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Die Leitlinien von 2014 befassen sich in besonderem Maß mit Entscheidungsprozessen bei der Behandlung von Patienten mit koronarer Herzerkrankung. In den aktuellen Leitlinien wird erneut die Wichtigkeit von Notfall- und dringlichen Revaskularisationen bei Patienten mit akutem ST-Streckenhebungsinfarkt oder akutem Koronarsyndrom ohne ST-Streckenhebung unterstrichen. Der Entscheidungsprozess ist demgegenüber bei Patienten mit stabiler koronarer Herzerkrankung aufgrund verschiedener zur Verfügung stehender Behandlungsmöglichkeiten eine größere Herausforderung. Tatsächlich haben patientenbezogene Faktoren einen starken Einfluss auf Entscheidungsprozesse insbesondere in Fällen, in denen die aktuelle Evidenz keinen klaren Überlebensvorteil für die eine oder andere Behandlungsoption bietet. Essenzieller Bestandteil des multidisziplinären Ansatzes ist das „Herzteam“, bestehend hauptsächlich aus nichtinvasiv tätigen und interventionellen Kardiologen sowie Herzchirurgen. Abgesehen von patientenindividuellen Heart-Team-Diskussionen sehen die Leitlinien aus 2014 weiterhin vor, dass Standardsituationen auf der Basis institutioneller Protokolle bearbeitet werden können. In diesen Protokollen ist festzulegen, welche Patienten in der regelmäßigen Heart-Team-Konferenz besprochen werden und für welche Patienten ein Ad-hoc-Treffen des Heart-Teams stattfinden sollte. Die „hausinternen“ Protokolle sollen nicht ausschließlich auf den aktuellen Erkenntnissen und Ergebnissen der Leitlinien zur myokardialen Revaskularisation basieren, sondern sich auch an der spezifischen Erfahrung und den Stärken der interventionellen, kardiologischen und herzchirurgischen Abteilungen vor Ort orientieren. The 2014 guidelines are mainly concerned with the decision-making process regarding the revascularization policy for patients with coronary artery disease. The need for emergency or urgent revascularization in patients with ST segment elevation myocardial infarction or non-ST segment elevation acute coronary syndromes is again highlighted in the current guidelines. The decision-making process is, however, more demanding for patients with stable coronary artery disease due to the variety of treatment options that are available. Indeed, patient-related factors may profoundly impact the decision-making process as long as existing evidence provides no clear survival advantages for one of the treatment options. An essential component of the multidisciplinary approach is the heart team, which is mainly made up of non-invasive cardiologists, cardiac surgeons and interventional cardiologists. Although the decision-making process should provide the best revascularization option for each patient, it should also support an efficient clinical workflow. For this reason, the interdisciplinary heart team is encouraged to formulate institutional protocols to guide revascularization strategies for common case scenarios. The institutional protocols are not only based on existing evidence as reflected in the current guidelines on myocardial revascularization but also on the specific experience and strengths of local departments of interventional cardiology and cardiac surgery.

Hintergrund:Über das Risiko einer Virusinfektion mit dem schweren akuten Atemwegssyndrom Coronavirus 2 (SARS-CoV-2) bei Krebspatienten, von denen viele immungeschwächt und damit anfälliger für eine Vielzahl von Infektionen sind, ist sehr wenig bekannt. Als Vorsichtsmaßnahme haben viele klinische Studien während der ersten Welle der weltweiten Pandemie des neuartigen Coronavirus (COVID-19) die Aufnahme von Patienten pausiert. In diesem Fallbericht beschreiben wir die erfolgreiche Behandlung eines Patienten mit rezidiviertem und refraktärem Multiplem Myelom (MM), der unmittelbar nach der klinischen Genesung von COVID-19 mit einer chimären Antigenrezeptor (CAR)-T-Zelltherapie mit Anti-B-Zellreifungsantigen (BCMA) behandelt wurde. Fallvorstellung:Der 57-jährige weiße männliche Patient war seit 4 Jahren an MM erkrankt und galt bei der Vorstellung zur CAR-T-Zelltherapie als pentarefraktär. Er hatte eine Immunsuppression in seiner medizinischen Vorgeschichte und er erhielt am Tag vor der COVID-19-Diagnose eine Dosis lymphdepletierender Chemotherapie (LDC). Dieser Patient konnte eine erhebliche Immunantwort gegen das SARS-CoV-2-Virus aufbauen, und antivirale Antikörper bleiben auch 2 Monate nach Erhalt einer Anti-BCMA-CAR-T-Zelltherapie noch nachweisbar. Die kürzliche SARS-CoV-2-Infektion bei diesem Patienten führte nicht zu einer Exazerbation des CAR-T-assoziierten Zytokin-Freisetzungssyndroms (CRS) und umgekehrt führte die CAR-T-Zelltherapie nicht zu Komplikationen im Zusammenhang mit COVID-19. Einen Monat nach der CAR-T-Zell-Infusion wurde bei dem Patienten ein unbestätigtes partielles Ansprechen nach den Kriterien der International Myeloma Working Group (IMWG) festgestellt. Schlussfolgerung:Unser Fall liefert einen wichtigen Kontext für die Wahl der Behandlung von MM-Patienten in Zeiten von COVID-19 sowie für die Frage, ob die CAR-T-Therapie auch bei Patienten verabreicht werden kann, die von COVID-19 genesen sind. Da die COVID-19-Pandemie weltweit anhält, ist eine umfangreiche Diskussion über die Entscheidung, ob mit der CAR-T-Zelltherapie fortgefahren werden soll, erforderlich, wobei die potenziellen Risiken und Vorteile der Therapie gegeneinander abgewogen werden müssen. Dieser Fall legt nahe, dass es möglich ist, die Anti-BCMA-CAR-T-Zelltherapie nach der Genesung von COVID-19 erfolgreich abzuschließen. Die Studie CRB-402 wurde am 6. September 2017 bei clinicaltrials.gov registriert (NCT03274219).

