Funktionelle Beeinträchtigung durch Chiasmasyndrome vor und nach der transsphenoidalen Operation von Hypophysenadenomen

Zielsetzung. Diese Studie hat zwei Ziele: 1. Analyse der Faktoren, die das präoperative Auftreten und den postoperativen Verlauf von Chiasmasyndromen bei Patienten mit transsphenoidal operierten Hypophysenadenomen beeinflussen. 2. Die erstmalige Beschreibung der funktionellen Beeinträchtigung der Patienten durch hypophysen-adenombedingte Chiasmasyndrome prä- und postoperativ (in Form des Grades der Behinderung). Patienten und Methoden. Die Daten einer großen, homogenen Serie von erstmalig transsphenoidal an einem Hypophysendenom operierten Patienten wurden retrospektiv erhoben. Hierzu gehörten: Alter, Geschlecht, Adenomart, Anamnesedauer, Leitsymptom, eventuelle corticotrope Einschränkung, größter Tumordurchmesser, eventuelle Infiltration des Sinus cavernosus, Visus, Perimetrieart und Leuchtdichteklasse, 90°-Gesichtsfeld, eventuelle Papillenblässe und augenärztliche Vorerkrankungen. Die funktionelle Bedeutung einer Visus- und/oder Gesichtsfeldeinschränkung wurde anhand des daraus folgenden Grades der Behinderung quantifiziert. Ein Grad der Behinderung ≥30 gilt als wesentlich. Ergebnisse. Die Serie umfasst 304 Patienten (medianes Alter 50 Jahre, 53,3% Männer). Die Hypophysenadenome waren in 54,6% der Fälle hormoninaktiv. Der mediane maximale Tumordurchmesser betrug 20 mm. Ein CS lag präoperativ bei 35,1% der Patienten vor. In der univariaten und in der logistischen Regressionsanalyse waren der größte Tumordurchmesser und das Vorliegen einer Papillenabblassung Variablen mit signifikantem Einfluss auf das Vorliegen eines präoperativen Chiasmasyndroms. Eine postoperative Visus- oder Gesichtsfeldverschlechterung trat bei keinem der Patienten auf, die präoperativ kein CS hatten. Bei Patienten mit präoperativem CS trat postoperativ eine Normalisierung in 42,9%, eine Besserung in 38,3%, ein unverändertes persistieren in 11,2% und eine Verschlechterung des Chiasmasyndroms in 7,4% der Fälle auf. Es wurden in der univariaten und in der logistischen Regressionsanalyse keine Variablen identifiziert, die die postoperative Erholung des Chiasmasyndroms signifikant beeinflusst haben. Bei Patienten mit präoperativem CS ist es postoperativ zu einer signifikanten Visusbesserung gekommen (Median rechts und links von 0,63 auf 0,8 bzw. von 0,56 auf 0,75; p jeweils ≤0,001). Bei Patienten mit präoperativem CS und sektorenförmigen (nicht jedoch bei konzentrischen) Gesichtsfeldausfällen ist es postoperativ zu einer signifikanten Besserung der Gesichtsfeldausfälle gekommen (rechts und links paarweise aufaddierte Zahl der ausgefallenen Quadranten: 2 (0; 8) vs. 0 (0; 8); pSchlussfolgerungen. Die überwiegende Mehrzahl der Patienten mit Chiasmasyndromen weist postoperativ ein gebessertes oder komplett regredientes CS auf. Postoperative Verschlechterungen des vorbestandenen Chiasmasyndroms sind selten. Es ist entscheidend, Patienten mit einem CS oder mit einem drohenden CS möglichst frühzeitig zu operieren, da die Patienten mit einem CS trotz operativer Entlastung postoperativ immer noch signifikant schlechtere ophthalmologische Befunde aufweisen als Patienten, die präoperativ kein CS hatten. Ophthalmologische Ausfälle infolge von Chiasmasyndromen führen präoperativ zu einem häufigen und erheblichen Grad der Behinderung. Postoperativ kommt es zu einer erheblichen Besserung sowohl der Prävalenz als auch der Ausprägung des GdB bei Patienten mit präoperativem CS. Der GdB in dieser Patientengruppe ist jedoch weiterhin höher als bei Patienten ohne präoperatives CS

