Microvascular structure and function in salt-sensitive hypertension

In many individuals with essential hypertension, dietary salt can further increase blood pressure by augmentation of an already elevated total peripheral resistance. There is little information on the microvascular changes that contribute to salt-sensitive hypertension in humans, but studies in the Dahl salt-sensitive rat have provided some knowledge of the microcirculation in this form of hypertension. These studies, most of which have used intravital microscopy or isolated vessel technology, are the focus of this review. The salt-induced exacerbation of hypertension in Dahl rats is due to a uniform increase in hemodynamic resistance throughout most of the peripheral vasculature. In the spinotrapezius muscle, this resistance increase is largely due to the intense constriction of proximal arterioles. The mechanisms responsible for this increased arteriolar tone include increased responsiveness to oxygen and a loss of tonic nitric oxide (NO) availability caused by reduced endothelial NO production and/or accelerated NO degradation by reactive oxygen species. Within the last decade, it has become increasingly clear that high salt intake can also lead to changes in microvascular structure and function in the absence of increased arterial pressure. This effect must also be considered when evaluating microvascular changes and their functional consequences in salt-sensitive hypertension.     

Heterogeneous Distribution of Tumor Blood Supply Affects the Response to Chemotherapy in Patients with Head and Neck Cancer

Objective : To evaluate if the heterogeneous distribution of tumor blood supply affects the response to chemotherapy in patients with head and neck cancer. Methods : We treated 25 stage III/IV patients with an intraarterial cisplatinum‐bleomycin regimen. Prior to treatment, a blue dye was injected directly to tumors through the catheter. Well‐stained areas were considered as profusely perfused areas whereas poorly stained areas were considered as poorly perfused areas. Biopsies of both areas of each tumor were taken prior to and after the treatment and the histopathological response was evaluated with the following grading: I, tumor disappearance; II, destruction of some tumor nests; III, no changes. Results : Grade I responses were attained in 13/25 (52%) of profusely perfused areas against 1/25 (4%) of poorly perfused areas (p < 0.001). Moreover, there were significant differences (p < 0.001) in the overall responses: 21/25 (84%) in the profusely perfused areas versus 7/25 (28%) in the poorly perfused areas; and in grade III responses (4/25, 16% vs. 18/25, 72%). To determine a possible correlation between the histopathological responses obtained in profusely perfused and in poorly perfused areas of each tumor, we then calculated the Kendall's tau‐b statistics, obtaining a τ value of 0.279 (p = 0.145). This data indicated that histopathological responses to chemotherapy of profusely perfused and poorly perfused areas were independent in each tumor. Conclusions : Heterogeneity in the distribution of tumor blood supply affects the response to chemotherapy by influencing the intratumoral delivery of therapeutic agents. After the administration of effective doses of anticancer drugs to a tumor, cells in profusely perfused areas receive enough to destroy them while cells in the poorly perfused areas are exposed to lower drug concentrations and, therefore, survive. This phenomenon could explain in part the difficulty in the treatment of human solid tumors.     

Fractal Characteristics of Tumor Vascular Architecture During Tumor Growth and Regression

Objective : Tumor vascular networks are different from normal vascular networks, but the mechanisms underlying these differences are not known. Understanding these mechanisms may be the key to improving the efficacy of treatment of solid tumors. Methods : We studied the fractal characteristics of two-dimensional normal and tumor vascular networks grown in a murine dorsal chamber preparation and imaged with an intravital microscopy station. Results : During tumor growth and regression, the vasculature in the tumor has scaling characteristics that reflect the changing state of the tissue. Growing tumors show vascular networks that progressively deviate from their normal pattern, in which they seem to follow diffusion-limited aggregation to a pathological condition in which they display scaling similar to percolation clusters near the percolation threshold. The percolation-like scaling indicates that the key determinants of tumor vascular architecture are local substrate properties rather than gradients of a diffusing substance, such as an angiogenic growth factor. During tumor regression, the fractal characteristics of the vasculature return to an intermediate between those of growing tumors and those of healthy tissues. Previous studies have shown that percolation-like scaling generally inhibits transport. Conclusions : In the present context, the percolation-like nature of tumor vasculature implies that tumor vascular networks possess inherent architectural obstacles to the delivery of diffusible substances such as oxygen and drugs.     

