残肾肾小球毛细血管增生及其意义的实验研究

为弄清肾小球毛细血管能否增生及其在慢性肾衰发生发展中的作用，采用毛细血管铸型、形态计量等方法，定量观察５／６肾切除大鼠（Ｂ组）残肾肾小球毛细血管形态演变和肾功能变化，并以假手术大鼠为对照（Ａ组）。发现Ｂ组大鼠术后残存肾小球体积逐渐增大，扫描电镜下发现肾小球毛细血管数目逐渐增多、分支增加，透谢电镜下在扩展的系膜区内发现新生的毛细血管，形态计量显示单个肾小球毛细血管长度和内表面积逐渐增加，而肾小球毛细血管长度密度、面积密度、以及肾实质体密度与Ａ组无显著差别。说明残肾之肾小球毛细血管能显著增生，这种增生是一种与肾小球囊腔扩大成比例的有功能的代偿性增生。     

缺碘大鼠甲状腺结构及其变化的体视学研究

本文对缺碘饮食喂养１２周大鼠的甲状腺进行了组织学观察，并应用ＭＩＡＳ－３００型图像分析系统对甲状腺滤泡、滤泡腔以及滤泡上皮细胞进行了体视学指标的测量，并与对照组进行了比较分析。结果表明，缺碘组大鼠甲状腺明显肿大，其重量约为对照组的５倍；甲状腺呈弥漫性增生性甲状腺肿改变，表现为小滤泡性增生，上皮细胞增生肥大。体视学参数测量结果表明，缺碘组甲状腺滤泡及滤泡腔的平均体积（Ｖ）和平均表面积（Ｓ）均明显低于对照组；而数密度（Ｎｖ）及比表面（Ｓ／Ｖ）明显高于对照组；体积密度（Ｖｖ）和表面积密度（Ｓｖ）也发生不同程度变化；滤泡上皮细胞的截面积显著大于对照组。上述体视学测量结果以定量数据佐证了缺碘性甲状腺肿的形态学变化     

肺癌组织内微血管定量与转移的研究

应用第Ⅷ因子相关抗原免疫组化方法，对６４例肺癌组织内微血管定量与肺门淋巴结转移的关系进行了研究。结果发现鳞状细胞癌微血管定量为４８１７±２５４个／ＨＰ，腺癌为６９３２±２７２个／ＨＰ，小细胞癌为７７６６±２３２个／ＨＰ。鳞状细胞癌微血管定量明显低于小细胞癌（Ｐ＜０００１）；无淋巴结转移组微血管定量（５４５±１３５个／ＨＰ）明显低于有转移组（７６３±１４６个／ＨＰ）。提示肺癌组织中微血管生成与癌细胞分化程度有密切关系，微血管定量高的肺癌可能预后不良和易发生转移     

过期与延期妊娠的胎盘床血管和胎盘形态计量学

本文应用图像分析技术对过期妊娠２０例（过期组）、延期妊娠１５例（延期组）和正常足月妊娠２９例（正常组）的胎盘绒毛和胎盘床螺旋小动脉进行形态计量学检测。结果：（１）过期组胎盘绒毛具有合体细胞结节、细胞滋养细胞增生、绒毛基底膜增厚和纤维素样坏死的绒毛数高于正常组（均Ｐ＜００５），血管合体细胞膜形成的绒毛数低于正常组（Ｐ＜００５）；延期组与对照组和过期组间均无显著区别。（２）过期组胎盘绒毛直经、周长和面积参数均小于正常组（均Ｐ＜００１）；延期组仅周长和面积参数小于正常组（Ｐ＜００５）。（３）过期、延期组胎盘床螺旋小动脉管壁增厚者高于正常组（Ｐ＜００５），而妊娠生理性改变、管壁纤维素样坏死以及急性动脉粥样化病变与对照组无明显区别。（４）过期、延期组羊水过少和羊水粪染的发生率高于正常组（均Ｐ＜００５），而新生儿低评分者发生率较高，但与正常组无明显区别。提示：过期和延期妊娠的子宫胎盘床血管和胎盘绒毛的形态学病变是导致胎盘功能逐渐低下以及胎儿预后不良的主要原因，尤其过期妊娠者更著     

