Holocene tree-line variability in the Kauner Valley, Central Eastern Alps, indicated by dendrochronological analysis of living trees and subfossil logs

The altitude of the Alpine tree-line has often been used as proxy for the climatic conditions in the Holocene epoch. The usual approach for establishing a record for this proxy is the analysis of pollen and macro remains. We analysed living trees and subfossil logs from the timberline ecotone in the innermost Kauner valley in the Central Eastern Alps in order to assemble a Holocene dendrochronological tree-line record. Data sets comprising age and height of living Stone Pines (Pinus cembra L.) were collected at one site. Sections of 170 subfossil Stone Pine logs from five other sites were dendrochronologically analysed and dated. Besides using dendrochronological analyses, radiocarbon dating served as a means of obtaining the age of some logs. For most of the samples we could provide dendrochronological dates (1-year dating precision, back to 5125 B.C.) or wiggle matched dates (between approx. 7100 and 5040 B.C., dating precision with 95% probability: +/- 7 years). In the first half of the 19th century the tree-line was located at about 2180 m a.s.l. in the innermost Kauner valley. After approximately A.D. 1860 the altitude of the upper limit of the occurrence of Pinus cembra individuals (tree-species-line) and, being closely linked, also that of the tree-line both rose. The current tree-line (trees > 2 m) is located at 2245 m a.s.l. due to climatic conditions around 1980. Additionally we observed saplings up to a present (A.D. 2000) tree-species-line at approx. 2370 m a.s.l. The dendrochronologically analysed subfossil logs found at up to 2410 m a.s.l. date from within the last 9000 years (between approx. 7100 B.C. and A.D. 1700). In the space of the last 4000 years the dendrochronological tree-line record is not continuous, probably due to human impact. Tree-line positions similar to or slightly above the 1980 tree-line are established for the time periods approx. 1000 to 640 B.C. and A.D. 1 to 330 respectively. For the time period between approx. 7100 and 2100 B.C. the dendrochronologically analysed logs show nearly continuous evidence of a tree-line above the 1980s limit. Very high elevation of the tree-line, between 120 and 165 m above the 1980s level (2245 m a.s.l.) and even higher than the A.D. 2000 tree-species-line (2370 m a.s.l.), are recorded for the periods 7090-6570, 6040-5850, 5720-5620, 5500-4370 B.C., approx. 3510-3350 B.C. and 2790-2590 B.C. Additionally, a tree-line which was located at least 50 m above the 1980s limit can be shown for the periods 6700-5430, 4920-3350 and 3280-2110 B.C. The dendrochronological record from the Kauner valley, showing high and very high tree-line positions between approx. 7100 and 2100 B.C. with only two gaps (around 6490 B.C. and from 3350 to 3280 B.C.), suggests that summer temperatures as observed in the late 20th century were at the normal or the lower limit of the temperature range which can be assumed for long periods of the early and middle Holocene epoch

The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1(−/−) mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo. In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4

Sequential Venous Percutaneous Transluminal Angioplasty and Balloon Dilatation of the Interatrial Septum during Percutaneous Edge-to-Edge Mitral Valve Repair

Percutaneous edge-to-edge mitral valve repair (PMVR) is widely used for selected, high-risk patients with severe mitral valve regurgitation (MR). This report describes a case of 81-year-old woman presenting with severe and highly symptomatic mitral valve regurgitation (MR) caused by a flail of the posterior mitral valve leaflet (PML). PMVR turned out to be challenging in this patient because of a stenosis and tortuosity of both iliac veins as well as sclerosis of the interatrial septum, precluding the vascular and left atrial access by standard methods, respectively. We managed to achieve atrial access by venous percutaneous transluminal angioplasty (PTA) and balloon dilatation of the interatrial septum. Subsequently, we could advance the MitraClip® system to the left atrium, and deployment of the clip in the central segment of the mitral valve leaflets (A2/P2) resulted in a significant reduction of MR

Resistance to renal denervation therapy — Identification of underlying mechanisms by analysis of differential DNA methylation

Factors causing resistance to renal denervation (RDN) for treatment of arterial hypertension are not known. In the current study, we sought to determine mechanisms involved in responsiveness to renal denervation therapy in patients with difficult-to-control and resistant hypertension. We evaluated the differential CpG methylation of genes in blood samples isolated from patients of a recently described cohort of responders or non-responders to renal denervation using microarray technique and measured protein levels of identified downstream effectors in blood samples of these patients by ELISA. Our analysis revealed up to 6103 methylation sites differing significantly between non-responders and responders to renal denervation therapy. Software based analysis showed several of these loci to be relevant for arterial hypertension and sympathetic nervous activity. Particularly, genes involved in glutamate synthesis, degradation and glutamate signaling pathways were differently methylated between both groups. For instance, genes for glutamate dehydrogenase 1 and 2 central to glutamate metabolism, genes for ionotropic (AMPA, NMDA) and metabotropic glutamate receptors as well as glutamate transporters revealed significant differences in methylation correlating with responsiveness to RDN. To underline their potential relevance for responsiveness to RDN, we measured plasma protein levels of norepinephrine, a downstream effector of the glutamate receptor pathway, which were significantly lower in non-responders to RDN. The present study describes novel molecular targets potentially contributing to reduction of blood pressure after RDN in some patients. Identifying patients with a high responsiveness to RDN could contribute to an individualized therapy in drug resistant hypertension

Improved mid-term stability of MR reduction with an increased number of clips after percutaneous mitral valve repair in functional MR

Background: Percutaneous mitral valve repair (PMVR) has evolved to be a standard procedure in suitable patients with mitral regurgitation (MR) not accessible for open surgery. Here, we analyzed the influence of the number and positioning of the clips implanted during the procedure on MR reduction analyzing also sub-collectives of functional and degenerative MR (DMR). Results: We included 410 patients with severe MR undergoing PMVR using the MitraClip® System. MR and reduction of MR were analyzed by TEE at the beginning and at the end of the PMVR procedure. To specify the clip localization, we sub-divided segment 2 into 3 sub-segments using the segmental classification of the mitral valve. Results: We found an enhanced reduction of MR predominantly in DMR patients who received more than one clip. Implantation of only one clip led to a higher MR reduction in patients with functional MR (FMR) in comparison to patients with DMR. No significant differences concerning pressure gradients could be observed in degenerative MR patients regardless of the number of clips implanted. A deterioration of half a grade of the achieved MR reduction was observed 6 months post-PMVR independent of the number of implanted clips with a better stability in FMR patients, who got 3 clips compared to patients with only one clip. Conclusions: In patients with FMR, after 6 months the reduction of MR was more stable with an increased number of implanted clips, which suggests that this specific patient collective may benefit from a higher number of clips