RUNX3蛋白在人结直肠癌中的表达及其临床意义

背景:Runx3(runt相关转录因子3)基因是一种新发现的抑癌基因,近年研究发现Runx3异常表达与人类多种消化系肿瘤的发生密切相关。目的:研究人结直肠癌中RUNX3蛋白的表达,分析其表达与结直肠癌临床病理特征的关系。方法:以免疫组化方法检测90例结直肠癌患者的癌组织和癌旁组织中RUNX3蛋白的表达。结果:结直肠癌组织中RUNX3蛋白的阳性表达率(47.8%,43/90)显著低于癌旁结直肠黏膜组织(100%,P<0.05)。RUNX3蛋白的表达与结直肠癌患者的性别、年龄、肿瘤部位、大小和组织学类型无关(P>0.05),与肿瘤浸润深度、分化程度、Dukes分期和有无淋巴结转移有关(P<0.05),浸润越深、分化程度越低、Dukes分期越晚和有淋巴结转移的癌组织,RUNX3蛋白低表达越明显。结论:RUNX3蛋白的表达可能与结直肠癌的浸润、分化和转移相关,提示RUNX3蛋白表达下调可能对结直肠癌的发生、发展具有重要作用。     

Host immune competence and local ischemia affects the functionality of engineered vasculature

Objective: Localized and sustained delivery of vascular endothelial growth factor (VEGF) is a promising approach to overcome the limited efficacy of bolus delivery. The authors examined the effects of host immune competence and local ischemia on the functionality of new vessel networks formed with this approach. Methods: Vessel structure and perfusion resulting from implantation of porous 85:15 poly(lactide-co-glycolide) scaffolds releasing VEGF₁₆₅ were measured in both subcutaneous tissue and ischemic hindlimbs of immune competent C57BL/6 and immune deficient SCID mice. Results: Sustained VEGF delivery resulted in a similar ∼100% increase in vessel density within scaffolds in both implant sites, and both animal models. However, the resulting perfusion within scaffolds implanted in subcutaneous tissue increased modestly versus control (18–35%), while perfusion increased 52–110% above control when VEGF-releasing scaffolds were placed in ischemic hindlimbs of C57BL/6 or SCID mice. VEGF delivery improved perfusion in the entire ischemic limb (55 ± 18% of the normal value by week 6; 138% increase over control) in SCID mice. Although C57BL/6 mice demonstrated spontaneous recovery from ischemia, VEGF delivery accelerated recovery as compared to control. Conclusions: Localized and sustained VEGF delivery can create functional vasculature that amplifies recovery of tissue ischemia. However, increases in local and regional perfusion were highly dependent on the implantation site and the animal model.     

survivin和PTEN蛋白在大肠癌中的表达及临床意义

目的探讨生存素(survivin)和磷酸脂酶(PTEN)蛋白表达与大肠癌浸润转移的关系及相关性。方法应用免疫组织化学技术,检测90例大肠癌组织中survivin和PTEN蛋白表达。结果90例大肠癌中survivin和PTEN蛋白阳性表达率分别为65.6%(59/90)和46.7(42/90)。survivin高表达及PTEN低表达与大肠癌Dukes分期、浆膜浸润、淋巴结转移、肝脏转移均呈正相关(P<0.05)。大肠癌中survivin表达与PTEN表达呈负相关(r=-0.50,P<0.05)。结论survivin和PTEN表达与大肠癌浸润转移密切相关。检测survivin和PTEN蛋白表达可作为判断大肠癌预后的客观指标。     

P53和PCNA蛋白在大肠癌中的表达及意义研究

目的研究P53蛋白和PCNA蛋白在肠癌中的表达及其生物学行为的关系。方法采用免疫组化技术（SP法）对50例肠癌组织进行P53和PCNA检测。结果 P53和PCNA阳性表达率分别为52.0%、76.0%,P53阳性表达率及PCNA强阳性表达率均与肠癌浸润深度、淋巴结转移密切相关,差异有统计学意义。结论 P53和PCNA蛋白可能与肠癌的浸润、转移及预后有关。     

Delivery of Molecular and Cellular Medicine to Solid Tumors

To reach cancer cells in a tumor, a blood-borne therapeutic molecule or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps experimentally and theoretically and then integrate the resulting information in a unified theoretical framework. This paradigm of analysis and synthesis has allowed us to obtain a better understanding of physiologic barriers in solid tumors and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.     

