Differential Expression of Vegfr-2 and Its Soluble Form in Preeclampsia

Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta.By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas.Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR-2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

The Quest for Reduced Overpotentials: Derivatisation of Polypyridyl Cobalt Based Water Reducing Catalysts

This thesis comprises three projects, aiming to reduce the overpotential of polypyridyl cobalt catalysts for the reductive half reaction of light-induced water splitting. In chapter 2, dinuclear cobalt complexes, also known as dualcores, are introduced. Dualcores are powerful catalysts. If their structures allow for intramolecular interactions of the two metal centers, the catalytic mechanisms may be changed and the overpotential can be reduced. In-depth analysis of physico-chemical parameters and performances with cyclic voltammetry, linear sweep voltammetry and chronoamperometric experiments particularly showed such beneficial interactions for a complex with a bridging pyrazinyl moiety between the two cobalt centers. The design of the ligand plays a key role in facilitating spatial proximity between the metal-ions. A bipyridyl-bridge between the Co-cores did not lead to synergies, neither did methylene moieties between the metal binding sites and the bridging pyrazinyl or pyridazyl linkers. The syntheses of ligands for dualcore-type molecules is challenging as they often require reactions between three individual molecules (two binding units and the linker). Modifications at the bridgehead methylene group of a series of polypyridyl water reducing catalysts are shown in chapter 3.3. Linear sweep voltammetry and photocatalytic experiments with inline H2-quantification were employed to investigate the impact of pendant N-heterocycles on the catalytic performance. Replacing pyridyl donors with pyrazinyls proved to be an effective strategy to improve photocatalytic performances and to anodically shift the redox potentials of the CoI/II couple, as is shown in chapter 4. Planar, anionic ligands with a pendant nitrile-group opened up new synthetic pathways, without a negative influence on the reducing potentials. The position of the pyrazinyl moiety within such ligands is of great importance, as photocatalytic experiments showed. Furthermore, replacing [Ru(bpy)3]Cl2 with a tris-rhenium complex as photosensitizer also led to improved photocatalytic performances, with the impact strongly depending on the structure of the catalyst

