Multi-organ system model of O2 and CO2 transport during isocapnic and poikilocapnic hypoxia

A multi-organ systems model of O(2) and CO(2) transport is developed to analyze the control of ventilation and blood flow during hypoxia. Among the aspects of the control processes that this model addressed are possible mechanisms responsible for the second phase of the ventilatory hypoxic response to mild hypoxia, i.e., hypoxic ventilatory decline (HVD). Species mass transport processes are described by compartmental mass balances in brain, heart, skeletal muscle, and "other tissues" connected in parallel via the circulation. In pulmonary and systemic capillaries and in the vasculature connecting the systemic tissues, species transport processes are represented by a one-dimensional, convection-dispersion model. The effects of bicarbonate acid-base buffering, hemoglobin, and myoglobin on the transport processes are included. The model incorporates feedback control mechanisms through a cardiorespiratory control system in which peripheral and central chemoreceptors sense O(2) and CO(2) partial pressures. Model simulations of the ventilatory responses to isocapnic and poikilocapnic hypoxia show two phases with distinct dynamics. A fast phase is discernable immediately after switching from normoxic to hypoxic conditions, while a delayed slow phase (HVD) typically becomes manifested after several minutes. Model simulations allow quantitative evaluation of several proposed mechanisms to account for HVD. Under isocapnic hypoxia, simulations indicate that an increase in brain blood flow has no effect on HVD, but that HVD can be entirely described by central ventilatory depression (CVD). Under poikilocapnic hypoxia, the hypocapnia caused by hypoxic hyperventilation has no effect on HVD.     

Histopathology and apoptosis in an animal model of reversible renal injury

High adenine phosphate (HAP) diet serves as an animal model of chronic renal failure (RF). Induction of RF and establishment of end organ damage require long exposure periods to this diet. Previously, we have shown that RF is reversible after diet cessation even after protracted administration. In this study, we explored the underlying renal changes and cellular pathways occurring during administration and after cessation of the diet. Kidneys were obtained from rats fed HAP diet for 7 weeks, and from rats fed HAP diet followed a 10 week recovery period on normal diet. The kidneys of HAP diet group were significantly enlarged due to tubular injury characterized by massive cystic dilatation and crystal deposition. Kidney injury was associated with markers of apoptosis as well as with activation of apoptosis related pathways. Diet cessation was associated with a significant reduction in kidney size, tubules diameter, and crystals deposition. The recovery from renal injury was coupled with regression of apoptotic features. This is the first study showing the potential reversibility of long standing RF model, allowing optimal evaluation of uremia-chronic effects.     

炎症性肠病动物模型的研究概况

The etiology and pathogenesis of inflammatory bowel disease are up to now still not clear and definite. Establishing the ideal animal model to study its cause and pathogenesis of this disease is very important. The ideal animal model should have the same manifestation with human inflammatory bowel disease on clinical and pathologic feature etc. In this article, the method, the pathologic character isfics and concerning pathogenesis, of a few common useful experiment animal models are discussed.     

Stress vulnerabilities in an animal model of post-traumatic stress disorder

We have studied the effects of inescapable electric foot shocks (ISs) on rats by using a subsequent avoidance/escape task performed in a shuttle box as an animal model of post-traumatic stress disorder (PTSD). In this study, the behavioral differences and the effects of chronic stress exposure prior to IS were examined among male rats of the Wistar, Fischer 344, and Lewis strains. In concordance with our previous report on the Wistar rats, we observed the characteristic features of PTSD in all three rat strains tested, that is, the hyperactive and hypoactive bidirectional behavioral changes that are associated with hypervigilant and hyperarousal behavior, and the numbing and avoidant behavior, respectively. The induction of hypoactive behaviors after IS was most exaggerated in the Fischer and Lewis strains. Although the count of hyperactive behaviors was maximal in the Fischer strain both at basal levels without IS and after IS, the increase in the rate of hyperactive behaviors by IS was the most prominent in the Lewis strain. In addition, preloaded chronic variable stress (CVS) enhanced the degree of hyperactive behavioral changes in the Wistar strain. Thus, we consider that the present study further validates the use of shuttle box paradigm as an animal model of PTSD by demonstrating the vulnerability due to genetic background and environmental preloaded stress.     

