Effect of adrenoblockaders on vascular reactions in sinocarotid baroreflexes]

Blood pressure in the common carotid artery, the tone of the cerebral and femoral vessels were recorded by resistography in acute experiments on nonanesthetized cats (local anesthetics, listenon) with artificial respiration. The increased pressure in isolated carotid sinuses was accompanied by a decrease in arterial pressure and in the tone of the cerebral and femoral vessels. In both cases the reaction of the cerebral vessels was less pronounced as compared to that shown by the femoral vessels. The blocking of alpha-adrenoreceptors with phentolamine reduced or abolished completely the reactions noted. After beta-adrenergic blockade with obsidan these reactions persisted. The role of carotid baroceptors in the regulation of cerebral circulation under orthostatic collapse is discussed.     

Signal analysis of the hemodynamics of extracorporeal circulation for the evaluation of patient status]

The present paper describes the intra-operative evaluation of circulation dynamics during open-heart surgery, with the aim of providing the anaesthetist with objective data for assessing patient status during the procedure. For this purpose, the parameters pulse wave velocity and biological impedance were used. With the aid of these parameters it is possible, in the extracorporeal model, to detect different kinds of stenosis, volume losses, vessel dilatation and vessel constriction. In addition, the influence of arteriosclerosis on circulation dynamics was investigated. The assignment of the parameters to various events is effected using a "decision tree" and a neural network. Finally, the technique is verified using data obtained from animal experiments.     

Cardiac activity of freshwater crayfish at wakefulness, rest, and “animal hypnosis”

In laboratory experiments, simultaneous continuous recording of the circadian cycle of behavioral reactions and cardiac activity of freshwater crayfish Astacus astacus and Procambarus clarkii was carried out. A non-invasive fiber-optic method of recording of the heart rate (HR) was used. The obtained data were analyzed by the method of variational pulsometry (VP). It was revealed that certain values of HR and characteristics of VP corresponded to the physiological states of active wakefulness and rest. It was found that during long immobilization of crayfish it is possible to identify the states of operative rest and sleep by the animal behavioral reactions and parameters of cardiac activity. Crayfish were studied in the state of artificially evoked immobilization (“animal hypnosis”). During this state, a high HR level, an increase of indexes of tension and autonomic equilibrium, and changes of other VP characteristics were observed. It is suggested that the different level of cardiac activity in different physiological states of crayfish (active wakefulness, operative rest, sleep, and “animal hypnosis”) is regulated by nervous influences analogous to sympathetic and parasympathetic influences in vertebrates. It was concluded that freshwater crayfish as a representative of the highly organized invertebrates can serve an effective model for studying mechanisms of sleep-like states and “animal hypnosis” in animals.     

血压自适应控制系统研究

本文设计一个自适应血压自动控制系统,首先,通过动物实验,获得了受控对象的参数变化范围的信息.在此基础上,我们应用参考模型和自校正调节器两种算法设计自适应控制系统.计算机仿真证明这两类算法均可成功地应用于血压的自适应控制,尽管受控对象存在未知时变延时,时间常数和增益的变化.最后,将设计的系统在动物(狗)中作了检验.在18条狗上作升压或降压试验证明,两种算法均有良好的过渡过程特性,这一系统将可应用于临床,以改进药物注射系统的性能.     

Arteriovenous ratios of angiotensin II during acute infusion experiments: a model-based nalysis

The hormone angiotensin II (AII) is a vascocontrictor known to participate in the natural regulation of blood pressure via the renin-angiotensin system. A third-order model was developed which describes the dynamics of venous and arterial plasma AII concentrations (PAC) and mean arterial blood pressure (BP) during acute constant rate AII infusion experiments. The model is calibrated using approximate blood circulation rates and steady-state PAC and BP data for published experiments in sheep. Analysis of the dynamic model demonstrates that local changes in PAC during the first several minutes of acute infusion are characterized by the comparatively rapid distribution of exogenous AII making its forward passage across the blood circulation, combined with the more gradual elevation of exogenous AII recycled through the circulation. This analysis explains the observed divergence in physiological levels of venous and arterial PAC at steady state in terms of the monotonic net clearance of elevated levels of circulating AII along the circulatory path between the point of infusion and the two sites at which the PAC measurements are taken. The model suggests that the differing arteriovenous AII concentration ratios and differing PAC and BP relationships reported for different dose-response experiments may be explained in part by differences in the specific infusion and measurement sites employed in those experiments.     

Endothelial cell capture of heparin-binding growth factors under flow

Circulation is an important delivery method for both natural and synthetic molecules, but microenvironment interactions, regulated by endothelial cells and critical to the molecule's fate, are difficult to interpret using traditional approaches. In this work, we analyzed and predicted growth factor capture under flow using computer modeling and a three-dimensional experimental approach that includes pertinent circulation characteristics such as pulsatile flow, competing binding interactions, and limited bioavailability. An understanding of the controlling features of this process was desired. The experimental module consisted of a bioreactor with synthetic endothelial-lined hollow fibers under flow. The physical design of the system was incorporated into the model parameters. The heparin-binding growth factor fibroblast growth factor-2 (FGF-2) was used for both the experiments and simulations. Our computational model was composed of three parts: (1) media flow equations, (2) mass transport equations and (3) cell surface reaction equations. The model is based on the flow and reactions within a single hollow fiber and was scaled linearly by the total number of fibers for comparison with experimental results. Our model predicted, and experiments confirmed, that removal of heparan sulfate (HS) from the system would result in a dramatic loss of binding by heparin-binding proteins, but not by proteins that do not bind heparin. The model further predicted a significant loss of bound protein at flow rates only slightly higher than average capillary flow rates, corroborated experimentally, suggesting that the probability of capture in a single pass at high flow rates is extremely low. Several other key parameters were investigated with the coupling between receptors and proteoglycans shown to have a critical impact on successful capture. The combined system offers opportunities to examine circulation capture in a straightforward quantitative manner that should prove advantageous for biologicals or drug delivery investigations.     

In vitro evaluation of flow divertors in an elastase-induced saccular aneurysm model in rabbit

Endovascular coiling is an acceptable treatment of intracranial aneurysms, yet long term follow-ups suggest that endovascular coiling fails to achieve complete aneurysm occlusions particularly in wide-neck and giant aneurysms. Placing of a stentlike device across the aneurysm neck may be sufficient to occlude the aneurysm by promoting intra-aneurysmal thrombosis; however, conclusive evidence of its efficacy is still lacking. In this study, we investigate in vitro the efficacy of custom designed flow divertors that will be subsequently implanted in a large cohort of animals. The aim of this study is to provide a detailed database against which in vivo results can be analyzed. Six custom designed flow divertors were fabricated and tested in vitro. The design matrix included three different porosities (75%, 70%, and 65%). For each porosity, there were two divertors with one having a nominal pore density double than that of the other. To quantify efficacy, the divertors were implanted in a compliant elastomeric model of an elastase-induced aneurysm model in rabbit and intra-aneurysmal flow changes were evaluated by particle image velocimetry (PIV). PIV results indicate a marked reduction in intra-aneurysmal flow activity after divertor implantation in the innominate artery across the aneurysm neck. The mean hydrodynamic circulation after divertor implantation was reduced to 14% or less of the mean circulation in the control and the mean intra-aneurysmal kinetic energy was reduced to 29% or less of its value in the control. The intra-aneurysmal wall shear rate in this model is low and implantation of the flow divertor did not change the wall shear rate magnitude appreciably. This in vitro experiment evaluates the characteristics of local flow phenomena such as hydrodynamic circulation, kinetic energy, wall shear rate, perforator flow, and changes of these parameters as a result of implantation of stentlike flow divertors in an elastomeric replica of elastase-induced saccular aneurysm model in rabbit. These initial findings offer a database for evaluation of in vivo implantations of such devices in the animal model and help in further development of cerebral aneurysm bypass devices.     

The consequence of passive administration of an anti-human immunodeficiency virus type 1 neutralizing monoclonal antibody before challenge of chimpanzees with a primary virus isolate.

