Ischemia/reperfusion injury: effect of simultaneous inhibition of plasma cascade systems versus specific complement inhibition.

Ischemia/reperfusion injury (IRI) may occur from ischemia due to thrombotic occlusion, trauma or surgical interventions, including transplantation, with subsequent reestablishment of circulation. Time-dependent molecular and structural changes result from the deprivation of blood and oxygen in the affected tissue during ischemia. Upon restoration of blood flow a multifaceted network of plasma cascades is activated, including the complement-, coagulation-, kinin-, and fibrinolytic system, which plays a major role in the reperfusion-triggered inflammatory process. The plasma cascade systems are therefore promising therapeutic targets for attenuation of IRI. Earlier studies showed beneficial effects through inhibition of the complement system using specific complement inhibitors. However, pivotal roles in IRI are also attributed to other cascades. This raises the question, whether drugs, such as C1 esterase inhibitor, which regulate more than one cascade at a time, have a higher therapeutic potential. The present review discusses different therapeutic approaches ranging from specific complement inhibition to simultaneous inhibition of plasma cascade systems for reduction of IRI, gives an overview of the plasma cascade systems in IRI as well as highlights recent findings in this field.

Improved star camera attitude data and their effect on the gravity field

Efforts are ongoing to decrease the noise of the GRACE gravity field models and hence to arrive closer to the GRACE baseline. The most significant error sources belong the untreated errors in the observation data and the imperfections in the background models. The recent study (Bandikova&Flury,2014) revealed that the current release of the star camera attitude data (SCA1B RL02) contain noise systematically higher than expected by about a factor 3-4. This is due to an incorrect implementation of the algorithms for quaternion combination in the JPL processing routines. Generating improved SCA data requires that valid data from both star camera heads are available which is not always the case because the Sun and Moon at times blind one camera. In the gravity field modeling, the attitude data are needed for the KBR antenna offset correction and to orient the non-gravitational linear accelerations sensed by the accelerometer. Hence any improvement in the SCA data is expected to be reflected in the gravity field models. In order to quantify the effect on the gravity field, we processed one month of observation data using two different approaches: the celestial mechanics approach (AIUB) and the variational equations approach (ITSG). We show that the noise in the KBR observations and the linear accelerations has effectively decreased. However, the effect on the gravity field on a global scale is hardly evident. We conclude that, at the current level of accuracy, the errors seen in the temporal gravity fields are dominated by errors coming from sources other than the attitude data.

Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level:: The Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study.

BACKGROUND Rivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk-benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. METHODS Prospective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow-up. RESULTS We enrolled 537 patients (73±11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2±1.3 and 2.4±1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naïve (VN-group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6±1.4 under VKA to 5.5±0.8 points (P<0.001), and overall physician satisfaction from 3.9±1.3 to 5.4±0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4±0.9) and physician's satisfaction (5.5±0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01-1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05-1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03-3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. CONCLUSION Initiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction.

Mechanical Thrombectomy for Isolated M2 Occlusions: A Post Hoc Analysis of the STAR, SWIFT, and SWIFT PRIME Studies.

BACKGROUND AND PURPOSE Mechanical thrombectomy is beneficial for patients with acute ischemic stroke and a proximal anterior occlusion, but it is unclear if these results can be extrapolated to patients with an M2 occlusion. The purpose of this study was to examine the technical aspects, safety, and outcomes of mechanical thrombectomy with a stent retriever in patients with an isolated M2 occlusion who were included in 3 large multicenter prospective studies. MATERIALS AND METHODS We included patients from the Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR), Solitaire With the Intention For Thrombectomy (SWIFT), and Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) studies, 3 large multicenter prospective studies on thrombectomy for ischemic stroke. We compared outcomes and technical details of patients with an M2 with those with an M1 occlusion. All patients were treated with a stent retriever. Imaging data and outcomes were scored by an independent core laboratory. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score of 2b/3. RESULTS We included 50 patients with an M2 and 249 patients with an M1 occlusion. Patients with an M2 occlusion were older (mean age, 71 versus 67 years; P = .04) and had a lower NIHSS score (median, 13 versus 17; P < .001) compared with those with an M1 occlusion. Procedural time was nonsignificantly shorter in patients with an M2 occlusion (median, 29 versus 35 minutes; P = .41). The average number of passes with a stent retriever was also nonsignificantly lower in patients with an M2 occlusion (mean, 1.4 versus 1.7; P = .07). There were no significant differences in successful reperfusion (85% versus 82%, P = .82), symptomatic intracerebral hemorrhages (2% versus 2%, P = 1.0), device-related serious adverse events (6% versus 4%, P = .46), or modified Rankin Scale score 0-2 at follow-up (60% versus 56%, P = .64). CONCLUSIONS Endovascular reperfusion therapy appears to be feasible in selected patients with ischemic stroke and an M2 occlusion.

