Developmental critical period in genetic redox dysregulation: animal and human studies in schizophrenia

Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the major cellular antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Importantly, abnormal GSH synthesis of genetic origin was observed: Two case-control studies showed an association with a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease associated genotypes (35% of patients) correlated with decreased GCLC protein, GCL activity and GSH content. Similar GSH system anomalies were observed in early psychosis patients. Such redox dysregulation combined with environmental stressors at specific developmental stages could underlie structural and functional connectivity anomalies. In pharmacological and knock-out (KO) models, GSH deficit induces anomalies analogous to those reported in patients. (a) morphology: spine density and GABA-parvalbumine immunoreactivity (PV-I) were decreased in anterior cingulate cortex. KO mice showed delayed cortical PV-I at PD10. This effect is exacerbated in mice with increased DA from PD5-10. KO mice exhibit cortical impairment in myelin and perineuronal net known to modulate PV connectivity. (b) physiology: In cultured neurons, NMDA response are depressed by D2 activation. In hippocampus, NMDA-dependent synaptic plasticity is impaired and kainate induced g-oscillations are reduced in parallel to PV-I. (c) cognition: low GSH models show increased sensitivity to stress, hyperactivity, abnormal object recognition, olfactory integration and social behavior. In a clinical study, GSH precursor N-acetyl cysteine (NAC) as add on therapy, improves the negative symptoms and decreases the side effects of antipsychotics. In an auditory oddball paradigm, NAC improves the mismatched negativity, an evoked potential related to pre-attention and to NMDA receptors function. In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysregulation of GSH synthesis combined with environmental insults in early development represent a major risk factor contributing to the development of schizophrenia

Uuden tiedon luominen maakuntalehden skenaarioprosessissa

Työssä tarkastellaan skenaariomenetelmän toimivuutta uuden tiedon luomisen välineenä ja eri teoreettisten mallien kykyä kuvata tiedon luomista tässä kontekstissa. Tutkimusmenetelminä käytetään osallistuvaa havainnointia skenaarioistunnossa, lomakekyselyä ja haastatteluja. Uuden tiedon luomista tarkastellaan erilaisten teoreettisten mallien kautta. Mukana on Nonakan SECI-malli ja Ba-käsite, Scharmerin piilevän tiedon luomisen spiraali, Snowdenin Cynefin-malli ja von Kroghin huolenpidon käsite. Työssä havaittiin, ettei mikään edellä mainituista uuden tiedon luomisen malleista ollut täysin tunnistettavissa skenaarioprosessissa, eikä mikään niistä kyennyt kuvaamaan uuden tiedon luomista kattavasti tässä kontekstissa. Erityisen vaikeaa tutkimustilanteessa oli tunnistaa kaaoksesta pulppuavaa, ei vielä muotoutunutta tietoa. Skenaariomenetelmä toimikin parhaiten strategisen ajattelun apuvälineenä. Tiedon luomisen kannalta se loi ennen kaikkea uutta ymmärrystä. Uusi tieto oli luonteeltaan synteesiä olemassa olevasta tiedosta, joka auttoi hahmottamaan menneisyyttä, nykyisyyttä ja tulevaisuutta.

Structural connectomics in brain diseases.

Imaging the connectome in vivo has become feasible through the integration of several rapidly developing fields of science and engineering, namely magnetic resonance imaging and in particular diffusion MRI on one side, image processing and network theory on the other side. This framework brings in vivo brain imaging closer to the real topology of the brain, contributing to narrow the existing gap between our understanding of brain structural organization on one side and of human behavior and cognition on the other side. Given the seminal technical progresses achieved in the last few years, it may be ready to tackle even greater challenges, namely exploring disease mechanisms. In this review we analyze the current situation from the technical and biological perspectives. First, we critically review the technical solutions proposed in the literature to perform clinical studies. We analyze for each step (i.e. MRI acquisition, network building and network statistical analysis) the advantages and potential limitations. In the second part we review the current literature available on a selected subset of diseases, namely, dementia, schizophrenia, multiple sclerosis and others, and try to extract for each disease the common findings and main differences between reports.

Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients.

BACKGROUND: Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited. STUDY DESIGN/METHODS: Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients' and their families' quality of life was assessed. RESULTS: The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents' point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls. CONCLUSION: Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.

Neuroligin-1 links neuronal activity to sleep-wake regulation.

Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.

Competitor Information andCompetitive Knowledge Management in a Large Industrial Organization

Thisthesis supplements the systematic approach to competitive intelligence and competitor analysis by introducing an information-processing perspective on management of the competitive environment and competitors therein. The cognitive questions connected to the intelligence process and also the means that organizational actors use in sharing information are discussed. The ultimate aim has been to deepen knowledge of the different intraorganizational processes that are used in acorporate organization to manage and exploit the vast amount of competitor information that is received from the environment. Competitor information and competitive knowledge management is examined as a process, where organizational actorsidentify and perceive the competitive environment by using cognitive simplification, make interpretations resulting in learning and finally utilize competitor information and competitive knowledge in their work processes. The sharing of competitive information and competitive knowledge is facilitated by intraorganizational networks that evolve as a means of developing a shared, organizational level knowledge structure and ensuring that the right information is in the right place at the right time. This thesis approaches competitor information and competitive knowledge management both theoretically and empirically. Based on the conceptual framework developed by theoretical elaboration, further understanding of the studied phenomena is sought by an empirical study. The empirical research was carried out in a multinationally operating forest industry company. This thesis makes some preliminary suggestions of improving the competitive intelligence process. It is concluded that managing competitor information and competitive knowledge is not simply a question of managing information flow or improving sophistication of competitor analysis, but the crucial question to be solved is rather, how to improve the cognitive capabilities connected to identifying and making interpretations of the competitive environment and how to increase learning. It is claimed that competitive intelligence can not be treated like an organizational function or assigned solely to a specialized intelligence unit.