层粘素和纤粘素在胃癌中的分布

采用层粘素（ＬＮ）多抗和纤粘素（ＦＮ）多抗检测７６例胃癌。证实癌细胞分化程度越低和局部浸润能力越强，造成的基底膜（ＢＭ）缺损越严重。证明反应性间质增生与癌肿的浸润转移趋势有关。癌细胞穿透基底膜进入间质，引起间质反应性增生，后者可促进癌细胞的浸润和转移。     

慢性炎症介导的基底膜改变在食管上皮癌变中的作用

背景与目的:基底膜对于食管上皮的分化、增殖和极性具有调节作用,其完整性的改变在上皮癌变过程中具有重要意义。本实验着重研究在食管上皮癌变过程中基底膜改变与上皮增殖的关系,探讨慢性炎症引起的基底膜改变在食管癌发生中的作用及可能机制。方法:采用过碘酸-雪夫氏(periodicacide-chiffstain,PAS)特殊染色观察200例食管癌手术标本癌旁组织、10例癌组织基底膜变化形态学类型与上皮炎症分数和增生类型的关系,对其中的51例基底膜变化典型标本进行层粘连蛋白(laminin,LN)、增殖细胞核抗原(proliferatingcellnuclearantigen,PCNA)、Ki-67免疫组织化学染色,观察LN改变与上皮细胞增殖变化的关系。结果:单纯增生、非典型增生、原位癌上皮和浸润癌基底膜可出现点状缺失、片状缺失、带状缺失、分支增厚等不同类型的形态学改变,基底膜的改变与食管上皮炎症分数具有相关性(rs=0.795,P<0.05);基底膜改变区邻近上皮细胞高表达PCNA、Ki-67(P<0.01)。结论:食管慢性炎症反应引起的基底膜改变与食管上皮细胞异常增生相关。     

米非司酮对人中期妊娠胎盘的影响

目的：探讨米非司酮对中期妊娠胎盘绒毛的影响程度，借此评价该药用于足月妊娠引产的安全性。方法：利用体视学原理，对８例胎龄１７～１９孕周妇女服用１５０ｍｇ米非司酮后行水囊引产的胎盘绒毛合体滋养细胞线粒体体视学参数、滋养细胞基底膜和毛细血管屏障厚度进行测算，并与８例胎龄１７～１９孕周水囊引产的胎盘组织对照。结果：米非司酮组合体滋养细胞线粒体的体积密度与对照组间无差异，而其表面积密度、比表面、数密度显著降低，平均体积则明显增大；其次米非司酮组滋养细胞基底膜与对照组相比明显增厚，绒毛间质毛细血管内皮细胞变薄。结论：米非司酮对中期妊娠胎盘组织具较强损伤作用。故在米非司酮用于足月妊娠引产的安全性未充分证实前，不宜将其用于足月妊娠引产中。     

维生素E对5/6肾切除所致慢性肾衰大鼠的保护作用

目的：观察抗氧化剂维生素Ｅ对慢性肾衰之残存肾组织和残肾功能的保护作用。方法：在５／６肾切除大鼠慢性肾衰模型上，以假手术大鼠为对照，采用形态计量和生化测定方法，对比分析术后３０、６０、９０、１２０ｄ给予或不给予维生素Ｅ治疗的慢性肾衰大鼠残肾纤维化程度，残肾功能及其活性氧化代谢状况等指标。结果：大鼠术后残存肾小球呈代偿性肥大、肾小球毛细血管代偿性增生的同时，有显著的氧自由基反应亢进、抗氧化能力减弱、肾小球硬化、滤过膜增厚、肾间质纤维化、肾组织羟脯氨酸含量增高、肾功能进行性恶化；而用维生素Ｅ治疗的大鼠，氧自由基反应和抗氧化能力趋于正常，肾小球硬化、滤过膜增厚、肾间质纤维化和肾组织羟脯氨酸含量增高的程度显著减轻，肾小球代偿性肥大和肾小球毛细血管代偿性增生的发生时间后移，肾功能恶化的速度显著减慢。结论：维生素Ｅ通过其抗氧化作用，显著抑制５／６肾切除所致慢性肾衰残肾组织纤维化，延缓残肾功能进行性恶化的速度，而对代偿性肾小球肥大和毛细血管增生无明显直接影响。     

