Interfering with the CCL2–glycosaminoglycan axis as a potential approach to modulate neuroinflammation

Multiple Sclerosis, a chronic inflammatory demyelinating disease of the central nervous system, involves an increased expression of monocyte chemotactic protein 1 MCP1-/CCL2. For exerting its chemotactic effects, chemokine binding to glycosaminoglycans (GAGs) is required and therefore this interaction represents a potential target for therapeutic intervention. We have designed an anti inflammatory decoy variant, Met-CCL2 (Y13AS21K Q23R), embodying increased affinity for GAGs as well as knocked out GPCR activation properties. This non-signalling dominant-negative mutant is shown here to be able to displace wild type CCL2 from GAGs by which it is supposed to interfere with the chemokine-related inflammatory response. In vivo, the anti-inflammatory properties were successfully demonstrated in a murine model of zymosan-induced peritonitis as well as in an experimental autoimmune encephalomyelitis, a model relevant for multiple sclerosis, where the compound lead to significantly reduced clinical scores due to reduction of cellular infiltrates and demyelination in spinal cord and cerebellum. These findings indicate a promising potential for future therapeutic development

Different abnormalities of electroencephalographic (EEG) markers in quiet wakefulness are related to motor visual hallucinations in patients with Parkinson's and Lewy body diseases

AbstractBackgroundParkinson's disease (PD) is the second‐most common neurodegenerative disorder that affects 2–3% of the population ≥ 65 years of age and may belong to cognitive deficits and dementia in 50% of cases. Disease with Lewy Bodies (DLB) is emerging as another important cause of dementia in pathological aging. PD and DLB are both due to intra‐neuronal Lewy bodies and are characterized not only by motor dysfunctions but also by cognitive and/or psychiatric symptoms. An open issue is the extent to which these diseases are distinct entities. In this respect, here we compared cortical sources of resting state eyes‐closed electroencephalographic (rsEEG) rhythms in PD and DLB patients having visual hallucinations.MethodClinical and rsEEG rhythms in demographic matched PD (N = 93), DLB (N = 46), Alzheimer's disease dementia (AD, N= 70) and healthy elderly (Nold, N = 60) subjects were available from an international archive. Pathological groups were matched for cognitive status. Individual alpha frequency peak was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were considered. The eLORETA freeware estimated rsEEG cortical sources.ResultAs a confirmation of previous studies, compared to the Nold subjects, the AD, LBD, and PD patients showed higher widespread delta source activities and lower posterior alpha source activities. Specifically, posterior alpha source activities were more abnormal in the AD than the LBD and PD groups, while widespread delta source activities were more abnormal in the PD and DLB than the AD group. As novel results, in relation to the LBD and PD patients without visual hallucinations and the control groups (Nold, AD), those with visual hallucinations were characterized by higher parietal delta source activities (LBD, Figure 1) and parieto‐occipital alpha sources activities (PD, Figure 2).ConclusionThese novel results suggest that in LBD and PD patients resting in the quiet wakefulness, abnormalities in cortical neural synchronization at delta and alpha frequencies in parietal cortex are differently related to visual hallucinations despite the essence of alpha‐synucleinopathy

Functional cortical source connectivity of resting state electroencephalographic alpha rhythms shows similar abnormalities in patients with mild cognitive impairment due to Alzheimer's and Parkinson's diseases

Objective: This study tested the hypothesis that markers of functional cortical source connectivity of resting state eyes-closed electroencephalographic (rsEEG) rhythms may be abnormal in subjects with mild cognitive impairment due to Alzheimer's (ADMCI) and Parkinson's (PDMCI) diseases compared to healthy elderly subjects (Nold). Methods: rsEEG data had been collected in ADMCI, PDMCI, and Nold subjects (N = 75 for any group). eLORETA freeware estimated functional lagged linear connectivity (LLC) from rsEEG cortical sources. Area under receiver operating characteristic (AUROC) curve indexed the accuracy in the classification of Nold and MCI individuals. Results: Posterior interhemispheric and widespread intrahemispheric alpha LLC solutions were abnormally lower in both MCI groups compared to the Nold group. At the individual level, AUROC curves of LLC solutions in posterior alpha sources exhibited moderate accuracies (0.70-0.72) in the discrimination of Nold vs. ADMCI-PDMCI individuals. No differences in the LLC solutions were found between the two MCI groups. Conclusions: These findings unveil similar abnormalities in functional cortical connectivity estimated in widespread alpha sources in ADMCI and PDMCI. This was true at both group and individual levels. Significance: The similar abnormality of alpha source connectivity in ADMCI and PDMCI subjects might reflect common cholinergic impairment. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth

Tourismus im Ausseerland - Rückkehr zur Sommerfrische?