Unraveling the Allosteric Mechanism of Serine Protease Inhibition by an Antibody

SummaryRecent structural studies have outlined the mechanism of protease inhibition by active site-directed antibodies. However, the molecular basis of allosteric inhibition by antibodies has been elusive. Here we report the 2.35 Å resolution structure of the trypsin-like serine protease hepatocyte growth factor activator (HGFA) in complex with the allosteric antibody Ab40, a potent inhibitor of HGFA catalytic activity. The antibody binds at the periphery of the substrate binding cleft and imposes a conformational change on the entire 99-loop (chymotrypsinogen numbering). The altered conformation of the 99-loop is incompatible with substrate binding due to the partial collapse of subsite S2 and the reorganization of subsite S4. Remarkably, a single residue deletion of Ab40 abolished inhibition of HGFA activity, commensurate with the reversal of the 99-loop conformation to its “competent” state. The results define an “allosteric switch” mechanism as the basis of protease inhibition by an allosteric antibody

Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis

There is growing evidence for an interplay between inflammatory and coagulation pathways in acute and chronic inflammatory diseases. However, it remains unclear whether components of the coagulation pathway, such as tissue factor (TF), contribute to intestinal inflammation, and whether targeting TF will blunt the inflammatory cell recruitment, tissue injury, and enhanced thrombus formation that occur in experimental colitis. Mice were fed 3% dextran sodium sulfate (DSS) to induce colonic inflammation, with some mice receiving a mouse TF-blocking antibody (muTF-Ab). The adhesion of leukocytes and platelets in colonic venules, light/dye-induced thrombus formation in cremaster muscle microvessels, as well as disease activity index, thrombin–antithrombin (TAT) complexes in plasma, and histopathologic changes in the colonic mucosa were monitored in untreated and muTF-Ab–treated colitic mice. In untreated mice, DSS elicited the recruitment of adherent leukocytes and platelets in colonic venules, caused gross and histologic injury, increased plasma TAT complexes, and enhanced thrombus formation in muscle arterioles. muTF-Ab prevented elevation in TAT complexes, reduced blood cell recruitment and tissue injury, and blunted thrombus formation in DSS colitic mice. These findings implicate TF in intestinal inflammation and support an interaction between inflammation and coagulation in experimental colitis

Lerouge davası

Émile Gaboriau'nun İkdam'da yayımlanan Lerouge Davası adlı romanının ilk ve son tefrikalar

Role of Coagulation Factors in Cerebral Venous Sinus and Cerebral Microvascular Thrombosis

Thrombus formation can occur in both macroscopic and microscopic blood vessels. In the brain, cerebral venous sinus thrombosis (CVST) and focal cortical infarctions can result from the formation of thrombi in these different sized vessels. In this study we define the relative contributions of three major pro- and anti-coagulation pathways (heparin-antithrombin, protein C, and tissue factor (TF)) in the thrombogenic responses that occur in large and small vessels of the brain

Myeloid Cell Tissue Factor Does Not Contribute to Venous Thrombogenesis in an Electolytic Injury Model

Tissue factor (TF) is a potent initiator of the extrinsic coagulation cascade. The role and source of TF in venous thrombotic disease is not clearly defined. Our study objective was to identify the contribution of myeloid cell TF to venous thrombogenesis in mice

Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets

Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection-associated thrombi are poorly understood. Here, using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI-mediated) platelet activation. After infection, IFN-ã release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-ã, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding

PAR-1 contributes to the innate immune response during viral infection

Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3–induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1–/– mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1+/+ mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1–/– mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1+/+ mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection