BACKGROUND & AIMS: :Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n = 15; mean age 27 +/- 2) and women (n = 15; mean age 28 +/- 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.

背景与目标： ：证据表明，肾素-血管紧张素系统（RAS）功能存在性别差异。据推测，妇女对RAS阻滞的反应也可能有所不同。在男性和女性中，检查了在8周内达到的肾血管和外周血流动力学对血管紧张素受体阻滞剂递增剂量的反应以及血管紧张素II（AngII）不敏感的程度。参加研究的是30名年轻健康男性（n = 15；平均年龄27/2）和女性（n = 15；平均年龄28/2），他们在每次研究前均接受钠和蛋白质的控制饮食1周。评估了对依贝沙坦递增剂量的体液，肾脏和全身反应（75 mg，4 wk，然后150 mg，4 wk），以及在2周时对AngII的升压反应（3 ng / kg / min）。间隔。在基线和8周后通过实时PCR方案评估皮肤活检中AngII 1型受体的表达。男性和女性的血压均显着下降。与较低剂量的男性相比，女性的AngII敏感性大大降低，厄贝沙坦在4 wk时未显示升压反应，而在150 mg / d的4 wk时，男性仍表现出升压反应。男性和女性在基线时的受体表达没有差异，但女性8周时显着降低，男性则保持不变。我们的发现表明，与女性相比，男性可能需要更大剂量的血管紧张素受体阻滞剂，并且BP反应不能用作肾微血管系统RAS充分阻断的替代指标。

BACKGROUND & AIMS: :In this issue of Immunity, Bezbradica et al., (2006) uncover an unsuspected role for the cytokine GM-CSF in the thymic development of invariant NKT cells, a role that licenses these cells to secrete effector cytokines upon activation in the periphery.

背景与目标： Bezbradica等人（2006）在此期《免疫》杂志中揭示了细胞因子GM-CSF在恒定NKT细胞的胸腺发育中的作用，这一作用并未受到人们的怀疑，该作用使这些细胞在外围激活后可以分泌效应细胞因子。

BACKGROUND & AIMS: BACKGROUND/AIMS:Apoptosis has been implicated in the pathogenesis of fulminant hepatic failure (FHF) potentially involving caspases. Thus far, apoptosis in FHF has mainly been studied in animal models while human data are sparse. METHODS:Caspases-3, -8 and -9 activities and Fas expression were analyzed in correlation to TdT-mediated dUTP nick end labelling (TUNEL) positive apoptotic cells in livers of patients with FHF (n=26), chronic liver disease (CLD) (n=60) and normal controls (NC) (n=10). RESULTS:Numbers of TUNEL-positive cells were higher in FHF than in CLD and NC (P<0.001) correlating to the intrahepatic activities of caspase-3. The highest caspase-3 activities were found in fulminant hepatitis B, significantly surpassing those in FHF of any other etiology. In fulminant hepatitis B, caspase-9 activity was also higher than in controls, while caspase-8 activation was not higher than in NC. Unlike caspase-3, caspases -8 and -9 activities were not correlated to the numbers of TUNEL positive cells. Fas expression was also the highest in FHF but did not differ between hepatitis B virus-FHF and other FHF. CONCLUSIONS:Our data indicate differential activation of intrahepatic caspases in FHF depending on the underlying etiology. Massive activation of caspases in fulminant hepatitis B confirms a pivotal role of apoptotic pathways in the pathogenesis of human fulminant hepatitis B.

