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71.
Inga Ebermann Jennifer B. Phillips Max C. Liebau Robert K. Koenekoop Bernhard Schermer Irma Lopez Ellen Sch?fer Anne-Francoise Roux Claudia Dafinger Antje Bernd Eberhart Zrenner Mireille Claustres Bernardo Blanco Gudrun Nürnberg Peter Nürnberg Rebecca Ruland Monte Westerfield Thomas Benzing Hanno J. Bolz 《The Journal of clinical investigation》2010,120(6):1812-1823
Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease. 相似文献
72.
The faster the better: anastomosis time influences patient survival after deceased donor kidney transplantation 下载免费PDF全文
Annemarie Weissenbacher Rupert Oberhuber Benno Cardini Sascha Weiss Hanno Ulmer Claudia Bösmüller Stefan Schneeberger Johann Pratschke Robert Öllinger 《Transplant international》2015,28(5):535-543
Despite a continuously growing knowledge of the impact of factors on kidney graft function, such as donor age, body mass index, and cold ischemia time, few data are available regarding anastomosis time (AT) and its impact on long‐term results. We investigated whether surgical AT correlates with patient and graft survival after kidney transplantation performing a retrospective analysis of 1245 consecutive deceased donor kidney transplantations between 01/2000 and 12/2010 at Innsbruck Medical University. Kaplan–Meier and log‐rank analyses were carried out for 1‐ and 5‐year patient and graft survival. AT was defined as time from anastomosis start until reperfusion. Median AT was 30 min. Five‐year survival of allografts with an AT >30 min was 76.6% compared with 80.6% in the group with AT <30 min (P = 0.027). Patient survival in the group with higher AT similarly was inferior with 85.7% after 5 years compared with 89.6% (P < 0.0001) [Correction added on February 18, 2015, after first online publication: the percentage value for patient survival was previously incorrect and have now been changed to 89.6%]. Cox regression analysis revealed AT as an independent significant factor for patient survival (HR 1.021 per minute; 95% CI 1.006–1.037; P = 0.006). As longer AT closely correlates with inferior long‐term patient survival, it has to be considered as a major risk factor for inferior long‐term results after deceased donor kidney transplantation. 相似文献
73.
Percutaneous Radiofrequency Ablation of Pulmonary Metastases from Colorectal Carcinoma: Prognostic Determinants for Survival 总被引:2,自引:0,他引:2
Yan TD King J Sjarif A Glenn D Steinke K Morris DL 《Annals of surgical oncology》2006,13(11):1529-1537
Background Preliminary results have shown that percutaneous radiofrequency ablation (RFA) may play a useful role in patients with inoperable lung tumors. This series evaluated the prognostic features for survival in nonsurgical candidates who underwent percutaneous RFA of pulmonary metastases from colorectal carcinoma.Methods Fifty-five patients not suitable for surgery underwent percutaneous RFA for colorectal pulmonary metastases. All clinical and treatment-related data were collected prospectively. The primary end point of the study was overall survival, defined from the time of RFA intervention. Univariate and multivariate analyses were performed to identify statistically significant prognostic parameters for overall survival.Results The overall median survival was 33 months (range, 4–40 months), with actuarial 1-, 2-, and 3-year survival of 85%, 64%, and 46%, respectively. Univariate analysis demonstrated that largest size of lung metastasis (P < .001), location of lung metastases (P = .032), and repeat percutaneous RFA for pulmonary recurrence (P = .024) were statistically significant for overall survival. Multivariate analysis demonstrated that largest size of lung metastasis >3 cm was independently associated with a reduced overall survival (P = .003).Conclusions Percutaneous lung RFA may play a useful role in nonsurgical candidates with colorectal pulmonary metastases. However, the survival benefit of this interventional procedure for patients with a pulmonary metastasis >3 cm was limited. 相似文献
74.
Bruno Märkl Katharina Wünsch Kai-Uwe Hebick Matthias Anthuber reas Probst Hans Martin Arnholdt & Hanno Spatz 《Histopathology》2009,54(4):433-441
Aims: Lymph node (LN) stage is still the strongest prognostic marker in potentially curable gastric cancer. Accuracy of histopathological lymph node assessment depends on the number of investigated LNs and detection rate of metastases and micrometastases. The aim was to perform a feasibility study employing intra-arterial methylene blue injection – a novel method to improve LN harvest – and ex vivo sentinel LN mapping.
Methods and results: A total of 33 cases were enrolled, including 14 retrospective cases that served as a control group. The methylene group showed a highly significant improved mean LN harvest compared with unstained cases, with 38 ± 14 versus 21 ± 10 LNs ( P < 0.001), respectively. The detection rate of ex vivo sentinel mapping was 88%. No skip metastases occurred.
