新型结核疫苗的研究进展

结核病(TB)仍然是世界上最致命的传染病之一,其发病率持续增高。如何对结核病进行有效的预防成了现在面临的主要问题。而目前广泛使用的卡介苗(BCG)疫苗仅对结核病提供有限的保护,特别是对成人型结核病起作用与否存有较大争议,因此新型的结核疫苗便成为抗结核的有利举措。本文把15个处于临床实验阶段的新型候选疫苗,按照免疫策略将其分为代替卡介苗的初选疫苗,BCG初免后的增强疫苗和预防感染者发病的治疗性疫苗加以综述,以期为防治结核病提供参考。     

结核分枝杆菌分泌蛋白64基因重组腺病毒疫苗的构建

卡介苗是当前惟一能够应用于人体的结核病疫苗,但对成人肺结核的保护效率很低.DNA、多肽及病毒等亚单位疫苗能够加强卡介苗或重组卡介苗的免疫保护效果,目前被认为是结核病疫苗研究的重要方向之一~([1-2]).同DNA疫苗和多肽疫苗相比,重组活的结核病亚单位疫苗能在体内持续表达MTB特异性抗原,使其具有高效和经济的优势.     

从卡介苗到核酸疫苗谈结核病的预防

目的讨论结核病的最佳预防手段。方法综述传统卡介苗和多种基因工程疫苗对结核病的保护作用和面临的问题。结果卡介苗作为一种传统的预防结核病的疫苗，在学术界其保护作用有争议，研发新的结核病疫苗已经成为趋势。结论基因工程疫苗将是下一个安全、有效、有可能代替卡介苗的结核病疫苗。     

卡介苗免疫小鼠T细胞亚群内穿孔素的表达及意义

卡介苗是目前许多国家批准应用于人体的惟一结核病疫苗[1-2].全世界对于卡介苗对人体抗结核保护性免疫作用各家报道差异甚大.我国是结核病高发国家,我国自卡介苗免疫接种后儿童中结核病的发病牢大幅度下降,特别是小儿结核性脑膜炎、血型播散性结核病发病明显减少,成为我国结核病控制策略中的重要武器.国内外许多学者的研究[3-8]已提示卡介苗对结核患者的免疫保护作用.为进一步明确卡介苗免疫对抗结核保护性免疫作用,进行了该项研究.     

卡介苗病2例报告及相关文献复习

卡介苗是一种用来预防儿童结核病的预防接种疫苗,接种后可使儿童产生对结核病的特殊抵抗力,是我国计划免疫的疫苗之一,能有效预防结核病的发生。卡介苗接种的主要对象是新生婴幼儿,卡介苗接种引起异常反应的发生率极低,Lotte对欧洲6国1977～1981年535万接种者的前瞻性研究,     

卡介苗接种对实验结核病影响的研究

1.本文报告用豚鼠88只分别在感染后11天、4周及9周后用皮内法及皮上法接种卡介苗,以及用豚鼠18只在成染后5周用异菸肼、键霉素治疗40天后,在病变已处在恢复阶段时,再用皮上法接种卡介苗,以观察卡介苗接种对进行性结核病以及恢复期结核病的影响问题。 2.实验结果证明:卡介苗接种对进行性结核病具有恶化的影响,达种影响的程度与结核病的重度相平行,并且有着个体的差异性。卡介苗接种对恢复期结核病无不良影响。 3.通过实验,我们认为卡介苗接种引起的机体反应结果,由于机体所处的免疫生物学状态的不同而有异。     

应用免疫学和分子遗传学方法合理设计抗结核病疫苗

罗伯特.柯霍(Robert Koch)因对结核病(TB)的贡献荣获诺贝尔奖已过去100年,Albert Calmette和Camille Guerin制备了减毒疫苗株--牛分枝杆菌卡介苗(BCG)也已过去85年,但是,至今仍然没有有效预防TB的方法.然而,21世纪的最初十年将会见证若干新型候选疫苗的临床试验.这些候选疫苗分为二类:1)亚单位疫苗旨在强化由BCG初免诱导的免疫反应,2)改进的重组BCG取代现有的疫苗株.分别使用合适的佐剂、递送系统的蛋白质和DNA疫苗、重组病毒载体如重组的改良疫苗病毒安卡拉(Ankara),用于强化免疫,现正在试验中.已经开发出重组卡介苗(rBCG)用于初免,这些疫苗株具有很高的免疫原性,或者主要抗原的高表达.这些候选疫苗会在2006年底前通过Ⅰ期临床试验.今后的目标是试验这些新候选疫苗的不同组合以促进最佳免疫接种方案的形成.     

结核疫苗研究的历史与现状

由于结核病缺乏有效的疫苗保护，发病率持续增高，成为人类传染病中继艾滋病之后的第二大杀手。减毒牛型结核分枝杆菌——卡介苗是目前许多国家批准应用于人体的惟一结核病疫苗。然而，卡介苗对成人肺结核的保护效率很低，研制新型结核病疫苗迫在眉睫。多种类型的新型疫苗，包括重组卡介苗疫苗、营养缺陷型结核分枝杆菌疫苗、蛋白质多肽疫苗、DNA疫苗、以病毒为载体的结核分枝杆菌亚单位疫苗等被广泛研究。至2005年，已有120种以上的疫苗进行了动物实验研究，至少有5个疫苗已进入Ⅰ期临床试验。     

ESAT-6家族在结核病方面的研究进展

结核病（tuberculosis，TB）是一种由结核分枝杆菌（Mycobacterium tuberculosis，MTB）引起的慢性传染病，已成为危害人们身体健康的最严重的疾病之一。现在用于预防结核病感染的唯一疫苗是卡介苗（Bacille Calmette Guerin，BCG），但其免疫保护效果不同地区存在着差异。对患有免疫功能严重损害的患者如AIDS、移植和肿瘤化疗后接种卡介苗，可能会导致严重的播散，所以改善卡介苗和开发新疫苗是必要的。     

结核病的预防

卡介苗接种许多年来,卡介苗接种是许多国家结核病防治规划的重要部分,并作为主要预防措施。 1974年WHO结核病专家委员会第九次报告中强调可以不做结素试验直接接种卡介苗,并可与麻疹疫苗,百日咳疫苗等免疫注射同时应用。在以往十年中世界上卡介苗接种规模在扩大。     

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.     

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.     

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.     

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.     

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.     

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.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.