血浆肿瘤坏死因子-α、白细胞介素-6和内皮素在高血压合并糖耐量异常患者中的变化及其意义

目的:观察原发性高血压(EH)合并糖耐量异常(IGT)患者血浆肿瘤坏死因子-α(tumornecrosisfactor-alpha,TNF-α)和白细胞介素-6(interleukin-6,IL-6)及内皮素(ET)水平的变化。方法:入选EH患者82例,其中合并IGT者42例,糖耐量正常(NGT)者40例;同时随机挑选血压正常健康人(NT)40例为NT组作为对照。采用ELISA法测定血浆中TNF-α、IL-6含量。结果:EH组血浆TNF-α、IL-6、ET明显高于NT组[TNF-α,EH组(27.80±4.73)ng/mL,NT组(23.83±2.28)ng/mL,P<0.05;IL-6,EH组(90.62±18.09)ng/mL,NT组(76.76±12.81)ng/mL,P<0.05;ET,EH组(39.46±10.77)ng/mL,NT组(30.92±4.0)ng/mL,P<0.01]。多因素logistic回归分析,EH合并IGT与TNF-α、IL-6、FPG、2hPG呈正相关(β为1.247、1.180、0.516、0.140,均P<0.05)。结论:EH合并IGT患者血浆TNF-α、IL-6、ET增高,提示EH合并IGT患者体内炎症反应进一步增加及ET水平进一步升高。     

糖耐量受损和2型糖尿病患者脂联素水平的相关性研究

目的探讨在糖耐量受损及2型糖尿病患者中血脂血糖、胰岛素抵抗和血清脂联素之间的关系。方法 166例分为正常对照组（29例）、糖耐量受损组（41例）和糖尿病组（96例）,分别检测血脂、血糖、血胰岛素水平和血清脂联素,采用HOMA-IR法计算胰岛素抵抗指数。分别对正常组是否进展为糖耐量受损,以及糖耐量受损是否进展为糖尿病进行二分类Logistic回归分析。结果正常对照组、糖耐量受损组和糖尿病组血清脂联素水平分别为（15.8±3.6）、（10.7±2.4）和（6.3±2.4）mg/L,3组间差异有显著统计学意义（P〈0.05）。糖耐量受损组的体质指数、总胆固醇、胰岛素水平和胰岛素抵抗显著高于正常组（P均〈0.05）。Logistic回归分析表明体质指数、高密度脂蛋白胆固醇、空腹胰岛素、胰岛素抵抗指数为正常对照进展为糖耐量受损的危险因素。当糖耐量受损组进展为糖尿病组时,空腹胰岛素是唯一有统计学差异的危险因素。脂联素在两个阶段中都为保护因素。结论在糖耐量受损时胰岛素抵抗水平升高,并已伴随脂联素水平下降。血清脂联素测定,可作为2型糖尿病的辅助诊断、及早干预的指标。     

毛细血管恢复率评估糖耐量异常者和2型糖尿病患者微循环功能

目的测定甲襞微循环毛细血管恢复率评价2型糖尿病和糖耐量异常患者的微血管舒张功能。方法2型糖尿病患者、糖耐量异常和糖耐量正常者各48例,微循环显微镜测定甲襞微循环毛细血管恢复率,比较微血管舒张功能差异。结果口服葡萄糖耐量试验正常者48例平均年龄（60.4±6.7）岁,平均毛细血管恢复率为（35.4±8.7）%;糖耐量异常者48例平均年龄（62.4±7.7）岁,平均毛细血管回复率（30.1±7.7）%比糖耐量正常者下降（P〈0.05）。2型糖尿病者48例平均年龄（64.3±8.1）岁,平均毛细血管恢复率（27.5±9.3）%,明显低于正常人和糖耐量异常者（P〈0.05）。在糖尿病患者,随病程延长,毛细血管恢复率呈递减趋势（P〈0.05）。结论糖耐量异常者已存在明显的微血管舒张功能降低,在糖尿病患者中这种微循环障碍进一步加重,提示糖代谢受损早期即出现微血管舒张功能障碍。     

糖耐量低减患者行为分阶段转变状况及其与社会支持的相关性

目的了解糖耐量低减(impaired glucosetolerance,IGT)患者行为分阶段转变状况及其与社会支持的相关性。方法采用行为分阶段转变问卷和社会支持评定量表,对200例IGT患者的行为和社会支持状况进行调查。结果患者各项行为状态在不同转变阶段均有分布,其中在饮食控制、体育锻炼、控制体重方面不良行为发生率均≥55.0%,而且>55.0%患者对于不良健康行为转变处于无意图期和意图期;在每天摄入总热量、合理配餐、摄入蔬菜水果、按医嘱用药、体育锻炼及控制体重方面,不同转变阶段患者社会支持水平比较,差异具有统计学意义(均P<0.01),行为处于行动期及维持期患者其社会支持得分相对较高。结论 IGT患者的不良行为发生率高,行为的转变呈阶段式变化,大多还处于转变的初级阶段(无意图期与意图期),处于行动期与维持期的患者所获得的社会支持较高。     

