氟伐他汀对家兔颈动脉粥样斑块巨噬细胞和基质金属蛋白酶的影响

目的观察高胆固醇血症家兔颈动脉粥样斑块内炎性巨噬细胞与MMP-2、MMP-9的表达情况，并研究氟伐他汀干预对巨噬细胞聚集和基质金属蛋白酶（MMPs）表达的影响，探索他汀类药物在稳定颈动脉斑块中的作用及机制。方法24只家兔随机分为对照组、高脂组和治疗组，每组8只，分别给予普通饲料、高脂饲料和高脂饲料加氟伐他汀喂养，测定不同时间点血清总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）水平。喂养第12月时处死动物，取颈动脉进行石蜡切片，测量并计算颈动脉I／M比值，SP法进行CD68、MMP-2和MMP-9免疫组织化学染色。结果治疗组血清TC、LDL-C浓度明显低于高脂组（P〈0．01）。治疗组I／M比值明显低于高脂组（P〈0．01）。高脂组颈动脉斑块中见大量CD68阳性细胞，而治疗组CD68阳性细胞数显著少于高脂组（P〈0．01）。颈动脉斑块中MMP-2、MMP-9阳性细胞和染色强度明显增加，治疗组MMP-2和MMP-9的表达较高脂组显著减少（P=0．002和P=0．016）。结论氟伐他汀治疗可以抑制高胆固醇血症家兔颈动脉粥样斑块的形成．减轻斑块内巨噬细胞的浸润并抑制MMP-2和MMP-9的产生，从而起到稳定斑块的作用。     

阿托伐他汀对兔动脉粥样硬化斑块近心端基质金属蛋白酶9表达的影响

目的 研究阿托伐他汀对兔主动脉粥样硬化斑块近心端基质金属蛋白酶9（MMP-9）表达的影响。方法 将30只雄性新西兰大白兔随机分为正常对照组（9只）、高脂饮食组（11只）、阿托伐他汀组（10只）。后两组给予高胆固醇饲料建立主动脉粥样硬化模型，至第9周始，高脂饮食组同时服用1．5mg·kg^-1·d^-1淀粉，阿托伐他汀组服用阿托伐他汀1．5mg·kg^-1·d^-1。处死兔后，对主动脉大体标本进行观察，发现内膜增生合并粥样斑块形成者视为模型建立成功。应用免疫组化法测定斑块近心端的巨噬细胞和平滑肌细胞阳性面积百分率以及MMP-9的表达。结果 ①高脂饮食组和阿托伐他汀组主动脉可见新生内膜形成，内一中膜厚度比值分别为1．41±0．34、0．63±0．12。②斑块中巨噬细胞分布部位正是MMP-9阳性表达区域，均聚集于斑块近心端。高脂饮食组和阿托伐他汀组主动脉斑块近心端巨噬细胞阳性面积百分比分别为（26．5±4．3）％、（12．4±1．5）％，MMP-9吸光度（A值）分别为0．081±0．014、0．022±0．004，两组比较差异均有统计学意义（P〈0．01）。③高脂饮食组与阿托伐他汀组平滑肌细胞阳性面积百分比分别为（47．2±12．3）％、（50．4±10．8）％，差异无统计学意义（P〉0．05）。结论 动脉粥样硬化斑块内巨噬细胞及MMP-9表达主要位于主动脉粥样硬化斑块近心端，阿托伐他汀能显著减少此区域巨噬细胞聚集及MMP-9的表达。     

高脂血症兔主动脉NF-κB、VCAM-1和VEGF的表达及氟伐他汀的影响

目的观察高脂饮食后兔主动脉NF-κB、VCAM－1、VEGF的表达及氟伐他汀的影响，探讨高脂血症引起动脉粥样硬化可能的分子生物学机制和氟伐他汀的作用。方法健康雄性新西兰大耳白兔30只，随机分为5组，高脂饮食4周、6周、8周组，正常饮食和高脂饮食加氟伐他汀组。到规定时间点，处死动物取主动脉标本，观察组织形态学变化，用免疫组化的方法检查NF-κB、VCAM－1和VEGF的表达。结果①高脂血症可以引起NF-κB、VCAM－1、VEGF增加，与对照组比较差异有统计学意义（P〈0．01）。②LDL水平与NF-κB表达呈显著正相关（r=0．922，P〈0．01）；NF-κB与VCAM－1、VEGF呈显著正相关（r＝0．937，P〈0．01，r=0．894，P〈0．01）。③氟伐他汀可以减少NF-κB、VCAM－1和VEGF的表达（P＜0．05）。结论NF-κB、VCAM－1和VEGF参与了动脉粥样硬化的进程，炎症是高脂血症的伴随因素，引起了细胞增殖，与动脉粥样硬化密切相关：氟伐他汀可以减少其表达起到抗动脉粥样硬化作用。     

