BACKGROUND & AIMS: OBJECTIVE:The mechanism behind the epidemiologically evident inverse relation between Helicobacter pylori seropositivity and risk of oesophageal adenocarcinoma (OAC) remains obscure. Severe corpus gastritis is unlikely to be in the causal pathway. With the hypothesis of a uniformly low risk, the associations of OAC with duodenal ulcer and gastric ulcer were explored, both linked to H pylori infection but with different patterns of bacterial colonisation and intragastric acidity. Possible associations of oesophageal squamous cell carcinoma (OSCC) with these ulcer types were also addressed. DESIGN AND PATIENTS:Retrospective cohorts of 61,548 and 81,379 unoperated patients with duodenal ulcer and gastric ulcer, respectively, recorded in the Swedish Inpatient Register since 1965, were followed from the first hospitalisation until the date of any cancer, death, emigration, definitive surgery, or 31 December 2003. Standardised incidence ratios (SIRs), with 95% CIs, expressed relative risk of oesophageal cancer, compared with the Swedish population matched for age, sex and calendar period. RESULTS:Contrary to expectation, patients with duodenal ulcer had a significant 70% excess risk of OAC (SIR 1.7, 95% CI 1.1 to 2.5). Gastric ulcer was unrelated to OAC (SIR 1.1, 95% CI 0.6 to 1.7). Although duodenal ulcer was non-significantly associated with a small excess of OSCC (SIR 1.3, 95% CI 0.96 to 1.8), gastric ulcer was linked to 80% increased risk (SIR 1.8, 95% CI 1.4 to 2.3). CONCLUSION:The inverse association between H pylori and OAC does not pertain to all infections. The pattern of gastric colonisation and/or impact on acidity may be important. With the reservation for the possibility of confounding, this study also provides some support for the importance of intragastric environment in the aetiology of OSCC.

背景与目标： 目的：幽门螺杆菌血清阳性与食管腺癌（OAC）风险之间的流行病学证据呈负相关。严重的胃炎胃炎不太可能在因果关系中。假设风险均一，探讨了OAC与十二指肠溃疡和胃溃疡的相关性，二者均与幽门螺杆菌感染有关，但细菌定植和胃内酸度不同。食管鳞状细胞癌（OSCC）与这些溃疡类型的可能关联也得到了解决。
设计和患者：自1965年以来在瑞典住院患者登记表中记录的分别有61,548和81,379例未手术的十二指肠溃疡和胃溃疡患者的回顾性队列，从首次住院治疗直至癌症，死亡，移民，定型手术，或2003年12月31日。与年龄，性别和日历时期相匹配的瑞典人群相比，具有95％CI的标准发生率（SIR）表示食道癌的相对风险。
结果：与预期相反，十二指肠溃疡患者发生OAC的风险显着增加70％（SIR 1.7，95％CI 1.1至2.5）。胃溃疡与OAC无关（SIR 1.1，95％CI 0.6至1.7）。尽管十二指肠溃疡与少量过量的OSCC无显着相关性（SIR 1.3，95％CI 0.96至1.8），但胃溃疡与80％的风险增加相关（SIR 1.8，95％CI 1.4至2.3）。
结论：幽门螺杆菌与OAC之间的负相关并不适用于所有感染。胃定植的模式和/或对酸度的影响可能很重要。由于保留了混淆的可能性，本研究还为胃内环境在OSCC病因中的重要性提供了一些支持。

