suggest an important role of disturbed kynurenine pathway and altered glutamatergic transmission in the pathogenesis of depression. In here, we focused on detailed analyses of kynurenic acid (KYNA) status in vivo following single and 14-day administration of selected tricyclic antidepressant drugs (TCAs) and serotonin selective reuptake inhibitors (SSRIs) in rats. METHODS: The effect of antidepressants on serum and brain KYNA levels, as well as on the activity of kynurenine aminotransferases (KATs I and II) and expression of Kat1 and Kat2 genes mRNA was studied in three brain regions. RESULTS: Chronic, but not acute, application of antidepressants invariably stimulated KYNA production in hippocampus (amitriptyline, imipramine, fluoxetine and citalopram) and sporadically in cortex (amitriptyline, fluoxetine), whereas no change in KYNA level was observed in striatum. Cortical and hippocampal expression of Kat1 and Kat2 genes was increased after chronic, but not single administration of all studied antidepressants. The activity of semi-purified enzymatic proteins, KAT I and II, was not paralleling changes of Kat1 and Kat2 genes. CONCLUSION: Our data indicate that prolonged administration of antidepressants targets expression of KYNA biosynthetic enzymes. Furthermore, post-translational modulation of KATs seems to play an important role in tuning of KYNA synthesis within brain structures. We suggest that consistent increase of hippocampal KYNA levels may represent hallmark of antidepressant activity. Mechanisms governing region- and drug-selective action of antidepressants require further investigations.

Altered circadian clock gene expression in patients with schizophrenia.

Impaired circadian rhythmicity has been reported in several psychiatric disorders. Schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα and DBP. In fibroblasts obtained from patients with chronic schizophrenia, we found a loss of rhythmic expression of CRY1 and PER2 compared to cells from healthy controls. We also estimated the sleep quality in these patients and found that most of them suffered from poor sleep in comparison with the healthy controls. In another patient sample, we analyzed mononuclear blood cells from patients with schizophrenia experiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular clock in schizophrenia and have important implications in our understanding of the aberrant rhythms reported in this disease.

Inhibition of hippocampal synaptic transmission by impairment of Ral function.

Large clostridial cytotoxins and protein overexpression were used to probe for involvement of Ras-related GTPases (guanosine triphosphate) in synaptic transmission in cultured rat hippocampal neurons. The toxins TcdA-10463 (inactivates Rho, Rac, Cdc42, Rap) and TcsL-1522 (inactivates Ral, Rac, Ras, R-Ras, Rap) both inhibited autaptic responses. In a proportion of the neurons (25%, TcdA-10463; 54%, TcsL-1522), the inhibition was associated with a shift from activity-dependent depression to facilitation, indicating that the synaptic release probability was reduced. Overexpression of a dominant negative Ral mutant, Ral A28N, caused a strong inhibition of autaptic responses, which was associated with a shift to facilitation in a majority (80%) of the neurons. These results indicate that Ral, along with at least one other non-Rab GTPase, participates in presynaptic regulation in hippocampal neurons.

[Swedish guidelines for prevention and treatment of pain in the newborn infant]. / Svenska riktlinjer för prevention och behandling av smärta hos nyfödda.

A Swedish national consensus statement concerning prevention and management of pain in the newborn infant has been prepared by members of the Swedish Paediatric Pain Society (Svensk Barnsmärtförening, SBSF). The document is based on the Consensus Statement for the Prevention and Management of Pain in the Newborn Infant by Anand et al [1].

Can early follow-up after deliberate self-harm reduce repetition? A prospective study of 325 patients.

BACKGROUND: Patients who deliberately harm themselves often repeat their self-destructive acts. The objective of this study was to assess whether a follow-up visit within 10 days to a psychiatric consultant could reduce the frequency of repeated deliberate self-harm (DSH). METHODS: A cohort of 325 consecutive DSH patients attending two large emergency departments in Stockholm, Sweden, were included and followed for 6 months. Any visit to a psychiatric consultant within 10 days was registered as an early follow-up. Repeated DSH episode within 6 months among the 325 patients was detected via nationwide registers. MAIN OUTCOME MEASURE: Repeated DSH within 6 months. RESULTS: At 6 months follow-up 22 (24%) of 92 patients with an early follow-up had repeated their DSH acts compared to 58 (25%) of 233 patients without an early follow-up (OR 1.06 (95% CI: 0.60-1.85) p-value 0.85). After adjustment for possible confounders, multivariable analysis showed an OR of 1.22 (95% CI: 0.62-2.38, p-value 0.56). LIMITATIONS: Early follow-up was registered as any visit to a psychiatric consultant and no information regarding actions taken at the visit were obtained. CONCLUSION: After adjusting for other factors associated with repetition there was an association of patients who were offered and thereafter attended an early follow-up visit and a decreased risk of repeated DSH.