血管性痴呆大鼠脑血流量及细胞凋亡的研究

目的　研究脑血流量及细胞凋亡在血管性痴呆 (VD)发病机制中的作用。方法　采用双侧颈总动脉永久结扎方法制备前脑缺血致血管性痴呆动物模型 ,利用激光多普勒血流仪检测各组大鼠术后不同时间点 (术后 2 4h、1周、0 .5、1、2、3及 4个月 )额叶皮质、海马区局部脑血流量 (rCBF) ;采用HE染色、光镜观察各组大鼠脑组织的形态学变化 ;采用流式细胞仪 (FCM) ,观察额叶皮质、海马区神经细胞凋亡时程变化情况。结果　大鼠术后额叶皮质、海马区的rCBF明显下降 ,以术后 2 4h最明显 ,至术后 4个月时仍明显低于正常 ;病理学研究发现 ,少数大鼠出现脑梗死灶。随着脑血流量持续下降 ,额叶皮质经历了从锥体细胞水肿、缺血、凝固性坏死到变性、脱失及星形胶质细胞增生的过程 ;海马CA1区锥体细胞从最初的缺血、水肿逐渐发展为严重脱失、基质疏松及微空泡形成。FCM结果显示 ,额叶皮质及海马区细胞凋亡均在 1周时最明显 ,额叶皮质至术后 2个月、海马区至术后 3个月时仍明显高于对照组。海马区凋亡细胞百分率明显高于额叶皮质。结论　持续性脑血流量下降引起神经细胞凋亡是导致血管性痴呆的主要原因之一。     

人大肠癌和癌旁组织消减cDNA文库的构建和鉴定

背景：抑制消减杂交(SSH)是一种较成熟的分离差异表达基因的方法，但用该方法构建大肠癌特异性基因消减cDNA文库和筛选相关基因的研究较少。目的：构建人大肠癌和癌旁组织的消减cDNA文库。方法：应用SSH技术分离大肠癌和癌旁正常组织差异表达基因的cDNA片段，将其与pGEM-T Easy载体连接，构建消减cDNA文库。将连接产物转化大肠杆菌DH5α进行文库扩增。随机挑取200个白色克隆，以聚合酶链反应(PCR)进行鉴定。结果：进行PCR扩增的200个克隆中，176个克隆有插入片段，片段分布于200～700bp。结论：成功构建了人大肠癌组织和癌旁组织差异表达基因的消减cDNA文库，为高通量筛选、克隆大肠癌特异性基因奠定了基础。     

Exercise training produces nonuniform increases in arteriolar density of rat soleus and gastrocnemius muscle

OBJECTIVE: Exercise training has been shown to increase regional blood flow capacity to muscle tissue containing fibers that experience increased activity during exercise. The purpose of this study was to test the hypothesis that the increased blood flow capacity is partially the result of increases in arteriolar density (number of arterioles/mm2 of tissue), specifically in skeletal muscle tissue, with the largest relative increase in muscle fiber activity during training bouts. METHODS: This hypothesis was tested by comparing and contrasting the effects of endurance exercise training (ET) and interval sprint training (IST) on arteriolar density in soleus muscle (S) red (Gr) and white (Gw) portions of gastrocnemius muscle of male Sprague Dawley rats. ET rats completed 10 weeks of treadmill training 30 m/min, 15% grade, 60 min/day, 5 days/week, while IST rats completed 10 weeks of IST consisting of six 2.5-min exercise bouts, with 4.5-min rest between bouts (60 m/min, 15% incline), 5 days/week. The hypothesis would be supported if ET increased arteriolar density in S and Gr and if IST increased arteriolar density in Gw. RESULTS: ET increased arteriolar density above values of sedentary rats (SED) in both the Gw (ET = 0.93 +/- 0.19 arterioles/microm2; SED = 0.44 +/- 0.09 arterioles/microm2) and Gr (ET = 0.97 +/- 0.1 arterioles/microm2; SED = 0.51 +/- 0.06 arterioles/microm2) muscles, but not in S (ET = 1.69 +/- 0.45 arterioles/microm2; SED = 1.51 +/- 0.34 arterioles/microm2) muscle. In contrast, IST did not alter arteriolar density in Gw or Gr muscle tissue. Although arterial wall thickness was greater in S (3.95 +/- 0.40 microm) and Gr (6.24 +/- 0.59 microm) than Gw (2.76 +/- 0.18 microm), neither ET or IST altered mean wall thickness in either muscle. CONCLUSION: Increases in blood flow capacity produced in Gr and Gw by ET appear to be due in part to increased arteriolar density. In contrast, increased arteriolar density does not contribute to increased blood flow capacity of Gw in IST rats.     