BACKGROUND & AIMS: To determine the efficacy of endoscopic variceal ligation (EVL) in prophylaxis on the rate of first esophageal variceal bleeding, we conducted a prospective, randomized trial in 126 cirrhotic patients with no history of previous upper gastrointestinal bleeding and with esophageal varices endoscopically judged to be at high risk of hemorrhage. The end-points of the study were bleeding and death. Life-table curves showed that prophylactic EVL significantly diminished the rate of variceal hemorrhage (12/62 [19%] vs. 38/64 [60%]; P = .0001) and overall mortality (17/62 [28%] vs. 37/64 [58%]; P = .0011). The 2-year cumulative bleeding rate was 19% (12/ 62) in the EVL group and 60% (38/64) in the control group. The 2-year cumulative mortality rate was 28% (17/62) in the EVL group and 58% (37/64) in the control group. Comparison of Kaplan-Meier estimates of the time to death of both groups showed significantly lower mortality in the ligation group (P = .001). Patients undergoing EVL had few treatment failures and died mainly of hepatic failure. The lower risk in the EVL group was attributed to a rapid reduction of variceal size. Prophylactic EVL was more efficient in preventing first bleeding in patients with good condition (Child A) than in those with decompensated disease (Child B and C). We conclude that prophylactic EVL can decrease the incidence of first variceal bleeding and death over a period of 2 years in cirrhotic patients with high-risk esophageal varices.

背景与目标： 为了确定内镜下静脉曲张结扎术（EVL）预防第一次食道静脉曲张破裂出血的疗效，我们对126例无既往有上消化道出血史且经内镜检查认为是食管静脉曲张的肝硬化患者进行了一项前瞻性随机试验。高出血风险。研究的终点是出血和死亡。生命表曲线表明，预防性EVL显着降低了曲张静脉出血的发生率（12/62 [19％] vs. 38/64 [60％]； P = .0001）和总死亡率（17/62 [28％] vs 37/64 [58％]； P = 0.0011）。 EVL组的2年累积出血率为19％（12/62），对照组为60％（38/64）。 EVL组的2年累积死亡率为28％（17/62），对照组为58％（37/64）。 Kaplan-Meier对两组死亡时间的估计值的比较表明，结扎组的死亡率显着降低（P = .001）。接受EVL的患者几乎没有治疗失败，主要死于肝功能衰竭。 EVL组中较低的风险归因于曲张静脉大小的迅速减小。预防性EVL预防状况良好的患者（儿童A）比失代偿性疾病的患者（儿童B和C）更有效地防止首次出血。我们得出结论，在高危食管静脉曲张的肝硬化患者中，预防性EVL可以在2年内降低首次静脉曲张破裂出血和死亡的发生率。

BACKGROUND & AIMS: :Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.

背景与目标： ：尽管在对抗胃癌方面取得了长足的进步，但它仍然是由特殊的组织学和分子学特征定义的复杂致死性疾病。本研究的目的是研究pRb2 / p130，VEGF，EZH2，p53，p16（INK4A），p27（KIP1），p21（WAF1），Ki-67的表达，并分析它们与临床病理因素的可能关系。通过免疫组织化学检查了47例患者的表达模式，其中27例为肠型，20例为弥散型，平均随访56个月，并通过Western blot检测AGS，N87，KATO-III和YCC-2 ，-3，-16个胃细胞系。总体而言，胃癌显示EZH2与高水平的p53，Ki-67和细胞质pRb2 / p130相关（分别为P <0.05和P <0.01）。在肠型中发现EZH2表达增加，并且与远处转移的风险相关（分别为P <0.05和P <0.01），表明该蛋白可能在这种类型的癌症中具有预后价值。有趣的是，观察到p27（KIP1）表达水平与晚期疾病和转移的风险之间存在强烈的负相关（P <0.05），而p21（WAF1）和低度胃癌（G1）的表达水平之间呈正相关。肿瘤（P <0.05），证实了这些肿瘤抑制基因在胃癌中的传统接受作用。最后，在核pRb2 / p130的表达水平与低度（G1）胃肿瘤的表达水平之间发现了直接相关性，具有统计学意义（P <0.05）。总之，这些数据可能有助于进一步阐明与两种主要胃癌组织学类型及其侵袭潜能有关的致病机制。