The French and the German Reforms of Contract Law

France and Germany do not only have very prominent private law codifications, but are also countries which have taken the EC Sales Directive 1999 (among other EU developments) as an invitation to engage in an overall reform of their old Codes at the wake of the 21st Century. This invites to a comparison, namely because one reform occurred when transposing the directive, within two years – the other, however, after almost 1 ½ decades of considerations and discussions. The common thrust is orienting the Codes more towards international models – the CISG in one case and different sets of principles developed during the 20 years around the turn of the Millenium (and to some extent inspired by the CISG) in the other. Another common thrust is simplification, in one case mainly the drastic reduction of forms of breach, their streamlining and the installation of a (more) coherent regime on the breach of contracts; in the other – later – case a more extensive overall endeavour of simplification – in many parts of the Code and its institutions. The most striking difference may well be that Germany, in its reform, chose to integrate consumer law into the old Civil Code – thus bringing the main part of European contract law into the Civil Code –, while France stayed with the model it had installed as a true protagonist in this respect. This is the model of splitting contract law into a Code civil and a Code de la consommation. Two different models of why parties in contractual relationships should be protected – for instance why and when they should be protected against ‘unfair’ contract terms – can be sensed behind these choices. Many other changes, albeit of high importance, may be seen as being more specific and narrower. In France, the most important single change seems to us not to be the one most severely criticized, the ‘abandon de la cause’, but the move towards a system where the good faith principle inspires all questions and all phases of contracting and thus assumes the role of a truly overarching principle. The development named second (but also the one named first) moves France more into the direction of what seemed to be a distinctive as well as a somewhat peculiar feature of the German development. Altogether, the two countries seem to be more internationally oriented and closer to each other in their grand Civil Codes after the respective reforms. The ‘grande réforme franҫaise’ – rather a step towards a common European model than one of splendid national isolation.La France et l’Allemagne ont en common non seulement d’avoir des codifications très importantes du droit privé, mais d’avoir pris la Directive Vente de 1995 (entre autres développements au niveau de l’Union) comme une occasion pour s’engager dans des réformes d’ensemble de leurs codes plus anciens, au tournant du 21ème siècle. Ceci invite à une comparaison, notamment parce que l’une des réformes s’est produite au moment de transposer la directive, dans un espace de deux ans, tandis que l’autre est intervenue après une décennie et demi de débats et de discussions. Mais elles ont en partage une orientation du code vers des modèles internationaux – la CVIM d’un côté, de l’autre les divers ensembles de principes développés pendant une 20aine d’années autour du millénaire (également inspirés dans une certaine mesure de la CVIM). Un autre point commun est celui de la simplification, dans un cas surtout la réduction drastique des formes de rupture, leur mise en ordre et l’instauration d’un régime (plus) cohérent; dans l’autre, plus tardivement, une tentative plus ample de simplification de l’ensemble du code et de ses institutions. La différence la plus marquante réside sans doute dans le fait que l’Allemagne, dans sa réforme, a choisi d’intéger le droit de la consommation dans l’ancien Code civil, y introduisant par la même la plus grande partie du droit européen des contrats, tandis que la France a gardé le modèle existant. Celui-ci consiste en une dissociation du Code civil et du Code de la consommation. Deux modèles différents correspondant à deux ensembles de raisons pour lesquelles des parties contractantes devraient être protégées – par exemple, quand et pourquoi elles devraient être protégées contre des clauses abusives – semblent soutendre ce choix. Bien d’autres changements, quoique de grande importance, peuvent être vus come étant plus spécifiques et étroits. En France, le changement le plus notable nous semble être non pas la très controversée “abandon de la cause”, mais l’évolution vers un système où le principe de bonne foi informe toutes les questions et toutes les phases du contrat, et revêt ainsi un rôle d’un véritable principe directeur. Ces derniers développements met la France en phase avec ce qui paraissait jusqu’alors être une ligne spécifiquement allemande. Ensemble, les deux pays semblent avoir une orientation plus internationale et en même temps plus proches l’un de l’autre qu’avant leurs réformes respectives. La “grande réforme française” est ainsi plutôt un pas vers un modèle européen commun plutôt qu’une expression de splendide isolement national.Frankeich und Deutschland sind nicht nur (die) Länder mit sehr prominenten Zivilgesetzbüchern, sondern auch diejenigen, die (am intensivsten) die EG-Kaufrechts-Richtlinie von 1999 zum Anlass genommen haben, diese Kodifikationen sehr grundlegend zu reformieren – gleichsam für das 21. Jahrhundert “fit zu machen”. Dieser Umstand lädt zu einem Vergleich ein, namentlich weil die eine Reform sofort – innerhalb von zwei Jahren – erfolgte, die andere nach 1 ½ Jahrzehnten des Nachdenkens und vielfachen Diskutierens. In der Hauptstoßrichtung gemeinsam ist die Orientierung an internationalen Modellen – dem UN-Kaufrecht in dem einen Fall, in dem anderen den Prinzipienkatalogen, die in den zwei Dekaden um die Jahrtausendwende entwickelt wurden (mit starkem Einfluss ebenfalls des UN-Kaufrechts). Eine andere Hauptstoßrichtung ist die der Vereinfachung – in dem einen Fall vor allem des Leistungsstörungsrechts, mit einer drastischen Reduktion der Verstoßtatbestände und der Einrichtung eines kohärenteren Gesamtsystems; in dem anderen – späteren – Fall ungleich allgemeiner, gleichsam über das gesamte Vertragsrecht im Code civil hinweg. Der wohl wichtigste Unterschied liegt darin, dass Deutschland diese Reform nutzte, um das Verbraucherrecht ins BGB zu integrieren, während Frankreich bei dem Modell blieb, das es selbst installiert und international durchgesetzt hatte – das einer Trennung von Zivil- und Verbrauchergesetzbuch (Code de la consommation). Hinter diesem Unterschied glaubt man auch unterschiedliche Schutz- und Verbraucherleitbilder in beiden Rechtsordnungen zu spüren – etwa in Begründung und Zuschnitt des AGB-Rechts. Viele weitere Neuerungen sind zwar ebenfalls wichtig, jedoch deutlich spezifischer. Den wichtigsten Einzelreformschritt in der französischen Reform würden wir nicht in der – viel kritisierten und hervorgehobenen – Aufgabe der Wirksamkeitsvoraussetzung der „cause” sehen, sondern darin, dass Treu und Glauben zu einem allgemeinen, alle Vertragsphasen und -fragen erfassenden allgemeinen Prinzip ausgebaut wurde. Beides, vor allem aber das zweite, rückt das französische Vertragsrecht in größere Nähe zum deutschen – in einem Punkt, der für Deutschland seit Jahrzehnten wichtig, aber lange Zeit auch etwas singulär war. Insgesamt erscheinen die Zivilrechtssysteme beider Länder – die beiden großen Zivilgesetzbücher – nach den jeweiligen Reformen zum einen internationaler aufgestellt, zum anderen jedoch auch einander näher. Die „grande réforme franҫaise” – also eher ein Schritt in Richtung Europäisierung.Peer Reviewe