Conclusion: Both techniques have the potential to improve the accuracy of histopathological LN staging and can be combined successfully. 相似文献
Methods and results: A total of 33 cases were enrolled, including 14 retrospective cases that served as a control group. The methylene group showed a highly significant improved mean LN harvest compared with unstained cases, with 38 ± 14 versus 21 ± 10 LNs ( P < 0.001), respectively. The detection rate of ex vivo sentinel mapping was 88%. No skip metastases occurred.
Conclusion: Both techniques have the potential to improve the accuracy of histopathological LN staging and can be combined successfully. 相似文献
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78.
Barbara Teuchner Eduard Schmid Hanno Ulmer Waldemar Gottardi Markus Nagl 《Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie》2008,246(12):1723-1730
Background N-chlorotaurine (NCT), an endogenous mild antiseptic, is well-tolerated by application to the human conjunctiva and has been
shown to offer beneficial effects in infectious conjunctivitis. Animal tests revealed improved efficacy of a combination of
NCT with ammonium chloride in adenoviral conjunctivitis. The aim of this study was to evaluate the tolerability of NCT plus
ammonium chloride in the healthy rabbit and human eye.
Methods First, a tolerability study was performed in rabbits. In a blinded and randomized fashion, one eye was treated with the test
medication, the other one with 0.9% saline. Twenty-one animals (three per concentration) were treated with one drop every
2 hours for 6 days. Second, in two volunteers one drop of a defined concentration was applied to one eye every 15 min for
1 hour, saline to the control eye. Four different concentrations were tested on different days. Third, a double-blind, randomized
phase 1 study in 13 healthy volunteers was performed. One drop of 0.1% NCT plus 0.1% NH4Cl versus saline was applied every 15 min within the first hour, followed by four drops every 2 hours. This regimen was done
daily for 5 days.
Results In rabbits, no side effects were seen with 0.1% NCT plus 0.1% NH4Cl, while higher concentrations sometimes caused short-time and minimal conjunctival injection and secretion after dosing.
By 1% NCT plus 1% NH4Cl, these effects were moderate, but disappeared again without any detectable residues. In the pilot study with two volunteers,
treatment with 0.5% NCT plus 0.1% NH4Cl caused medium-scale eye burning for 30 seconds, while 0.1% NCT plus 0.1% NH4Cl was very well-tolerated, with no or minimal burning for a few seconds. In the subsequent phase 1 study, 0.1% NCT plus 0.1%
NH4Cl was well-tolerated by all subjects except for minimal eye burning for a few seconds after dropping. No objective signs
of eye changes could be detected in the human beings.
Conclusion The results of this study clearly demonstrate the good tolerability of a promising NCT formulation with improved activity. 相似文献
79.
80.
NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle 下载免费PDF全文
Stasch JP Schmidt P Alonso-Alija C Apeler H Dembowsky K Haerter M Heil M Minuth T Perzborn E Pleiss U Schramm M Schroeder W Schröder H Stahl E Steinke W Wunder F 《British journal of pharmacology》2002,136(5):773-783
1. Soluble guanylyl cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO) and is intimately involved in many signal transduction pathways, most notably in regulating vascular tone and platelet function. sGC is a heterodimeric (alpha/ss) protein that converts GTP to cyclic GMP; NO binds to its prosthetic haem group. Here, we report the discovery of a novel sGC activating compound, its interaction with a previously unrecognized regulatory site and its therapeutic implications. 2. Through a high-throughput screen we identified BAY 58-2667, an amino dicarboxylic acid which potently activates sGC in an NO-independent manner. In contrast to NO, YC-1 and BAY 41-2272, the sGC stimulators described recently, BAY 58-2667 activates the enzyme even after it has been oxidized by the sGC inhibitor ODQ or rendered haem deficient. 3. Binding studies with radiolabelled BAY 58-2667 show a high affinity site on the enzyme. 4. Using photoaffinity labelling studies we identified the amino acids 371 (alpha-subunit) and 231 - 310 (ss-subunit) as target regions for BAY 58-2667. 5. sGC activation by BAY 58-2667 results in an antiplatelet activity both in vitro and in vivo and a potent vasorelaxation which is not influenced by nitrate tolerance. 6. BAY 58-2667 shows a potent antihypertensive effect in conscious spontaneously hypertensive rats. In anaesthetized dogs the hemodynamic effects of BAY 58-2667 and GTN are very similar on the arterial and venous system. 7. This novel type of sGC activator is a valuable research tool and may offer a new approach for treating cardiovascular diseases. 相似文献