The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 β2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-α-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML.

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP+=not reached, CIMP-=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+=2.34, A-CIMP-=1.00; P=0.01). Hypermethylation in A-CIMP+favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP+was enriched in CEBPA(P=0.002) and WT1mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP+function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP+AML should be validated prospectively.

In patients with multiple myeloma, bendamustine monotherapy is effective as 1stand 2ndline therapy. However, data for patients with advanced multiple myeloma is rare. In this retrospective analysis we have identified 39 patients with relapsed or refractory multiple myeloma by means of case research, who have been treated at our institution with bendamustine as salvage therapy. After in median 2 lines of prior therapy (range:1-5) patients received in median 3 (range: 1-10) cycles of bendamustine. Bendamustine dosage was 80-150 mg on day 1+2 of a monthly cycle. Bendamustine was administered as monotherapy in 39% of patients, whereas 61% received concomitant steroids. Toxicity was mild to moderate. Response rates were as follows: 3% vgPR, 33% PR, 18% MR, 26% SD and 20% PD. The median event-free and overall survival were 7 and 17 months, respectively. In conclusion, in patients with advanced multiple myeloma bendamustine is effective and associated with mild toxicity. Therefore, the role of bendamustine in patients with multiple myeloma should be investigated in further clinical trials.

The linear discriminant analysis (LDA) is a common technique used in machine learning and pattern recognition for dimensionality reduction problems. Here, the LDA is applied to detect faults‐scarps in high‐resolution bathymetric profiles in the Southern Pescadero Basin (SPB) in the Gulf of California. The LDA uses fault scarps and cuestas (sloping topography) identified by a geomorphologist in the neighboring Alarcón Rise (AR). These geometric representations are transformed into a parametric space by an idealized fault‐scarp degradation model. Through inversion, we extracted the product of the mass diffusion coefficient with time (τ), scarp height (u0), and goodness of fit of the model on the scarp profiles and cuestas (ε). The LDA transforms the parametric space τ, u0, εby the Fisher’s criterion into a 1D dimensional space that maximizes separability of classes. Then, the classification is performed by Bayes decision rule using the probability density functions (PDF) built from the 1D projected data for each class (fault‐scarps and cuestas). The implementation results in cross‐sectional profiles across the SPB show the ability to detect faults in the deepest part of the basin where the flat basin floor is interrupted by morphologically young fault‐scarp arrays. The LDA interpretation outperforms manual identification, particularly in faults scarps that are longer than ∼3 km, whereas shorter faults are challenging to discern from other linear features like channels. The model can extract information about the state of degradation of the scarps. This application allows the identification of fault generation episodes and resolves kinematic interactions between faults. Geologists often have to investigate large amounts of data to identify new ideas about the processes that sculpt the Earth’s surface. The data are usually not sufficiently classified, making structure identification a time‐consuming task. The effort is especially challenging in submarine environments, given their inaccessibility and difficulty in collecting direct observations. We present a semi‐automated method for detecting faults in high‐resolution gridded bathymetry data collected by an autonomous underwater vehicle. We use a machine‐learning technique to classify fault‐line scarps based on key geomorphological attributes measured from the scarp’s erosion. The detection technique uses a brute‐force approach that systematically scans all the bathymetry data and searches for fault‐line scarps. The results of the proposed method detect fault‐scarps of different sizes and stages of degradation. Moreover, the method is robust to moderate noise (i.e., random topography and data collection artifacts) and correctly handles different fault dip angles. Tests show that both isolated and linkage fault configurations are detected and tracked reliably. The method can also get relative timing information of the faulting episodes. Getting all this information is valuable to understand the processes that shape submarine geomorphology. Feature extraction using the solution of the diffusion equation for modeling fault‐scarp degradation by erosionLinear discriminant analysis technique is used for fault‐line scarp classification plus a windows search approach for detectionThe method provide information of spatial distribution, slip, timing and mode of growth of fault‐line scarps Feature extraction using the solution of the diffusion equation for modeling fault‐scarp degradation by erosion Linear discriminant analysis technique is used for fault‐line scarp classification plus a windows search approach for detection The method provide information of spatial distribution, slip, timing and mode of growth of fault‐line scarps

Knowledge on interplay between the cardiac molecular response to transplantation-induced stress and primary graft dysfunction (PGD) is limited. A cDNA array identified HIF-1, EGR-1, NAB-2, VEGF-A and uPA as mediators of cardiac tissue response to transplantation-induced stress. mRNA expression of these molecules was measured in left ventricular biopsies from 200 donors before and after aortic cross-clamping and at 10-, 30- and 60-min reperfusion by real-time RT-PCR. HIF-1? expression at two time points was significantly associated with PGD, as shown by univariate analysis, receiver operating characteristic curve and multivariate logistic regression. At a cut-off level of 200 arbitrary units, HIF-1? after aortic cross-clamping in donors (78 sensitivity, 83 specificity) and at 10-min reperfusion (85 sensitivity, 83 specificity) identified PGD. HIF-1? demonstrates the potential to be a predictive marker for PGD; however, as multiple factors were tested at different time points, prospective evaluation is clearly necessary to confirm this observation.

