AHAA- Agile, Hybrid Assessment Method for Automotive, Safety Critical SMEs

The need for software is increasingly growing in the automotive industry. Software development projects are, however, often troubled by time and budget overruns, resulting in systems that do not fulfill customer requirements. Both research and industry lack strategies to combine reducing the long software development lifecycles (as required by time-to-market demands) with increasing the quality of the software developed. Software process improvement (SPI) provides the first step in the move towards software quality, and assessments are a vital part of this process. Unfortunately, software process assessments are often expensive and time consuming. Additionally, they often provide companies with a long list of issues without providing realistic suggestions. The goal of this paper is to describe a new low-overhead assessment method that has been designed specifically for small-to-medium-sized (SMEs) organisations wishing to be automotive software suppliers. This assessment method integrates the structured-ness of the plan-driven SPI models of Capability Maturity Model Integration (CMMI) and Automotive SPICETM with the flexibleness of agile practices

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Endogenous kynurenic acid and schizophrenia : Physiological and pharmacological aspects

Kynurenic acid is a glutamate receptor antagonist with a preferential action at the glycine/Dserine site of the N-methyl-D-aspartic acid (NMDA) receptor. The compound is a metabolite of tryptophan and is synthesized in astrocytes. Previous studies have shown increased levels of kynurenic acid in the CSF and post mortem in the prefrontal cortex of patients with schizophrenia. The aim of the present thesis was to further investigate in the rat the physiological significance of kynurenic acid as well as its importance for the pathophysiology of schizophrenia. Studies include a disclosure of a prostaglandin-mediated regulation of kynurenic acid synthesis and analysis of the role of the compound in the regulation of firing activity of dopamine neurons in ventral tegmental area (VTA). Furthermore, an interaction of the antipsychotic drug clozapine with endogenous kynurenic acid is analyzed and the significance of kynurenic acid for behavior is studied using prepulse inhibition (PPI) methodology. Systemic administration of diclofenac and indomethacin, inhibitors with a preferential selectivity for cyclooxygenase (COX)-1, was associated with an increased formation of kynurenic acid in brain, whereas meloxicam and parecoxib, selective COX-2 inhibitors, decreased brain kynurenic acid formation. Both the elevation and the lowering in brain kynurenic acid levels following administration of the COX inhibitors were effectively prevented by the prostaglandin E1/E2 analog misoprostol. Pharmacological manipulation of kynurenic acid synthesis with COX inhibitors thus enabled us to study a role of the compound in the control of firing of midbrain dopamine neurons. An increase in brain kynurenic acid concentration (by 150-300%), induced by indomethacin, increased firing rate and burst firing activity of VTA dopamine neurons whereas a reduction in brain kynurenic acid concentration (by 39-44%) elicited by parecoxib, was associated with a clearcut reduction in firing activity of these neurons. Thus, endogenous brain concentrations of kynurenic acid appear to be of critical physiological importance for maintaining neuronal activity of VTA dopamine neurons. In the next series of experiments we investigated the effects of clozapine and haloperidol on VTA dopamine neurons in rats with attenuated NMDA receptor function induced by increased levels of endogenous brain kynurenic acid. Here, clozapine, in contrast to haloperidol, was found to interact with the NMDA receptor complex. We propose a novel mechanism of action of the atypical antipsychotic drug clozapine, i.e. stimulation of the glycine/D- serine site of the NMDA receptor. Elevated levels of endogenous kynurenic acid induced by systemic administration of kynurenine or PNU 156561A were associated with a disruption in PPI, an effect that could be reversed by antipsychotic drugs. It is proposed that kynurenic acid acts as an endogenous modulator of the PPI response. Taken together, the results of the present thesis suggest that endogenous kynurenic acid in the brain is involved in the physiological regulation of glutamate neurotransmission. Hereby, this endogenous NMDA receptor antagonist may participate in the pathophysiology of schizophrenia

Chronic Antipsychotic Treatment in the Rat – Effects on Brain Interleukin-8 and Kynurenic Acid

Schizophrenia is associated with activation of the brain immune system as reflected by increased brain levels of kynurenic acid (KYNA) and proinflammatory cytokines. Although antipsychotic drugs have been used for decades in the treatment of the disease, potential effects of these drugs on brain immune signaling are not fully known. The aim of the present study is to investigate the effects of chronic treatment with antipsychotic drugs on brain levels of cytokines and KYNA. Rats were treated daily by intraperitoneally administered haloperidol (1.5 mg/kg, n = 6), olanzapine (2 mg/kg, n = 6), and clozapine (20 mg/kg, n = 6) or saline ( n = 6) for 30 days. Clozapine, but not haloperidol or olanzapine-treated rats displayed significantly lower cerebrospinal fluid (CSF) levels of interleukin-8 compared to controls. Whole brain levels of KYNA were not changed in any group. Our data suggest that the superior therapeutic effect of clozapine may be a result of its presently shown immunosuppressive action. Further, our data do not support the possibility that elevated brain KYNA found in patients with schizophrenia is a result of antipsychotic treatment

The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions

The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n=27, males=12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF