Blood Perfusion in a Murine Fibrosarcoma Tumor Model After Direct Current Electrotherapy a Study with 86Rb Extraction Technique

Electrotherapy with low-level direct current (DC) can induce antitu-mor effects in various tumor models. Applied in combination with certain anticancer drugs, it can significantly increase their effectiveness. It has been suggested that the demonstrated effects of electrotherapy arise from its modification of tumor blood flow. The effect of such treatment on blood perfusion of solid subcutaneous Sa-1 fibrosarcoma tumors in A/J mice was investigated with a ⁸⁶rubidium extraction technique. Following electrotherapy, the relative tissue perfusion of tumors was decreased by more than 50%. Three days after treatment, partial reperfusion of tumors occurred. The dynamics of the perfusion changes induced by electrotherapy are in agreement with tumor growth dynamics following this procedure. The effect of electrotherapy on the blood supply of tumors may be the major mechanism of antitumor action in our model. Electrotherapy could be useful as an adjuvant local procedure to other treatment modalities that require a hypoxic environment for their effectiveness.     

用于核磁共振检测的离体心脏灌流模型

本报告是关于核磁共振研究生理学问题的灌流模型。我们解决了Ｌａｎｇｅｎｄｏｒｆｆ灌流装置用于核磁共振研究时存在的问题,如远距离灌流、保温、保氧和灌流液回收等,建立了稳定的可供核磁共振测量用的灌流模型。在这个装置中离体大鼠心脏的节律性活动可维持９０ｍｉｎ以上。     

Effects of noradrenaline and the blood perfusion rate on the oxygen consumption of intact and isolated muscles of cold-acclimated rats

The authors studied the effect of the blood perfusion rate and of noradrenaline (NA) on the oxygen consumption of the isolated hind limb and on the partly - and vascularly completely - isolated cranial gracilis muscle of cold-acclimated rats. Oxygen consumption of the limb was stimulated by a raised perfusion rate together with growth of the oxygen extraction coefficient and by NA, which also raised oxygen consumption when the perfusion rate was constant. Oxygen consumption of the partly isolated muscle was likewise stimulated by a raised perfusion rate, but without a simultaneous increase in the oxygen extraction coefficient. In the vascularly completely isolated muscle, a raised perfusion rate had only a transient stimulant effect on oxygen consumption. In the partly and the completely isolated muscle, NA raised the arteriovenous difference in the blood oxygen content and organ resistance independently of each other. The calorigenic effect of NA, which was determined by the ratio of the two effects, did not exceed 34% above the resting level. The conclusions that the thermogenesis of resting muscle can be controlled by the blood flow on the basis of a mechanism other than the limitation of oxygen or substrates supply, and that NA acts independently of oxygen extraction from the blood and of the blood flow, show the blood flow to be a mechanism at organ level, which participates in the control of nonshivering thermogenesis in skeletal muscle.     

A new apparatus and surgical technique for the dual perfusion of human tumor xenografts in situ in nude rats

We present a new perfusion system and surgical technique for simultaneous perfusion of 2 tissue-isolated human cancer xenografts in nude rats by using donor blood that preserves a continuous flow. Adult, athymic nude rats (Hsd:RH-Foxn1(rnu)) were implanted with HeLa human cervical or HT29 colon adenocarcinomas and grown as tissue-isolated xenografts. When tumors reached an estimated weight of 5 to 6 g, rats were prepared for perfusion with donor blood and arteriovenous measurements. The surgical procedure required approximately 20 min to complete for each tumor, and tumors were perfused for a period of 150 min. Results showed that tumor venous blood flow, glucose uptake, lactic acid release, O(2) uptake and CO(2) production, uptake of total fatty acid and linoleic acid and conversion to the mitogen 13-HODE, cAMP levels, and activation of several marker kinases were all well within the normal physiologic, metabolic, and signaling parameters characteristic of individually perfused xenografts. This new perfusion system and technique reduced procedure time by more than 50%. These findings demonstrate that 2 human tumors can be perfused simultaneously in situ or ex vivo by using either rodent or human blood and suggest that the system may also be adapted for use in the dual perfusion of other organs. Advantages of this dual perfusion technique include decreased anesthesia time, decreased surgical manipulation, and increased efficiency, thereby potentially reducing the numbers of laboratory animals required for scientific investigations.     

