Regeneration of the endothelium in vascular injury

The endothelium mediates relaxations (dilatations) of the underlying vascular smooth muscle cells. The endothelium-dependent relaxations are due to the release of non-prostanoid vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also release substances (endothelium-derived hyperpolarizing factor, EDHF) that cause hyperpolarization of the cell membrane of the underlying vascular smooth muscle. The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive Gi (alpha2-adrenergic activation, serotonin, thrombin) and insensitive Gq (adenosine diphosphate, bradykinin) coupling proteins. The ability of the endothelial cell to release relaxing factors can be upregulated by impregnation with estrogens, exercise and antioxidants, and down-regulated by oxidative stress and increased presence of oxidized LDL. Following injury or apoptotic death, the endothelium regenerates. However, in regenerated endothelial cells, there is an early selective loss of the pertussis-toxin sensitive mechanisms of EDRF-release. Functional studies suggest that abnormal handling of LDL because of increased oxidative stress play a key role in this selective loss. Genomic analysis demonstrates the emergence of fatty acid binding protein-A (A-FBP) and metalloproteinase-7 (MMP7) in regenerated endothelial cells. The reduced release of NO resulting from the endothelial dysfunction in regenerated areas creates a locus minoris resistentiae which favors the occurrence of vasospasm and thrombosis as well as the initiation of atherosclerosis. © Springer Science+Business Media, LLC 2010.postprin

The Endothelial Saga: From Function to Dysfunction

Conference Theme: Resilience, Ingenuity, and RebirthJPS Plenary LectureEndothelium-dependent dilatations are due mainly to the release of nitric oxide (NO) which is formed by the constitutive endothelial NO synthase (eNOS). NO diffuses to the underlying vascular smooth muscle and stimulates soluble guanylyl cyclase with the resulting production of cyclic GMP. The release of NO from the endothelium can be mediated by both pertussis toxin-sensitive Gi - (e.g. α2-adrenergic agonists, serotonin) and insensitive Gq- (adenosine diphosphate, bradykinin) proteins. The ability of the endothelial cell to release NO can be down-regulated by oxidative stress and increased presence of oxidized low density lipoproteins (LDL). It is reduced chronically by aging, smoking, environmental pollution and in hypertension and diabetes. Following injury or apoptotic death, the endothelium regenerates. However, in regenerated endothelial cells, there is an early selective loss of the pertussis-toxin sensitive mechanisms of NO-release. Functional studies suggest that abnormal handling of LDL because of increased oxidative stress play a key role in this selective loss. Genomic analysis demonstrates the emergence of fatty acid binding protein-A (A-FABP)) in regenerated endothelial cells. To verify the role of oxidative stress and A-FABP in the genesis of coronary atherosclerosis, endothelial regeneration was induced in the coronary artery of pigs treated chronically with BMS309403 (A-FABP inhibitor) or apocynin (anti-oxidant) for 28 days before functional examination and histological analysis of the coronary arteries (with native or regenerated endothelium). Both the antioxidant treatment and inhibition of A-FABP normalized the diminished Gi -protein mediated relaxations to serotonin and reduced the intima-medial thickening caused by endothelial regeneration. These treatments did not affect the response to bradykinin or endothelium-independent agonists (detaNONOate and isoproterenol). These experiments confirm the crucial role of oxidative stress and of the emergence of A-FABP in the initiation of endothelial dysfunction and subsequent coronary atherosclerosis.published_or_final_versio

Het Romeinse castellum van Oudenburg (prov. West-Vlaanderen) herontdekt: de archeologische campagne van augustus 2001 tot april 2005 ter hoogte van de zuidwesthoek. Interim-rapport