阿托伐他汀对动脉粥样硬化兔脑组织炎性反应的干预作用

目的 观察阿托伐他汀对动脉粥样硬化兔脑组织血管紧张素Ⅱ（AngⅡ），核转录因子κB（NF—κB）和诱导型一氧化氮合酶（iNOS）水平的影响，探讨其改善动脉粥样硬化性脑血管病的机制。方法 24只新西兰白兔随机分为正常对照组、高脂饮食组及阿托伐他汀组，每组8只兔。正常对照组每日给予普通颗粒兔饲料100g／d，高脂饮食组每日给予普通颗粒兔饲料100g＋1．5％胆固醇；阿托伐他汀组每日给予高脂饮食组相同饲料喂养同时给予阿托伐他汀（2．5mg／kg）。喂饲8周后，测定血清总胆固醇及低密度脂蛋白胆固醇的浓度；取颈总动脉行苏丹Ⅳ染色，光镜下观察；取海马区脑组织，用免疫组化法检测AngⅡ、NF—κB的表达；Western印迹测定NF—κB的表达；分光光度法测定iNOS的活力。结果 以下各项的结果描述按高脂饮食组、阿托伐他汀组、正常对照组顺序①光镜下检查：高脂饮食组可见大量泡沫细胞聚集、炎性细胞浸润；阿托伐他汀组仅有少量泡沫细胞及炎性细胞浸润；正常对照组细胞结构正常。②免疫组织化结果：3组AngⅡ阳性单位分别为17．1±2．7、15．3±1．7、5．2±1．3，NF—κB为22．2±2．6、9．5±1．1、6．9±1．6，与高脂饮食组比较，阿托伐他汀组AngⅡ、NF—κB表达差异均有统计学意义（P〈0．01）。③Western印迹：NF—κB吸光度值3组分别为0．9988±0．0041、0．5810±0．0020及0．5621±0．0024，高脂饮食组NF—κB表达较正常对照组及阿托伐他汀组明显升高（P〈0．01）。④iNOS的活力：3组iNOS吸光度值分别为10．0±0．9、4．8±0．6、3．4±0．4，阿托伐他汀组较高脂饮食组显著降低（P〈0．01），但是仍然高于正常对照组（P〈0．01）。结论 阿托伐他汀能通过抑制AngⅡ，NF—κB，iNOS的表达减轻高脂血症对脑组织的炎性损伤。     

拜阿司匹林对小鼠主动脉核转录因子-κB与基质金属蛋白酶-9表达的调控

目的：观察拜阿司匹林对小鼠主动脉核转录因子-κB（NF--κB）与基质金属蛋白酶-9（MMP-9）表达的调控作用。方法：40只13周龄小鼠分为拜阿司匹林组（给高脂饲料。拜阿司匹林6mg／kg灌胃），氟伐他汀组（给高脂饲料，氟伐他汀3mg／kg灌胃），模型组（给高脂饲料，生理盐水1ml灌胃），正常对照组（给予普通饲料·生理盐水1ml灌胃），每组10只，17周后，取主动脉，以免疫组化法观察其NF—κB和MMP-9表达的程度。结果：较之对照组模型组，小鼠主动脉粥样斑块的NF--κB与MMP-9表达明显增加，拜阿司匹林组和氟伐他汀组均显著降低其表达（P均〈0.01），拜阿司匹林组和氟伐他汀组间其表达水平无显著差异（P〉0.05）。结论：拜阿司匹林可以降低NF-κB与MMP-9的表达．从而抑制血管内炎症反应和基质纤维蛋白的降解，起到治疗动脉粥样硬化的作用。     

