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991.
Lukas Moleda Lars Jurzik Matthias Froh Erwin Gbele Claus Hellerbrand Rainer H Straub J&#;rgen Schlmerich Reiner Wiest 《World journal of gastroenterology : WJG》2010,16(15):1837-1844
AIM:To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension. METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinep... 相似文献
992.
Anne S. Soehn Thomas Franck Saskia Biskup Emilie Giaime Christian Melle Ruth Rott Daniel Cebo Hubert Kalbacher Erwin Ott Jens Pahnke Thomas Meitinger Rejko Krüger Thomas Gasser Daniela Berg Ferdinand von Eggeling Simone Engelender Cristine Alves da Costa Olaf Riess 《Neurogenetics》2010,11(2):203-215
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein and its interactor synphilin-1 are major components of these inclusions. Rare mutations in the α-synuclein and synphilin-1 genes have been implicated in the pathogenesis of PD; however, the normal function of these proteins is far from being completely elucidated. We, thus, searched for novel synphilin-1-interacting proteins and deciphered periphilin as new interactor. Periphilin isoforms are involved in multiple cellular functions in vivo, and the protein is broadly expressed during embryogenesis and in the adult brain. We show that periphilin displays an overlapping expression pattern with synphilin-1 in cellular and animal models and in Lewy bodies of PD patients. Functional studies demonstrate that periphilin, as previously shown for synphilin-1, displays an antiapoptotic function by reducing caspase-3 activity. Searching for mutations in the periphilin gene, we detected a K69E substitution in two patients of a PD family. Taken together, these findings support for the first time an involvement of periphilin in PD. 相似文献
993.
Plate and screw fixation (PSF) has always been the more common surgical treatment of humeral shaft fractures. However, intramedullary nailing (IMN) of the humerus has gained in popularity over the last two decades. The purpose of this retrospective study was to evaluate the clinical outcome of plate fixation versus intramedullary nailing of midshaft humeral fractures. The study included 91 patients treated at the department of Trauma Surgery of the University hospital of Leuven; 42 fractures had been treated by plate fixation and 49 by IM nailing. Union, functional outcome, possible complications and the need for additional surgery were compared between the IMN and PSF group. No significant difference in terms of fracture union and functional recovery was noted between the two groups. There were four cases of postoperative radial nerve palsy in the PSF group, versus two in the IMN group (non significant difference). A significantly larger number of patients with restrictive pain and/or functional hindrance in the shoulder or elbow was noted in the IMN group (p = 0.0053). Problems with osteosynthesis material occurred as often in the PSF group as in the IMN group. One patient developed wound infection at the shoulder after antegrade nailing. A significantly larger number of complications was seen in the IMN group than in the PSF group (p = 0.05). A reoperation was necessary in 143% of the PSF patients and 163% of the IMN patients (non significant difference). In this retrospective study, IMN did not achieve better results than PSF of humeral midshaft fractures and was associated with more postoperative complications. Based on these findings, we suggest that plating of humeral shaft fractures should be considered as the primary treatment for all surgical indications, except for some open fractures requiring temporary external fixation, pathological fractures, humeral shaft fractures in morbidly obese and osteopenic patients, and large segmental fractures of the humerus. 相似文献
994.
Jae Sung Lee Won-Kyung Ho Erwin Neher Suk-Ho Lee 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(37):15079-15084
Recruitment of release-competent vesicles during sustained synaptic activity is one of the major factors governing short-term plasticity. During bursts of synaptic activity, vesicles are recruited to a fast-releasing pool from a reluctant vesicle pool through an actin-dependent mechanism. We now show that newly recruited vesicles in the fast-releasing pool do not respond at full speed to a strong Ca2+ stimulus, but require approximately 4 s to mature to a “superprimed” state. Superpriming was found to be altered by agents that modulate the function of unc13 homolog proteins (Munc13s), but not by calmodulin inhibitors or actin-disrupting agents. These findings indicate that recruitment and superpriming of vesicles are regulated by separate mechanisms, which require integrity of the cytoskeleton and activation of Munc13s, respectively. We propose that refilling of the fast-releasing vesicle pool proceeds in two steps, rapid actin-dependent “positional priming,” which brings vesicles closer to Ca2+ sources, followed by slower superpriming, which enhances the Ca2+ sensitivity of primed vesicles.The release rate of a synaptic vesicle (SV) is governed by two factors, the intrinsic Ca2+ sensitivity of the vesicle fusion machinery and the distance of the SV to Ca2+ channels. As Munc13s and Munc18s confer fusion competence on a docked SV, the regulation of release rate by Munc13s and Munc18s is called “molecular priming” (1). It is distinguished from “positional priming,” a process that is thought to regulate the proximity of an SV to the calcium source (2, 3). However, it is not known how these two priming mechanisms are manifested in the kinetics of quantal release. Deconvolution analyses of excitatory postsynaptic currents (EPSCs) evoked by long presynaptic depolarizations at the calyx of Held (a giant nerve terminal in the auditory pathway) showed that releasable SVs can be separated into fast-releasing pools (FRPs) and slowly releasing pools (SRPs) (4). The differences in SV priming that underlie the differences in release kinetics between SVs in the FRP and the SRP are currently unclear (3, 5). Wadel et al. (3) found that SVs in the SRP can be released by homogenous Ca2+ elevation only 1.5 to 2 times slower than SVs in the FRP, even though they are released 10 times slower by depolarization-induced Ca2+ influx. This was interpreted as evidence that the differences in their release kinetics arise from differences primarily in positional priming. In contrast, Wölfel et al. (5) showed that release with two kinetic components is even observed if the intracellular Ca2+ concentration is homogenously elevated throughout the calyx terminal, indicating that SVs in the FRP and the SRP differ with regard to their molecular priming.We found recently that SVs in the SRP rapidly convert into the FRP after specific FRP depletion by a short depolarizing pulse (6). Such rapid refilling of the FRP with SRP vesicles, which is referred to as SRP-dependent recovery (SDR), was suppressed by actin depolymerization or inhibition of myosin, implying that SDR involves a transport process, steering docked and partially primed vesicle toward Ca2+ channels. In the same study, we noted that the time constant of release τ from newly primed FRP SVs after FRP depletion is initially slower than the time constant of FRP release τ under resting conditions. This finding is in agreement with the previously published notion that the Ca2+-sensitivity of SVs after a specific depletion of the FRP is 1.5 to 2 times lower than that of SVs under control conditions (3, 7). Thus, an additional SV maturation process, which is closely related to the Ca2+-sensitivity of vesicle fusion, appears to be required for newly primed FRP SVs to acquire full release competence.In the present study, we characterize this maturation step, which we refer to as “superpriming“ (see also ref. 8). We show that the mechanism regulating recovery of Ca2+ sensitivity is distinct from that regulating recovery of the FRP size, in that the former and the latter require activation of Munc13s and the integrity of the cytoskeleton, respectively. The Ca2+ sensitivity is known to be profoundly affected by phorbol esters, which lower the energy barrier for vesicle fusion (9, 10). Munc13 has been identified as a presynaptic receptor of phorbol esters together with PKC (11–13). We therefore propose that the recovery of Ca2+ sensitivity represents a final step in the maturation of the intrinsic properties of newly recruited SVs involving Munc13 proteins, whereas the FRP size represents the number of release-competent SVs close to Ca2+ sources. 相似文献
995.
996.
997.
Ajay K. Parsaik MD Balwinder Singh MD Osama Altayar MD Soniya S. Mascarenhas RN Shannon K. Singh Patricia J. Erwin M. Hassan Murad MD MPH 《Journal of general internal medicine》2013,28(11):1496-1503
OBJECTIVE
To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH).METHODS
We searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies.RESULTS
Seven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg (p?=?0.65) and the mean change in mean arterial pressure from supine to standing was ?1.7 mmHg (p?=?0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg (p?<?0.001). A significant improvement was seen in patients’ and investigators’ global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30–1.09; p?<?0.001] and 0.80 [95 % CI 0.76–0.85; p?<?0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias.CONCLUSION
There is insufficient and low quality evidence to support the use of midodrine for OH. 相似文献998.