A method for producing regional hypoglycemia in blood perfused tissue

Numerous studies have focused on the metabolic contributions of glucose and other substrates in isolated tissue preparations by examining the effects of eliminating glucose from the physiologic perfusate or bath solution. To date, however, an effective method of glucose removal from the blood supply to selected tissue in the whole animal model has not been available. We have developed a method for blood glucose removal by continuous flow dialysis. This method was used to generate isolated coronary hypoglycemia for an investigation of myocardial metabolic substrate selection during hypoperfusion in open-chest, anesthetized dogs. Arterial blood was passed through the dialysis system against an isotonic and physiologic dialysate solution prior to controlled coronary perfusion. During normal perfusion pressure (100 mmHg), with a coronary blood flow of 32 ± 4 ml/min, arterial blood glucose was reduced from 3.26 ± 0.31 to 0.54 ± 0.14 mM. When blood flow was reduced to 12 ± 3 ml/min with lower perfusion pressure (40 mmHg), dialysis reduced arterial glucose from 3.53 ± 0.36 to 0.15 ± 0.03 mM. We conclude that this is an effective method for producing regional hypoglycemia.     

Characterization of mechanical in vitro hemolysis and sub-hemolysis. 2: Variables of state and dimensionless characteristic values of hemolysis]

Blood damaging effects of artificial perfusion devices such as assist devices, heart valve prostheses, for example, must be evaluated in vitro before being used in the clinical setting. For this purpose, mainly animal blood has been used, and a number of associated problems are currently being discussed. Differences in the use of the term hemolysis--meaning breakdown of erythrocytes or increased plasma hemoglobin, result in incompatibility among different authors. In addition, subhemolytic damage and its quantification has not been investigated to any extent. Another problem are the differences in the mechanical fragility of erythrocytes from different animal species, and the question of transferability to the in vivo situation. Furthermore, the variability of mechanical stability within a given species is often greater than the differences between one species and another. International efforts are now being made to standardize haemolytic test conditions and the present study is meant as a contribution to this. In the first part we describe an extension of our LYSE number model. Characteristically, the model uses dimensionless similarity numbers, LY and MY, thus making the results obtained under different test conditions comparable with one another. The LY number reflects the breakdown of cells (decreasing hematocrit), the MY number an increase in plasma hemoglobin. Differences between LY and MY are an indication of subhemolytic events.     

The effect of cryopreservation and transplantation factors on the morphofunctional state of the thyroid in dogs

Influence of transplantation of non-specific factors (denervation, delymphatization, surgical trauma, ischemia, changes in blood supply conditions) as well as the effect of cryopreservation (-196 degrees C) on morphological structure and ability for secretion of thyroid hormones and response to TS stimulation were studied using the model of extracorporal biological perfusion in isolated thyroid of dogs. The results of biochemical and morphological investigations of thyroid in different conditions of perfusion showed, that it had preserved its main functional and morphological characteristics under the action of transplantation of nonspecific factors and extremely low temperatures.     

Elasticity and geometry: a computational model of the Heineke–Mikulicz strictureplasty