Experimental evaluation of pharmacokinetic profile and biological effect of a novel paclitaxel microcrystalline balloon coating in the iliofemoral territory of swine

New paclitaxel coated balloons (PCB) developments have been proposed to maintain therapeutic levels of drug in the tissue while decreasing particle release. In this series of studies, we evaluated the pharmacokinetic profile and biological effects after paclitaxel delivery via novel microcrystalline PCB coating (mcPCB, Pax^®, Balton) in porcine iliofemoral arteries. Methods: Ten domestic swine were enrolled yielding 24 iliofemoral segments for evaluation. In the pharmacokinetic study, nine mcPCBs were dilated for 60 sec and animals sacrificed after 1 hr, 3 and 7 days. Studied segments were harvested and tissue paclitaxel concentration was analyzed utilizing HPLC. In the biological response evaluation, self‐expandable stents were implanted followed by post dilation with either mcPCB (n = 10) or POBA (n = 5). After 28 days, angiography was performed, animals were sacrificed and stented segments harvested for histopathological evaluation. Results: The 1‐hr, 3 and 7 days vessel paclitaxel concentrations were 152.9 ± 154.5, 36.5 ± 49.5, and 0.9 ± 0.7 ng/mg respectively. In the biological response study, stents in the mcPCB group presented lower angiographic measures of neointimal hyperplasia as expressed by late loss when compared to POBA (?0.43 ± 0.9 vs. 0.23 ± 1.2; P = 0.24) at 28 days. In the histopathological evaluation, percent area of stenosis (%AS) was reduced by 42% in the mcPCB group (P < 0.05). The healing process in mcPCB group was comparable to POBA with regard to fibrin deposition (0.7 vs. 0.7; P = ns), neointimal maturity (1.97 vs. 1.93; P = ns), inflammation score (0.92 vs. 1; P = ns) and endothelialization score (1.77 vs. 1.73; P = ns). The mcPCB group did however display a greater tendency of medial cell loss and mineralization (60% vs. 0; P = 0.08). Conclusions: Delivery of paclitaxel via a novel mcPCB resulted in low long‐term tissue retention of paclitaxel. However, this technological approach displayed reduced neointimal proliferation and favorable healing profile. © 2013 Wiley Periodicals, Inc.     

The bronchial circulation—worth a closer look: A review of the relationship between the bronchial vasculature and airway inflammation

Until recently, the bronchial circulation has been relatively ignored in the research and clinical arenas, perhaps because of its small volume and seeming dispensability relative to the pulmonary circulation. Although the bronchial circulation only receives around 1% of the cardiac output in health, it serves functions that are critical to maintaining airway and lung function. The bronchial circulation also plays an important role in many lung and airway diseases; through its ability to increase in size, the bronchial circulation is able to provide lung parenchymal perfusion when the pulmonary circulation is compromised, and more recently the role of the bronchial circulation in the pathogenesis of inflammatory airway disease has been explored. Due to the anatomic variability and small volume of the bronchial circulation, much of the research to date has necessitated the use of animal models and invasive procedures. More recently, non‐invasive techniques for measuring bronchial blood flow in the mucosal microvascular network have been developed and offer a new avenue for the study of this circulation in humans. In conjunction with molecular research, measurement of airway blood flow (Q_aw) may help elucidate the role of the bronchial circulation in inflammatory airway disease and become a useful tool for monitoring therapy. Pediatr Pulmonol. 2010; 45:1–13. © 2009 Wiley‐Liss, Inc.