Pathologic analysis of right-lobe graft failure in adult-to-adult live donor liver transplantation

Live donor adult liver transplantation (LDALT) utilizing right-lobe grafts is now acceptable as an alternative to cadaveric orthotopic liver transplantation (OLT). However, some LDALTs fail and require urgent OLT or result in recipient death. Our aim was to determine the basis of LDALT failure. Liver specimens from 49 LDALT recipients were evaluated and the findings correlated with clinical outcome. Ten patients (20.4%) had either early (< or = 1 month) or late (> 1 month) graft failure. Eight early failures, 7 of which occurred among our first 25 cases, were due to extensive liver parenchymal necrosis as a result of hepatic artery thrombosis (n=3), portal vein thrombosis (n=1), hyperperfusion syndrome (n=1), complete graft thrombosis (n=1) with Factor V Leiden on a regimen of therapeutic heparin (n=1), sepsis and concomitant graft dysfunction with venous outflow tract injury (n=1), and venous outflow tract thrombosis and parenchymal thermal injury with sepsis (n=1). Preoperative, intraoperative, or postoperative severe vessel wall injury was evident in 6/8 early failures. Two patients had late graft failure, 1 from recurrent hepatitis C and 1 with sepsis/multisystem organ failure. There were no significant differences in graft size, rejection episodes, or operative or ischemic times between patients with and without graft failure. In conclusion, LDALT failed in 10/49 (20%) of our patients, with 8/10 occurring within 1 month post-LDALT owing to vascular/thrombotic complications experienced during the early phase of our institutional experience. Perioperative vessel wall injury appeared to be a major factor in predicting early graft loss.     

Changes induced by vascular antigens in the aorta of guinea-pigs: immunological and morphological studies

The effects have been studied of human vessel wall on the cell-mediated and humoral immune response, as well as the morphological changes produced in the aorta in guinea-pigs. In animals immunized with calcium chloride-tris-citrate extracts of the aortic and vessel wall a definite cell-mediated and humoral immune response was observed. A cross-reaction was found between the 2 vessel wall extracts in the skin test and in the migration inhibition test. The induction of desoxyribonucleic acid synthesis was found to be specific. Antibody production as well as the concentration of IgG in the serum was increased. Simultaneously with increased production of the antibodies the cellular immune response did not diminish util the 9th week. A definite alteration was found in the aortic intima by histological, histochemical, immunofluorescence and electron microscopic methods. In addition some slight changes could be observed in the media and in the aventitia of the aorta.     

Changes induced by vascular antigens in the aorta of guinea-pigs: immunological and morphological studies.

The effects have been studied of human vessel wall on the cell-mediated and humoral immune response, as well as the morphological changes produced in the aorta in guinea-pigs. In animals immunized with calcium chloride-tris-citrate extracts of the aortic and vessel wall a definite cell-mediated and humoral immune response was observed. A cross-reaction was found between the 2 vessel wall extracts in the skin test and in the migration inhibition test. The induction of desoxyribonucleic acid synthesis was found to be specific. Antibody production as well as the concentration of IgG in the serum was increased. Simultaneously with increased production of the antibodies the cellular immune response did not diminish util the 9th week. A definite alteration was found in the aortic intima by histological, histochemical, immunofluorescence and electron microscopic methods. In addition some slight changes could be observed in the media and in the aventitia of the aorta.     

Vessel ultrastructure in APP23 transgenic mice after passive anti-Abeta immunotherapy and subsequent intracerebral hemorrhage

Passive immunization of amyloid precursor protein (APP) transgenic mice with anti-amyloid beta (Abeta) antibodies was shown to reduce Abeta-deposition in brain and to improve cognition. However, immunotherapy may also be accompanied by a significant increase in the frequency of intracerebral hemorrhages. Because hemorrhages are associated with amyloid-laden vessels, this raises the question whether high concentrations of anti-Abeta antibodies may directly or indirectly lead to a structural destabilization of the vessel wall. To address this point, transmission electron microscopy was performed and the ultrastructure of bleeding and non-bleeding vessels in immunized and non-immunized APP23 transgenic animals was analyzed. To localize bleeding vessels, hemosiderin-positive macrophages were visualized by pre-embedding Perl's Berlin Blue histochemistry. Vessels were analyzed morphologically, anomalies evaluated and quantified. Bleeding vessels were, furthermore, reconstructed in three dimensions to analyze the spatial distribution of amyloid deposits and other pathological changes of the vessel wall. This in-depth morphological analysis revealed that bleeding vessels in immunized as well as in non-immunized APP23 mice were surrounded by a higher number of macrophages compared to non-bleeding vessels in the same animals. However, no differences in the number of macrophages or other structural parameters, such as amyloid deposition, were observed between bleeding vessels of immunized and non-immunized mice. No pathologies which may indicate impending bleeding were observed in the vascular wall of non-bleeding vessels. We conclude, that the increased hemorrhage frequency observed after passive immunization with anti-Abeta antibodies does not lead to overt structural changes in the vessel wall of APP23 transgenic mice. Minor structural alterations of the vessel wall, however, cannot be excluded due to the sample size of our study and the high complexity of the three-dimensional vessel wall ultrastructure.     