Crohn’s disease is a challenging inflammatory process with a propensity for focal gastro-intestinal tract inflammation and stricture. Surgically, Crohn’s is often treated with resection. However, a subtype of diffuse disease with multiple strictures is treated by strictureplasty procedures in hope of avoiding short-gut syndrome. Prior work by Pocivavsek et al. defined the geometry of a Heineke–Mikulicz strictureplasty. Here, we bring this analysis one step closer to clinical and biological relevance by calculating the mechanical stresses and strains that the strictureplasty deformation generates on a model intestinal wall. The small bowel is simulated as a linearly elastic isotropic deformable cylindrical shell using finite element modeling. Data show a divergence in elastic response between the anti-mesenteric and mesenteric halves. The anti-mesenteric surface shows a bending dominated elastic response that correlates with the prior purely geometric analysis. However, the mesenteric half is not a neutral bystander during strictureplasty formation, as geometric arguments predict. Strong in-plane stretching strains develop in a rim around the image of the transverse closure, which may impact local perfusion and serve as sites of disease recurrence. Lastly, nearly all the deformation energy is stored in the central vertex stitch, placing this part at highest risk of dehiscence. This study enhances our understanding of mechanical response in complex nonlinear cylindrical geometries like the surgically manipulated intestinal tract. The developed framework serves as a platform for future addition of more complex clinically relevant parameters to our model, including real tissue properties, anisotropy, blood supply modeling, and patient deriver anatomic factors.     

A stochastic simulator of a blood product donation environment with demand spikes and supply shocks

The availability of an adequate blood supply is a critical public health need. An influenza epidemic or another crisis affecting population mobility could create a critical donor shortage, which could profoundly impact blood availability. We developed a simulation model for the blood supply environment in the United States to assess the likely impact on blood availability of factors such as an epidemic. We developed a simulator of a multi-state model with transitions among states. Weekly numbers of blood units donated and needed were generated by negative binomial stochastic processes. The simulator allows exploration of the blood system under certain conditions of supply and demand rates, and can be used for planning purposes to prepare for sudden changes in the public's health. The simulator incorporates three donor groups (first-time, sporadic, and regular), immigration and emigration, deferral period, and adjustment factors for recruitment. We illustrate possible uses of the simulator by specifying input values for an 8-week flu epidemic, resulting in a moderate supply shock and demand spike (for example, from postponed elective surgeries), and different recruitment strategies. The input values are based in part on data from a regional blood center of the American Red Cross during 1996-2005. Our results from these scenarios suggest that the key to alleviating deficit effects of a system shock may be appropriate timing and duration of recruitment efforts, in turn depending critically on anticipating shocks and rapidly implementing recruitment efforts.     

A numerical model of the fracture healing process that describes tissue development and revascularisation

A dynamic model was developed to simulate complex interactions of mechanical stability, revascularisation and tissue differentiation in secondary fracture healing. Unlike previous models, blood perfusion was included as a spatio-temporal state variable to simulate the revascularisation process. A 2D, axisymmetrical finite element model described fracture callus mechanics. Fuzzy logic rules described the following biological processes: angiogenesis, intramembranous ossification, chondrogenesis, cartilage calcification and endochondral ossification, all of which depended on local strain state and local blood perfusion. In order to evaluate how the predicted revascularisation depended on the mechanical environment, we simulated two different healing cases according to two groups of transverse metatarsal osteotomies in sheep with different axial stability. The model predicted slower revascularisation and delayed bony bridging for the less stable case, which corresponded well to the experimental observations. A revascularisation sensitivity analysis demonstrated the potential of the model to account for different conditions regarding the blood supply.     

A numerical model of the fracture healing process that describes tissue development and revascularisation

A dynamic model was developed to simulate complex interactions of mechanical stability, revascularisation and tissue differentiation in secondary fracture healing. Unlike previous models, blood perfusion was included as a spatio-temporal state variable to simulate the revascularisation process. A 2D, axisymmetrical finite element model described fracture callus mechanics. Fuzzy logic rules described the following biological processes: angiogenesis, intramembranous ossification, chondrogenesis, cartilage calcification and endochondral ossification, all of which depended on local strain state and local blood perfusion. In order to evaluate how the predicted revascularisation depended on the mechanical environment, we simulated two different healing cases according to two groups of transverse metatarsal osteotomies in sheep with different axial stability. The model predicted slower revascularisation and delayed bony bridging for the less stable case, which corresponded well to the experimental observations. A revascularisation sensitivity analysis demonstrated the potential of the model to account for different conditions regarding the blood supply.     