氟伐他汀对高胆固醇血症患者血管内皮功能及胰岛素抵抗的影响

目的探讨氟伐他汀对高胆固醇血症患者血管内皮功能及胰岛素抵抗的影响。方法测定47例高胆固醇血症患者调脂治疗（氟伐他汀20mg／d，治疗8周）前后的血脂，血管内皮细胞（VEC）计数，血浆内皮素（ET-1），一氧化氮（NO），血糖（GLU），血胰岛素（INS）。结果高胆固醇血症患者经氟伐他汀治疗后血NO较治疗前显著上升（P〈0．01）。VEC计数、ET-1水平、血INS水平较治疗前明显降低（P〈0．01），胰岛素敏感性指数（ISI）明显升高（P〈0．05）。血脂水平治疗后较治疗前明显降低（P〈0．01）。结论氟伐他汀在降低胆固醇的同时，可改善血管内皮功能及胰岛素抵抗。     

小剂量氟伐他汀联合非诺贝特治疗老年混合型高脂血症的临床研究

目的观察小剂量氟伐他汀联合非诺贝特治疗老年混合型高脂血症的疗效及安全性。方法将入选的70例老年混合型高脂血症患者，随机分为氟伐他汀单药治疗组（12=35，20mg／d），氟伐他汀（20mg／d）、非诺贝特（200mg，隔日1次）联合治疗组（12=35），疗程均为12周。结果联合治疗组血脂参数变化最显著，降低低密度脂蛋白胆固醇、三酰甘油和升高高密度脂蛋白胆固醇的能力明显优于单药组（P〈0．01或P〈0．05），且未发现明显不良反应。结论小荆量氟伐他汀与非诺贝特联合治疗可以更有效地改善老年混合型高脂血症患者的血脂异常，具有良好的安全性和耐受性。     

氟伐他汀对急性冠状动脉综合征患者基质金属蛋白酶和高敏C反应蛋白的影响

目的探讨氟伐他汀对急性冠状动脉综合征（ACS）患者血浆高敏C反应蛋白（hs—CRP）和基质金属蛋白酶9（MMP-9）的影响。方法60例ACS患者随机分为两组，常规治疗组和氟伐他汀治疗组，治疗前后分别测定血浆hs-CRP和MMP-9的浓度，并与健康对照组比较。结果ACS患者血浆hs-CRP和MMP-9的测定值高于健康对照组（P〈0．05）；氟伐他汀治疗组治疗后血浆hs-CRP和MMP-9的测定值分别显著低于治疗前水平（P〈0．05）。结论氟伐他汀通过抗炎等机制对防治ACS患者早期动脉粥样硬化及稳定斑块起着重要的作用。     

辛伐他汀与氟伐他汀调脂疗效的比较

目的：观察比较辛伐他汀（simvastatin,商品名：舒降之,默沙东公司生产）与氟伐他汀（fluvastatin,商品名,来适可,诺华制药公司生产）临床调脂疗效及耐受性,方法：将100例TC＞5．2mmol/L伴或不伴TG＞1．7mmol/L的对象随机分成辛伐他汀组（n=50)与氟伐他汀组（n=50),辛伐他汀组给予辛伐他汀20mg/d,氟伐他汀组给予氟伐他汀40mg/d,两组疗程均为12周,治疗．前,治疗后6周,12周分别测定TC,TG,HDL－C,LDL－C以及ALT,AST,CK值,结果：两组治疗6周后及治疗12周后,TC,TG,LDL－C水平与治疗前比较均有显著下降（P＜0．01）,治疗12周HDL－C水平与治疗前比较明显升高（P＜0．01）,两组间比较,治疗6周后,TC降低判别有非常显著意义（P＜0．01）,治疗12周后,TC,LDL－C降低判别有显著意义（P分别＜0．05和＜0．01）,HDL－C升高差别有显著意义（P＜0．05）。两组均未见明显不良反应,结论：辛伐他汀20mg/d,氟伐他汀40mg/d调脂疗效均较好且完全,其中,辛伐他汀在降低TC,LDL－C水平以及升高HDL－C水平优于无氟伐他汀,但对肝功能影响辛伐他汀氟伐他汀大。     