Physically Damaged Extracellular Matrix Induces TNF-α Secretion by Interacting Resting CD4+ T Cells and Macrophages

T lymphocytes and macrophages (Mø) are seen to accumulate at sites of lesions in blood vessel walls, suggesting that these cells may contribute to the initiation of the local inflammatory reaction. Tumour necrosis factor-α (TNF-α), a cytokine produced by both cell types, plays a major role in inflammatory reactions, in blood vessel formation, in thrombosis and in atherosclerosis. We now report that secretion of TNF-α by CD4⁺ T cells and Mø can be induced in vitro in the absence of antigen, in an MHC-II-independent manner by immobilized extracellular matrix (ECM), Moreover, the level of TNF secretion is greatly enhanced in the presence of physically damaged ECM (dECM), This mode of TNF secretion is regulated primarily by the fibronectin or laminin glycoprotein components of ECM, Thus, a multicellular interaction with ECM proteins exposed as a consequence of vascular wall injury can serve to signal the secretion of TNF-α by both cell types which induces the recruitment of additional immune cells to the developing lesion.     

间充质干细胞对系统性红斑狼疮免疫性血栓形成的调控

背景：系统性红斑狼疮是一种复杂的自身免疫性疾病,其主要病理机制与T、B淋巴细胞异常活化有关,由于系统性红斑狼疮产生多种病理性自身抗体和免疫复合物,沉积在中小血管或抗体直接侵袭血管导致管壁的炎性坏死,使血管腔变窄,促进血栓形成,导致局部组织缺血和功能障碍。间充质干细胞具有抗炎、调节系统性红斑狼疮的T、B细胞免疫紊乱、修复免疫炎性血栓形成的作用。 目的：总结系统性红斑狼疮免疫性血栓形成的发病机制,介绍间充质干细胞治疗系统性红斑狼疮免疫性血栓形成的机制及临床应用前景。 方法：以“systemic lupus erythematosus,mesenchymal stem cell,thrombosis,T cells,B cell,immunity”为检索词,检索Pubmed数据库、Springlink数据库、ScienceDirect数据库、HighWire数据库,检索年限为1990年1月至2013年6月,限定语种为英文;以“系统性红斑狼疮、间充质干细胞、血栓形成、T细胞、B细胞、炎症因子”为检索词,检索CNKI数据库、万方数据库、维普数据库,检索年限为1990年1月至2013年6月,限定语种为中文。共检索267篇文献,选择其中48篇文献进行分析。 结果与结论：间充质干细胞具有高度自我更新能力和多向分化潜能,它通过抑制T细胞的增殖活化,改变T细胞亚群比例,抑制T细胞因子γ-干扰素、白细胞介素4分泌,从而协调系统性红斑狼疮体内的免疫平衡。间充质干细胞抑制B细胞的增殖趋化功能,抑制B细胞分泌致病性免疫球蛋白IgM、IgG、IgA,减少系统性红斑狼疮体内抗体及免疫复合物的沉积,使血管壁免遭其侵袭破坏,炎症细胞因子分泌减少,维持凝血-抗凝系统平衡,改变系统性红斑狼疮的血栓形成。     

Pathogenesis of portal sclerosis in the liver with idiopathic portal hypertension. Observations of 19 autopsy cases and animal experiments

The pathomorphological changes of intrahepatic portal veins were studied in 19 autopsy cases of idiopathic portal hypertension (IPH), and the pathogenesis of portal sclerosis was discussed by the observations on the human and experimental materials. The degree and morphological appearance of intimal lesions vary from vessel to vessel. Fibro-cellular proliferation of subendothelial tissue and incorporation of organized mural thrombi were suggested as the cause of intimal thickening in the portal veins. Animal experiment showed that injury of portal vein wall was followed by intimal hyperplasia and/or incorporation of mural thrombi, and resulted in portal sclerosis similar to that of IPH liver. The cause of portal phlebosclerosis in IPH can not be explained by passive congestion alone. There might be a certain possibility of direct injurious effect in the vessel wall in the pathogenesis of portal lesions of IPH. The following pathogenesis of portal sclerosis in IPH is postulated: phlebo-sclerotic changes of the portal veins are initiated by injury to the vessel wall due to unknown cause(s) and accelerated by secondary thrombosis and/or mechanical injury due to increased portal pressure.     