下呼吸道不动杆菌医院感染的危险因素及耐药性分析

目的了解引起下呼吸道医院感染的不动杆菌耐药现状及存在的危险因素。方法用常规的方法对下呼吸道的标本进行病原菌的培养及分离,用全自动微生物分析仪VITEK 2对细菌进行鉴定及药物敏感性试验,同时对由不动杆菌引发的158例院内感染患者的危险因素进行分析。结果不动杆菌引起下呼吸道医院感染相关的危险因素主要为使用糖皮质激素类药物或机械插管或患有糖尿病等;除亚胺培南、左氧氟沙星、头孢吡肟、头孢哌酮、头孢哌酮/舒巴坦及头孢他啶等对不动杆菌有较好的体外抗菌活性外(耐药率小于40.0%),临床常用的其他多种抗菌药物耐药较严重,耐药率均在40.0%以上。结论糖皮质激素,机械插管,糖尿病等是不动杆菌引起下呼吸道医院感染的主要危险因素,不动杆菌对临床常用的抗生素有多重耐药性。     

In vivo functional NMR imaging of resistance artery control

Arterial spin labeling (ASL) in combination with NMR imaging is an in vivo technique that quantifies tissue perfusion in absolute values (ml blood x min(-1) x g tissue(-1)) with high temporal (1-10 s) and spatial (0.1-3 mm) resolution. It uses the arterial water spins as endogenous freely diffusible markers of perfusion and, hence, is a totally noninvasive method. The technique has been successfully applied to quantify baseline perfusion in many organs, including the heart, in humans and animals, and results were validated by comparison with gold standards, PET and microspheres, respectively. Because of the high sampling rate of perfusion with ASL and the possibility that measurements could be obtained without harm over indefinite periods of time, the technique has the potential for use in functional investigations of microcirculation regulation and resistance artery control in vivo. We describe examples of the use of ASL to this end. With use of specific technological developments, ASL determination of perfusion can be coupled with simultaneous acquisitions of (1)H and (31)P NMR spectroscopy data. These protocols offer new possibilities whereby the microcirculatory control of cell oxygenation and high-energy phosphate metabolism can be explored.     

Uterine blood flow in the pregnant rabbit.

Two methods are described for the measurement of uterine blood flow in the pregnant rabbit. The first involves the use of a Parks ultrasonic Doppler probe placed over the exposed uterine artery. The second method uses a drop counter system connected between the uterine and jugular veins. The Doppler flowmeter was used to measure uterine arterial blood flow in twenty rabbits on Day 28 or 29 of pregnancy. No significant difference was observed between blood flow on these 2 days and the absolute blood flow to one horn (plus or minus S. E.) was found to be 16.8 plus or minus 1.4 ml/min, equivalent to 27.1 plus or minus 1.8 ml/100 g tissue/min. Using the drop recorder technique, the flow to one uterine horn in eleven rabbits on Day 27 or 28 of pregnancy was 12.5 plus or minus 1.9 ml/min, equivalent to 23.6 plus or minus 3.2 ml/100 g tissue/min. The pressure-flow relationship in the uterine vascular bed was studied using the Doppler flowmeter and graded mechanical occlusion of the arterial supply. Within the range of pressures studied, the flow was found to be linearly related to the arterio-venous pressure difference. This suggests that the uterine vascular bed was fully dilated under the conditions of study.     

Effects of gastric distension on the cardiovascular system in rainbow trout (Oncorhynchus mykiss)

When animals feed, blood flow to the gastrointestinal tract increases to ensure an adequate oxygen supply to the gastrointestinal tissue and an effective absorption of nutrients. In mammals, this increase depends on the chemical properties of the food, as well as, to some extent, on the mechanical distension of the stomach wall. By using an inflatable nitrile balloon positioned in the stomach, we investigated the cardiovascular responses to mechanical stretch of the stomach wall in rainbow trout (Oncorhynchus mykiss). Distension with a volume equivalent to a meal of 2% of the body mass increased dorsal aortic blood pressure by up to 29%, and central venous blood pressure increased transiently nearly fivefold. The increase in arterial pressure was mediated by an increased vascular resistance of both the systemic and the intestinal circulation. Cardiac output, heart rate, and stroke volume (SV) did not change, and only transient changes in gut blood flow were observed. The increase in arterial pressure was abolished by the alpha-adrenergic antagonist prazosin, indicating an active adrenergic vasoconstriction, whereas the venous pressor response could be the consequence of a passive increase in intraperitoneal pressure. Our results show that mechanical distension of the stomach causes an instantaneous increase in general vascular resistance, which may facilitate a redistribution of blood to the gastrointestinal tract when chemical stimuli from a meal induce vasodilation in the gut circulation. The normal postprandial increase in gut blood flow in teleosts is, therefore, most likely partly dependent on mechanical stimuli, as well as on chemical stimuli.     