氟伐他汀和缬沙坦联合治疗改善原发性高血压患者高脂餐后纤溶功能

目的观察氟伐他汀和缬沙坦联合治疗对原发性高血压患者高脂餐后血浆纤溶酶原激活物抑制剂1（PAI-1）和组织型纤溶酶原激活剂（t-PA）抗原浓度的即期影响。方法原发性高血压患者53例随机分成对照组（安慰剂n=13）、氟伐他汀组（40mg／d，n=13）、缬沙坦组（80mg／d，n=14）和联合组（氟伐他汀：40mg／d＋缬沙坦：80mg／d，n=13）4组治疗1周，禁食12h后测高脂餐前（空腹，F）、后（4h，P）的血浆可溶性P选择素、PAI-1和t-PA抗原及血脂浓度。4组分别治疗1周后再重复以上实验1次，并测量4组治疗前、后的血压。结果高脂餐后血浆三酰甘油（TG）IF：（1．94±0．91）比P：（3．15±1．48）mmol／L]、可溶性P选择素IF：（259．8±124．0）比P：（345．7±138．4）ng／mL]、PAI-I[F：（36．4±13．1）比P：（48．7±18．5）ng／mL]和t-PA抗原[F：（9．6士3．2）比P：（13．5±6．0）ng／mL]浓度升高，差异有非常显著意义。高脂餐后血浆TG浓度分别与高脂餐后可溶性P选择素（r=0．430）、PAI-1抗原（r=0．421）浓度显著相关（P〈0．01）。治疗1周后，缬沙坦组和氟伐他汀组的高脂餐后血浆可溶性P选择素、PAI-1和t-PA抗原浓度较各自空腹水平差异无统计学意义。联合组的空腹和高脂餐后血浆可溶性P选择素、PAI-1和t-PA抗原浓度较治疗前基础水平显著降低（P〈0．05）。联合治疗一周后也明显地抑制了高脂餐后可溶性P选择素、PAI-1与t-PA，虽然仍有轻度增加，但差异无统计学意义（P〉0．05）。上述指标的变化发生在血脂变化之前。结论与氟伐他汀或缬沙坦的单用相比，极短期两药联合应用有效地降低了原发性高血压患者空腹和高脂餐后的血浆PAI-1和t-PA抗原浓度。     

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.     

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.     

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.     

Serological survey of HIV and syphilis in pregnant women in Madagascar

Objectives Peripartal transmission of human immunodeficiency virus (HIV) and Treponema pallidum, the causative agent of syphilis, leads to severe consequences for newborns. Preventive measures require awareness of the maternal infection. Although HIV and syphilis testing in Madagascar could be theoretically carried out within the framework of the national pregnancy follow‐up scheme, the required test kits are rarely available at peripheral health centres. In this study, we screened blood samples of pregnant Madagascan women for HIV and syphilis seroprevalence to estimate the demand for systemic screening in pregnancy. Methods Retrospective anonymous serological analysis for HIV and syphilis was performed in plasma samples from 1232 pregnant women that were taken between May and July 2010 in Ambositra, Ifanadiana, Manakara, Mananjary, Moramanga and Tsiroanomandidy (Madagascar) during pregnancy follow‐up. Screening was based on Treponema pallidum haemagglutination tests for syphilis and rapid tests for HIV, with confirmation of positive screening results on line assays. Results Out of 1232 pregnant women, none were seropositive for HIV and 37 (3%) were seropositive for Treponema pallidum. Conclusions Our findings are in line with previous studies that describe considerable syphilis prevalence in the rural Madagascan population. The results suggest a need for screening to prevent peripartal Treponema pallidum transmission, while HIV is still rare. If they are known, Treponema pallidum infections can be easily, safely and inexpensively treated even in pregnancy to reduce the risk of transmission.     

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.     

Variabilité des concentrations plasmatiques de l’angiotensinogène et risque d’hypertension artérielle chez le rat transgénique

Aim

Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5 mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors.

Methods

Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n = 3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction).

Results

At baseline, transgenic rats had +18 mmHg higher bood pressure and –8% lower body weight compared to non-transgenic rats (P < 0.05) without significant changes for the vehicle groups throughout the study (P > 0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P < 0.05) in transgenic and +25%, +5.3% and +6.7% (P > 0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P > 0.05).

Conclusion

Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.