Mapping of a gene responsible for dermatitis in NOA (Naruto Research Institute Otsuka Atrichia) mice, an animal model of allergic dermatitis

The NOA (Naruto Research Institute Otsuka Atrichia) mouse is an animal model of allergic or atopic dermatitis, a condition characterized by ulcerative skin lesions with accumulation of mast cells and increased serum IgE. These features of the murine disease closely resemble human atopy and atopic disorders. We performed linkage analysis in NOA back-cross progeny, as a step toward identifying and isolating a gene responsible for the NOA phenotype. We crossed NOA mice with five other murine strains (C57BL/6J, IQI, C3H/HeJ, DBA/2J, and BALB/cByJ) and then bred back-cross animals. Using microsatellite markers, we scanned the entire genomes of 559 N2 offspring from the five parental strains. Linkage analysis revealed a significant association between ulcerative skin lesions and markers on murine chromosome 14. Statistical analysis indicated that the critical region was assigned to the vicinity of D14Mit236 and D14Mit160. Received: July 5, 1999 / Accepted: August 12, 1999     

Accuracy of pulse oximetry at various haematocrits and during haemolysis in anin vitro model

In situations in which it may be impossible and/or unethical to evaluate pulse oximetry in humans, an in vitro model with circulating blood may be a necessity. The main objective was to develop such an in vitro model and, in this model, validate the pulse oximetry technique at various haematocrit levels. The pulsating character of arterial blood flow in a tubing system was simulated by using a specially constructed pressure-regulated roller pump. The tubing system was designed to minimise damage to red blood cells. The pulse oximeter readings (SpO₂) were compared with oxygen saturation analyses by a haemoximeter (SaO₂). The pulse oximetry readings were recorded at various haematocrit levels and during haemolysis in the SaO₂ range 60–100 per cent. At a haematocrit level of 41–44 per cent, there was no correlation between SaO₂ and SpO₂ readings. After diluting the blood with normal saline to a haematocrit of 10–11 per cent, a good correlation between SaO₂ and SpO₂ was found. Following haemolysis, the agreement between SaO₂ and SpO₂ was further improved. Using the developed in vitro model, the results indicate that the accuracy of a pulse oximeter may be dependent on the haematocrit level.     

Computer graphics analysis of stresses in blood flow through a prosthetic heart valve

Fluid dynamics principles and numerical analysis techniques are applied to the study of stress distribution in blood caused by the motion of the occluder in a prosthetic heart valve. An interactive computer graphics program is developed for the simulation of the flow process and the pictoral presentation of the solution for analysis. Resulting graphics displays show the stress distribution and other flow parameters which describe the movement of a disc occluder from fullclosed position to an almost full-open position. The possible contributions of this study to the understanding of hemolysis and thrombosis associated with prosthetic heart valves are discussed.     

大鼠生殖道炎症动物模型的构建

目的:构建苯酚胶浆致大鼠阴道及宫颈炎动物模型。方法:切除双侧大白鼠卵巢,注射苯甲酸雌二醇和氢化可的松,造成假动情期和全身免疫功能低下,然后每鼠阴道内注入苯酚胶浆0.1 ml,隔天一次共3次,每天观察并记录外阴变化,术后第15 d称重后眼球取血以显微镜计数法测定白细胞总数,断颈处死取阴道及宫颈进行病理学检查。结果:大鼠阴道口红肿、有的有脓性物流出;宫颈肥大,阴道及宫颈黏膜上皮细胞变性坏死或脱落,形成溃疡,膜下有充血水肿、炎细胞浸润、腔内有大量炎性或脓性渗出物及坏死组织;腺体有不同程度增生及鳞状化生;白细胞总数明显增高;体重减轻。结论:成功构建了阴道宫颈炎大鼠动物模型,为进一步研究HMGN家族等分子在调控女性生殖道炎症发生发展的机制研究打下了基础。     

实验性子宫内膜异位症动物模型研究

目的　利用大鼠子宫内膜异位症动物模型 ,探讨卵巢切除术和丹那唑治疗对大鼠子宫内膜异位症的影响。方法　将已成模大鼠随机分为 3组 :对照组 (n =2 3)、卵巢切除术组 (n =2 4)和丹那唑组 (n =2 9) ,在行双侧卵巢切除术或丹那唑治疗后的 2、4、6和 8周处死大鼠 ,同时观察移植物的生长情况。结果　卵巢切除术组和丹那唑组大鼠移植物体积均明显缩小 ,并且 4、6和 8周与 2周相比 ,作用更明显。组织学检查 ,对照组异位子宫内膜呈增生状态 ,而卵巢切除术组和丹那唑组呈萎缩状态。结论　卵巢切除术和丹那唑治疗可使大鼠异位子宫内膜逐渐萎缩退化 ,但未能使其消失 ,丹那唑的治疗作用具有时间相关性。     

Computer analysis of bowel sounds

An automatic method of analysis of bowel sound recordings has been developed. A PDP8/I computer, equipped with DECtape and interfaced with a TR48 analog computer was used for the analysis. It was found that the probability of a sound occurring followed a law similar to that of Poisson's phenomenon. Mean energy, sound duration and silence duration in the postmeal situation were respectively, 0·1589 V R.M.S., 4·5 msec, and 31·7 msec. No frequency exceeded 3000 Hz. This method of analysis was applied to experimental situations to study the importance of various parameters influencing the genesis of bowel sounds.     