Knowledge on interplay between the cardiac molecular response to transplantation‐induced stress and primary graft dysfunction (PGD) is limited. A cDNA array identified HIF‐1, EGR‐1, NAB‐2, VEGF‐A and uPA as mediators of cardiac tissue response to transplantation‐induced stress. mRNA expression of these molecules was measured in left ventricular biopsies from 200 donors before and after aortic cross‐clamping and at 10‐, 30‐ and 60‐min reperfusion by real‐time RT‐PCR. HIF‐1α expression at two time points was significantly associated with PGD, as shown by univariate analysis, receiver operating characteristic curve and multivariate logistic regression. At a cut‐off level of 200 arbitrary units, HIF‐1α after aortic cross‐clamping in donors (78% sensitivity, 83% specificity) and at 10‐min reperfusion (85% sensitivity, 83% specificity) identified PGD. HIF‐1α demonstrates the potential to be a predictive marker for PGD; however, as multiple factors were tested at different time points, prospective evaluation is clearly necessary to confirm this observation.

Bevor das Rauchgas in die Gasturbine eintritt, muss es soweit gereinigt sein, dass die Einleitkriterien (Partikelgehalt, Alkaligehalt) erfüllt sind. Die Reinheit des Rauchgases muss daher stets kontrolliert und gewährleistet werden. Vorgestellt wird eine neue Partikeldiagnostik, mit der es möglich ist, den Staubgehalt und den mittleren Partikelradius in situ zu kontrollieren und die Daten online der Messwarte zur Verfügung zu stellen.

Background:A fall in old age is known as a common consequence of frailty and decline as well as a risk factor for further falls. Studies identifying hip fracture patients who are at risk of a further fall are lacking. Therefore it was of interest to evaluate the risk factors for falling in a high-risk population, i.e., patients during rehabilitation after recent proximal femur fracture. Methods:935 consecutive patients who had surgical intervention after acute fracture of the proximal femur underwent a multidimensional assessment within the first two days after admission to the rehabilitation ward. Falls during the stay on the rehabilitation ward were registered. The baseline data were compared between fallers and non-fallers. Findings:11.8% of the patients fell during rehabilitation. Risk factors associated with a fall were increasing age, male gender, type of surgery, the use of a rollator and nocturnal urinary incontinence. The risk of falling increased in the middle of the second week of rehabilitation, when frailer patients gained mobility and ability to walk by themselves, while they were not yet safe enough. Interpretation:It was possible to compose a risk profile for future falls. Those identified as ’at risk of a further fall‘ should be selectively offered protective devices and special training programs in order to prevent future fractures. As for the surgical intervention, the type of surgery in relation to age and long-term outcome is of particular interest since the use of the more expensive total hip arthroplasty procedure may be more cost effective in the long term. Hintergrund:Stürze sind bekannte Folgen von allgemeiner Schwäche und Gebrechlichkeit älterer Menschen, gleichzeitig aber auch der wichtigste Risikofaktor für einen weiteren Sturz. Es fehlen Studien, die das Sturzrisiko von Patienten nach Schenkelhalsfraktur evaluieren. Deshalb wurden Patienten im Rahmen der Rehabilitation nach hüftgelenksnaher Femurfraktur bezüglich ihres weiteren Sturzrisikos evaluiert. Patienten und Methode:Es wurden 935 Patienten nach chirurgischer Sanierung einer hüftgelenksnahen Femurfraktur im Rahmen der Aufnahmeuntersuchung zur Rehabilitation im Sinne eines multidimensionalen Geriatrischen Assessment untersucht. Die Stürze während der Rehabilitation wurden exakt dokumentiert und die Basisdaten des Assessments zwischen „Stürzern“ und „Nicht-Stürzern“ verglichen. Ergebnisse:11,8% der Patienten stürzten während der Rehabilitation. Als spezielle Risikofaktoren konnten das Alter per se, das männliche Geschlecht, der Bedarf eines Rollators und nächtliche Inkontinenz identifiziert werden. Das Sturzrisiko nahm während der zweiten Woche signifikant zu. Bei zunehmender Mobilität, ohne gleichzeitige Sicherheit, stieg das Sturzrisiko insbesondere für die gebrechlichen Patienten. Diskussion:Im Rahmen der Studie konnte ein besonderes Risikoprofil in dieser Hochrisikogruppe identifiziert werden. Jenen Patienten sollte während der Rehabilitation spezielle Trainingsprogramme und protektive Maßnahmen angeboten werden, um eine weitere Fraktur zu verhindern. Gleichzeitig bedarf es weiterer Studien, um den Einfluss der verwendeten Osteosynthese auf das Sturzrisiko zu überprüfen.