Can repetition of deliberate self-harm be predicted? A prospective multicenter study validating clinical decision rules.

BACKGROUND: Clinical decision rules have been developed to help identify patients at high risk of repeating deliberate self-harm actions. The objective of this study was to prospectively validate the clinical decision rules', Södersjukhuset Self-Harm Rule and Manchester Self-Harm Rule, ability to predict repetition of deliberate self-harm (DSH). METHODS: A consecutive series of 325 patients attending two large emergency departments in Stockholm, Sweden due to DSH were included and followed for six months. Predictive factors were collected from hospital charts at the emergency department. A nationwide register-based follow-up of new DSH within six months was used. We calculated the sensitivity and specificity to evaluate the different decision rules' ability to identify repetition of DSH. Main outcome measure repeated DSH within six months. RESULTS: The cumulative incidence for patients repeating within six months was 24.6% (95% CI: 19.9-29.3). Application of Södersjukhuset Self-Harm Rule yielded a sensitivity of 89% (95%CI: 79.2-94.4) and a specificity of 11% (95%CI: 7.9-16.2). Application of Manchester Self-Harm Rule to our material yielded a sensitivity of 94% (95%CI: 85.4-97.7) and a specificity of 18% (95%CI: 13.8-23.9). LIMITATIONS: If data regarding predictive factors were missing it was not possible to investigate this further and in the statistical analysis missing data was classified as no. This would imply that the predicted risks may be underestimated. CONCLUSION: Clinical decision rules could be used as a compliment providing important additional information regarding risk of repetition in an ED setting when focusing on high sensitivity.

Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine.

Accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, or their combinations, in cells exposed to exogenous kynurenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1ß, IL-6, IFN-γ + TNF-α, or IFN-γ + IL-1ß, as well as between schizophrenia case status and IL-1ß, IFN-γ + TNF-α, or IFN-γ + IL-1ß, in terms of higher 3-HK. Noteworthy, no case-treatment interactions in terms of KYNA production were found. Observed changes did not appear to correlate with the expression of genes encoding kynurenine aminotransferases (KATs), kynureninase (KYNU) or kynurenine-3-monooxygenase (KMO). The single nucleotide polymorphisms (SNPs), rs1053230 and rs2275163, in KMO influenced KYNA levels yet did not explain the case-treatment discrepancies. In conclusion, our present findings indicate the utility of skin-derived fibroblasts for kynurenines research and support the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases.

Increased plasma levels of thioredoxin-1 in patients with first episode psychosis and long-term schizophrenia.

Excessive level of radicals and/or dysfunctional antioxidant response, oxidative stress, is implicated in the pathogenesis of schizophrenia. A condition of oxidative stress has been detected in the brain, peripheral tissues and fluids including plasma. Plasma thioredoxin-1 (Trx1) is well characterized and a putative marker for oxidative stress and recently shown to be increased in plasma at the onset of schizophrenia. The present study aimed to explore whether Trx1 can be used as a marker to identify schizophrenic patients at the time-point when patients have their first episode of psychosis as compared to patients with long-term schizophrenia and mentally healthy patients, respectively. Plasma samples obtained from 18 patients at first episode of psychosis, from 49 long-term schizophrenic patients and from 20 mentally healthy controls (admitted with minor physical injury to the general ward) where analyzed by ELISA for Trx1. The patients with first episode of psychosis were diagnosed at least 6 months later and shown to constitute various psychotic syndromes, including schizophrenia, or affective disorder. The concentration of Trx1 in the patients with first episode of psychosis was 1.5 ± 1.0 ng/ml and 0.8 ± 0.6 ng/ml in controls. In the long-term schizophrenic patients the plasma concentration was 1.5 ± 0.7. The differences between the groups of acute psychotic or long-term schizophrenia patients to controls were significant (p < 0.016 and p < 0.001, respectively). Our data indicate that Trx1 may not be used as an early marker to identify schizophrenic patients in a mixed population of first episode psychotic patients. Further, Trx1 did not discriminate with reliable accuracy patients with psychotic disorder from mentally healthy controls on an individual basis due to overlap in levels of Trx1. However, our observations show that psychotic patients in general are in a significant long-term condition of oxidative stress, with possible implications for the profound morbidity and mortality found in this patient population.