实验性再狭窄动物模型研究

目的　为弄清经皮冠状动脉腔内形成术后动脉再狭窄的发生机制 ,本实验研究建立再狭窄动物实验模型。方法　采用右髂动脉球囊内皮剥脱术加高胆固醇喂饲家兔。结果　经血管造影检查 ,血管成形术前右髂动脉平均狭窄程度在6 0 %以上 ,血管成形术后 5周右髂动脉平均再狭窄程度在 5 0 %以上 ;病理切片和组织生化显示 ,内膜明显增厚 ,可见大量泡沫细胞 ,脂质沉积显著增加 ;透射电镜和免疫组织化学鉴定显示 ,增生内膜主要是平滑肌细胞增殖。结论　采用本方法成功地建立了再狭窄动物实验模型。     

Computer systems analysis of spaceflight induced changes in left ventricular mass

Circulatory adaptations resulting in postflight orthostasis have frequently been observed in response to space travel. It has been postulated that a decrement in left ventricular mass (LVM) found after microgravity exposure may be the central component in this cardiovascular deconditioning. However, a physiologic mechanism responsible for these changes in the myocardium has not been determined. In this study, we examined the sequential alterations in echocardiographic measured LVM from preflight to landing day and 3 days into the postflight recovery period. In a previous study in returning astronauts we found a comparative 9.1% reduction in postflight LVM that returned to preflight values by the third day of recovery. This data was further evaluated in a systems analysis approach using a well-established advanced computer model of circulatory functioning. The computer model incorporates the physiologic responses to changes in pressures, flows and hydraulics within the circulatory system as affected by gravitational forces. Myocardial muscle progression to atrophy or hypertrophy in reaction to the circulatory load conditions is also included in the model. The integrative computer analysis suggests that these variations in LVM could be explained by simple fluid shifts known to occur during spaceflight and can reverse within a few days after reentry into earth's gravity. According to model predictions, the reductions in LVM found upon exposure to microgravity are a result of a contraction of the myocardial interstitial fluid space secondary to a loss in the plasma volume. This hypothesis was additionally supported by the published ground-based study in which we followed the alterations in LVM and plasma volume in normal subjects in which hypovolemia was induced by simple dehydration. In the hypovolemic state, plasma volume was reduced in these subjects and was significantly correlated with echocardiographic measurements of LVM. Based on these experimental findings and the performance of the computer systems analysis it appears that reductions in LVM observed after spaceflight may be secondary to fluid exchanges produced by common physiologic mechanisms. Reductions in LVM observed after microgravity exposure have been previously postulated to be a central component of spaceflight-induced cardiovascular deconditioning. However, a recent study has demonstrated a return of astronauts' LVM to preflight values by the third day after landing through uncertain mechanisms. A systems analysis approach using computer simulation techniques allows for a dissection of the complex physiologic control processes and a more detailed examination of the phenomena. From the simulation studies and computer analysis it appears that microgravity induced reductions in LVM may be explained by considering physiologic fluid exchanges rather than cardiac muscle atrophy.     

脊髓型颈椎病动物模型的初步建立

目的　建立脊髓型颈椎病动物模型。方法　 36只短毛豚鼠按处理方法不同随机分成 3组 ,A组 :在C4～C5或C5～C6 椎间盘后缘植入骨形态发生蛋白 (BMP)与聚乙烯吡咯烷酮 (PVP)复合制剂 ;B组 :在椎间盘后缘植入PVP ,C组系假手术组。分别于手术后 4、8、1 2周以斜板试验观察实验动物的运动功能 ,并按计划处死动物 ,对实验节段颈椎进行组织学观察。结果　A组术后 8周起出现运动功能减退 ;B组和C组动物术后各期运动功能无改变。组织学观察 ,A组术后 4周起出现椎体后缘骨质增生 ,占据椎管 ,并出现不同程度的脊髓受压变形和脱髓鞘、神经元脱失等改变 ;B、C组术后各期椎管形态、脊髓等无改变。结论　植入颈椎间盘后缘的BMP可诱导椎间盘及韧带组织骨化、椎体后缘骨质增生 ,并对颈脊髓造成恒定的慢性压迫 ,为开展脊髓型颈椎病的实验研究提供了重要的动物模型。     