背景与目标： 背景/目的：细胞凋亡与可能涉及胱天蛋白酶的暴发性肝衰竭（FHF）的发病机制有关。迄今为止，主要是在动物模型中研究了FHF中的细胞凋亡，而人类数据却很少。
方法：分析FHF（n = 26），慢性肝病（CLD）患者肝脏中Taspase-3，-8和-9的活性以及Fas表达与TdT介导的dUTP缺口末端标记（TUNEL）阳性凋亡细胞的相关性。 ）（n = 60）和正常对照（NC）（n = 10）。
结果：与caspase-3的肝内活性相关，FHF中TUNEL阳性细胞数高于CLD和NC（P <0.001）。在暴发性乙型肝炎中发现最高的caspase-3活性，大大超过了其他任何病因的FHF中的caspase-3活性。在暴发性乙型肝炎中，caspase-9的活性也高于对照组，而caspase-8的激活并不高于NC。与胱天蛋白酶3不同，胱天蛋白酶-8和-9的活性与TUNEL阳性细胞的数量无关。 Fas表达在FHF中也最高，但在乙型肝炎病毒FHF和其他FHF之间没有差异。
结论：我们的数据表明FHF肝内胱天蛋白酶有不同的激活作用，这取决于潜在的病因。暴发性乙型肝炎中胱天蛋白酶的大量激活证实了凋亡途径在人类暴发性乙型肝炎发病机理中的关键作用。

BACKGROUND & AIMS: OBJECTIVES:The role of surgery in stage IV gallbladder (GB) cancer is not well established. This study analyses prognostic factors in patients with stage IV GB cancer following surgical resection with the aim of identifying a subgroup of patients who might benefit from surgical resection. METHODS:Clinicopathological details were analysed for 94 patients who were surgically treated for stage IV GB cancer at Seoul National University Hospital. RESULTS:Median survival was 8 months in patients with either stage IVa or IVb disease. Sixteen patients (17.0%) underwent resection with curative intent, which increased overall survival over that in patients undergoing palliative surgery (P < 0.001). No survival benefit was seen following surgery with curative intent in patients with stage IVa disease (P = 0.764). Surgery with curative intent resulted in a survival benefit in patients with stage IVb disease, patients with an isolated liver metastasis near the GB bed (median survival: 31 months vs. 9 months; P < 0.001) and patients with limited numbers of peritoneal implantations (median survival: 20 months vs. 6 months; P = 0.002). Preoperative serum carcinoembryonic antigen (CEA) (P = 0.018), surgery with curative intent (P = 0.045) and adjuvant chemotherapy (P = 0.002) were independent prognostic factors in patients with stage IV GB cancer. CONCLUSIONS:Surgery in combination with systemic chemotherapy may be beneficial in carefully selected patients with stage IVb GB cancer.

背景与目标： 目的：手术在IV期胆囊癌中的作用尚不明确。这项研究分析了手术切除后Ⅳ期GB期癌症患者的预后因素，目的是确定可能从手术切除中受益的患者亚组。
方法：分析了首尔国立大学医院94例行IV型GB癌症手术治疗的患者的临床病理学细节。
结果：IVa或IVb期患者的中位生存期为8个月。 16例（17.0％）接受根治性切除术的患者，与接受姑息手术的患者相比，总体生存率有所提高（P <0.001）。 IVa期疾病患者经根治性手术后未见生存获益（P = 0.764）。具有治愈意图的手术可为IVb期疾病患者，GB床附近发生单纯肝转移的患者（中位生存期：31个月对9个月； P <0.001）和腹膜植入次数有限的患者带来生存益处（中位生存期：20个月与6个月； P = 0.002）。 Ⅳ期GB期癌症患者的术前血清癌胚抗原（CEA）（P = 0.018），有根治性手术（P = 0.045）和辅助化疗（P = 0.002）是独立的预后因素。
结论：外科手术结合全身化学疗法可能对精心挑选的IVb GB期癌症患者有益。