Was seinerzeit dem Adel und dem Bürgertum, den Künstler_innen und Literaten vorbehalten war, erfreute sich im Laufe der Zeit wachsender Beliebtheit: Der mehrwöchige Aufenthalt der städtischen Bevölkerung auf dem Lande. (vgl. POZDENA-TOMBERGER 1994: 35-43) Die vorliegende Diplomarbeit befasst sich mit dem touristischen Konzept der Sommerfrische und geht der Frage nach, ob gegenwärtig von einer Renaissance der Sommerfrische gesprochen werden kann. Das Hauptaugenmerk liegt dabei auf der Region „Ausseerland-Salzkammergut“, einem ländlichen Raum im Nordwesten der Steiermark, der in dieser Hinsicht auf eine lange Tradition zurückblickt. Basierend auf der facheinschlägigen Literatur, den analysierten Statistiken sowie den durchgeführten Expert_inneninterviews kann dahingehend festgehalten werden, dass der Tourismus im Allgemeinen sowie die Sommerfrische im Speziellen einen hohen Stellenwert im Ausseerland aufweisen und sich bereits im 19. Jahrhundert als wesentliche Wirtschaftsfaktoren etablierten. Die Auseinandersetzung mit der Thematik hat zusammenfassend gezeigt, dass nur bedingt von einer Rückkehr zur Sommerfrische im klassischen Sinne gesprochen werden kann. So wird der Begriff gegenwärtig zwar gerne im Marketing genutzt, da er gewisse positive Assoziationen bei potentiellen Gästen hervorruft und darüber hinaus auf der Gefühlsebene operiert. Gerade der Hinweis auf Assoziationen zeigt, dass es kein einheitliches Konzept der Sommerfrische gibt, sondern heterogene subjektive Erwartungen diese Idee nähren. Demgegenüber offenbart ein historischer Vergleich zu früheren Entwicklungen jedoch, dass von einer tatsächlichen Rückkehr zur Sommerfrische, wie sie damals vorherrschte, kaum gesprochen werden kann. Vor allem gesellschaftliche und ökonomische Entwicklungen sowie Verbesserungen im Bereich der Infrastruktur haben dies begünstigt

Fetal Human Keratinocytes Produce Large Amounts of Antimicrobial Peptides: Involvement of Histone-Methylation Processes

Antimicrobial peptides (AMPs), an important part of the innate immune system, are crucial for defense against invading microorganisms. Whereas AMPs have been extensively studied in adult skin, little is known about the impact of AMPs in the developing human skin. We therefore compared the expression and regulation of AMPs in fetal, neonatal, and adult keratinocytes (KCs) in vitro. The constitutive expression of human β-defensin-2 (HBD-2), HBD-3, S100 protein family members, and cathelicidin was significantly higher in KCs from fetal skin than in KCs from postnatal skin. The capacity to further increase AMP production was comparable between prenatal and postnatal KCs. Analysis of skin equivalents (SEs) revealed a strong constitutive expression of S100 proteins in fetal but not in neonatal and adult SEs. The elevated AMP levels correlated with reduced H3K27me3 (tri-methyl-lysine 27 on histone H3) levels and increased expression of the histone demethylase JMJD3. Knockdown of JMJD3 in fetal KCs elevated H3K27me3 levels and significantly downregulated the expression of HBD-3, S100A7, S100A8, S100A9, and cathelicidin. Our data indicate a crucial contribution of histone modifications in the regulation of AMP expression in the skin during ontogeny. The elevated AMP expression in prenatal skin might represent an essential defense strategy of the unborn

Secretome of peripheral blood mononuclear cells enhances wound healing.

Non-healing skin ulcers are often resistant to most common therapies. Treatment with growth factors has been demonstrated to improve closure of chronic wounds. Here we investigate whether lyophilized culture supernatant of freshly isolated peripheral blood mononuclear cells (PBMC) is able to enhance wound healing. PBMC from healthy human individuals were prepared and cultured for 24 hours. Supernatants were collected, dialyzed and lyophilized (SEC(PBMC)). Six mm punch biopsy wounds were set on the backs of C57BL/6J-mice and SEC(PBMC) containing emulsion or controls were applied daily for three days. Morphology and neo-angiogenesis were analyzed by H&E-staining and CD31 immuno-staining, respectively. In vitro effects on diverse skin cells were investigated by migration assays, cell cycle analysis, and tube formation assay. Signaling pathways were analyzed by Western blot analysis. Application of SEC(PBMC) on 6 mm punch biopsy wounds significantly enhanced wound closure. H&E staining of the wounds after 6 days revealed that wound healing was more advanced after application of SEC(PBMC) containing emulsion. Furthermore, there was a massive increase in CD31 positive cells, indicating enhanced neo-angiogenesis. In primary human fibroblasts (FB) and keratinocytes (KC) migration but not proliferation was induced. In endothelial cells (EC) SEC(PBMC) induced proliferation and tube-formation in a matrigel-assay. In addition, SEC(PBMC) treatment of skin cells led to the induction of multiple signaling pathways involved in cell migration, proliferation and survival. In summary, we could show that emulsions containing the secretome of PBMC derived from healthy individuals accelerates wound healing in a mouse model and induce wound healing associated mechanisms in human primary skin cells. The formulation and use of such emulsions might therefore represent a possible novel option for the treatment of non-healing skin ulcers