重组干扰素α-2a,α-2b治疗慢性乙型肝炎疗效比较

探讨不同亚型α干扰素（IFNα-2α，IFNα-2b）治疗慢性乙型肝炎的疗效差异。110例慢性乙型肝炎（CHB）患者被随机分为IFNα-2α，治疗组（52例）和IFNα-2b治疗组（58例）。IFNα-2α治疗组采用IFNα-2a（因特芬）每日3MU肌注，IFNα-2b治疗组采用IFNα-2b（隆化诺）每日3MU肌注，30天后改隔日3MU肌注，疗程6月。观察两组用药3月，6月后血清ALT昨常率，HBeAg阴转率，HBV－DNA阴转率和治疗反应率。ALT复常率两组无明显差异（P＞0．05）。HBeAg阴转率：IFNα－2b治疗组（51.7%,67.2%)，明显优于IFNα－2a治疗组（32.7%,44.2%)，两组差异明显（P＜0．05）。HBV DNA阴转率：6月后IFNα－2b治疗组（58．6％），明显优于IFNα-2α治疗组（34．6％），两组差异明显（P＜0．05）。治疗后完全反应率：IFNα－2b治疗组（46．6％） ，明显优于IFNα-2α治疗组（21．2％），两组间有极显著差异（P＜0．01）。干扰素α-2b亚型治疗慢性乙型肝炎疗效明显优于干扰素α-2α，亚型。     

干扰素联合羟基脲治疗15例慢性粒细胞性白血病临床观察

目的观察干扰素α-2b（IFNα-2b）联合羟基脲（Hu）治疗慢性粒细胞白血病（简称慢粒）的疗效。方法采用IFNα-2b（300万U,隔天1次）联合Hu治疗慢粒慢性期（CP）15例。结果 IFNα-2b＋Hu治疗6个月后血液学完全缓解率（CHR）达73.3%,减少了慢粒加速期和急变期,生存率明显提高。结论慢粒（CP）患者采用IFNα-2b＋Hu治疗可显著提高慢粒患者的CHR率,延长慢粒生存期。     

甲磺酸伊马替尼治疗120例慢性髓性白血病的临床研究

目的观察甲磺酸伊马替尼（IM）治疗Ph染色体阳性和（或）BCR／ABL基因阳性的慢性髓性白血病（CML）的疗效和安全性。方法对90例Ph染色体阳性和（或）BCR／ABL基因阳性CML慢性期（CP）患者,持续口服IM,400mg／d;30例CML疾病进展期（加速期／急变期）患者,持续口服IM,600mg／d。服药期间定期复查血常规、骨髓细胞学、染色体和（或）BCR／ABL基因等指标,并随访观察。结果（1）CML—CP患者总的完全血液学缓解率（CHR）、完全细胞遗传学缓解率（CCyR）和完全分子遗传学疗效（CMR）分别为73．3％（66／90）、66．7％（60／90）、54．4％（49／90）;治疗前是否接受过干扰素治疗对CHR、CCyR和CMR均无明显影响;服药前病程≤6个月的CMR优于〉6个月者。初次达到CHR的时间与首次达CCyR的时间、首次达CCyR的时间与BCR／ABL首次转阴时间之间均存在相关性,而初次达CHR的时间与BCR／ABL首次转阴时间则无明显相关性。（2）进展期CML患者的CHR、CCyR、CMR分别为43．3％（13／30）、25．9％（7／27）、25．0％（7／28）,总病死率为30．0％（9／30）。（3）年龄≤25岁患者的病死率高于〉25岁者,差异有统计学意义（P〈0．05）。（4）白细胞减少达Ⅲ级者有19例（16．0％）,发生于治疗后5～20周。血小板减少达Ⅲ级者有21例（18．0％）,发生于治疗后3～16周。主要的非血液系统毒性为双下肢水肿、骨痛和皮疹等,但均程度轻微。结论IM对初治CML及经干扰素治疗失败的CML有较高的CHR及CCyR且起效迅速,对CML—CP疗效显著优于进展期;不良反应程度轻微,患者易于耐受。     

应用间期荧光原位杂交技术评估干扰素治疗慢性粒细胞白血病的疗效

目的　探讨间期荧光原位杂交技术 (FISH)检测慢性粒细胞白血病 (CML)干扰素 (IFN)治疗后体内残留Ph阳性细胞的可行性。方法　应用间期FISH对 7例未治疗CML患者和 17例IFN α 2b长期治疗CML患者检测体内Ph阳性细胞变化情况。结果　正常对照组假阳性率为 ( 3 87± 0 94 ) % ,确定正常值为小于 6 68% (x± 3s)。未治疗组Ph阳性细胞平均为 89 2 1%。干扰素治疗组Ph阳性细胞平均为 4 4 86% ,与未治疗组相比无显著性差异 ( P >0 0 5 )。细胞遗传学有效患者 (CGR 4例 ,PGR 2例 ,共 8个标本 )Ph阳性细胞平均为 2 6 3 0 % ,与未治疗组相比有显著性差异 (P <0 0 5 )。而且Ph阳性细胞的减少与INF用药总剂量具有相关性 (r =-0 666,P =0 0 0 2 )。结论　间期FISH检测比染色体核型、RT PCR技术更能准确地评价干扰素治疗后体内存有的白血病细胞的负荷量 ,评价干扰素治疗CML的疗效     