血管生成在乳腺非典型增生及癌变过程中的作用

为探讨乳腺非典型增生至癌变过程中血管生成的作用及其规律以及血管生成与非典型增生程度及癌变的关系，本研究应用免疫组化法，以ＦⅧ为标志物对８６例良、恶性乳腺病变组织中的血管内皮细胞进行组化染色。分别以微机图像分析系统和人工计数对微血管内皮细胞面积（ＭＥＡ）和微血管密度（ＭＶＤ）进行定量分析。结果发现，中重度非典型增生及癌变组织中的血管生成量ＭＥＡ和ＭＶＤ均明显高于正常乳腺、单纯上皮增生和轻度非典型增生（Ｐ＜０．０５）。结论：乳腺非典型增生过程中已有血管生成并随非典型增生程度的增加而增多；乳腺增生组织中的血管生成可反映乳腺癌前病变的恶性倾向     

乳腺癌与乳腺增生性病变C-erbB-2免疫组化的定量研究

应用免疫组化和图像定量分析对４０例乳腺良恶性病变中ＣｅｒｂＢ２的定位，分布面积及相对含量进行图像定量和病理学研究。结果显示：乳腺增生性病变中非典型性增生与乳腺癌的发生有关，ＣｅｒｂＢ２的定位方式，阳性表达的分布面积与相对含量在乳腺癌与增生性病变之间均存在显著差异性（Ｐ＜０．０１），ＣｅｒｂＢ２可以作为乳腺良恶性病变鉴别诊断的重要指标     

Microcirculatory studies in rat mammary carcinoma. I. Transparent chamber method, development of microvasculature, and pressures in tumor vessels

Fragments of a mammary adenocarcinoma were implanted into transparent tissue chambers in the dorsal skin flaps of female inbred F344 rats. A chamber modification permitted repeated access to the tissue without infection, vessel disruption, or impairment of tumor growth. Tumors completely filled the chambers after 26-30 days. Development of tumor microvasculature was characterized by increase in number, length, and diameter of vessels. These changes were much more pronounced in capillaries and venules than in arterioles. Direct blood pressure measurements were performed in microvessels throughout the tumor during the first 3 weeks of growth as well as in microvessels of tumor-free control preparations containing subcutaneous tissue. Average pressures in arterioles of 40- to 11-micron diameter were between 23.0 and 17.3 cm H2O in tumors versus 25.5 and 16.2 cm H2O in controls. Average pressures in venous capillaries, venules, and veins up to 150-micron diameter were between 9.1 and 8.1 cm H2O in tumors and between 13.4 and 11.0 cm H2O in controls.     

Changes in human skin blood flow by hyperthermia

The heat-induced changes in blood circulation in human forearm skin were studied. With the use of laser Doppler flowmetry, it was possible to noninvasively monitor the velocity and volume of red cells, and thus the flow rate of red cells or blood flow in the human skin. When the skin surface was heated at 35 degrees -43 degrees C for 60 min, the laser Doppler flow (LDF) changed dynamically, indicating that the blood flow in human forearm skin could increase as much as 15-20 times during heating at 43 degrees C. Such an increase in laser Doppler flow resulted from dilation of arterioles and recruitment of capillaries, and also to a lesser extent, from an increase in the velocity of red cell flux. The increase in the velocity of red cell flux implies that arteriovenous anastomoses exist in the human forearm skin, in contradiction to the common view that human forearm skin is devoid of arteriovenous anastomosis.     

Target organ disposition and plasma pharmacokinetics of doxorubicin incorporated into albumin microspheres after intrarenal arterial administration

We synthesized doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-loaded human albumin microspheres (containing approximately 1% doxorubicin w/w) between 15 and 20 micron in diameter. Intrarenal arterial administration of 99mTC-labeled microspheres demonstrated a high renal entrapment ratio (97% of recovered radioactivity). The pharmacokinetics and metabolism of doxorubicin are different when it is administered in microspherical form. Peak plasma levels are lower (16 ng/ml versus 135 ng/ml) compared with treatment by a doxorubicin solution. Histologic studies showed that the microspheres were trapped within capillaries and small arterioles in the renal vascular arcade. It is apparent that chemoembolization with doxorubicin-loaded microspheres significantly reduces systemic exposure to the antineoplastic agent, and maintains intrarenal drug levels.     

Microangiopathic hemolytic anemia (MAHA) observed after administration of mitomycin C (MMC)

An autopsy case of MAHA induced by MMC is reported. The patient received MMC and tegafur following operation for colon adenocarcinoma. Five months after the operation, the patient developed MAHA, thrombocytopenia, and renal impairment. MAHA was exacerbated by blood transfusions and he died of extensive pulmonary edema. Autopsy findings showed no residual carcinoma but microangiopathies of the kidney, such as fibrinoid necrosis of the small arteries, arterioles, and glomerular capillaries, and intimal proliferation in the small arteries were evident. As renal impairment is usually irreversible in MAHA by MMC, careful follow-up of renal function should be emphasized in patients receiving MMC.     