The bleed off perfusion term in the Weinbaum-Jiji bioheat equation.

The microvascular organization and thermal equilibration of the primary and secondary arteries and veins that comprise the bleed off circulation to the muscle fibers from the parent countercurrent supply artery and veins are analyzed. The blood perfusion heat source term in the tissue energy equation is shown to be related to this vascular organization and to undergo a fundamental change in behavior as one proceeds from the more peripheral tissue, where the perfusion term is proportional to the Ta--Tv difference in the parent supply vessels, to the deeper tissue layers where the bleed off vessels themselves form a branching countercurrent system for each muscle tissue cylinder and the venous return temperature can vary between the local tissue temperature and Ta. The consequences of this change in behavior are examined for the Weinbaum-Jiji bioheat equation and a modified expression for the effective conductivity of perfused tissue is derived for countercurrent bleed off exchange.     

Comparative evaluation of hyperthermia heating modalities. II. Application of the acceptable power range technique

The acceptable power range technique previously described in a companion paper [R. B. Roemer, T. C. Cetas, J. R. Oleson, S. Halac, and A. Y. Matloubieh, Radiat. Res. 100, 450-472 (1984)] is applied to two heating modalities to demonstrate its application to simulated clinical situations. Comparisons of the abilities of the different modalities to heat given tumors are made using the relative sizes of the acceptable power ranges obtained for each modality. Similar comparisons are also possible for determining the efficacy of physiological manipulations and adjustments in power deposition patterns for a given heating modality. Predictions of the ability of modalities and configurations to properly heat tumors are made using the bracketing nature of the uniform and annular tumor perfusion models. These comparisons and predictions are possible because a single measure of the ability of any heating technique to heat an arbitrary tumor in any location is utilized (the size of the acceptable power range). While relatively simple models are presently utilized, this approach can be extended to take into account a host of physical and biological conditions that model the patient-device interaction to an arbitrarily high degree of detail. These refinements will be based on extended clinical and experimental data, particularly as tumor and normal tissue blood perfusion characteristics either become better known in general cases or can be specified for each real tumor. The applications of this approach should be far-reaching and complementary to clinical hyperthermia, especially as further model refinements are incorporated. Additional data are presented which reinforce the bracketing nature of the uniform and annular tumor perfusion models presented in the companion paper.     

Neuropeptide Y-like immunoreactivity in perivascular nerve fibres of the guinea-pig

The distribution of perivascular nerve fibres displaying neuropeptide Y-like immunoreactivity was studied in the guinea-pig. Generally, neuropeptide Y fibres were numerous around arteries and moderate in number around veins. In the heart, immunoreactive fibres were numerous in the auricles and the atria (epi- and endocardium) whereas the ventricles had a more scarce supply. The coronary vessels were richly supplied with fibres. Around large elastic and muscular arteries the fibres formed well developed plexuses. Small arteries in the respiratory tract, the gastrointestinal tract and the genito-urinary tract received a particularly rich supply. In the liver, spleen and kidney only few perivascular fibres were seen. Since immunoreactive fibres around blood vessels disappeared upon surgical or chemical sympathectomy, and sequential immunostaining with antisera against dopamine-beta-hydroxylase (a marker for adrenergic neurons) and against neuropeptide Y revealed their co-existence, it is concluded that neuropeptide Y fibres around blood vessels are sympathetic and adrenergic.