BACKGROUND & AIMS: BACKGROUND:Several studies described the benefits of the heparin-surface-modified intraocular tens (HSM IOL) with regard to the reduced inflammation in routine extracapsular cataract extractions. However, limited information is available about the advantages of the HSM IOL in patients with an intraocular inflammation. AIM:To assess the eventual benefits of the HSM IOL compared to the regular polymethylmethacrylate intraocular lens (PMMA IOL) in patients with uveitis. METHODS:A retrospective study of 43 patients with uveitis of various origins who underwent an extracapsular cataract extraction (24 with HSM, 19 with PMMA IOL). The activity of intraocular inflammation, visual acuity, eventual complications, and medications were examined. Standardized follow-up dates were used (before surgery, one and fourteen days, five and eleven months after surgery.) RESULTS:No difference in the inflammatory, activity was noted between HSM and PMMA groups; neither at short term clinical evaluation, nor at five months after surgery. Despite a slightly better visual acuity in the HSM group before surgery, no long term differences were observed. After surgery the increase in visual acuity was similar for both groups, as well as the frequency of cystoid macular oedema (CMO) and synechiae. Fewer patients in HSM group required Nd:YAG posterior capsulotomy, but the difference was not significant. CONCLUSION:No clinical advantage was found when the HSM IOL was compared with the regular PMMA IOL in 43 patients with uveitis.

背景与目标： 背景：多项研究描述了肝素表面修饰的眼内张力（HSM IOL）在常规囊外白内障摘除术中减少炎症方面的益处。但是，关于眼内炎症患者中HSM IOL的优势的信息很少。
目的：评估与常规聚甲基丙烯酸甲酯人工晶状体（PMMA IOL）相比，HSM IOL在葡萄膜炎患者中的最终益处。
方法：回顾性研究43例不同来源葡萄膜炎患者的囊外白内障摘除术（24例行HSM，19例行PMMA IOL）。检查眼内炎症，视力，最终并发症和药物的活动。使用标准化的随访日期（手术前，手术后的第1天，第14天，手术后的第5个月和第11个月）。
结果：HSM和PMMA组之间在炎症，活性方面没有差异；既不进行短期临床评估，也不在术后五个月进行评估。尽管术前HSM组的视敏度稍好，但未观察到长期差异。手术后，两组的视敏度增加，囊状黄斑水肿（CMO）和粘连的发生率相似。 HSM组需要Nd：YAG后囊切开术的患者较少，但差异无统计学意义。
结论：将HSM IOL与常规PMMA IOL相比较在43例葡萄膜炎患者中未发现临床优势。

BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.

背景与目标： ：肿瘤浸润基质细胞（TISC）以及肿瘤本身都被认为与肿瘤相关的免疫抑制有关，这是肿瘤逃避免疫监视的关键机制之一。然而，由于在已建立的肿瘤中TISC的比例很小，因此TISC的制备是困难的。因此，通常被认为与肿瘤相关的免疫抑制有关的细胞是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中，我们开发了一种从已建立的肿瘤中直接制备TISC的方法，以分析其功能。使用绿色荧光蛋白（GFP）转基因（Tg）小鼠和移植有GFPTg小鼠骨髓（BM）细胞的C57BL / 6小鼠，我们检测到TISC的三个亚群：一个与源自BM的未成熟髓样细胞（ImC）相容。其他两个亚群CD11b（）细胞和CD11b（-）细胞并非源自BM。在存在GM-CSF的情况下与肿瘤培养后，TISC包括这些亚群，但并非每个亚群独立地抑制由抗CD3诱导的T细胞增殖。在我们的系统中，肿瘤并未直接抑制T细胞反应，但来自肿瘤的未知因素影响了TISC的免疫抑制。

BACKGROUND & AIMS: :The aim of this study was to analyse the acting forces and moments induced by a special orthodontic appliance, the Pendulum K, for molar distalization in the transverse and sagittal planes. The purpose-designed test set-up (artificial maxilla with anchorage unit and two electrothermodynamic molars, an electronic measuring unit, a unit with force-moment sensor, an analogue/digital converter, and a data read-out unit) allowed simulation of in vivo conditions on the one hand and precise determination of the force systems on the other. The appliances investigated were three specimens of the Pendulum K. In vitro measurement of the resulting force systems revealed that the forces and moments in the transverse and sagittal planes remained almost constant over a 3 mm measuring increment when the distal screw was continuously activated (10 activations/mm). Without reactivation of the incorporated distal screw, however, a marked decline in the force systems was recorded. The Pendulum K allows translatory distalization of the upper molars and thus dental arch expansion, dispensing with the need for permanent teeth to be extracted, subject to a corresponding indication. This is achieved by continuous adjustment of an incorporated distal screw and by specific pre-activations of the Pendulum springs.