A family with thromboembolic disease associated with deficient fibrinolytic activity in vessel wall

Defective fibrinolytic activity is often a contributory factor in deep venous thrombosis. A family with a high incidence of venous thrombosis in association with such a defect is presented. Of 13 family members who had had thrombosis, 12 showed a defective capacity to release fibrinolytic activity from vessel wall after venous occlusion and/or infusion of DDAVP, a vasopressin derivative. The fibrinolytic activator activity of the vessel wall was normal in all cases. This seems to be the first family in which there is evidence of an inherited abnormal fibrinolytic activity.     

Immunological characterisation of plasminogen activators in the human vessel wall.

A histochemical technique was used to identify the activity of the plasminogen activator (PA) in the vessel wall of veins. Antibodies against melanoma cell activator and urokinase (UK), both raised in goats, were mixed into the fibrin film. The PA activity was quenched by the antibodies against melanoma activator but remained unchanged when antibodies against UK, or an IgG preparation of normal goat serum, was mixed in the fibrin film. The results of this study show that the PA activity in the vein vessel wall is immunologically similar to or identical to the PA derived from melanoma cells which has previously been shown to cross-react with the tissue-like PA. No UK-like activity was present in the vessel wall.     

Warner-Lambert/Parke-Davis Award Lecture. Viral pathogenesis of atherosclerosis. Impact of molecular mimicry and viral genes.

Human atherogenesis is a pleiotropic process with an undefined cause. Several pathologic factors have been linked to the disease process, including arterial injury or activation of the endothelium, which may injury or activation of the endothelium, which may initiate proatherosclerotic events in the vessel wall. Atherosclerotic lesions are characterized, in part, by the presence of activated immune cells, abnormal cell proliferation, and altered cholesterol metabolism. These activated immunocompetent cells in plaques produce vasoactive mediators that can alter homeostasis and may promote the arteriopathy. Both molecular and structural evidence is presented that herpesviruses, by way of induction of altered gene function and cellular cholesterol metabolism, coupled with their ability to activate coagulation and a monocyte receptor on the infected endothelium, are involved in major pathogenic events associated with atherosclerosis and thrombosis. Work from the author's laboratory, as well as from other research groups, have shown that avian and human herpesviruses act specifically to induce alterations to the surface and inner layers of the blood vessel wall that may predispose to atherosclerosis and its attendant clinical complications.     

PATHOGENESIS OF PORTAL SCLEROSIS IN THE LIVER WITH IDIOPATHIC PORTAL HYPERTENSION

The pathomorphological changes of intrahepatic portal veins were studied in 19 autopsy cases of idiopathic portal hypertension (IPH), and the pathogenesis of portal sclerosis was discussed by the observations on the human and experimental materials. The degree and morphological appearance of intimal lesions vary from vessel to vessel. Fibrocellular proliferation of subendothelial tissue and incorporation of organized mural thrombi were suggested as the cause of intimal thickening in the portal veins. Animal experiment showed that injury of portal vein wall was followed by intimal hyperplasia and/ or incorporation of mural thrombi, and resulted in portal sclerosis similar to that of IPH liver. The cause of portal phlebosclerosis in IPH can not be explained by passive congestion alone. There might be a certain possibility of direct injurious effect in the vessel wall in the pathogenesis of portal lesions of IPH. The following pathogensis of portal sclerosis in IPH is postulated: phlebosclerotic changes of the portal veins are initiated by injury to the vessel wall due to unknown cause (s) and accelerated by secondary thrombosis and/ or mechanical injury due to increased portal pressure.TA PATHOL. JPN. 35: 299–314, 1985.     