Mery Cortes-Bergoderi Kashish Goel Mohammad Hassan Murad Thomas Allison Virend K Somers Patricia J. Erwin Ondrej Sochor Francisco Lopez-Jimenez 《European Journal of Internal Medicine》2013,24(8):791-799
BackgroundHispanics, the largest minority in the U.S., have a higher prevalence of several cardiovascular (CV) risk factors than non-Hispanic whites (NHW). However, some studies have shown a paradoxical lower rate of CV events among Hispanics than NHW.ObjectiveTo perform a systematic review and a meta-analysis of cohort studies comparing CV mortality and all-cause mortality between Hispanic and NHW populations in the U.S.MethodsWe searched EMBASE, MEDLINE, Web of Science, and Scopus databases from 1950 through May 2013, using terms related to Hispanic ethnicity, CV diseases and cohort studies. We pooled risk estimates using the least and most adjusted models of each publication.ResultsWe found 341 publications of which 17 fulfilled the inclusion criteria; data represent 22,340,554 Hispanics and 88,824,618 NHW, collected from 1950 to 2009. Twelve of the studies stratified the analysis by gender, and one study stratified people by place of birth (e.g. U.S.-born, Mexican-born, and Central/South American-born). There was a statistically significant association between Hispanic ethnicity and lower CV mortality (OR 0.67; 95% CI, 0.57–0.78; p < 0.001), and lower all-cause mortality (0.72; 95% CI, 0.63–0.82; p < 0.001). A subanalysis including only studies that reported prevalence of CV risk factors found similar results. OR for CV mortality among Hispanics was 0.49; 95% CI 0.30–0.80; p-value < 0.01; and OR for all-cause mortality was 0.66; 95% CI 0.43–1.02; p-value 0.06.ConclusionThese results confirm the existence of a Hispanic paradox regarding CV mortality. Further studies are needed to identify the mechanisms mediating this protective CV effect in Hispanics. 相似文献
999.
Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor
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Fischer S Gerriets T Wessels C Walberer M Kostin S Stolz E Zheleva K Hocke A Hippenstiel S Preissner KT 《Blood》2007,110(7):2457-2465
Cell injury leads to exposure of intracellular material and is associated with increased permeability of vessels in the vicinity of the damage. Here, we demonstrate that natural extracellular RNA as well as artificial RNA (poly-I:C), or single-stranded RNA but not DNA, significantly increased the permeability across brain microvascular endothelial cells in vitro and in vivo. RNA-induced hyperpermeability of tight monolayers of endothelial cells correlated with disintegration of tight junctions and was mediated through vascular endothelial growth factor (VEGF), reminiscent of heparin's activities. Antisense oligonucleotides against VEGF-receptor 2 (VEGF-R2) prevented the permeability-inducing activity of extracellular RNA and heparin completely. Hence, these polyanionic substances can lead to mobilization/stabilization of VEGF with the subsequent activation of VEGF-R2. In accordance with these functional data, strong binding of VEGF as well as other growth factors to RNA was demonstrable. In in vivo rat models of FeCl(3)-induced sinus sagittal is superior thrombosis and stroke/brain edema, pretreatment of animals with RNase (but not DNase) resulted in a significant reduction of vessel occlusion, infarct volume, and prevention of brain edema formation. Together, these results identify extracellular RNA as a novel natural permeability factor, upstream of VEGF, whereas counteracting RNase treatment may serve as new vessel-protective modality. 相似文献
1000.
Chung PY Beyens G Guañabens N Boonen S Papapoulos S Karperien M Eekhoff M Van Wesenbeeck L Jennes K Geusens P Offeciers E Van Offel J Westhovens R Zmierczak H Devogelaer JP Van Hul W 《Calcified tissue international》2008,83(1):34-42
Paget's Disease of Bone (PDB) is one of the most frequent metabolic bone diseases, affecting 1-5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4-9.3% of nonfamilial PDB cases, with the 1215C-->T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch (n = 82), and Spanish (n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients (7.3%), three Dutch patients without a family history (3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms (SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG (H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB. 相似文献