The important functions promoted by powdered flux added over the liquid steel surface in continuous casting moulds are strongly affected by the thickness of the liquid layer that forms as a result of the heat absorbed. The present work discusses the results of a three-dimensional steady state model, developed to represent the coupled fluid flow and heat transfer phenomena that determine thickness profiles of the liquid flux layer. Since the laminar flow of the liquid slag layer depends on the shearing imposed on it by the turbulent motion of the liquid steel beneath it, and since additionally this motion is strongly influenced by the flow characteristics of the steel stream poured into the mould through the submerged entry nozzle (SEN), separate turbulent flow models for the liquid steel in the SEN and the mould were also developed. The consistency among the models and their accuracy was judged by comparing thickness and temperature flux profiles measured in plant against predicted ones; the comparison showed good agreement. The effects of casting speed, mould width, and flux viscosity and heat of melting on the liquid layer thickness were investigated. The last variable was found to exert the most marked influence. Different from conventional casting moulds, where the liquid layer thickness increases with increasing casting speed, in compact strip process moulds the thickness remains almost constant with increasing casting speed. This difference is well accounted for by the model, which suggests that this behaviour stems from the different slag flow patterns generated in straight, wide moulds and in thin moulds having a central upper funnel shaped section.

In a composite material reinforced by short random fibers, damage results from different elementary failure mechanisms such as matrix microcracking, fiber pull out, failure of the fiber/matrix interface, failure of fibers, etc. These damages influence greatly the macroscopic behavior of composite materials. To obtain good mechanical performance of a composite material, it is important to optimize the fiber ratio and the quality of the fiber/matrix interface, which have a direct influence on the damage mentioned above. The main objective of this study is to determine the influence of structural parameters on the evolution of damage for two types of polypropylene glass-fiber reinforced composites. In parallel with the classical approach of the mechanical theory of damage, which consists in load–unload tensile tests, the use of acoustic emission allows one to follow in real time the character and the importance of damage mechanisms in the course of loading. In addition, fractographic analysis makes it possible to confirm different assumptions and conclusions from this study.

Pathogenetisch liegt der instabilen Angina pectoris meist eine Ruptur der fibrösen Kappe einer lipidreichen Plaque zugrunde. Dies führt zur Aktivierung, Adhäsion und Aggregation von Thrombozyten, also zu Thrombose und Gefäßverschluß. Weitgehend belastungsunabhängig treten Ischämiesymptome auf und werden im Gegensatz zur stabilen Angina pectoris, deren Ischämiesymptome belastungsabhängig sind, als instabile Angina pectoris bezeichnet. Die vorliegende Übersicht zeigt den derzeitigen Stand der Behandlungskonzepte für die instabile Angina pectoris auf, die ebenso wie beim Myokardinfarkt in Richtung interventioneller Maßnahmen gehen, medikamentös kombiniert mit Azetylsalizylsäure, niedermolekularem Haprin und Glykoprotein (GP) IIb/IIIa Rezeptorantagonisten. Dabei wird die PTCA immer häufiger durch Stentimplantation ergänzt. Die Dynamik dieser Entwicklung läßt sich allein daraus ablesen, daß die erste koronare Stentimplantation gerade erst ein gutes Dezennium (1987) zurückliegt. Ob sich eine so aktiv vorgehende Therapiestrategie “flächendeckend” in Deutschland durchführen läßt, stimmt nachdenklich und muß aus Organistations- und Kostengründen dahingestellt bleiben. Wünschenswert wäre das im Hinblick auf die wesentliche Risikoverbesserung akuter Konorarsyndrome natürlich. Organisatorisch ist neben qualitätssichernden Maßnahmen auch eine vertretbare Entfernung zur nächstgelegenen Herzchirurgie erforderlich, falls weiterführende operative Maßnahmen geboten sind.

Optimized geometries of the conformers of permethylated linear pentasilane, n-Si5Me12, were calculated by the HF/3-21G*, MM3, MM2, and MM+ methods, which predict eight, nine, six, and six energetically distinct enantiomeric conformer pairs, respectively, at geometries representing various combinations of the anti (~165°), ortho (~90°), and gauche (~55°) SiSiSiSi dihedral angles in the backbone. The results of the MM2 and MM+ methods, based on the same force field, differ insignificantly. The barriers between conformers appear to be exaggerated by the molecular mechanics methods, particularly MM2. Contour maps showing the ground-state energy as a function of the full range of two backbone SiSiSiSi dihedral angles, with all other geometrical variables optimized, computed by each of the methods (only a limited range of angles near the anti,anti geometry in the case of HF/3-21G*) are compared with each other and with analogous results for a model compound, Si4Me10. Conformer interconversion paths are discussed, and two meso transition states for enantiomer interconversion have been located at the HF/3-21G* level of calculation. At the eight HF/3-21G* optimized geometries, single-point energies (HF/6-31G* and MP2/6-31G*) and vibrational frequencies (HF/3-21G*) were computed. The predicted IR and Raman spectra suggest that about half of the expected conformers will be identifiable by vibrational spectroscopy under conditions of matrix isolation. Relative conformer energies calculated by the MM2 and HF methods are similar and favor the anti dihedral angles over gauche and ortho, in agreement with results of solution experiments. Those calculated by the MM3 and MP2 methods are similar to each other and favor both anti and gauche dihedral angles nearly equally over ortho, in agreement with indications provided by gas-phase experiments. A rationalization of these solvent effects is proposed. The energies of the conformers of Si4Me10 and Si5Me12 were used to set up a system of additive increments at the MM2, MM3, HF/3-21G*, HF/6-31G*, and MP2/6-31G* levels of calculation, which can be used to predict conformational energies of longer permethylated oligosilanes. An intrinsic energy value is assigned to each of the a, o, and g dihedral angles, and interaction energy values are assigned to each combination of two dihedral angles. The interaction values follow the expected rules in that equal twist sense is favored for adjacent aa, ag, oo, and gg pairs, whereas opposite twist sense is generally favored for adjacent ao and go pairs. The MM3-derived set of increments has been tested against results computed for Si6Me14 and found to perform well.