The french and the german reforms of contract law

Abstract. France and Germany not only have very prominent private law codifications, but are also those countries which have taken the EC Sales Directive 1999 (among other EU developments) as an invitation to engage in an overall reform of their old Codes at the wake of the 21st Century. This invites to a comparison, namely because the one reform occurred when transposing the directive, within two years, the other after almost 1 ½ decades of considerations and discussions.France and Germany not only have very prominent private law codifications, but are also those countries which have taken the EC Sales Directive 1999 (among other EU developments) as an invitation to engage in an overall reform of their old Codes at the wake of the 21st Century. This invites to a comparison, namely because the one reform occurred when transposing the directive, within two years, the other after almost 1 ½ decades of considerations and discussions

The French and the German Reforms of Contract Law

This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Frankeich und Deutschland sind nicht nur (die) Länder mit sehr prominenten Zivilgesetzbüchern, sondern auch diejenigen, die (am intensivsten) die EG-Kaufrechts-Richtlinie von 1999 zum Anlass genommen haben, diese Kodifikationen sehr grundlegend zu reformieren – gleichsam für das 21. Jahrhundert “fit zu machen”. Dieser Umstand lädt zu einem Vergleich ein, namentlich weil die eine Reform sofort – innerhalb von zwei Jahren – erfolgte, die andere nach 1 ½ Jahrzehnten des Nachdenkens und vielfachen Diskutierens. In der Hauptstoßrichtung gemeinsam ist die Orientierung an internationalen Modellen – dem UN-Kaufrecht in dem einen Fall, in dem anderen den Prinzipienkatalogen, die in den zwei Dekaden um die Jahrtausendwende entwickelt wurden (mit starkem Einfluss ebenfalls des UN-Kaufrechts). Eine andere Hauptstoßrichtung ist die der Vereinfachung – in dem einen Fall vor allem des Leistungsstörungsrechts, mit einer drastischen Reduktion der Verstoßtatbestände und der Einrichtung eines kohärenteren Gesamtsystems; in dem anderen – späteren – Fall ungleich allgemeiner, gleichsam über das gesamte Vertragsrecht im Code civil hinweg. Der wohl wichtigste Unterschied liegt darin, dass Deutschland diese Reform nutzte, um das Verbraucherrecht ins BGB zu integrieren, während Frankreich bei dem Modell blieb, das es selbst installiert und international durchgesetzt hatte – das einer Trennung von Zivil- und Verbrauchergesetzbuch (Code de la consommation). Hinter diesem Unterschied glaubt man auch unterschiedliche Schutz- und Verbraucherleitbilder in beiden Rechtsordnungen zu spüren – etwa in Begründung und Zuschnitt des AGB-Rechts. Viele weitere Neuerungen sind zwar ebenfalls wichtig, jedoch deutlich spezifischer. Den wichtigsten Einzelreformschritt in der französischen Reform würden wir nicht in der – viel kritisierten und hervorgehobenen – Aufgabe der Wirksamkeitsvoraussetzung der „cause” sehen, sondern darin, dass Treu und Glauben zu einem allgemeinen, alle Vertragsphasen und -fragen erfassenden allgemeinen Prinzip ausgebaut wurde. Beides, vor allem aber das zweite, rückt das französische Vertragsrecht in größere Nähe zum deutschen – in einem Punkt, der für Deutschland seit Jahrzehnten wichtig, aber lange Zeit auch etwas singulär war. Insgesamt erscheinen die Zivilrechtssysteme beider Länder – die beiden großen Zivilgesetzbücher – nach den jeweiligen Reformen zum einen internationaler aufgestellt, zum anderen jedoch auch einander näher. Die „grande réforme franҫaise” – also eher ein Schritt in Richtung Europäisierung.France and Germany do not only have very prominent private law codifications, but are also countries which have taken the EC Sales Directive 1999 (among other EU developments) as an invitation to engage in an overall reform of their old Codes at the wake of the 21st Century. This invites to a comparison, namely because one reform occurred when transposing the directive, within two years – the other, however, after almost 1 ½ decades of considerations and discussions. The common thrust is orienting the Codes more towards international models – the CISG in one case and different sets of principles developed during the 20 years around the turn of the Millenium (and to some extent inspired by the CISG) in the other. Another common thrust is