Buerger's disease: clinical and histomorphological study

There is an extremely high prevalence of Thromboangiitis Obliterans (TAO) or Buerger's disease (BD) in India among people of low socioeconomic class who smoke beedies (homemade cigarettes with raw tobacco). The aim of this study was to study the clinical and histo-morphological aspects of Buerger's disease with relevance to age at presentation in the local population. The study comprised of 25 cases (all were men and were smokers) of clinically diagnosed BD based on Shionoya's criteria. The mean age was 47 years. The specimens consisted of 21 biopsies, 2 end-arterectomies and 2 amputations. Formalin fixed, routinely processed, paraffin embedded tissue sections were stained with Haematoxylin and Eosin (H and E) and Verhoeff's elastic stain. They had claudication pain either in the ankle (5) or in the calf (2) or both (13). 24 had infrapopliteal disease and 9 showed upper limb involvement. 21 showed migratory thrombophlebitis also. Histomorphological presentation included the following features: Luminal thrombosis (14), fresh thrombosis (4), chronic inflammation in the vessel wall (10), within the thrombus (1) and around perivascular channels and nerve bundles (4). Internal elastic lamina showed reduplication in 13, undulation in 9 and fragmentation in 9 cases. Media of the vessel showed the following features: fibrosis (9), hypertrophy (9) and calcification (5) Adventitial haemorrhage, cholesterol clefts and atherosclerotic plaque formation were the other changes seen. In our study the following histopathological features were consistently seen. Thrombus (with or without recanalisation), inflammatory cell infiltrate (within the thrombus wall or periadventitial tissue), subintimal and medial fibrosis and changes in internal elastic lamina. These features were also highlighted in other studies. However in our study, medial hypertrophy and calcification were observed as additional features.     

Vascular damage in giant cell arteritis

Immune-mediated damage to medium-sized arteries results in wall remodeling with intimal hyperplasia, luminal stenosis and tissue ischemia. In the case of the aorta, vasculitis may result in dissection, aneurysm or rupture. The response-to-injury program of the blood vessel is a concerted action between the immune system and wall-resident cells, involving the release of growth and angiogenic factors from macrophages and giant cells and the migration and hyperproliferation of vascular smooth muscle cells. Innate immune cells, specifically, dendritic cells (DC) positioned in the vessel wall, have been implicated in the earliest steps of vasculitis. Pathogen-derived molecular patterns are capable of activating vascular DC and initiating adaptive immune responses. The pattern of the emerging vessel wall inflammation is ultimately determined by the initial insult. Ligands to toll-like receptor (TLR) 4, such as lipopolysaccharides, facilitate the recruitment of CD4 T cells that invade deep into the wall and distribute in a panarteritic pattern. Conversely, ligands for TLR5 condition vascular DC to support perivasculitic infiltrates. In essence, both innate and adaptive immune reactions collaborate to render the arterial wall susceptible to inflammatory damage. Unique features of the tissue microenvironment, including specialized DC, shape the course of the inflammatory response. Differences in vascular damage pattern encountered in different patients may relate to distinct instigators of vasculitis.     

Immunological comparison between human and rat plasminogen activators in blood and the vessel wall.

To evaluate the rat as an experimental model for plasminogen activator research, the ability of antibodies specific for human tissue type plasminogen activator and urokinase to suppress the plasminogen activator activity in whole plasma and in the vessel wall was studied in both rat and man. Plasminogen activator activity in plasma was assayed on fibrin plates containing plasminogen. Plasminogen activator in the vessel wall was shown by the fibrin side technique. Antibodies against human tissue type melanoma cell activator and urokinase were raised in goats and mixed into the fibrin film or the fibrin plates. In both species antibodies to melanoma cell activator were able to suppress the plasminogen activator activity completely in plasma and in the vessel wall. Anti-urokinase, however, had no suppressing effect. In rat plasma the inhibitory effect on the fibrinolytic activity was seen only with high concentrations of antibodies against melanoma cell activator, which suggests that rat plasminogen activator in plasma and vessel walls is similar to, but not identical with, human tissue type plasminogen activator.     

冠脉内支架临床发展策略

冠脉内支架是临床上预防ＰＴＣＡ并发症的有效措施，但金属支架固有的血栓菜成原性和对血管壁组织的永久性刺激可导致院内心脏事件和再狭窄。为解决上述问题，作者提出，血管内支架联合靶向药物传输离子照射或基因治疗、基因修饰的内皮细胞的种植支架、吱物可吸收缓释药物支架材料研制为临床冠脉内支架开辟了广阔的发展前景。     

Effective immunity to dental caries: gastric intubation of Streptococcus mutans whole cells or cell walls induces protective immunity in gnotobiotic rats.

