Cell-cell interactions in diabetic angiopathy.

Normally, both ECs and mural cells, pericytes in the microvasculature and SMCs in large vessels of the mature vasculature, are under stringent growth control and remain quiescent. Regulation of vascular growth is a complex process that is likely to take place at multiple levels. Evidence indicates that intercellular communication, which may take several forms, including diffusible factors, gap junctions, and CAMs underlies the maintenance of normal vessels. A disruption or imbalance in any of these factors may be responsible for the vascular remodeling associated with macro/microangiopathy.     

Serum siderophilin (transferrin) and ekkrinosiderophilin (lactoferrin) as non-specific microbiostatic agents in human health and disease: clinical implications (author's transl)]

A short historical review of the antimicrobial effects of siderophilin, the iron chelator in human plasma and serum, is followed by a presentation of the rational basis for assigning it a role in the overall defence mechanisms of the host against infectious disease. Details are given of the qualitative and quantitative activities of normal and pathological sera on the growth and nutrition of several pathogenic bacteria and the fungus Candida albicans as governed by the percentage iron saturation of their contained siderophilin. Staphylococcus aureus is differentiated from Staphylococcus albus by its ability to grow in normal serum whose percentage iron saturation affects not only the metabolism of Staphylococcus aureus but also its production of diffusible factors and sensitivity to antibiotics. The protein iron chelator of bodily secretions, ekkrinosiderophilin, found in relatively high concentrations in human milk is likewise evaluated for its antimicrobial properties and their relevance to the health of the newborn.     

Collagen Biosynthesis in Normal Human Skin, Normal and Hypertrophic Scar and Keloid

Summary. A comparison of the rates of synthesis of collagen in normal skin, normal and hypertrophic scars, and keloids has been made by measuring the rate of incorporation of [¹⁴C]-proline into peptide-bound [¹⁴C]-hydroxyproline by tissue minces in vitro. The rate of synthesis of collagen, as measured by this technique, was significantly higher in skin than in normal scars whether the incorporation of radioactivity into hydroxyproline were expressed in terms of wet weight of tissue, weight of tissue DNA or weight of tissue hydroxyproline. The abnormal scar types exhibited similar rates of collagen synthesis, which were significantly higher than the rate in normal scars. Although the rates in both abnormal scar types appeared to be similar to that in normal skin when expressed in terms of wet weight of tissue, and weight of tissue hydroxyproline, they were seen to be lower than in skin in terms of weight of tissue DNA. The rate of synthesis of proteins generally, as measured by total radioactivity in non-diffusible peptides, was highest in normal skin and hypertrophic scar and lowest in keloid. The ratio of radioactivity in non-diffusible hydroxyproline to total non-diffusible radioactivity was almost twice as high in keloid as in normal scar, with intermediate values being observed in hypertrophic scar and normal skin. This indicated that collagen accounted for a higher proportion of the proteins being synthesised in keloid than in normal scar. The results confirm previous conclusions, from determination of the activity of the enzyme collagen proline hydroxylase, that the excessive accumulation of collagen in hypertrophic scars and keloids may, at least in part, be due to abnormally high rates of collagen synthesis in comparison to normal scars.     

骨骼肌纤维化的细胞与分子机制研究进展

骨骼肌是具有完全再生能力的组织,在急性创伤性损害后骨骼肌多能完成再生修复。当出现慢性退行性病变如进行性肌营养不良和反复肌纤维损伤时,骨骼肌修复过程常伴随着纤维化的发生。通过近十余年来对骨骼肌纤维化机制的研究,发现多种细胞和系列调控分子参与该过程,特别是肌卫星细胞来源的肌成纤维细胞等相关细胞和转化生长因子β(TGF-β)等促纤维化发展的生长因子。本文就骨骼肌纤维化的细胞分子机制及相关拮抗策略进行综述。     

Stimulation of granulocytopoiesis by a diffusible factor in vivo

A millipore diffusion chamber system was used to cultivate mouse marrow in the abdomens of irradiated and unirradiated host mice for 24 hr. When the irradiated hosts were 72, 96, or 120 hr postirradiation, the number of blasts and promyelocytes in the implanted chambers after cultivation was greater than those in the same marrow cultivated in unirradiated hosts. These data indicate that in vivo, there is stimulation of granulocytopoiesis by a diffusible factor or factors.     