As the temperature dependence of relative apparent whole blood viscosity ηrelis still controversial, the relation between the temperature dependence of red cell aggregation (RCA) and that of ηrelwas examined in normal donors and in patients with venous ulcers of the leg. Apparent whole blood viscosity was measured in the DEER-rheometer (0.01Pa < τ< 2.9Pa) at 10°C, 20°C, 30°C and 37°C. The instrument was calibrated for each temperature to correct for changes in viscometer geometry. Simultaneously the minimal shear stress τTminto keep RCA dispersed was determined by photometric aggregometry. ηrelwas found to increase with decreasing temperature. By basing the relative cold induced increase in ηrelon the state of RCA as defined by the ratio of τ/τTminthe relation between both features is verified: With increaslng RCA the cold induced increase in ηrelis progressively enhanced.

Abstract: Objective: Altered platelet function plays a role in the pathophysiology of multiple organ failure in sepsis. The purpose of the present study was to evaluate various aspects of platelet adhesive function in septic patients and its putative relevance for prognosis. Design: Prospective clinical study. Setting: Intensive Care Unit of the University Hospital. Patients and methods: A total of 41 patients admitted to the medical Intensive Care Unit were studied. On the day of admission, patients were evaluated by intensive care scoring systems (Elebute, APACHE II) to assess the severity of sepsis and multiple organ dysfunction syndrome (MODS), and platelet function tests were performed. All patients were observed for 28 days to assess their clinical outcomes. Eleven patients revealed septicemia without MODS (Elebute ≥12, APACHE II <20) and 20 septic patients suffered from MODS (Elebute ≥12, APACHE II ≥20). Ten non-septic patients without MODS served as a control group (Elebute <12, APACHE II <20). Flow cytometric determination of the activated fibrinogen (fg) receptor GPIIb-IIIa and as well as thrombospondin (TSP) on platelets and platelet-neutrophil adhesion (CD41 immunofluorescence) ex vivo was performed using monoclonal antibodies. The effect of plasma obtained from patients on normal platelet aggregation in vitro, and adhesion to cultured endothelial cells was evaluated. Results: The surface expression of TSP on platelets was increased in septic patients with MODS compared to controls (p<0.03). Platelet-neutrophil adhesion was not significantly altered in septicemia (p<0.09) but decreased significantly in the presence of MODS (p<0.05) when compared to controls. Logistic regression analysis showed that platelet-neutrophil adhesion was an independent predictor for poor clinical outcome (p<0.01). Plasma from septic patients sensitized normal platelets to hyperaggregate and to adhere to cultured endothelium (p<0.01). Conclusion: In septic patients platelets become activated and are hyperadhesive to other vascular cells including neutrophils and endothelium. This may induce sequestration of platelets and microcirculatory arrest, thus the development of MODS.

Summary: o| li]1.|Myocardial hypertrophy, for instance in patients with hypertensive heart disease, is characterized by a reduction of coronary vascular reserve, even in the presence of normal coronary arteries. In hypertensive animals, on the microcirculatory level functional changes can be observed before the onset of any structural rarefications. In 10 rats with renal hypertension and pressure-induced left ventricular hypertrophy (LVH), the microcirulation of the left ventricular myocardium was studied using in vivo fluorescence microscopy and morphometric analysis. Renal hypertension was provoked by clipping of the left renal artery. After 8 weeks, systolic blood pressure in LVH rats averaged 172 ± 8 mmHg, compared to 91 ± 2 mmHg in 10 normotensive (NT) rats. In LVH rats, distances of plasma-perfused capillaries were significantly increased (NT = 17.7; LVH = 20 μm;p < 0.001). Volume density, surface density, and length density of capillaries in LVH rats were reduced by 20% compared to NT rats. Capillary red cell content as measured by the ratio of capillaries filled with red cells to those containing plasma alone (Q) in LVH animals exceeded that in NT rats (LVH: Q = 0.83 ± 0.04; NT: Q = 0.77 ± 0.04;p < 0.025). During hypoxia (H, 5% O2) capillary red cell recruitment in LVH rats (Q: control c = 0.83; H = 0.95) was diminished by 33% as compared to NT rats (Q: c = 0.77; H = 0.95). Thus, in addition to the decreased capillary density, the reduction of capillary red cell recruitment may be responsible for chest pain in patients with LVH and normal coronary arteries. li]2.|In 11 rats, the microcirculation of the repeatedly ischemic (stunned) left ventricular myocardium (SM) was studied using in vivo fluorescence microscopy. Stunning was provoked by 6 subsequent 10 minute ligations of the left anterior descending coronary artery, each of them followed by a 20 min reperfusion period. In the SM showing hypokinetic wall motion mean capillary blood flow velocity was markedly reduced (control c = 1312; SM = 694 μm/sec;p < 0.001): myocardial blood flow (hydrogen clearance) in the SM dropped by 55%. In SM, leukocytes often appeared in slow-flow capillaries plugging capillary branches: the percentage of capillaries and postcapillary venules with adherent leukocytes was markedly increased (c = 3%; SM = 68%). In close link to leukocyte adherence, a rise of microvascular permeability was documented by extravascular clouds of fluorescent dextran. The ratio of capillaries filled with red cells to those containing plasma alone was diminished in SM (c = 0.77; SM = 0.65;p < 0.001). In the SM there are microcirculatory disturbances which occur before the onset of detectable structural alterations of both the microvasculature and the myocyte.