背景与目标： ：这项研究的目的是分析由特殊的正畸矫治器Pendulum K引起的作用力和力矩，以在横断面和矢状面上进行磨牙远侧。专门设计的测试装置（带有锚固单元和两个电热磨牙的人工上颌骨，一个电子测量单元，一个带有力矩传感器的单元，一个模拟/数字转换器和一个数据读出单元）允许模拟一方面是体内条件，另一方面是精确确定力系统。所研究的器具是Pendulum K的三个标本。对最终产生的力系统进行的体外测量显示，当连续激活远端螺钉（10次激活）时，横向和矢状面的力和力矩在3 mm的测量增量内几乎保持恒定。 /毫米）。然而，在没有重新激活所结合的远端螺钉的情况下，记录了力系统的显着下降。摆K允许上颌臼齿的平移远侧移动，从而使牙弓扩张，并在需要相应指示的情况下无需拔出恒牙。这是通过不断调整内置的远端螺钉并通过对摆弹簧进行特定的预激活来实现的。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： ：热休克蛋白90（HSP90）是结构折叠和维持各种蛋白质（包括与细胞信号相关的几种蛋白质）构象完整性的必需。利用HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向于多发性骨髓瘤（MM）患者，我们首先通过免疫荧光和流式细胞术分析了骨髓瘤细胞系（U266）和原发性骨髓瘤细胞中HSP90的表达。在证明HSP90在骨髓瘤细胞中表达后，通过免疫过氧化物酶染色分析了32例MM患者的档案样本。在所有患者中，骨髓瘤细胞在所有样品中均显示出强烈的HSP90细胞质表达，并且55％的患者还表现出并发的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266细胞和原代MM细胞可导致凋亡明显增加。分析与17-AAG孵育的MM细胞中的抗凋亡BCL2家族蛋白和akt，表明BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但是17AAG和硼替佐米治疗的组合显示出对U266细胞系的协同凋亡作用。这些数据表明，针对HSP90的靶向抑制可能被证明是开发MM患者未来治疗选择的有效且创新的策略。

BACKGROUND & AIMS: :With currently available combination chemotherapy regimens, the outcome of the patients newly diagnosed with aggressive non-Hodgkin's lymphoma (NHL) identified as 'high' and 'high-intermediate' risk groups according to the international prognostic index (IPI) is still unsatisfactory and a more innovative therapy is urgently required to improve the survival of the patients. The purpose of this study was to compare the efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and ESHAP (etoposide, methylprednisolone, high-dose Ara-C, cisplatin) vs CHOP-ESHAP and upfront high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) vs standard CHOP in patients aged < or = 65 years old newly diagnosed with 'high' and 'high-intermediate' risk aggressive lymphoma enrolled onto two consecutive treatment trials at the institute. Between May 1995 - July 2002, 84 patients, aged 15 - 65 years old, with newly diagnosed aggressive NHL and an age-adjusted IPI of 2 or 3 were enrolled. The median age of the patients was 38 years (range 15 - 65). The baseline demographic features, in particular the major prognostic variables, were similar between the treatment groups. Patients treated with rituximab-CHOP-ESHAP received eight cycles of rituximab (375 mg m(-2) on day 1 of cycles 1 - 6 and days 21 and 28 of cycle 7) plus CHOP (day 3 of cycles 1, 3 and 5) and ESHAP (day 3 of cycles 2, 4 and 6 and day 1 of cycle 7) at 21-day intervals. Patients enrolled onto the CHOP-ESHAP-HDT arm (n = 23) were treated with three courses of CHOP and then switched to two or four cycles of ESHAP followed by HDT. Patients treated with CHOP alone (n = 25) were treated with the standard eight cycles of CHOP. The rate of complete remission was significantly improved with rituximab-CHOP-ESHAP compared with either CHOP-ESHAP-HDT or CHOP alone (67% compared with 44% and 36%, respectively; p = 0.043). With a median follow-up time of 53 months, the 5-year overall survival (OS) was improved by the addition of rituximab-61% with rituximab-CHOP-ESHAP, compared with 43% for CHOP-ESHAP-HDT and 24% for CHOP alone (p = 0.088). Significant increases in failure-free survival (FFS) and disease-free survival (DFS) (61% and 96%), compared with CHOP-ESHAP-HDT (34% and 90%) and CHOP (16% and 44%; p = 0.002 and p < 0.001, respectively) were observed. Compared to CHOP, rituximab-CHOP-ESHAP yielded significantly superior OS (p = 0.014), FFS (p < 0.001) and DFS (p < 0.001). The survivals, however, were not significantly different from patients treated with CHOP-ESHAP-HDT. It is concluded that rituximab-ESHAP-CHOP is superior over standard CHOP and fares comparably to upfront HDT/ASCT in previously untreated patients with aggressive lymphoma. A prospective randomized controlled trial is warranted to confirm these results.

