间充质干细胞治疗终末期肝病的临床研究进展

终末期肝病(ESLD)包括失代偿期肝硬化和肝衰竭，其病情凶险，预后不佳。肝移植是唯一可以治愈ESLD的方法，但因肝源短缺、免疫排斥和费用昂贵等问题，其在临床中的应用受到很大限制。间充质干细胞(MSC)可分化为肝细胞样细胞，并可通过旁分泌调节机体免疫功能，改善肝纤维化，在治疗ESLD领域具有极广的应用前景。很多临床研究已经证明输注MSC治疗ESLD在短期内是安全有效的，其长期应用的安全性和有效性也有一定的临床证据支持。MSC分泌的外泌体没有完整的细胞结构，可通过多种机制促进肝细胞再生，其临床应用价值日益受到重视，但与之相关的临床研究仍寥寥可数。干细胞治疗ESLD的核心机制、制备干细胞的标准化流程等是当下亟待解决的问题。     

MSCs分化为功能性肝细胞的研究进展

间充质干细胞(mesenchymal stemcells,MSCs)来源于中胚层间充质,广泛存在于骨髓、脐带组织、脐血、外周血、脂肪等组织中.在特定条件下,可以分化为骨、脂肪、神经细胞及肝细胞等多种细胞,进而作为一种替代器官移植的新的治疗方法.近年来,肝硬化等终末期肝病的发病率日益上升,成为影响人类健康的重大疾病之一.肝源紧张、免疫排斥限制了肝移植的临床应用,然而众多研究证实MSCs对肝纤维化、肝硬化等肝病的治疗作用可能与其分化为功能性肝细胞有关,但具体机制尚不十分清楚.本文就MSCs的分化能力及其分化的调控、分子机制和不同来源干细胞对肝纤维化的治疗作用作一综述.     

肝硬化的治疗进展

肝硬化是由各种因素导致慢性肝损害的一类晚期肝纤维化疾病。简述了肝硬化的病因及相关并发症的治疗进展,指出肝移植作为治疗肝硬化唯一有效的治疗手段,但却受到供肝及费用等问题限制,而干细胞具有治疗肝硬化的巨大潜力,成为研究热点,但其作用机制尚未明确,仍有很多问题尚未解决。     

人脐带间充质干细胞治疗肝硬化的研究进展

我国肝硬化发病率逐年升高,每年约有100万人死于肝硬化,严重威胁人类健康.而终末期肝硬化的内科治疗效果不佳,原位肝移植(orthotopic liver transplantation,OLT)被认为是最有效的治疗手段,但因供肝紧缺、费用昂贵、手术风险大、移植后免疫排斥反应等问题,限制了OLT的广泛开展.随着干细胞移植技术的深入研究,人脐带间充质干细胞(human umbilical cord mesenchymal stem cells,HUC-MSCs)因其来源丰富、易于采集保存、增殖分化能力强、免疫源性低、无伦理争议等独特优势,展现出广阔的临床应用前景,有望成为治疗各类肝硬化的有效方式.本文就其生物学特性、肝硬化治疗的理论基础、临床应用进展、存在的问题及展望作一综述.     

干细胞移植术治疗肝硬化的临床应用

肝硬化是消化系统最常见的一种慢性疾病,是由病毒( HBV、HCV)、酒精等一种或多种原因引起的肝细胞广泛变性、坏死,肝脏弥漫性纤维化病变,进而形成再生结节和假小叶,导致正常肝小叶结构破坏,进一步发展为肝硬化,从而出现腹水、消化道出血、肝性脑病等一系列严重并发症,危及患者生命.目前,我国肝病患者大约7000万人,每年约有100多万人发展为肝硬化,数十万人死于肝硬化.原位肝移植是治疗肝硬化患者最理想的治疗选择,但因供体紧缺、免疫排斥、费用高等原因,导致临床应用十分有限,很难成为常规的治疗手段.随着干细胞的深入研究,近几年干细胞移植治疗肝硬化逐渐成为研究的热点,干细胞移植治疗可能成为继原位肝移植后又一条治疗肝硬化的有效途径.     

自体骨髓干细胞治疗肝硬化的应用及管理

肝移植被认为是治疗肝硬化的最佳方式,但因供体不足、费用较高、免疫排斥等原因而受到限制。近年来骨髓干细胞在治疗肝硬化上展示出了广阔前景。目前已有大量临床试验表明自体骨髓干细胞治疗肝硬化是一种安全、有效的治疗方式,但其机制并不清楚,且治疗方案有多种选择。就骨髓干细胞治疗肝硬化的机制、骨髓干细胞输入通路、疗效评估指标、细胞输入剂量等进行综述。     

肝纤维化治疗进展

正肝纤维化是各种慢性肝病发展至肝硬化的必经之路,肝硬化临床以门静脉高压和肝功能减退为特征,常因并发消化道出血、肝性脑病、继发感染等而死亡。早期有效的抗肝纤维化治疗能控制疾病进展,降低病死率。随着对肝纤维化细胞和分子基础研究有了长足的进步,对纤维化治疗也有了新的认识和进展。本文重点介绍了病因治疗,抗纤维化药物,原位肝移植和基于细胞疗法及中医治疗等。肝纤维化持续进展是慢性肝病发展至肝硬化的关键。慢     

肝纤维化发病机制

在多种慢性肝病进展中,由于胶原蛋白等细胞外基质蛋白(extracellular matrix,ECM)过度沉积而造成肝纤维化,并同时常有炎症反应的伴发,进而会发展为肝硬化、肝功能衰竭、门静脉血压过高,往往需要进行肝移植[1],肝纤维化日益成为严重危害人类健康的疾病之一。因此积极探索肝纤维化发病机制,     

利用肝前体细胞治疗肝纤维化

正肝纤维化是肝损伤后细胞外基质沉积或瘢痕形成的动态过程,可持续进展为肝硬化,甚至肝癌等终末期肝脏疾病。美国食品和药物管理局(FDA)目前尚无批准用于治疗肝纤维化的药物,现阶段肝移植是少数发生肝硬化相关并发症(例如肝癌和肝衰竭)的患者唯一的治疗手段。但由于器官短缺的客观问题存在,促进成人肝脏修复和再生的特异细胞和分子机制的研究迫在眉睫。同时,对于机制的进一步研究有助于确定临床治疗靶点。成年人急性肝损伤后,肝细胞的再生往往通过剩余健康肝细胞和胆管细胞的增殖和扩增实现,而肝前体细胞的参与则很少。相比之下,慢性肝损伤的修复涉及肝前体细胞的增殖和具     

肝纤维化发生机制及治疗研究进展

肝纤维化是各种病因引起的慢性肝病进展至肝硬化的必经阶段,迄今为止临床上尚缺乏特异性针对肝纤维化的有效逆转或阻止其进展的药物.肝纤维化是一个由多种细胞因子和分子途径参与的复杂病理变化,深入探究肝纤维化的细胞分子机制从而发掘出特异性的抗纤维化治疗靶点并将其转化为临床治疗具有重大意义.     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Language of CTO interventions – Focus on hardware

The knowledge of variety of chronic total occlusion (CTO) hardware and the ability to use them represents the key to success of any CTO interventions. However, the multiplicity of CTO hardware and their physical character and the terminology used by experts create confusion in the mind of an average interventional cardiologist, particularly a beginner in this field. This knowledge is available but is scattered. We aim to classify and compare the currently used devices based on their properties focusing on how physical character of each device can be utilized in a specific situation, thus clarifying and simplifying the technical discourse.