Dynamic contrast enhanced optical imaging of capillary leakage

We studied in vivo the vascular permeability of two fluorescent contrast agents in three types of capillary, using a fibered confocal fluorescence microscopy system. Mice were imaged after injection of a macromolecular (albumin FITC 68,000 daltons) or low-molecular-weight contrast agent (FITC 389 daltons). We studied continuous capillaries in muscles (FITC n = 4, albumin FITC n = 6), fenestrated capillaries in mesenteries (FITC n = 8, albumin FITC n = 10), and discontinuous capillaries in xenografted tumors (FITC n = 2, albumin FITC n = 4). Signal intensity (SI) was measured in capillary and interstitial regions, and time-enhancement curves were drawn. Two-compartment models were constructed to determine quantitative microcirculation parameters. The arrival of the bolus of the two different contrast agents was observed in mesentery and muscle capillaries but not in tumor capillaries. Interstitial leakage of the low-molecular-weight contrast agent was observed almost instantaneously, whereas the macromolecular agent remained within the vessels. Signal intensity declined over the observation period, specifically in the tumor. No quantitative microcirculation parameters could be obtained with either of two bi compartmental models, owing to model instability. This study shows that the microcirculation can be reproducibly observed in different types of capillary in vivo with this fibered fluorescence imaging device. Further work is required to quantify microvascular parameters.     

Implications of the analogy between recombinant cytokine toxicities and manifestations of hantavirus infections

The etiologic hantavirus of the 1993 emergence of an acute pulmonary failure syndrome in the area around northwestern New Mexico was quickly recognized as related to the Hantaan virus responsible for the outbreak of Korean epidemic hemorrhagic fever (EHF) among UN troops in 1951. Discovery of the new disease which was named the hantavirus pulmonary syndrome (HPS) and its causative agent the Sine Nombre virus (SNV) inspired detailed comparisons between the two disorders. Major damage to the epithelial cells of the capillaries and arterioles throughout the body leading to extensive capillary leak and subsequent hypotension and shock was the common denominator. The lung capillaries and arterioles were the focus of attack that could lead to rapid pulmonary failure in HPS and the corresponding renal and retroperitoneal vessels that caused a more protracted illness in EHF, but both displayed remarkably similar peripheral blood abnormalities including abnormal mononuclear cells, immature neutrophilia, thrombocytopenia, and hemoconcentration characteristic enough to make blood smear examination a useful tool in early diagnosis. There are evidences that a heavy virus presence in the involved endothelial cells is accompanied by various mononuclear cells capable of generating potent immune response in these areas. Relevant toxic effects of systemically-administered high-dose interleukin-2 for resistant cancers include fever, chills, diarrhea, renal dysfunction, capillary leak syndrome accompanied by hypotension requiring aggressive pressor support, and occasional pleural effusions with diffuse pulmonary infiltrates and hypoxia severe enough to require ventilatory assistance. Peripheral blood mononuclear cells cultured in vitro with IL-2 secrete secondary cytokines such as IL-1, TNF-alpha, and interferon-gamma (IFN-gamma). TNF-alpha, implicated in the pathophysiology of septic shock, is capable of inducing adult respiratory distress syndrome (ARDS) in experimental animals and humans. The strong similarity of these effects to the manifestations noted in the hantavirus diseases justifies the conviction that these and other cytokines involved in potent immune responses would constitute the pathogenic toxic substances predicted by perceptive early investigators of EHF. This concept is favored by clear indications that in both diseases active virus infection disappears the first few days and the ages of involvement correlate with periods of immunocompetence. The paradox of systemic injections of IL-2 that risk hantavirus-type toxicities for treating renal cell carcinoma and melanoma might be avoided by giving potentially more efficacious plant mitogens like PHA as previously reported. The expanded disclosure of a collaborator's method suggesting superior potential for cancer cure involves a unique application of pokeweed mitogen that delivers various cellular and cytokine responses directly to the tumor.     

Electrocardiographic and pathological studies of the heart in experimental guinea pig leukemia.