The anti-gp41 virus neutralizing monoclonal antibody 2F5 was infused into chimpanzees, which were then given an intravenous challenge with a primary human immunodeficiency virus type I (HIV-1) isolate. In two control animals, the infection was established immediately, as evidenced by positive cell-associated DNA PCR and serum RNA PCR tests within 1 week, seroconversion by 4 weeks, and development of lymphadenopathy in this acute phase. Serum RNA PCR tests were negative in one of the two antibody-infused animals until week 8 and in the other antibody-infused animal until week 12; both animals seroconverted at week 14. The peak of measurable virus-specific serum RNA was delayed until week 16 in one antibody-infused animal. Virus-specific RNA in the other animal did not reach levels comparable to those in the other animals through 1 year of follow-up studies. Virus was isolated from the week 16 blood sample from one infused animal. Virus was not isolated from peripheral blood of the second animal but was isolated from lymph node cells taken at week 36. The infection of untreated chimpanzees with this primary isolate appears robust. Use of this isolate should widen the scope of possible experiments in the chimpanzee model. This antibody infusion study indicates that neutralizing antibody, when present at the time of challenge, affects the timing and level of infection and remains influential after it can no longer be detected in the peripheral circulation. It is possible that preexisting, neutralizing antibodies (passively administered or actively elicited) affect the course of acute-phase virus replication in humans. It remains to be established whether these immunologically mediated early effects will influence the course of HIV-1 disease.     

~(60)Co辐射对在体红细胞微观流变特性的影响

采用 60Co大剂量全身均匀急性辐射的方法,使动物造血系统受到严重破坏,造血机能大大减弱,在大约30天时间内,循环系统中的红细胞计数明显下降,从而造成一种辐射贫血的动物模型。以便较长时间内连续研究60Co大剂量辐射对在体红细胞流变特性的影响。采用一种在低粘切变流场中能将红细胞变形指数DI分解为取向指数 (DI)or和小变形指数 (DI)d的新型激光衍射法 [1],研究了 60Co大剂量辐射对在体红细胞变形性、全血粘度、沉降率和红细胞计数等血液流变学特性的影响 ,并与正常对照组红细胞的相应参数作比较 ,发现在60Co大剂量辐射后 ,开始这些参数变得明显异常 ,40天后逐渐接近于正常对照组水平。这表明 60Co大剂量急性辐射对动物体内造血系统的影响是长期的、严重的。将这种 60Co辐射造成的贫血模型与文宗曜等提出的用抗体诱导的大量同步化的球形红细胞贫血模型相比较 ,发现后者作为在体贫血动物模型具有更明显的优点。同时为研究辐射对血液流变特性的影响及正确地挑选红细胞衰老模型提供了理论与实验的基础。     

~(60)Co辐射对在体红细胞微观流变特性的影响

采用＾６０Ｃｏ大剂量全身均匀急性辐射的方法,使动物造血系统受到严重破坏,血造机能大大闰弱,在大约３０天时间内,循环系统中的红细胞计数明显下降,从而造成一种辐射贫血的动物模型,以便时间内连续研究＾６０Ｃｏ大剂量辐射对在体红细胞流变特性的影响。采用一种在低粘切变流场中能将红细胞变形指数ＤＩ分角为取向指数（ＤＩ）ｏｒ和小变形指数（ＤＩ）ｄ的新型激光衍射法,研究了＾６０Ｃｏ大剂量辐射对在体红细胞变形性、全     

Increasing batch-to-batch reproducibility of CHO-cell cultures using a model predictive control approach

By means of a model predictive control strategy it was possible to ensure a high batch-to-batch reproducibility in animal cell (CHO-cell) suspensions cultured for a recombinant therapeutic protein (EPO) production. The general control objective was derived by identifying an optimal specific growth rate taking productivity, protein quality and process controllability into account. This goal was approached indirectly by controlling the oxygen mass consumed by the cells which is related to specific biomass growth rate and cell concentration profile by manipulating the glutamine feed rate. Process knowledge represented by a classical model was incorporated into the model predictive control algorithm. The controller was employed in several cultivation experiments. During these cultivations, the model parameters were adapted after each sampling event to cope with changes in the process’ dynamics. The ability to predict the state variables, particularly for the oxygen consumption, led to only moderate changes in the desired optimal operational trajectories. Hence, nearly identical oxygen consumption profiles, cell and protein titers as well as sialylation patterns were obtained for all cultivation runs.     