GROWTH OF THE FOWL CORYZA BODIES IN TISSUE CULTURE AND IN BLOOD AGAR

Evidence is presented that the growth capacity of chick embryo tissue for the fowl coryza bodies is conditioned by a diffusible cellular component which is essential for their multiplication. This growth factor is inactivated at pH 6, but withstands a temperature of 100°C. for 60 minutes. An amount sufficient to promote a normal growth of the specific bodies may be present in tissue culture supernatants long after its content in the tissue is exhausted. Postembryonic tissue (liver and spleen) contains a variable amount of growth factor and is not a satisfactory substitute for the chick embryo. Multiplication of recently isolated fowl coryza bodies is not demonstrable in nutrient media enriched with blood. Experiments with one strain, however, indicate that an adaptation to fluid blood in an agar medium may take place after many generations in tissue culture. The probable bacterial nature of the fowl coryza bodies is discussed on the basis of their cultural requirements.     

慢性移植肾肾病纤维化发病机制及病理学变化

器官移植已达到相当成功的水平,这与免疫抑制剂的临床应用是分不开的.然而,慢性移植肾肾病肾组织纤维化是导致移植肾长期失败的主要原因.各种肾脏疾病发展至肾纤维化都是一个缓慢的动态过程,涉及到细胞、细胞因子和细胞外基质等多种因素、多个环节的相互作用和相互调节.近年来,转化生长因子β_1、基质金属蛋白酶、树突状细胞和结缔组织生长因子在肾纤维化中的作用备受关注.文章对它们的结构、生物学功能及其作用机制作以介绍,并探讨了近年来国外关于它们在肾脏中的表达以及在肾脏纤维化中作用机制方面的研究进展.     

Mesenchymal-stem-cell-based experimental and clinical trials: current status and open questions

INTRODUCTION: Mesenchymal stem cells (MSCs) possess remarkable self-renewal ability and are able to differentiate into various cell lineages. MSCs can also enhance tissue repair and angiogenesis through a paracrine mechanism. It has been recognized that these cells hold great promise for tissue regeneration and treatment of immune-related diseases. AREAS COVERED: This review aims at discussing the mechanisms of MSC-mediated immunomodulation and tissue repair and the related clinical trials, with special emphasis on factors that influence the efficiency of MSC-based therapy, including the source of MSCs, cell passage, cell dose, timing and route of administration. EXPERT OPINION: MSCs may facilitate tissue repair through cell replacement and/or improving the microenvironment by releasing growth factors. Some of these factors also mediate the immunomodulatory effects of MSCs. It is important to establish global guidelines, protocols and standards for production and clinical trials of MSCs, so that MSCs can become a therapeutic agent with a reliable efficacy and good safety.     

The pleiotropic effects of antihypertensive agents: do they account for additional cardiovascular benefit beyond BP reduction?

Hypertension commonly clusters with other cardiovascular risk factors, giving rise to the concept that hypertension is a multifaceted disease that potentially shares common pathogenic pathways with other risk factors. The renin-angiotensin-aldosterone system has a central role in the shared mechanisms of hypertension and cardiovascular disease, primarily through angiotensin II. Increased levels of angiotensin II disrupt the balance of vasoactive substances and growth factors that regulate endothelial structure and function, and inhibition of the renin-angiotensin-aldosterone system with an angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker helps restore this equilibrium. Some pathogenic mechanisms may also be favorably affected by calcium channel blockade. While the relative contribution of pleiotropic effects to clinical benefit is difficult to quantify, based on recent data it is reasonable to consider using newer antihypertensive agents in selected high-risk patients to realize the benefits that may derive from interfering with pathogenic mechanisms of disease.     

Endocrine tumors and growth factors

A number of studies have revealed that various growth factors are produced in the malignant progression of endocrine tumors. Growth factors, classified based on their signal transduction pathways, exert the functions by binding to cell surface specific receptors, and promote the growth of tumors by autocrine and paracrine mechanisms. Growth factors such as VEGF and bFGF are also detected in endocrine tumors, and play an important role in the growth and metastasis of tumors via induction of angiogenesis. In the signal transduction pathways growth factors activate various kinases such as mitogen-activated protein kinase and/or phosphatidylinositol 3-kinase/Akt. Signaling cross-talk of growth factors, cytokines and steroid hormones has been observed in various endocrine tumors.     

Angiogenesis and anti-angiogenesis in hematological malignancies

Although it is well established that the growth of solid tumors requires vigorous neovascularization, it has been assumed that leukemias and other hematological malignancies do not depend on angiogenesis. However, the role of angiogenesis in growth and survival of neoplastic cells of the hematopoietic system has recently been recognized, and provides a rationale for novel therapeutic approaches to hematological malignancy. This review summarizes the literature concerning the relationship between angiogenesis and disease progression of several hematological malignancies. It is becoming increasingly evident that agents that interfere with blood vessel formation also block tumor progression, and, accordingly, antiangiogenic therapy has gained much interest as a potential adjunct to conventional therapy of many hematological malignancies. Recent successful applications of antiangiogenic agents that interfere or block the progression of hematological malignancies are evaluated in light of recent demonstrations of potent angiogenic activity of several hematopoietic growth factors. A novel finding regarding the role of angiogenesis in hematological malignancies, which accounts for many clinical observations as well as the apparent independence of these tumors on marrow vascularity, is presented. The information presented in this review will facilitate the design of future clinical trials using antiangiogenic agents for the treatment of hematological malignancies and will provide a basis for the design of experiments undertaken to define the mechanisms involved, mechanisms that may shed new light on the pathology of hematological malignancies.     