To investigate the temperature-dependence of red cell aggregation 20 blood samples of normal donors and 20 blood samples of patients with venous ulcers of the leg were examined by photometric aggregometry at 3° C, 10° C, 20° C, 30° C and 37° C. With decreasing temperature red cell aggregates become more resistant to hydrodynamic dispersion and they become more prone to growing under low shear stress. It is concluded that a decrease in temperature causes an increase in adsorptive energy of red cell aggregation, which is most likely due to an increase in molecular adsorption stress. Red cell aggregate formation as an overall process is retarded by a decrease in temperature, which is primarily due to an increase in plasma viscosity causing increased damping of aggregate formation. Accordingly the rate constant of aggregate formation corrected for plasma viscosity increases with decreasing temperature. The temperature-dependence of the kinetic parameters can be explained by a theoretical model that suggests the increase in contact area between aggregating red blood cells as the rate-limiting step of red cell aggregation. As a whole red cell aggregation is favoured by lowering of temperature.

Pregnant rats were treated with 40 mg spironolactone (sp) po from the 13th to the 21st day p.c. The foetuses were prepared and histologically examined on day 22. The male foetuses showed distinct signs of feminization especially of the external genitalia. The anogenital distance was nearly 48% shorter than that of the controls. The prostatic utricle persisted more distinctly, and the number and size of the prostatic buds were significantly reduced. The degree of feminization of the male foetuses which is achieved under the influence of sp (40 mg/day) is the same as that which can be induced by 1–3 mg cyproterone acetate.

The hormone dependency of the vaginal SA content in mice has been investigated in the present study.In intact animals, the SA concentration is significantly higher in diestrus than estrus. In ovariectomized animals, natural sex steroids have characteristic effects on the SA content:E2at a small dose produces a slight increase in the vaginal SA concentration as the result of the moderate mucification of the epithelium. With increasing doses, the SA concentration is decreased, thereby the vaginal epithelium is cornified and stratified. Progesterone, given alone, has no effect, but it increases the SA concentration on the simultaneous administration of E2. The extensive mucification is induced by the combined treatment.Testosterone produces also a slight increase in the SA concentration due to mucification. This androgen restores the E2effect on the SA content up to the level of the castrated control.These results with natural sex steroids are discussed in relation to their histomorphological effects on some of the female sexual organs.

Two types of so-called "depot contraceptives", long-acting steroids which are of interest for human use, were studied in animals.Norethisterone oenanthate, mainly gestagenic in the human and other species, turned out to be predominantly oestrogenic in rats. This oestrogenicity caused indirectly, viaan enhanced hypophysial prolactin secretion, the well-known hypophysial and mammary tumours in rats.Another synthetic gestagen, 4,6-dichloro- 17- acetoxy- 16α-methyl-4,6-pregnadiene-3,20-dione, which might be considered in its biological actions similar to preparations containing chlormadinone acetate or medroxy-progesterone acetate, induced no signs of oestrogenicity in dogs. It is surmised that its gestagenic influence indirectly, and probaby, viaan enhanced hypophysial prolactin secretion caused "mammary nodules" in this "non-rodent" species. These studies have born out mainly two facts:A synthetic steroid, norethisterone oenanthate, exerted different biological effects in different species: it was a gestagen in the rabbit, whereas in rats, its predominant influence was oestrogenic.The hypophysial prolactin secretion was enhanced in various species by different mechanisms: in rats, the oestrogenicity caused an increased prolactin plasma level, whereas in dogs, a gestagen with obviously no inherent oestrogenicity, 4,6-dichloro-17-acetoxy-16α-methyl-4,6-pregnadiene-3,20-dione, converted the histological appearance of the anterior pituitary into a condition with a greatly increased number of eosinophils. This histological finding was interpreted as an indicator for a hypersecretion of prolactin.Hence, animal work with "gestagens" has only limited predictive value with respect to their possible effects in the human species. Therefore, inflexible recommendations are not helpful in solving the safety problem of long-acting steroids which affect primarily reproductive processes.