Waše cís. král. Milosti! Přeswědčeni jsouce, že staré akademické ústawy nemohou wíce odolati bouřim nynějšího wěku ...

Welsch (Projektbearbeiter): Bitte von Vertretern der Prager Studentenschaft um akademische Reformen: Glaubens- , Lehr- u. Lernfreiheit, Zweisprachigkeit, Korporationsfreiheit

A Metalloproteinase Mirolysin of Tannerella forsythia Inhibits All Pathways of the Complement System

Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. In this study, we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4, whereas inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium.

Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency.

The congenital form of thrombotic thrombocytopenic purpura (TTP) is caused by genetic mutations in ADAMTS13. Some, but not all, congenital TTP patients manifest renal insufficiency in addition to microangiopathic hemolysis and thrombocytopenia. We included 32 congenital TTP patients in the present study, which was designed to assess whether congenital TTP patients with renal insufficiency have predisposing mutations in complement regulatory genes, as found in many patients with atypical hemolytic uremic syndrome (aHUS). In 13 patients with severe renal insufficiency, six candidate complement or complement regulatory genes were sequenced and 11 missense mutations were identified. One of these missense mutations, C3:p.K155Q mutation, is a rare mutation located in the macroglobulin-like 2 domain of C3, where other mutations predisposing for aHUS cluster. Several of the common missense mutations identified in our study have been reported to increase disease-risk for aHUS, but were not more common in patients with as compared to those without renal insufficiency. Taken together, our results show that the majority of the congenital TTP patients with renal insufficiency studied do not carry rare genetic mutations in complement or complement regulatory genes.

A nearby M Star with tree Transitting Supter-Earths Discovered by K2

Small, cool planets represent the typical end-products of planetary formation. Studying the architectures of these systems, measuring planet masses and radii, and observing these planets' atmospheres during transit directly informs theories of planet assembly, migration, and evolution. Here we report the discovery of three small planets orbiting a bright (K-s = 8.6 mag) M0 dwarf using data collected as part of K2, the new ecliptic survey using the repurposed Kepler spacecraft. Stellar spectroscopy and K2 photometry indicate that the system hosts three transiting planets with radii 1.5-2.1 R-circle plus, straddling the transition region between rocky and increasingly volatile-dominated compositions. With orbital periods of 10-45 days the planets receive just 1.5-10x the flux incident on Earth, making these some of the coolest small planets known orbiting a nearby star; planet d is located near the inner edge of the system's habitable zone. The bright, low-mass star makes this system an excellent laboratory to determine the planets' masses via Doppler spectroscopy and to constrain their atmospheric compositions via transit spectroscopy. This discovery demonstrates the ability of K2 and future space-based transit searches to find many fascinating objects of interest.

"Star of Israel" [Rezension]

Arno Nadel

Star mit Wurm [Illustration] : (Bronze)

Siegfried Wagner

Street-Ball: The Myth of the Ghetto Basketball Star

In recent decades, countless scholars have examined the developing trend of African American dominance in United States’ professional sports. Many have hypothesized that this over-representation is caused by the presumed reliance on sports as an avenue out of poverty for the African American youths. This trend, it is believed, has a highly detrimental effect the African American community. In actuality, this argument is flawed because it works under the stereotypical assumption that the overwhelming majority of African Americans come from abject poverty. To dispel this fallacy, the author has analyzed the upbringings of each All-National Basketball League First Team player over the past thirty years. The author discovered that while the majority of the players selected were African American, only a small percentage of these athletes were raised in a poverty-stricken environment. Logically, this would not be the case if poor African Americans relied more heavily on sports than middle-class African Americans. This data proves that stereotypes, not empirical evidence, are the substance of nearly every previous study conducted on the topic.

Variational Calculation of the Hydrogen Molecular Cation using Maple (II). The pi and pi-star Orbitals

The pi and pi-star orbitals of the hydrogen molecular cation are obtained using Maple in the same manner as the sigma and sigma-star orbitals were obtained in paper-36.

Der Star (Sturnus vulgaris)

Von Hugo Otto