Gnotobiotic rats were given Streptococcus mutans 6715 whole cells (WC), purified cell walls (CW), or cell wall lysate by gastric intubation (GI), and assessments were made of humoral immune responses in serum and saliva and of caries protection. Levels of secretory immunoglobulin A (IgA) and IgG antibodies to S. mutans WC in saliva samples from experimental rats were determined by an enzyme-linked immunosorbent assay. Serum antibody levels of the IgM, IgG, and IgA isotypes were also determined. Similar levels of salivary antibodies were induced in rats given S. mutans WC or CW by GI, whereas lower salivary antibody titers were observed in rats given cell wall lysate by the oral route. The level of serum antibodies in the various groups of rats also reflected the oral antigen used. The specificity of salivary IgA and serum IgG antibodies in the various groups of rats was determined by enzyme-linked immunosorbent assay with lipoteichoic acid, serotype g carbohydrate, dextran, CW, and WC as coating antigens. Salivary IgA and serum IgG antibodies in rats given S. mutans WC or CW by GI were primarily directed to lipoteichoic acid and serotype g carbohydrate. The presence of salivary IgA antibodies to S. mutans in rats given either S. mutans WC or CW by GI correlated with a significant reduction in the levels of plaque, numbers of viable S. mutans in plaque, and caries scores when compared with the control animals (infected only). These results demonstrate that particulate antigens of S. mutans induce salivary immune responses when given by GI to gnotobiotic rats and that the presence of these antibodies correlates with caries protection.     

A Magnetic Approach to Decrease Stent Graft Endoleak: <Emphasis Type="Italic">Ex-Vivo</Emphasis> Validation

Stent graft endoleak is a major problem in endovascular aneurysm repair (EVAR). Endoleak occurs after EVAR and may lead to aneurysm rupture, acute vessel thrombosis or occlusion. This study presents a novel design to potentially reduce endoleak with use of magnets. A ferromagnetic stent is deployed into the vessel lumen, and two external flexible magnetic rings are used to clamp on the proximal and distal necks of the stent. The rings impose epivascular magnetic pressure on the vessel wall to prevent the vessel wall from separating from the stent under elevated blood pressure. The geometry and magnetic properties of the stent and rings were designed to produce sufficient pressure, without overly compressing the vessel wall. Feasibility of this design was demonstrated with in vitro experiments using porcine abdominal aortas. The experiments showed that magnetic ring significantly improved the seal between the stent and vessel wall with use of moderate-sized stent. For aortas subjected to physiological axial stretch, rings that generate magnetic pressure of about 45 mmHg were found sufficient to prevent endoleak at pressure of 140 mmHg. Evaluation of this design in an in vivo animal model of aortic aneurysm is warranted.     

Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture

Intimal thickening, the accumulation of cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation, especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction.     

HIT: lessons learned

The peculiar pathogenesis of heparin-induced thrombocytopenia (HIT), involving a "self" antigen-platelet factor 4 (PF4) bound to heparin-and resulting antibody-mediated platelet activation, is a model for thrombosis triggered by drug-induced autoimmunity. The high probability of forming an immune response to heparin, and the highly-variable clinical significance of a positive laboratory test-depending on the type of assay and the magnitude of a given positive test result-provides lessons regarding appropriate interpretation of diagnostic laboratory testing in the context of pretest probability. The relatively high risk of inducing microvascular thrombosis due to coumarin-induced vitamin K antagonism attests to the dangers of a compromised protein C natural anticoagulant system in the setting of a hypercoagulability state such as HIT. Unusual immunologic features of HIT, such as the dissociation between immunogenicity (induction of immune response) and cross-reactivity (capacity to form the antigens recognized by HIT antibodies)of the implicated polysaccharide anticoagulants, and the generally rapid formation and disappearance of anti-PF4/heparin antibodies, suggest that further lessons regarding HIT immunopathogenesis remain to be learned.     

Computer simulation and geometric design of endarterectomized carotid artery bifurcations

The main goal of this computational study is to establish surgical guidelines for optimal geometries of carotid endarterectomy reconstructions that may measurably reduce postoperative complications, that is, thrombosis, stroke, and/or restenosis. The underlying hypotheses are that nonuniform hemodynamics, or "disturbed flows," are linked to arterial diseases and consequently that minimization of "disturbed flow" indicators leads to geometric bifurcation designs that lower postoperative complication rates. Considering transient 3-D laminar blood flow in partially occluded, in-plane, rigid-wall carotid artery bifurcations, the results presented include time-averaged indicators of "disturbed flow", such as the wall shear stress, spatial wall shear stress gradient, and wall shear stress angle deviation. In addition, trajectories and deposition patterns of critical blood particles (i.e., monocytes) are shown and evaluated. Within given physiological constraints, the vessel geometry was then changed in order to reduce the magnitudes of key indicators associated with thrombosis (i.e., blood clot formation) or restenosis (e.g., renewed atherosclerosis and/or hyperplasia). The quantitative results and knowledge base generated will be crucial for future clinical trials.