BACKGROUND & AIMS: BACKGROUND:Patients with early-stage, nonbulky classic Hodgkin lymphoma (cHL) undergo intensive posttreatment radiologic surveillance despite having a low risk of disease recurrence. The current study attempted to evaluate the risk of disease recurrence and the value of radiologic surveillance in patients treated with the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone who achieved a complete remission (CR) as noted on posttreatment positron emission tomography (PET). METHODS:Forty-seven patients who underwent therapy with interim and/or posttreatment PET scans were evaluated for disease recurrence during ≥ 24 months of follow-up. Their presenting characteristics and imaging results were assessed and interpreted in relation to clinical outcome. RESULTS:All 47 patients were eligible for analysis. The majority of patients were female (35 patients) with a median age of 28 years (range, 17 years-65 years.). The nodular sclerosing subtype was the predominant histology (41 patients). A total of 34 patients were staged with IIA disease, 6 with IA disease, 6 with IIB disease, and 1 with IIEA disease (lung) (according to Cotswolds modification of the Ann Arbor staging system). All patients completed 6 cycles of planned ABVD therapy and achieved a CR. Two had a positive PET scan (1 interim scan and 1 posttreatment scan); both were biopsy-proven sarcoidosis. Two patients developed disease recurrence at 7 months and 24 months, respectively, after negative interim and posttreatment imaging. One case of recurrence was identified through surveillance imaging and the other was identified simultaneously by the patient and surveillance scan. A total of 45 patients experienced a durable CR; 21 had additional unscheduled imaging/workup during surveillance to investigate symptoms or imaging signs of concern. CONCLUSIONS:Because of a low risk of disease recurrence, posttreatment radiologic surveillance appears to be unnecessary in patients with early-stage, nonbulky (CD20 negative) cHL who achieve a PET-detected CR with the ABVD combination alone. This will reduce cumulative radiation exposure and health care costs in a predominantly young patient population.

背景与目标： 背景：患有早期非大块经典霍奇金淋巴瘤（cHL）的患者尽管发生疾病的风险较低，但仍接受了强化的放射治疗后监测。当前的研究试图评估仅接受阿霉素，博来霉素，长春碱和达卡巴嗪（ABVD）联合治疗的患者的疾病复发风险和放射学监测的价值，这些患者如治疗后正电子发射中所述达到完全缓解（CR）断层扫描（PET）。
方法：对接受中期和/或治疗后PET扫描治疗的47例患者在≥24个月的随访中进行了疾病复发评估。他们的表现特点和影像学结果进行了评估和解释与临床结果。
结果：所有47例患者均符合分析条件。大多数患者为女性（35例患者），中位年龄为28岁（范围17岁至65岁）。结节性硬化亚型是主要的组织学（41例）。根据Cotswolds对Ann Arbor分期系统的修改，共有34例患者患有IIA疾病，6例IA疾病，6例IIB疾病和1例IIEA疾病（肺）。所有患者均完成了6个计划的ABVD治疗周期并获得了CR。 2例PET扫描阳性（1例中期扫描和1例治疗后扫描）；两者均为活检证实的结节病。两名患者在中期和阴性影像学检查后分别于7个月和24个月出现疾病复发。一例复发病例是通过监视影像学发现的，另一例是通过患者和监视扫描同时发现的。共有45例患者出现了持久性CR。 21例在监视期间进行了额外的计划外成像/检查，以调查所关注的症状或成像迹象。
结论：由于疾病复发的风险低，对于单独使用ABVD组合即可实现PET检测的CR的早期非大体（CD20阴性）cHL早期患者，似乎无需进行放射治疗后监测。这将减少主要是年轻患者人群的累积辐射暴露量和医疗保健费用。

BACKGROUND & AIMS: AIM:To identify the changes of mitochondrial protein expression in diabetic renal parenchyma and to characterize their molecular functions and biological processes in diabetes. METHODS:Mitochondrial proteins extracted from renal parenchyma mitochondria of streptozotocin-induced diabetic rats and normal rats were separated by two-dimensional polyacrylamide gel electrophoresis and identified by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. RESULTS:Eleven proteins from 533 visualized protein spots displayed significant different expressions in mitochondria of diabetic kidneys compared with those in normal ones. Among these altered proteins, two proteins with the most obvious changes in protein expression were identified as alpha-2u globulin (mature protein, named A2) and its proteolytically modified form (named A2-fragment) respectively. These proteins were found in mitochondria of male rat renal parenchyma and were proved to be down-regulated in diabetic rats simultaneously. CONCLUSION:Our results suggest that down-regulation of alpha-2u globulin may be associated with an abnormal β-oxidation of long-chain fatty acids during diabetes. The decreased expression of A2-fragment in renal mitochondria of diabetic nephropathy may reduce fatty acid β-oxidation, which leads to a diminished energy supply from mitochondria to kidney tissue and the deposition of a large number of fatty acids in the kidney, ultimately causing and aggravating kidney damage. In conclusion, these findings may be helpful for understanding the molecular mechanism of diabetic nephropathy.