Pregnant guinea-pigs were given cyproterone acetate intramuscularly from the 15th to the 40th day post coitum (p.c.). The dose for each group was 50, 75 or 100 mg/kg/day. On the 46th day p.c., the fetuses were removed and the internal and external genitalia of the genetically female guinea-pigs were examined. Virilization effects were seen in all the female fetuses examined ; there was stimulation of the epididymal tubules, development of the Wolffian ducts and prostate, but no stimulation of the seminal vesicles. There was distinct virilization of the external genitalia; the vagina was considerably shortened in favour of the sinus urogenitalis. The balanopreputial fold was completely closed over in some animals, resembling that normally found in the external genitalia of male guinea-pig fetuses. It was not possible to influence the differentiation of the gonads or the Müllerian ducts. These effects were not dose-dependent, and it was not possible to reach any conclusions about this paradoxical masculinizing action of cyproterone acetate, although a number of possible explanations are discussed.

Female guinea-pigs were treated with 50 mg cyproterone acetate (CA)/kg body weight/day from the 30th to the 45th day of pregnancy. Fifteen of their male offspring were reared and their sexual behaviour was observed. Eleven of the test males showed no signs of male sexual behaviour when in contact with females in oestrus. All the masculine behaviour patterns were observable in only one test male. When in contact with normal male animals, the test males showed signs of feminine sexual behaviour, but spontaneous lordosis reactions were not observed.After castration and treatment with 50 μg testosterone propionate per day, the male offspring of sows which had received CA treatment showed reduced masculine sexual behaviour by comparison with control animals which had undergone the same treatment.After treatment with 3 μg oestradiol benzoate and 0·2 mg progesterone, significantly longer lordosis reactions were observed in the test males than in the control males which had received the same treatment, but the reactions were significantly shorter than in ovariectomized females treated with oestradiol benzoate and progesterone.

Recent studies have improved our understanding of the beneficial actions of calcium antagonists on myocardial microcirculation and metabolism. The effect of calcium antagonists on the microcirculation of the left ventricular rat myocardium was studied using in vivomicroscopic techniques. Intravenous verapamil 0.3 mg/kg and nifedipine 75 µg/kg produced a 15 to 18% increase in the diameter of larger A1and A2coronary arterioles (range 31 to 300µm); diameters of terminal (A4) arterioles and capillaries did not change significantly. Furthermore, verapamil significantly (p < 0.001) increased the ratio of capillaries filled with red cells to those containing plasma alone. Verapamil pretreatment produced a similarly selective dilatation of larger coronary arterioles and protected against the ischaemia-induced fall in capillary red cell content. Spectroscopic data show that verapamil also produces an increase in myocardial phosphocreatine and preservation of adenosine triphosphate (ATP) during ischaemia in the Langendorff-perfused heart. In patients with exercise-induced angina, gallopamil decreased global myocardial 201Tl and 123I phenylpentadecanoic acid (IPPA) uptake due to a reduction in myocardial oxygen consumption. Regional 201Tl and IPPA uptake as well as IPPA clearance in poststenotic areas tended to rise after gallopamil treatment. Thus, the beneficial effects of calcium antagonists such as verapamil or gallopamil in patients with ischaemic heart disease may result from dilatation of predominantly larger arterioles. Consequently, there is an improvement in regional perfusion and free fatty acid utilisation in reversibly ischaemic regions.

In sexual-hormone activity differences arise when only a minimum change in the structure of a known molecule is made. Even the physiological hormones have similar structures but extremely different properties. Small variations of the steroid molecule lead to orally active progestogens and estrogens. The discovery of orally active androgens and the development of anabolic agents and antiandrogens proceeds also by very small changes of known structures. Out of a million possible variations of the steroid molecule, the synthesis of approximately 80 000 structures has been realized.

Summary I. Myocardial hypertrophy, for instance in patients with hypertensive heart disease, is characterized by a reduction of coronary vascular reserve, even in the presence of normal coronary arteries. In hypertensive animals, on the microcirculatory level functional changes can be observed before the onset of any structural rarefications.

ObjectiveTo investigate single neutrophil flow resistance in coronary artery disease, including myocardial infarction before initiation of reperfusion therapy.DesignNeutrophil flow resistance was measured in 93 subjects in five groups: (group 1) 28 patients within 12 hours after the onset of myocardial infarction, before reperfusion therapy; (group 2) 18 with unstable angina; (group 3) 13 with stable angina; (group 4) 13 age matched patients without coronary disease, and (group 5) 21 healthy volunteers.Main parametersSingle neutrophil transit times through 8 μm oligopore filters determined with a modified cell transit analyser.ResultsLeucocyte count (10⁹/l) was increased in coronary disease, especially in myocardial infarction and unstable angina (mean and 95% confidence intervals for groups 1 to 5: 12·6 (11.0 to 14·2), 11·3 (8·5 to 14·1), 8·5 (7·4 to 9·6), 8·0 (6·0 to 10·0), 7·0 (6·1 to 7·9)). Polymorphonuclear granulocyte (PMN) flow resistance correlated negatively with white blood cell (WBC) count and was significantly decreased in coronary artery disease (CAD), especially in myocardial infarction; mean transit times (ms) for groups 1 to 5 were: 13·6 (11·8 to 15·4), 16·9 (13·9 to 19·0), 16·9 (12·8 to 21·0), 22·0 (19·6 to 24·4), and 18·6 (15·7 to 21·5).ConclusionNeutrophil flow resistance was decreased in CAD, especially in myocardial infarction before reperfusion therapy. In contrast to previous findings in reperfused myocardial infarction, the present study showed that stiffened PMNs were not yet present in the circulating blood pool. Thus a pharmacological approach aimed at suppressing leucocyte activation before or during reperfusion therapy may be feasible.