The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model

Neurodegenerative diseases provoke robust immunological reactions in the central nervous system (CNS), which further deteriorate the neural tissue damage. We hypothesized that the expression levels of indoleamine 2,3-dioxygenase (IDO), an enzyme that has potent immune suppressive activities, in neural stem cells (NSCs) would have synergistic therapeutic effects against neurodegenerative diseases, since NSCs themselves have low IDO expression. In this study, the synergistic immune suppressive effects of rat fetal NSCs expressing IDO (rfNSCs-IDO) were validated by mixed leukocyte reaction (MLR) in vitro and an experimental autoimmune encephalomyelitis (EAE) animal model in vivo. rfNSCs-IDO showed significantly more suppressive effects on T cell proliferation in the MLR compared to control rfNSCs (rfNSCs-Cont). Importantly, IDO inhibition using 1-methyl-DL-tryptophan (1-MT), an IDO inhibitor, reversed the synergistic effects, confirming IDO-specific effects in rfNSCs-IDO. In the EAE animal model, systemic rfNSCs-IDO injections resulted in significant local immune suppression in the cervical lymph nodes and CNS, evidenced by a reduction in the number of activated T lymphocytes and an increase in regulatory T cell numbers, which induced significantly fewer clinical symptoms and faster recovery. In contrast, rfNSCs-Cont failed to reduce symptoms in the EAE animal models, although they showed local immune suppression, which was significantly less than that in rfNSCs-IDO. Taken together, IDO expression in NSCs synergistically potentiates the immune suppression activities of NSCs and could be applicable for the development of therapeutic modalities against various neurodegenerative diseases.     

Resuscitation of warm ischaemia predamaged porcine kidneys by fibrinolytic preflush with streptokinase: reduction of animal experiments

In order to reduce the number of animal experiments, the use of non-heart-beating donors (NHBDs) from a commercial abattoir has been proposed. Since the use of slaughterhouse organs is legally not defined as animal experiment, this would fulfil international standards as an alternative to animal experiments. The development of intravascular thrombosis after cardiac arrest negatively impacts organ preservation and thus viability during ischaemic storage and reperfusion. A fibrinolytic preflush with streptokinase might overcome these limitations. Therefore, the functional and histomorphological integrity of kidneys preserved immediately with intact circulation (control group A) and kidneys preserved after cardiac arrest with a 30 min period of warm ischaemia (WI) (group B) was compared with kidneys preflushed with 12.5 kU/L (group C) or 50 kU/L streptokinase (group D) after 30 min WI prior to preservation. We could demonstrate that kidneys preflushed with 12.5 kU/L streptokinase (group C) performed better than those without streptokinase pretreatment after WI (group B). Parameters like oxygen consumption, perfusion pressure, laboratory values, lactate dehydrogenase level and lipidperoxidation were closer to that of the control (group A) than in groups B and D. The higher streptokinase concentration of 50 kU/L (group D) resulted histologically in a more pronounced tissue damage and an attenuated renal function, indicating toxic effects. On the basis of our results we believe streptokinase preflushed slaughterhouse kidneys to be an adequate alternative to organs from laboratory animals with the potential to further reduce the number of animal experiments.     

Further evidence for the presence ofγ-aminobutyric acidA (GABAA) receptors on the cytoplasmic side of deiters' membrane

1. The permeation of labeled Cl- across single nerve membranes microdissected from rabbit Deiters' neurons was studied in a microchamber system. The in----out permeation of the ions was evaluated under control conditions and in the presence of either 10(-6) M GABA or 10(-6) M GABA plus 10(-5) M bicuculline methiodide (BMI) on the membrane cytoplasmic side. 2. In 32 experiments, involving one animal each, at least two membranes served as controls and at least two others were studied with the addition of GABA. Within each experiment all the membranes were obtained from the same animal. 3. In an additional 10 experiments, involving one animal each, at least two membranes served as controls and at least two others were studied in the presence of GABA plus bicuculline methiodide on the membrane cytoplasmic side. 4. The data show that 10(-6) M GABA on the Deiters' membrane cytoplasmic side stimulates Cl- permeation in----out by 42% (P = 0.0000001). When 10(-5) M BMI was present together with GABA, no stimulation of Cl- in----out permeation occurred.     

Compensation of exocrine pancreatic insufficiency during its partial, subtotal and total resection

Chronic experiments on dogs have shown that the damage of extra-secretory pancreatic function by duct ligation caused marked compensatory changes of stomach function. The increase in gastric juice secretion and gastric juice proteolytic activity was accompanied by the reduction in its acidity. In addition to quantitative changes, qualitative shifts were revealed (amylolytic activity in strongly acid pH-reaction), never observed in the gastric juice of intact animals. Partial pancreas resection (up to 75%) both in control and test animals 10-14 months after pancreatic duct ligation was not accompanied by significant changes in gastric juice secretion. Total pancreas resection in dogs with previous pancreatic duct ligation caused neither prompt animal death, as in the control, nor the inhibition of compensatory reactions of gastric juice secretion.     