Electrocardiographic tracings were performed on 26 strain 2 guinea pigs in which leukemia was induced by inoculation of L2C leukemic cells. All inoculated animals developed leukemia. In terminal phases of this disease significant electrocardiographic changes were observed in 20 of the 26 animals; in 5 animals the electrocardiograms were normal and in 1 guinea pig the changes were borderline. The most significant changes consisted of the onset of a Q-wave or a T-wave inversion or both. Pathological examination of the heart removed in the terminal phase of the disease revealed infiltration of the endocardium and epicardium and in the capillaries of the myocardium. Such areas of infiltration, when viewed with the electron microscope, revealed the presence of leukemic cells within the lumen of capillaries and in areas immediately surrounding the capillaries. Infiltration of myocardial fibers was not observed. The electrocardiographic changes observed in guinea pig leukemia may be related to the leukemic infiltration of myocardial capillaries and the resulting anoxia.     

Stereologic evaluation of the vasculature in a MX1 xenotransplanted tumour model after combinations of treatment with ifosfamide,hyperthermia and irradiation

The vascularization of tumours is a critical parameter of their growing and metastatic behaviour. However, little is known about the morphologic reactions of the microvasculature, especially the capillary bed of tumours and the adjacent tissue. In this study, the vessels in MX1 xenotransplants in athymic nu/nu nude mice were quantified and the angioarchitecture was visualized with the aim of presenting stereologic parameters of vessels based on a morphometric analysis of post mortem tissue blocks which were processed by standard histological procedures. In order to study changes of the microvasculature of MX1 tumours, the xenotransplanted nude mice were treated by different therapeutic regimens. Standardized hyperthermia, ifosfamide and irradiation therapies were applied. Special interest was focused on early changes of capillaries and of the pre- as well as post-terminal vascular bed. The stereologic evaluation of capillaries and larger vessels immediately after the therapy with ifosfamide and hyperthermia shows an increase of the mean capillary sizes. Furthermore, tumour samples after the 5th day of irradiation (5.2 Gy) and combinations of irradiation and chemotherapy treatment have been investigated. After 5 days of irradiation, a significant decrease of the vascular density was found. The results presented here clearly show that the timing and the mode of therapy influence the capillary morphology and periterminal vasculature of xenotransplanted MX1 tumours.     

Stereologic evaluation of the vasculature in a MX1 xenotransplanted tumour model after combinations of treatment with ifosfamide, hyperthermia and irradiation.

The vascularization of tumours is a critical parameter of their growing and metastatic behaviour. However, little is known about the morphologic reactions of the microvasculature, especially the capillary bed of tumours and the adjacent tissue. In this study, the vessels in MX1 xenotransplants in athymic nu/nu nude mice were quantified and the angioarchitecture was visualized with the aim of presenting stereologic parameters of vessels based on a morphometric analysis of post mortem tissue blocks which were processed by standard histological procedures. In order to study changes of the microvasculature of MX1 tumours, the xenotransplanted nude mice were treated by different therapeutic regimens. Standardized hyperthermia, ifosfamide and irradiation therapies were applied. Special interest was focused on early changes of capillaries and of the pre- as well as post-terminal vascular bed. The stereologic evaluation of capillaries and larger vessels immediately after the therapy with ifosfamide and hyperthermia shows an increase of the mean capillary sizes. Furthermore, tumour samples after the 5th day of irradiation (5 x 2 Gy) and combinations of irradiation and chemotherapy treatment have been investigated. After 5 days of irradiation, a significant decrease of the vascular density was found. The results presented here clearly show that the timing and the mode of therapy influence the capillary morphology and periterminal vasculature of xenotransplanted MX1 tumours.     

Metastatic breast carcinoma presenting as a large pulmonary embolus: case report and review of the literature

Involvement of the pulmonary vasculature by carcinoma of the breast typically occurs in the form of microscopic tumor emboli involving the small arteries, arterioles, or capillaries. Obstruction of a large pulmonary artery by a tumor embolus has not been reported. We describe a patient with a history of breast carcinoma diagnosed 5 years previously who sought treatment for dyspnea and a large mass in the right pulmonary artery suggestive of a pulmonary embolus. After failure of both systemic and intraarterial thrombolytic therapy, a biopsy of the mass was obtained, which revealed adenocarcinoma of the breast. Systemic chemotherapy with doxorubicin and cyclophosphamide was initiated and resulted in the complete resolution of her symptoms.