背景与目标： ：根据目前的联合化疗方案，根据国际预后指标（IPI），新诊断为侵袭性非霍奇金淋巴瘤（NHL）的患者的预后仍然不理想，并且迫切需要一种更具创新性的疗法来提高患者的生存率。这项研究的目的是比较利妥昔单抗与CHOP（环磷酰胺，阿霉素，长春新碱，泼尼松）和ESHAP（依托泊苷，甲基强的松龙，大剂量Ara-C，顺铂）联合使用的利妥昔单抗与CHOP-ESHAP和前期高剂量联合治疗的疗效在该研究所进行的两项连续治疗试验中，对新诊断为“高”和“高中度”风险性侵袭性淋巴瘤的年龄≤65岁的患者进行剂量治疗（HDT）和自体干细胞移植（ASCT）与标准CHOP对照。在1995年5月至2002年7月之间，纳入了84例年龄在15至65岁之间，新诊断为侵袭性NHL且年龄校正后的IPI为2或3的患者。患者的中位年龄为38岁（范围15-65）。治疗组之间的基线人口统计学特征，尤其是主要的预后变量相似。接受利妥昔单抗-CHOP-ESHAP治疗的患者接受了八个周期的利妥昔单抗（第1-6周期的第1天以及第7周期的第21和28天）（375 mg m（-2））加CHOP（第1、3和5周期的第3天） ）和ESHAP（周期2、4和6的第3天和周期7的第1天），间隔为21天。入组CHOP-ESHAP-HDT组（n = 23）的患者接受了三个疗程的CHOP治疗，然后切换到ESSHAP的两个或四个周期，然后进行HDT。单独接受CHOP治疗的患者（n = 25）接受了标准的八个CHOP周期治疗。与单独使用CHOP-ESHAP-HDT或CHOP相比，利妥昔单抗-CHOP-ESHAP的完全缓解率显着提高（分别为67％，44％和36％； p = 0.043）。中位随访时间为53个月，利妥昔单抗-CHOP-ESHAP加利妥昔单抗-61％改善了5年总生存（OS），相比之下，CHOP-ESHAP-HDT和43％改善了5年总生存率仅适用于CHOP（p = 0.088）。与CHOP-ESHAP-HDT（34％和90％）和CHOP（16％和44％）相比，无失败生存率（FFS）和无病生存率（DFS）显着增加（61％和96％）；分别观察到= 0.002和p​​ <0.001）。与CHOP相比，利妥昔单抗-CHOP-ESHAP产生显着优越的OS（p = 0.014），FFS（p <0.001）和DFS（p <0.001）。但是，其存活率与用CHOP-ESHAP-HDT治疗的患者无明显差异。结论是，对于以前未经治疗的侵袭性淋巴瘤患者，利妥昔单抗-ESHAP-CHOP优于标准CHOP，且其费用可与前期HDT / ASCT相提并论。必须进行前瞻性随机对照试验来证实这些结果。