Behavioral phenotyping enhanced--beyond (environmental) standardization

It is basic biology that the phenotype of an animal is the product of a complex and dynamic interplay between nature (genotype) and nurture (environment). It is far less clear, however, how this might translate into experimental design and the interpretation of animal experiments. Animal experiments are a compromise between modelling real world phenomena with maximal validity (complexity) and designing practicable research projects (abstraction). Textbooks on laboratory animal science generally favour abstraction over complexity. Depending on the area of research, however, abstraction can seriously compromise information gain, with respect to the real world phenomena an experiment is designed to model. Behavioral phenotyping of mouse mutants often deals with particularly complex manifestations of life, such as learning, memory or anxiety, that are strongly modulated by environmental factors. A growing body of evidence indicates that current approaches to behavioral phenotyping might often produce results that are idiosyncratic to the study in which they were obtained, because the interactive nature of genotype-environment relationships underlying behavioral phenotypes was not taken into account. This paper argues that systematic variation of genetic and environmental backgrounds, instead of excessive standardization, is needed to control the robustness of the results and to detect biologically relevant interactions between the mutation and the genetic and environmental background of the animals.     

Effect of a local disorder of bronchial patency on the circulation and gas exchange in the lungs

Acute and chronic experiments on dogs have demonstrated the onset of local alveolar hypoxia in disturbed bronchial patency. Alveolar hypoxia caused a rise in the pulmonary vascular resistance. Pulmonary hypertension is predetermined by an increased number of pulmonary zones of hypoxic vasoconstriction due to higher incidence and degree of bronchial obstruction. Despite pulmonary circulation redistribution confirmed by radioactive indicator 99mTc distribution, the perfusion of hypoventilated pulmonary regions is retained leading to venous shunt generation and the reduction of oxygen tension in the arterial animal blood.     

Oxygen consumption in the lungs of dogs with external hemorrhage and after reinfusion of blood

In experiments on 10 dogs with external blood loss and reinfusion it was demonstrated, that in hemorrhagic and posthemorrhagic periods oxygen consumption by the organism is determined not only by O2 demands of the large circulation tissues, but to a great extent by demands in O2 in the system of lesser circulation, what is being evidenced by activation of the metabolic function of the lungs. It turned out that in pathogenesis of postinfusion respiratory insufficiency reactions of lipid oxidation in the lungs play a significant role.     

Development and evaluation of a multi-applicator system of endocavitary radiothermotherapy of gynecologic tumors

An applicator system for the radiothermotherapy of gynecological tumors has been developed. The concept is based on combining high-dose rate afterloading therapy with local hyperthermia (27.12 MHz). The main applicator, the rf-gamma applicator consists of a guide tube for the gamma source, an electrode system and a cooling system. Isodoses and isotherms can be adapted to the individual anatomical-pathological situation presenting. For therapy planning the interaction between the applicators and the perfused tissue was investigated in a theoretical FEM model. In the first step, the SAR-function in the vicinity of the rf-applicator was determined by means of a 2D FEM calculation. In a second step, the 3D temperature fields was determined using linear shape functions. The results of these calculations showed that in every case the hot spots shifted from the applicator surface into the depths of the tissue. With the aid of an infrared camera and a split phantom the calculations were examined in a homogeneous non-perfused tissue model. Thermometry confirmed the accuracy of the results obtained. The radiothermotherapy system described here was tested in animal experiments, and is presently being used in a clinical pilot study.     

Experimentelle Untersuchungen zur akustischen Kommunikation bei im Zoo gehaltenen Schabracken- und Flachlandtapiren (Tapirus indicus und Tapirus terrestris)

Until now, unlike their relatives, rhinos and horses tapirs have received considerably less attention in studies about communication. Therefore, it was the aim of this study to test which stimuli contain acoustical information for tapirs. For this purpose, the reactions of tapirs on acoustical stimuli (playback of different animal voices) were examined. Research visits took place at the zoos of Berlin, Dortmund, Heidelberg, Munich, Nuremberg and Osnabrück during the year 2005. A total of 20 individuals, thereof 8 (4.4) Malayan tapirs (Tapirus indicus) and 12 (4.8) Lowland tapirs (Tapirus terrestris) attended the experiments. The playback experiments showed that tapirs distinguish between the voices of different animal species. The results point to the conclusion that the reactions of the tapirs relate to phylogeny. The most intense interest was taken in their own species followed by the closely related ones.