可移植性Balb/c小鼠急性红白血病动物模型的建立

目的建立稳定的可移植性Balb/c小鼠的急性红白血病动物模型。方法将2×106个的EL9611红白血病细胞通过尾静脉输注每只Balb/c(H-2d)小鼠(n=10),体内传代建立EL9611红白血病动物模型,通过15代的连续传代观察模型的可靠性,以健康BALB/c鼠(n=4)作为正常对照。观察小鼠腹部、肝脾重量,计数实验组和正常对照组的外周血白细胞数,取发病晚期小鼠的外周血涂片行Giemsa染色观察,肝脾组织经10%甲醛固定、石蜡切片、HE染色检查,计算小鼠平均生存时间、发病率和死亡率。结果接种2×106个EL9611白血病细胞后实验组平均生存时间(MST)为(14.5±2.1)d,生存时间与正常对照组相比,P<0.01,经15代的连续传代,未见自发缓解,发病率和死亡率均为100%,无性别选择性,发病晚期小鼠出现肝脾肿大和外周血WBC升高等典型白血病的表现,死亡时肝重(2.40±0.48)g,脾重(0.84±0.20)g,与正常对照组相比,P<0.01,死亡前外周血WBC计数为(3.33±0.27)×107/mL,与正常对照组比,P<0.05,外周血中可见多量异形白血病细胞,病理检查示肝脾正常组织结构破坏,大量白血病细胞浸润。结论采用EL9611红白血病细胞2×106静脉输注体内传代的方式可建立起稳定的可移植性Balb/c小鼠的急性红白血病动物模型。     

周围神经缺血再灌注损伤动物模型的改良

目的研究周围神经缺血再灌注损伤动物模型的改良与建立。方法采用无损伤动脉夹暂时阻断大鼠一侧髂总动脉起始处血流,同时夹闭髂内、髂外动脉,一段时间后打开动脉夹,观察不同缺血再灌注时间下动物肢体功能情况,以及周围神经缺血导致的脊髓电镜下超微结构的改变,明确改良动物模型的实验效果。结果缺血时间的延长动物后肢的瘫痪症状逐渐加重。电镜观察脊髓神经元显示随再灌注时间的延长,神经元损害明显加重。结论用无损伤动脉夹阻断一侧髂总动脉和髂内、髂外动脉的周围神经缺血再灌注损伤的动物模型是对以往模型的改良。该模型制备操作简单,对动物的损伤更小,可得到理想的实验效果。     

单侧腮腺放射性损伤动物模型的建立

目的建立猪单侧腮腺放射性损伤动物模型。方法年满4月大梅杂交猪8头,4头双侧唾液腺造瘘,15MV-X线单侧腮腺照射,5Gy/次,3次/W,总量40Gy/8次/17d,为实验组;对侧未照射腮腺为自身对照组;2头单纯造瘘为阴性对照组;余下2头不做任何处理,为病理对照组。观察照射动物临床征象变化;每日记录唾液总量,采用SPSS11.0最小显著性差异(LSD)检验比较实验组、自身对照组、阴性对照组分泌量差异;2月后取腮腺病理学检查,比较4组腮腺显微结构变化。结果照射猪饮食下降、活动减少,进食期间频繁饮水;照射组于照射开始13±2d起分泌明显减少,LSD处理显示试验组分泌量减少、自身对照组分泌量增多、与阴性对照组间两两比较差异均有显著意义。病理学检查显示,照射腮腺总体结构尚存,细胞排列轻度紊乱,细胞数目无明显减少,部分胞核增大,胞浆相对增加,凋亡细胞少见,有区域分布趋势,阴性对照组细胞无明显变化。结论成功建立了腮腺放射性损伤模型。     

Exploring an animal model of amodiaquine-induced liver injury in rats and mice

Amodiaquine (AQ) is associated with a relatively high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. A previous study reported that a combination of high dose AQ and glutathione (GSH) depletion led to liver injury. However, the characteristics of this toxicity were very different from AQ-induced liver injury in humans. We developed a model of AQ-induced liver injury with characteristics similar to the injury in humans by treating mice with lower doses of AQ for several weeks. In this study we found that not only did GSH depletion not increase AQ covalent binding to hepatic proteins at this lower dose, but also it paradoxically prevented the liver injury. We extended the model to rats and found AQ treatment led to a mild delayed onset liver injury that resolved despite continued treatment with AQ. Immunohistochemistry indicated the presence of Kupffer cell activation, apoptosis and hepatocyte proliferation in the liver. There was also an increase in serum IL-2, IL-5, IL-9, IL-12, MCP-1 and TGFβ, but a decrease in leptin. Coincident with the elevated serum ALT, the number of liver CD4⁺ T-cells, IL-17 secreting cells and T_H17/T_reg cells increased at Week 3 and decreased during continued treatment. Increases in NK1.1+ cells and activated M2 macrophages were also observed during liver injury. These results suggest that the outcome of the liver injury was determined by the balance between effector and regulatory cells. Co-treatment with cyclosporin prevented AQ-induced liver injury, which supports an immune mechanism. Retinoic acid (RA), which has been reported to enhance natural killer (NK) cell activity, exacerbated AQ-induced liver injury. These results suggest that AQ-induced IDILI is immune mediated and the subsequent adaptation appears to represent immune tolerance.