BACKGROUND & AIMS: :Priority setting of health interventions is often ad-hoc and resources are not used to an optimal extent. Underlying problem is that multiple criteria play a role and decisions are complex. Interventions may be chosen to maximize general population health, to reduce health inequalities of disadvantaged or vulnerable groups, ad/or to respond to life-threatening situations, all with respect to practical and budgetary constraints. This is the type of problem that policy makers are typically bad at solving rationally, unaided. They tend to use heuristic or intuitive approaches to simplify complexity, and in the process, important information is ignored. Next, policy makers may select interventions for only political motives. This indicates the need for rational and transparent approaches to priority setting. Over the past decades, a number of approaches have been developed, including evidence-based medicine, burden of disease analyses, cost-effectiveness analyses, and equity analyses. However, these approaches concentrate on single criteria only, whereas in reality, policy makers need to make choices taking into account multiple criteria simultaneously. Moreover, they do not cover all criteria that are relevant to policy makers. Therefore, the development of a multi-criteria approach to priority setting is necessary, and this has indeed recently been identified as one of the most important issues in health system research. In other scientific disciplines, multi-criteria decision analysis is well developed, has gained widespread acceptance and is routinely used. This paper presents the main principles of multi-criteria decision analysis. There are only a very few applications to guide resource allocation decisions in health. We call for a shift away from present priority setting tools in health--that tend to focus on single criteria--towards transparent and systematic approaches that take into account all relevant criteria simultaneously.

背景与目标： ：卫生干预措施的优先级设置通常是临时的，资源没有得到最佳利用。潜在的问题是，多个标准起着作用，并且决策很复杂。可以选择干预措施，以最大程度地提高总体人口健康，减少弱势或弱势群体的健康不平等，广告/或应对威胁生命的情况，所有这些都涉及实际和预算方面的限制。这是决策者通常无助于理性解决的典型问题。他们倾向于使用启发式或直观的方法来简化复杂性，并且在此过程中，重要的信息将被忽略。接下来，政策制定者可能只出于政治动机选择干预措施。这表明需要采取合理和透明的方法来确定优先事项。在过去的几十年中，已经开发出许多方法，包括循证医学，疾病负担分析，成本效益分析和公平性分析。但是，这些方法仅集中于单个标准，而实际上，决策者需要在选择时同时考虑多个标准。此外，它们并未涵盖与决策者相关的所有标准。因此，有必要开发一种确定优先级的多标准方法，并且最近确实将其确定为卫生系统研究中最重要的问题之一。在其他科学学科中，多准则决策分析已经得到了很好的发展，已经得到了广泛的认可并被常规使用。本文介绍了多准则决策分析的主要原理。只有很少的应用程序可以指导健康状况中的资源分配决策。我们呼吁从目前卫生领域的优先重点设定工具（倾向于只关注单一标准）转变为同时考虑所有相关标准的透明，系统的方法。

BACKGROUND & AIMS: :Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+ CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.

背景与目标： 已经证明：Foxp3对于小鼠中天然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。用IPEX突变的Scurfy小鼠中的Foxp3和人类中的FOXP3突变可导致致命的早期发作的自身免疫性疾病，并证明FOXP3在维持免疫稳态方面的关键作用。 FOXP3蛋白编码几个功能域，包括C2H2锌指，亮氨酸拉链和带翼螺旋/叉头（FKH）域。先前我们已经证明FOXP3充当转录阻遏物，并抑制激活诱导的IL-2基因转录。为了表征每个预测的功能域对FOXP3体内活性的作用，我们评估了在一大批患有免疫功能异常，多内分泌病，肠病，X连锁综合征（IPEX）的患者中鉴定出的点突变的位置，并发现它们主要聚集在FKH结构域和亮氨酸拉链中，但也存在于蛋白质的N末端定义不明确的区域。研究了每个IPEX靶向域的分子功能。我们显示FOXP3组成性地定位于原子核，并且此定位需要在其FKH域的氨基和C末端都具有序列。此外，发现FOXP3通过其亮氨酸拉链同源二聚体。我们还确定了FOXP3 N末端一半内的一个新功能域，这是FOXP3介导的从组成型活性启动子和NF-AT诱导型启动子转录抑制所必需的。此外，我们证明这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关，从而证实了它们的体内相关性。