Tussen augustus 2001 en april 2005 werd door het VIOE grootschalig archeologisch noodonderzoek uitgevoerd in het stadscentrum van Oudenburg, meer bepaald centraal in het woonblok tussen de Mariastraat, Kerkstraat, Hoogstraat en Weststraat. Directe aanleiding voor de archeologische opgravingen waren de bouwplannen voor een supermarkt. Het bouwterrein bevond zich ter hoogte van de zuidwesthoek van het Romeinse castellum. Vroeger onderzoek door J. Mertens had immers de contouren van het fort in het Oudenburgse stadscentrum vastgelegd. Door de bouwwerken zou dus een belangrijk stuk bodemarchief verloren gaan. Archeologische opgravingen waren dan ook noodzakelijk en vormden een unieke gelegenheid om gedetailleerd en systematisch onderzoek uit te voeren binnen de kampmuren. Het terrein besloeg zon 3150 m2 waarvan ongeveer 1800 m2 in detail kon worden onderzocht. De opgravingen gingen van start op 1 augustus 20014 en konden begin april 2005 volledig worden afgerond. Sindsdien is de verwerking en de studie van de opgravingsgegevens en vondsten volop aan de gang. Dit interim-rapport geeft een overzicht van de nieuwe inzichten in de ruimtelijke organisatie van deze castellum-zone en haar evolutie in de loop van de 3de en 4de eeuw

A heretical tale about heresy or when words do matter

What came first, heresy or orthodoxy? Walter Bauer's book Orthodoxy and Heresy in Earliest Christianity, published in 1934, seems to have unleashed the demons of scholars of early Christianity. Partisanship has, however, starkly coloured the still ongoing discussion. Denominational and scholarly belonging, as the work of Bart Ehrman and of his opponents like Andreas Köstenberger and Darrell Bock has widely shown, has so taken the upwind and signed this discussion that a full investigation into the meaning and the history of the concepts at hand has been 'forgotten'. The customary and common understanding of the concepts of orthodoxy and, in particular, heresy, are, however, completely inadequate for this discussion. Ignoring the enormous cultural heritage of the concept of heresy (αἵρεσις) – which we intend to unveil in this article – has made for the word-bullets in this historical battle to turn out to be little more than blanks in a sham-war. Time has come to end this battle, which is the scope of this article