利巴韦林联合不同剂量普通干扰素α-2b治疗基因2、3型慢性丙型肝炎的疗效观察

目的观察利巴韦林（RBV）联合不同剂量干扰素（IFN）OL-2b治疗基因2、3型慢性丙型肝炎的临床疗效。方法将2009年4月至2012年1月收治的46例基因2、3型慢性丙型肝炎患者分为治疗组24例和对照组22例,两组均在第1个月每日肌肉注射IFNα-2b6MU1次;治疗组在第2个月隔日肌肉注射IFNα-2b6MU1次,在第3个月及以后隔日肌肉注射IFNα-2b3MU1次;对照组在第2个月及以后隔日肌肉注射IFNα-2b6MU1次;两组均每日分3次口服RBV900～1200mg,疗程均为6个月;两组获得治疗结束时病毒学应答（ETVR）的患者在疗程结束后6个月时随访;无应答（NR）的患者延长疗程3个月。比较两组治疗后快速病毒学应答（RVR）、早期病毒学应答（EVR）、治疗结束时病毒学应答（ETVR）、无应答（NR）和持久病毒学应答（SVR）情况;比较两组治疗费用和不良反应。计数资料组间比较采用,检验。结果治疗组24例和对照组22例获得RVR、EVR、EVR均较高,分别为15例（62．50％）和13例（59．09％）（X^2=0．056,P〉0．05）、17例（70．83％）和15例（68．18％）（X^2=0．038,P〉0．05）、20例（83．33％）和19例（86．36％）（X^2=0．082,P〉0．05）;治疗组和对照组NR均较低,分别为4例（16．67％）和3例（13．64％）（X^2=0．082,P〉0．05）;治疗组和对照组获得SVR也较高,分别为18例（75．00％）和17例（77．27％）（X^2=0．033,P〉0．05）,差异均无统计学意义。治疗组使用IFNα-2b的总量及治疗费用比对照组少近30％,药物不良反应也较轻。结论RBV联合IFNα-2b“诱导疗法”治疗基因2、3型慢性丙型肝炎可获得较高的RVR、EVR,减少IFN剂量的维持治疗也能获得较高的ETVR和SVR,能减轻患者经济负担和药物不良反应。     

慢性丙型肝炎干扰素治疗后复发患者干扰素联合利巴韦林再治疗

目的 探讨干扰素（IFN）治疗后复发的慢性丙型肝炎（CHC）患者对IFN联合利巴韦林再治疗的应答情况及影响因素。方法 100例IFN治疗后复发的CHC患者中，50例使用聚乙二醇干扰素α-2a（PEG—IFNα-2a），50例使用重组人干扰素α-1b（CIFNα—1b），均联合利巴韦林再治疗，联合治疗48周，停药随访24周，分析HCVRNA载量、病毒基因型、药物种类对联合治疗疗效的影响。结果 100例复发患者联合再治疗后，36．00％取得持续病毒学应答（SVR），其中PEG-IFNα-2a组48．00％取得SVR，显著高于CIFNα—1b组（24．00％，P〈0．05）。56例低病毒载量（HCV-RNA〈1×10^5拷贝／mL）患者中，PEG—IFNα-2a组28例，其中57．14％取得SVR，显著高于CIFNα—1b组（25．00％，P〈0．05）。HCV非基因1（2a或2b）型组29例，其中55．17％取得SVR，显著高于基因1型组（28．20％，P〈0．05）；在CIFNα—1b治疗组，病毒非基因1型17例患者，其中47．06％取得SVR，明显高于基因1型患者（12，12％，P〈0．01）；在基因1型组，PEG—IFNα-2a组38例，其中42．11％取得SVR，显著高于CIFNα—1b组（12．12％，P〈0.01）。结论 IFN治疗后复发的CHC患者IFN联合利巴韦林再治疗存在部分患者无应答；对于HCV病毒载量低、基因1型的复发患者，聚乙二醇干扰素联合利巴韦林再治疗疗效明显优于普通干扰素的联合治疗。     

聚乙二醇化干扰素α-2b与干扰素α-2b治疗e抗原阳性慢性乙型肝炎的疗效和安全性的随机对照多中心研究

目的比较聚乙二醇化干扰素α-2b（PEG-1FN α-21））和干扰素α-2b（IFNα-2b）治疗HBeAg阳性慢性乙型肝炎患者的疗效和安全性。方法选择HBeAg阳性慢性乙型肝炎患者230例，按照1：1的比例随机给予PEGIFN α-2b（1．0μg／kg．每周1次、皮下注射）或IFNα-2b（3MU、每周3次、皮下注射）治疗24周，停药后随访24周。结果（I）治疗24周和随访24周时，PEGIFNα-2b治疗组的完全应答率、HBVDNA阴转率、HBeAg血清转换率、HBeAg阴转率均高于IFNα-2b组，但除随访24周时的HBeAg阴转率外，差异均无统计学意义。（2）治疗过程中两组患者血清中HBVDNA均持续下降。24周时PEG—IFNα-2b治疗组病毒量平均下降值明显大于IFNα-2b组（2、22log10对1．68log10，P〈0.05）。（3）两组总的不良事件发生率．药物相关的不良事件种类及各自的发生率差异无统计学意义。结论PEG—IFN、α-2b（1．0μg／kg、每周1次、皮下注射）治疗HBeAg阳性慢性乙型肝炎的应答率，从数值上看优于IFNα-2b（3MU／次，每周3次、皮下注射），但除随访24周时的HBeAg阴转率外，差异均无统计学意义。两组的安全性相似。     