Some groups, including ours, have been generating arterial tree models using constrained constructive optimization (CCO). Arterial trees have been grown to arbitrary resolution without input of anatomical data. We performed this study to learn about the shortcomings that might have resulted from neglecting the anatomical data in CCO models. In a total of 450 segments obtained from 4 human cast hearts, the ratio of bifurcating daughter segment radii (0 &lt; Sbif = r(2)/r(1) &lt; 1) was examined, which corresponds to the split of the total flow of the mother segment. For any complete bifurcation, where the radii of the parent segments and the radii of daughters were known, the area expansion ratio was computed (Aexp = [r(1)² + r(2)²]/ r(parent)²). The bifurcating ratio was found to be distributed in a nonnormal fashion, with a median of 0.76. The average area expansion ratio Aexp, characterizing the change of cross-sectional area of the vasculature from proximal to distal, was 0.93 ± 0.26. The ‘rate of branching’ (d(i)/(d(0)) was defined by the segment diameter relative to the diameter of the root segment. Averaging the rate of branching over segments within each bifurcation level resulted in a decreasing function of bifurcation level. This article provides new experimental data on branching geometry of coronary arteries (i.e., the trees evaluated in this study are purely delivering rather than conveying). Based on these facts, we suggest that the analytical bifurcation law in CCO might be replaced by the bifurcation rule obeyed on a stochastic basis only. Anat. Rec. 251:50–59, 1998. © 1998 Wiley-Liss, Inc.

The effect of three cardioplegic protocols on perioperative myocardial injury was studied in 62 coronary artery bypass grafting (CABG) patients randomized into three groups with either antegrade or retrograde cold blood cardioplegia, or coronary sinus occlusion during antegrade supply. During the aortic cross-clamp time anterior and posterior septal temperatures were recorded, indicating the distribution of cardioplegic solution within the myocardium. Serum creatine kinase (CK), CK-isoenzyme MB and myoglobin as well as 12-lead electrocardiograms (ECG) were analyzed. Statistical analysis showed no effect of the cardioplegic protocol, whereas the patient's preoperative status, aortic cross-clamp time and intraoperative myocardial temperature had significant (P < 0.05) effects on immediate postoperative CK and CK-MB enzyme release. Creatine kinase-MB peak values were significantly increased in patients with major vessel disease and reduced left ventricular function (92 +/- 53 U/l versus 67 +/- 25 U/l). Both CK and CK-MB values were significantly higher in patients with aortic cross-clamp times of more than 1 h than in patients with shorter clamping times (661 +/- 188 and 78 +/- 40 U/l versus 500 +/- 200 and 57 +/- 24 U/l). Patients with 22 +/- 3 degrees C myocardial temperature before terminal cardioplegia had significantly elevated CK as compared to patients with temperatures of 15 +/- 2 degrees C (665 +/- 185 U/l versus 510 +/- 211 U/l). However, enzyme peak values had only poor predictive power for postoperative ECG changes, suggesting that enzyme peaks were not necessarily a sign of perioperative ischemia. Patients with major vessel disease and reduced myocardial function, with aortic cross-clamp time of more than 1 h and/or inadequate intraoperative myocardial cooling may be highly susceptible to global ischemia and operative procedures, and therefore show elevated peak enzyme levels shortly after surgery. In contrast, elevated myoglobin peaks within 1 h after aortic declamping were significantly correlated to perioperative signs of transient ischemia (P < 0.02).

The effect of the antioestrogen tamoxifen (TA) was investigated in different types of steroid-induced benign prostatic hyperplasia (BPH) in the castrated dog by histological, histochemical and biochemical analysis. A 6 months treatment with oestradiol-17β (E2) alone resulted in cystic and stromal hyperplasia and squamous epithelial metaplasia with a striking prostatic weight increase. DNA and RNA content of the total glands increased significantly. The histochemical results and zinc values indicated the loss of normal epithelial function due to metaplatic transformation. The E2induced cystic and metaplastic hyperplasia was prevented by TA while the stromal proliferation was significantly decreased but not abolished. Biochemical determinations revealed an effect similar to castration. After combined treatment with E2and 3α-androstanediol (3α-diol) TA completely suppressed squamous metaplasia. A 3α-diol induced glandular proliferation, monitored by a positive histochemical reaction, and significantly elevated zinc, DNA and RNA contents prevailed. A partial stromal stimulation indicates stimulating effects of 3α-diol too on the stroma. The antioestrogenic effects of tamoxifen on experimentally induced BPH mainly manifest at the E2induced epithelial alterations. The abolishing effects at the stromal level are distinct but not so impressive.