Neurophysiological aspects of speech perception and production in stuttering

Stuttering is a speech disorder in which the smooth succession of speech sounds is interrupted by frequent blocks, prolongations and/or repetitions of sounds or syllables. When stuttering manifests itself for the first time during childhood, it is called developmental stuttering. When stuttering is of non-developmental origin, it is referred to as acquired stuttering. Acquired stuttering mostly derives from damage to the central nervous system which is called neurogenic stuttering. Neurologically, stuttering is characterized by alterations in cortical and subcortical brain regions related to speech motor planning, initiation, execution and monitoring. Neurological research in stuttering contains a plethora of spatial neuroimaging studies (e.g. fMRI) but a dearth of neurophysiological studies, especially when it comes to speech motor control. However, fluent speech does not only require the appropriate amount of (de)activation of specific brain regions, it also needs a timely and precise coordination of these brain regions. Therefore, the present thesis aimed to identify neurophysiological characteristics of speech motor control in stuttering by the use of electro-encephalography. First, temporal coordination of motor related activity during a visual word recognition task was assessed. Time points of motor related activity during hand action and non-action verb processing were compared in a group of fluent speakers and a group of adults with developmental stuttering. Secondly, speech motor preparatory activity preceding single word production was measured in real time by evoking a contingent negative variation (CNV) during a picture naming task. The CNV is an event-related potential reflecting motor preparatory activity in the basal ganglia-thalamo-cortical – loop. Speech motor preparation was compared between fluent speakers, and both fluent and stuttered words of stuttering speakers. Thirdly, although developmental and neurogenic stuttering are suggested to share common neural substrates, both types of stuttering were compared to assess whether this also accounts for speech motor preparatory activity. To that purpose, the same CNV picture naming task was performed in a case of neurogenic stuttering. Timing of motor related activation was considerable altered in the stuttering group, even during a silent reading task without (speech) movement requirements. The time point of maximal motor difference between both verb types was delayed with 100 ms and showed a reversed activation pattern compared to that of fluent speakers. This reversal is hypothesized to encompass two different motor abnormalities: a general motor hyperactivation, presenting during non-action verb processing, and a specific hand motor deficit, causing decreased excitability of this region during hand action verb processing. These findings confirm that temporal alterations in neural motor activations in stuttering are not restricted to overt speech production. Secondly, speech motor preparatory activity generated by the basal ganglia-thalamo-cortical – loop was found to have a crucial role in stuttering. Not only has its amount of activation a determining role in the actual moment of a stutter, its activation seems also related to the underlying stuttering pathology. An important divergence between left and right hemisphere is seen in this respect. When motor preparatory activity in right basal ganglia-thalamo-cortical – loop is markedly increased, no stutter will occur. The more frequent and/or the more severe a person stutters, the higher this increase is or must be to enable fluent speech production. The lower the motor preparatory activity preceding a stutter in the left basal ganglia-thalamo-cortical – network, the more this person will stutter in general. As such, left basal ganglia-thalamo-cortical – loop is suggested to have a link with the stuttering pathology. These findings concur with a growing amount of studies stating that right hemisphere alterations are related to (successful) compensation strategies, while the left hemisphere would contain the primary cause of stuttering. Thirdly, important differences emerged when comparing the findings concerning speech motor preparatory activity of the developmental stuttering group and the case with neurogenic stuttering. Roughly speaking, an increase in stuttering frequency was associated with an increase in CNV slope in the developmental stuttering group and a decrease in CNV in the case of neurogenic stuttering. Although neurogenic and developmental stuttering are believed to share common neural characteristics, these may be restricted to neuroanatomical findings. Both types of stuttering may show considerable variation in neurophysiological functioning, probably related to a difference in lesion localisation. Finally, when findings of the present studies are placed within a broader framework, the importance of the motor loop of feedforward processing in stuttering is highlighted. All observed motor alterations presented without simultaneous deficits in feedback processing or without obvious inferences of language impairments. Overall, the present thesis evidences that neurophysiology is able to discover interesting and intriguing neural findings that may aid in unravelling the enigma of stuttering

Hedonic and eudemonic wellbeing.

info:eu-repo/semantics/publishe

Quantitative analysis of language production in Parkinson's disease using a cued sentence generation task

The present study examined language production skills in Parkinson's disease (PD) patients. A unique cued sentence generation task was created in order to reduce demands on memory and attention. Differences in sentence production abilities according to disease severity and cognitive impairments were assessed. Language samples were obtained from 20 PD patients and 20 healthy control participants matched for age, sex and educational level. In addition, a cognitive test for verbal memory and resistance to cognitive interference was administered. Statistical comparisons revealed significant language changes in an advanced stage of the disease. Advanced PD patients showed a reduction in lexical diversity in notional verbs, which was absent in nouns. Cognitive dysfunctions such as impaired verbal memory are suggested to contribute to the typical noun/verb dissociation in PD patients. In addition, advanced PD patients produced more semantic perseverations, which may be related to set-switching problems. In conclusion, whether language disturbances in PD are the result of non-linguistic cognitive dysfunctions or reflect pure language deficits exacerbated by cognitive impairments, remains a matter of debate. However, the negative impact of cognitive dysfunctions may be important

EDHF: An update

The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term 'endothelium-derived hyperpolarizing factor' (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H 2O 2, CO, H 2S and various peptides can be released by endothelial cells. These factors activate different families of K + channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca 2+ concentration of the endothelial cells, followed by the opening of SK Ca and IK Ca channels (small and intermediate conductance Ca 2+-activated K + channels respectively). These channels have a distinct subcellular distribution: SK Ca are widely distributed over the plasma membrane, whereas IK Ca are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SK Ca activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IK Ca activation, K + efflux can activate smooth muscle Kir2.1 and/or Na +/ K +-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases. © The Authors Journal compilation © 2009 Biochemical Society.postprin

Tissues cIMPly do not lie

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