simplification, in one case mainly the drastic reduction of forms of breach, their streamlining and the installation of a (more) coherent regime on the breach of contracts; in the other – later – case a more extensive overall endeavour of simplification – in many parts of the Code and its institutions. The most striking difference may well be that Germany, in its reform, chose to integrate consumer law into the old Civil Code – thus bringing the main part of European contract law into the Civil Code –, while France stayed with the model it had installed as a true protagonist in this respect. This is the model of splitting contract law into a Code civil and a Code de la consommation. Two different models of why parties in contractual relationships should be protected – for instance why and when they should be protected against ‘unfair’ contract terms – can be sensed behind these choices. Many other changes, albeit of high importance, may be seen as being more specific and narrower. In France, the most important single change seems to us not to be the one most severely criticized, the ‘abandon de la cause’, but the move towards a system where the good faith principle inspires all questions and all phases of contracting and thus assumes the role of a truly overarching principle. The development named second (but also the one named first) moves France more into the direction of what seemed to be a distinctive as well as a somewhat peculiar feature of the German development. Altogether, the two countries seem to be more internationally oriented and closer to each other in their grand Civil Codes after the respective reforms. The ‘grande réforme franҫaise’ – rather a step towards a common European model than one of splendid national isolation.La France et l’Allemagne ont en common non seulement d’avoir des codifications très importantes du droit privé, mais d’avoir pris la Directive Vente de 1995 (entre autres développements au niveau de l’Union) comme une occasion pour s’engager dans des réformes d’ensemble de leurs codes plus anciens, au tournant du 21ème siècle. Ceci invite à une comparaison, notamment parce que l’une des réformes s’est produite au moment de transposer la directive, dans un espace de deux ans, tandis que l’autre est intervenue après une décennie et demi de débats et de discussions. Mais elles ont en partage une orientation du code vers des modèles internationaux – la CVIM d’un côté, de l’autre les divers ensembles de principes développés pendant une 20aine d’années autour du millénaire (également inspirés dans une certaine mesure de la CVIM). Un autre point commun est celui de la simplification, dans un cas surtout la réduction drastique des formes de rupture, leur mise en ordre et l’instauration d’un régime (plus) cohérent; dans l’autre, plus tardivement, une tentative plus ample de simplification de l’ensemble du code et de ses institutions. La différence la plus marquante réside sans doute dans le fait que l’Allemagne, dans sa réforme, a choisi d’intéger le droit de la consommation dans l’ancien Code civil, y introduisant par la même la plus grande partie du droit européen des contrats, tandis que la France a gardé le modèle existant. Celui-ci consiste en une dissociation du Code civil et du Code de la consommation. Deux modèles différents correspondant à deux ensembles de raisons pour lesquelles des parties contractantes devraient être protégées – par exemple, quand et pourquoi elles devraient être protégées contre des clauses abusives – semblent soutendre ce choix. Bien d’autres changements, quoique de grande importance, peuvent être vus come étant plus spécifiques et étroits. En France, le changement le plus notable nous semble être non pas la très controversée “abandon de la cause”, mais l’évolution vers un système où le principe de bonne foi informe toutes les questions et toutes les phases du contrat, et revêt ainsi un rôle d’un véritable principe directeur. Ces derniers développements met la France en phase avec ce qui paraissait jusqu’alors être une ligne spécifiquement allemande. Ensemble, les deux pays semblent avoir une orientation plus internationale et en même temps plus proches l’un de l’autre qu’avant leurs réformes respectives. La “grande réforme française” est ainsi plutôt un pas vers un modèle européen commun plutôt qu’une expression de splendide isolement national.Peer Reviewe