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host epithelial cells, invading tumor cells, stromal fibroblasts, inflammatory cells, proliferating endothelial cells, an altered extracellular matrix, and growth factors activating oncogenic signaling pathways by autocrine and paracrine mechanisms. Hence, the tumor microenvironment is a dynamic process promoting tumor growth and invasion through mechanisms likely to include anoikis resistance, genomic instability, and drug resistance. Cell coculture models, murine models (xenograft and genetic), and gene expression profiling studies on human PDA biopsies have identified several key molecules, such as collagen type I, fibronectin, laminin, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of MMP), growth factors (transforming growth factor beta, platelet-derived growth factor, connective tissue growth factor, and hepatocyte growth factor), chemokines, and integrins as constituents of the DR. Despite these findings, it is unclear which molecular-cellular events initiate and drive desmoplasia in PDA. Accumulating evidence indicates that pancreatic stellate cells when activated switch to a myofibroblast phenotype that produces components of the extracellular matrix, MMPs, and tissue inhibitors of MMPs by activating the mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) pathway. Based on current evidence, several therapeutic strategies are been evaluated on identified potential therapeutic targets. This review summarizes our current understanding of the mechanisms that potentially drive the DR in PDA and future possibilities for therapeutic targeting of this critical process.     

THE INFLUENCE OF INFLAMMATION ON THE ABSORPTION OF SUBSTANCES OF VARIED DIFFUSIBILITY

1. Inflammation retards the absorption of horse serum globulin and crystalline egg albumin from the peritoneal cavity and subcutaneous tissue, but retardation of the absorption of crystalline egg albumin is less than that of globulin, which is less diffusible. 2. Inflammation retards the absorption of the specific polysaccharide of pneumococcus Type I from the peritoneal cavity; inflammation may accelerate, but does not hinder, the absorption of glucose from the peritoneal cavity. 3. Inflammation retards the spread of trypan blue in the skin, but accelerates absorption from the skin of the more diffusible dye, brom phenol blue. 4. Phenol red is excreted in the urine with equal rapidity after injection into normal and into inflamed subcutaneous tissue or into normal and into inflamed peritoneal cavities. Direct extractions of phenol red from inflamed subcutaneous sites indicate that inflammation accelerates the absorption of the dye from these areas. 5. Inflammation retards the absorption of the indiffusible proteins, carbohydrates and dyes; it tends to accelerate the absorption of the diffusible carbohydrates and dyes.     

成纤维细胞生长因子21在动脉粥样硬化发病机制中的研究进展

成纤维细胞生长因子21(FGF21)是一种脂肪细胞因子,是FGFs超家族成员之一。从代谢角度讲,FGF21可以降低体重、调节血脂,改善胰岛素抵抗、降低血糖,减轻炎症因子刺激,因此,FGF21几乎贯穿了动脉粥样硬化发病的各个环节。本篇综述将总结FGF21在动脉粥样硬化发病机制中的直接作用和间接作用,并展望FGF21的研究方向,对其在转化医学中的作用作思考。     

Physiological angiogenesis]

Physiological angiogenesis occurs during embryonic development but also in adults, during the female reproductive cycle (in the endometrium, corpus luteum and placenta), exercise or in wound-healing processes. Regulation of angiogenesis is classically understood as a dynamic balance between activators and inhibitors. It requires the combined activities of numbers of growth factors such as VEGF and angiopoietins. VEGF is essential from the earliest stages of vascular formation. It induces endothelial cell differentiation, migration and proliferation. Angiopoietins participate in maturation and stabilization of blood vessels and, in some conditions, in vascular regression. Comprehension of the molecular and cellular mechanisms that regulate physiological angiogenesis contributes to advances in understanding of tumoural vascularization and to the identification of potential new therapeutic targets.     

Concentration of pefloxacin in feces during infection prophylaxis in neutropenic patients.

Pefloxacin (400 mg twice daily) was administered orally for infection prophylaxis in neutropenic patients. Diffusible fecal pefloxacin concentration was determined by bioassay during 24 neutropenic periods. The median diffusible fecal pefloxacin concentration was 187 micrograms/g. This concentration was comparable with those found in volunteers following oral and intravenous administration of pefloxacin (400 mg twice daily) (median of 171 and 155 micrograms/g, respectively). From this study, it is concluded that pefloxacin administered orally results in a predictable high diffusible fecal concentration which leads to effective elimination of susceptible aerobic gram-negative bacilli from the colonic flora.     