定量PCR监测干扰素联合阿糖胞苷治疗慢性粒细胞白血病患者bcr/abl基因表达的临床意义

目的:评价bcr／ab1融合基因作为观察治疗慢性粒细胞白血病(CML)疗效指标的临床价值。方法:采用荧光定量逆转录-聚合酶链反应技术检测28例经干扰素(IFN)联合阿糖胞苷(Ara-C)治疗的CML患者bcr／ab1 mRNA水平。结果:骨髓Ph染色体数与bcr／ab1融合基因水平具有较强的相关性(r=1．74,P<0．01)。IFN联合Ara-c治疗CML 6个月后完全持续缓解8例,部分缓解11例,主要细胞遗传学反应为67．85％。结论: bcr／ab1融合基因可能是治疗CML疗效观察和微小残留病灶监测的有效指标。     

干扰素α-1b联合抗-HBV特异性主动免疫疗法治疗慢性乙型肝炎的临床研究

目的探讨普通干扰素α-1b（IFNα-1b）联合抗HBV特异性主动免疫疗法（SAI）治疗慢性乙型肝炎（CHB）患者的疗效。方法292例诊断为有活动性病毒复制（HBeAg阳性、HBVDNA〉1×10％opies／m1），ALT≥2×ULN）的慢性乙型肝炎患者，随机分为A、B、C、D4组。A组用IFNα-1b加SAI联合治疗；B、C两组分别用IFNα-1b与SAI单一疗法；D组作为对照组用常规保肝治疗。治疗前及治疗后第12月比较各组患者HBVDNA、HBeAg血清学转换及ALT复常，并在大部分患者比较治疗前后肝组织Knodell炎症坏死与Ishak纤维化计分情况。结果在治疗终点，A、B、C、D4组HBVDNA达到测不出水平的百分率分别为64．8％、32．4％、30．8％与2．8％；HBeAg血清转换分别为41．6％、27．0％、16．6％与5．6％；ALT复常率分别为89．2％、70．3％、83．3％与44．4％；Knodell与Ishak计分缓解率分别为45．8％、18．8％、12．9％、0．0％与39．4％、34．4％、30．4％、0．0％。结论IFNα-1b加SAI联合疗法对有活动性病毒复制的慢性乙型肝炎患者的疗效优于IFNα-1b或SAI单一疗法。     

宿主细胞因子及黏病毒抵抗蛋白A基因多态性与干扰素治疗慢性乙型肝炎疗效的相关性

目的：探讨IFN治疗慢性乙型肝炎（CHB）患者的疗效与TNF—α启动子-238、-857、-863位点，IL-10启动子-1082、-592位点及黏病毒抵抗蛋白A（MxA）启动子-88位点单核苷酸多态性（SNP）的关系。方法：305例CHB患者IFNα-1b治疗12个月，随访至停药后6个月判断疗效，分为持续应答（SR）和非持续应答（NSR）组。应用PCR及限制性片段长度多态性方法，检测TNF-α-238、-857、-863和IL-10—592、-1082及MxA-88位点的SNP。判断SNP与IFN疗效的关系。结果：本研究失访43例。262例CHB患者IFNα-1b疗效SR为50例，占19．1％；NSR212例，占80．9％。在MxA-88位点，GT型分别与GG型、TT型患者IFN疗效比较，差异均有统计学意义（x^2=20．119，OR：5．302，95％CI：2．458～11．433，P〈0．01；x^2=13．071，OR：4．110，95％CI：1．858～9．092，P〈0．01）。在TNF—α-863位点，CC型分别与CA型、AA型患者疗效比较，差异均有统计学意义（x^2=29．628，0R：7．578，95％CI：3．444～16．672，P〈0．01；x^2=13．543，0R：4．513，95％CI：1．966～10．357，P〈0．01）。在TNF-α-857位点，CC与CT型患者疗效比较，差异有统计学意义（x^2=12．927，OR：0．293，95％CI：0．146～0．586，P〈0．01）。在IL广10-592位点，AA与CC型患者疗效比较，差异有统计学意义（x^2=8．984，OR：3．380，95％CI：1．484～7．697，P〈0．01）。结论：MxA-88位点为GT杂合型，TNF—α-863 CC纯合型，IL-10—592AA纯合型的CHB患者对IFNα-1b治疗反应好，可作为预测IFN疗效的参考指标之一。     

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.     

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.     

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.