Structure and biosynthesis of xenoamicins from entomopathogenic xenorhabdus

During the search for novel natural products from entomopathogenic Xenorhabdus doucetiae DSM17909 and X. mauleonii DSM17908 novel peptides named xenoamicins were identified in addition to the already known antibiotics xenocoumacin and xenorhabdin. Xenoamicins are acylated tridecadepsipeptides consisting of mainly hydrophobic amino acids. The main derivative xenoamicin A (1) was isolated from X. mauleonii DSM17908, and its structure elucidated by detailed 1 D and 2 D NMR experiments. Detailed MS experiments, also in combination with labeling experiments, confirmed the determined structure and allowed structure elucidation of additional derivatives. Moreover, the xenoamicin biosynthesis gene cluster was identified and analyzed in X. doucetiae DSM17909, and its participation in xenoamicin biosynthesis was confirmed by mutagenesis. Advanced Marfey's analysis of 1 showed that the absolute configuration of the amino acids is in agreement with the predicted stereochemistry deduced from the nonribosomal peptide synthetase XabABCD. Biological testing revealed activity of 1 against Plasmodium falciparum and other neglected tropical diseases but no antibacterial activity

Hypomania and saccadic changes in Parkinson's disease: influence of D2 and D3 dopaminergic signalling

In order to understand the influence of two dopaminergic signalling pathways, TaqIA rs1800497 (influencing striatal D2 receptor density) and Ser9Gly rs6280 (influencing the striatal D3 dopamine-binding affinity), on saccade generation and psychiatric comorbidities in Parkinson's disease, this study aimed to investigate the association of saccadic performance in hypomanic or impulsive behaviour in parkinsonian patients; besides we questioned whether variants of D2 (A1+/A1-) and D3 (B1+/B1-) receptor polymorphism influence saccadic parameters differently, and if clinical parameters or brain connectivity changes modulate this association in the nigro-caudatal and nigro-collicular tract. Initially, patients and controls were compared regarding saccadic performance and differed in the parameter duration in memory-guided saccades (MGS) and visually guided saccades (VGS) trials (p < 0.0001) and in the MGS trial (p < 0.03). We were able to find associations between hypomanic behaviour (HPS) and saccade parameters (duration, latency, gain and amplitude) for both conditions [MGS (p = 0.036); VGS (p = 0.033)], but not for impulsive behaviour. For the A1 variant duration was significantly associated with HPS [VGS (p = 0.024); MGS (p = 0.033)]. In patients with the B1 variant, HPS scores were more consistently associated with duration [VGS (p = 0.005); MGS (p = 0.015), latency [VGS (p = 0.022)]] and amplitude [MGS (p = 0.006); VGS (p = 0.005)]. The mediation analysis only revealed a significant indirect effect for amplitude in the MGS modality for the variable UPDRS-ON (p < 0.05). All other clinical scales and brain connectivity parameters were not associated with behavioural traits. Collectively, our findings stress the role of striatal D2 and D3 signalling mechanisms in saccade generation and suggest that saccadic performance is associated with the clinical psychiatric state in Parkinson's disease