Klotho蛋白在甲状旁腺细胞弥漫性增生与结节性增生中的不同表达探讨

目的 探讨Klotho蛋白在慢性肾衰竭继发性甲状旁腺功能亢进症（secondary hyperparathyroidism,SHPT）甲状旁腺细胞不同增生类型中表达的意义.方法 选取在武警总医院肾内科住院行甲状旁腺全切术的SHPT患者50例为SHPT组,尸体甲状旁腺组织供体8例为健康对照组,收集其血清及甲状旁腺组织标本,SHPT组甲状旁腺组织按病理表现分为结节性增生组和弥漫性增生组,检测血成纤维细胞生长因子-23（fibroblast growth factor-23,FGF-23）及甲状旁腺激素（parathyroid hormone,PTH）水平,免疫组化检测甲状旁腺组织中Klotho蛋白及增殖指标Ki67的表达.结果 ①SHPT患者血FGF-23[（1316.80±375.15）pg/ml]与PTH[（2106.00±806.78） pg/ml]呈正相关（r=0.438,P=0.001）.②SHPT患者血FGF-23与甲状旁腺组织中Klotho的表达呈负相关（r=-0.379,P=0.007）,血PTH与Klotho蛋白呈负相关（r=0.361,P=0.01）.③SHPT组甲状旁腺细胞中Ki67的表达显著高于对照组（F=54.417,P=0.000）,Klotho蛋白的表达显著低于对照组（F49.243,P=0.000）;SHPT组结节性增生甲状旁腺组织中Ki67的表达显著高于弥漫性增生组（t=3.760,P=0.001）,Klotho蛋白的表达显著低于弥漫性增生组（t=6.039,P=0.000）.结论 结节性增生甲状旁腺组织中Klotho蛋白表达低于弥漫性增生组织可能是导致SHPT患者甲状旁腺呈不同增生方式的重要原因.     

Growth and nutrition in Rett syndrome

Purpose / Method : In this paper we review the existing literature on factors that contribute to growth failure in Rett syndrome (RS) with particular emphasis on the extent and nature of the feeding difficulties that arise. Data on growth and feeding related problems, collected over four years in a specialized clinic for females with Rett syndrome are presented and management protocols developed in the clinic discussed. Results / Conclusion : Feeding related problems and growth failure occur commonly in Rett syndrome yet our understanding of the mechanisms causing growth failure are poorly understood. Both nutritional and non-nutritional factors are thought to contribute and it has not been possible to develop efficacious intervention strategies. Consequently, clinical management of growth failure in Rett syndrome is not evidence based.     

Measurement of total and diffusible serum fluoride.

This article describes a technique for the measurement of total and diffusible F content of serum, at clinical significant concentrations of F (1-10 microM). The proposed procedure avoids the interference of unknown serum components with the ion-specific electrode. Sample F is concentrated fivefold through distillation of hydrofluoric acid (Taves' method). Ionic fluoride is presented to the electrode in a simple solution at concentrations within the linear response of the electrode. Average recoveries of F from serum or its ultrafiltrate were 96+/-7% (21%) and 97+/-12% (53%) (mean+/-SEM [CV]), respectively. With four replicates of each sample, the technique produce within-run standard deviations of 0.6 microM and 2.2 microM at 1 and 10 microM F, respectively. Total precision assessment gave standard deviations of 0.6 microM and 2.6 microM at 1 and 10 microM F, respectively. The fasting serum F levels of normal climacteric women, 45 to 65 years, showed an asymmetric distribution. The data obtained started at the detection limit of the technique (0.1 mM). The 75 percentile was 1.85 microM for total and 0.5 microM for diffusible F. In patients (n = 25) treated with NaF (30 mg F/day) the fasting levels of total serum F (4.5 +/-1.7 microM) did not differ from those of diffusible F (4.2+/-1.5 microM). In patients (n = 50) treated with sodium monofluorophosphate (15 mg F/day) the fasting levels of total and diffusible serum F were 6.5+/-1.7 microM and 0.5+/-0.03 microM, respectively. In conclusion, this paper establishes the presence of two fractions of serum fluorine: diffusible and nondiffusible (or protein bound) and describes a technique for their clinical estimation. In untreated subjects and in patients receiving NaF, the former fraction contains ionic fluoride. In patients treated with MFP, diffusible serum fluorine is composed by ionic fluoride and low molecular weight, peptide-bound, acid-labile fluorine.