背景与目标： 目的：确定糖尿病肾实质中线粒体蛋白表达的变化，并对其在糖尿病中的分子功能和生物学过程进行表征。
方法：采用二维聚丙烯酰胺凝胶电泳分离从链脲佐菌素诱导的糖尿病大鼠和正常大鼠的肾实质线粒体中提取的线粒体蛋白，并通过基质辅助激光解吸/电离串联时间质谱法进行鉴定。
结果：533个可视化蛋白斑点中的11种蛋白在糖尿病肾线粒体中的表达与正常肾脏相比明显不同。在这些改变的蛋白质中，两个蛋白质表达变化最明显的蛋白质分别被鉴定为alpha-2u球蛋白（成熟蛋白质，称为A2）及其蛋白水解修饰形式（称为A2片段）。这些蛋白在雄性大鼠肾实质的线粒体中发现，并被证明在糖尿病大鼠中同时被下调。
结论：我们的结果表明，糖尿病患者中α-2u球蛋白的下调可能与长链脂肪酸的β-氧化异常有关。糖尿病肾病肾脏线粒体中A2片段的表达降低可能会降低脂肪酸β氧化，从而导致线粒体向肾脏组织的能量供应减少以及大量脂肪酸在肾脏中的沉积，最终导致和加重肾脏损害。总之，这些发现可能有助于理解糖尿病性肾病的分子机制。

BACKGROUND & AIMS: :Statistics on treatment rates for patients with end stage renal disease (ESRD) show that the number of ESRD patients per million population in the United Kingdom has increased slowly in recent years. The British Transplantation Society issued questionnaires in 1983 and 1984 to determine the number of patients transplanted, the number of suitable patients, and the facilities needed to enable all suitable patients to receive treatment. While there is a high transplant rate, the percentage of ESRD patients on dialysis is low, and there is a "socially unacceptable deficit" with respect to treatment of diabetics and the elderly.

背景与目标： ：晚期肾病（ESRD）患者治疗率的统计数据表明，近年来，英国每百万人口中ESRD患者的数量增长缓慢。英国移植学会在1983年和1984年发布了调查表，以确定移植的患者数量，合适的患者数量以及使所有合适的患者都能接受治疗所需的设施。尽管移植率很高，但接受透析的ESRD患者的比例却很低，并且在糖尿病患者和老年人的治疗方面存在“社会上无法接受的缺陷”。

BACKGROUND & AIMS: BACKGROUND:This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era. METHODS:Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (M1) and the elderly (aged≥75y). RESULTS:A total of 4,217 patients with mRCC were identified, including 1,533 patients with M1 and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (≥75 vs.<75y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, M1, and elderly populations. CONCLUSION:This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in M1 and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age.

背景与目标： 背景：这项回顾性研究调查了瑞典转移性肾细胞癌（mRCC）患者在治疗前（2002-2005），早期（2006-2008）和晚期（2009-2012）的总生存（OS）和影响OS的因素。靶向治疗（TT）时代。
方法：瑞典的三个国家登记册确定了mRCC患者。中位数操作系统是使用Kaplan-Meier方法估算的。使用Cox比例风险回归进行多变量分析。对同步转移患者（M1）和老年人（年龄≥75岁）进行亚组分析。
结果：共鉴定出4,217例mRCC患者，其中1,533例M1患者和1,275例老年患者。对于2002年至2005年，2006年至2008年以及2009年至2012年诊断为mRCC的患者，中位OS​​为10.0、13.0和18.0个月。同样，M1和老年人口的OS中位数有所改善。老年患者接受TT的可能性较小（≥75vs. <75y）：18.3 vs. 63.5％（在2006-2008年）和28.6％vs. 55.9％（在2009-2012年）。 2009年至2012年，对mRCC的诊断，肾切除术和TT处方与总mRCC，M1和老年人口的OS改善相关。
结论：这项现实世界的研究表明，在TT时代后期，包括M1和老年人群，mRCC OS持续显着改善。对于所有mRCC患者，无论年龄大小，均应考虑TT。