不同方式的干预措施对糖耐量受损患者的影响

目的：探讨糖耐量受损患者不同方式干预措施的临床效果。方法：对112例糖耐量受损患者分别采用安慰剂、行为干预、药物、行为干预加药物治疗的措施，均达1年以上，监测人体质量指数、空腹血糖、餐后2h血糖、糖基化血红蛋白变化。结果：对照组在给予安慰剂治疗1年后，人体质量指数、空腹血糖、餐后2h血糖、糖基化血红蛋白有上升趋势，但差异无统计学意义（P〉0．05）；行为干预组及药物治疗组在干预治疗1年后，人体质量指数、空腹血糖、餐后2h血糖、糖基化血红蛋白等均有不同程度的下降，但差异亦无统计学意义（P〉0．05）；行为干预加药物治疗组人体质量指数、空腹血糖、餐后2h血糖、糖基化血红蛋白明显下降，差异有统计学意义（P〈0．05）。结论：糖耐量受损患者在控制饮食、坚持体育运动基础上，有必要结合药物干预治疗。     

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β‐lactams in the late 1970s, mainly active against aerobic Gram‐negative bacteria, has introduced a new approach in the design and development of novel antibacterial β‐lactam agents. The main goal was the derivatization of the azetidin‐2‐one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β‐lactamase stability. In that respect, our review covers the updates in the field of monocyclic β‐lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β‐lactams, classified according to their N‐substituent, and the associated antibacterial or β‐lactamase inhibitory activities is provided. The different paragraphs disclose a number of well‐established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β‐lactams and concludes by highlighting the recent developments on siderophore‐conjugated classes of monocyclic β‐lactams.     

血管内超声对合并糖耐量减低的冠心病患者临界病变的临床研究

目的对于冠脉造影提示临界病变的患者,通过血管内超声检查,了解冠心病合并糖耐量减低的冠脉病变斑块情况,探讨糖耐量减低对冠状动脉病变的影响。方法89例l临床诊断为冠心病的患者,分为合并2型糖尿病（T2DM）组（A组）、糖耐量减低（IGT）组（B组）、糖代谢正常组（NDM）（c组）,所有患者均进行冠状动脉造影检查,明确至少有一支主要冠状动脉狭窄程度在40％～70％,所有患者均行血管内超声检查,测量临界病变处血管外弹力膜面积（EEMA）、斑块面积（PA）、最小管腔面积（MLA）、斑块负荷（PB）,并分析斑块性质。结果A组与B组合并高血压及高血脂的发生率较C组高,A组与B组间无显著差别;A组与B组MLA明显〈c组,而EEM、PA和PB明显〉c组。A组与B组软斑块及血栓形成病例均较c组多见。结论在冠脉造影提示临界冠脉病变的冠心病患者中,合并糖耐量减低患者与合并糖尿病患者一样,冠脉病变均较严重,且斑块不稳定,故对合并糖耐量减低的冠心病患者应及早干预,积极控制血糖。     

A mutation in the β3 cytoplasmic tail causes variant Glanzmann thrombasthenia by abrogating transition of αIIbβ3 to an active state

Summary. Background: The cytoplasmic tails of α_IIb and β₃ regulate essential α_IIbβ₃ functions. We previously described a variant Glanzmann thrombasthenia mutation in the β₃ cytoplasmic tail, IVS14: ?3C>G, which causes a frameshift with an extension of β₃ by 40 residues. Objectives: The aim of this study was to characterize the mechanism by which the mutation abrogates transition of α_IIbβ₃ from a resting state to an active state. Methods: We expressed the natural mutation, termed 742ins, and three artificial mutations in baby hamster kidney (BHK) cells along with wild‐type (WT) α_IIb as follows: β₃‐742stop, a truncated mutant to evaluate the effect of deleted residues; β₃‐749stop, a truncated mutant that preserves the NPLY conserved sequence; and β₃‐749ins, in which the aberrant tail begins after the conserved sequence. Flow cytometry was used to determine ligand binding to BHK cells. Results and conclusions: Surface expression of α_IIbβ₃ of all four mutants was at least 60% of WT expression, but there was almost no binding of soluble fibrinogen following activation with activating antibodies (anti‐ligand‐induced‐binding‐site 6 [antiLIBS6] or PT25‐2). Activation of the α_IIbβ₃ mutants was only achieved when both PT25‐2 and antiLIBS6 were used together or following treatment with dithiothreitol. These data suggest that the ectodomain of the four mutants is tightly locked in a resting conformation but can be forced to become active by strong stimuli. These data and those of others indicate that the middle part of the β₃ tail is important for maintaining α_IIbβ₃ in a resting conformation.     

二甲双胍对糖耐量减低患者血浆内皮功能及炎性反应因子的影响

目的观察糖耐量减低（IGT）患者应用二甲双胍治疗前后血浆内皮素（ET）、一氧化氮（NO）、C反应蛋白（CRP）水平的变化。方法服75g葡萄糖耐量试验筛查出IGT患者90例,对其进行为期15周的随机、双盲、安慰剂对照试验及二甲双胍干预治疗试验。试验前后观察血浆ET、NO、CRP变化情况。结果IGT患者应用二甲双胍治疗15周后,血浆ET、CRP显著下降,NO上升,差异有统计学意义（P〈0．05）,而对照组3项指标均无显著改变。结论二甲双胍可改善IGT患者血浆ET、NO及CRP水平。     

团队干预对妊娠期糖耐量异常孕妇血糖与自我管理能力的影响

目的探讨实施团队干预对妊娠期糖耐量异常孕妇血糖与自我管理能力的影响。方法将60例糖耐量异常孕妇分为对照组30例和实验组30例。对照组按照常规方法,实验组在此基础上由产科医师、内分泌科医师、营养师和专科护士等7名成员组成干预团队,对孕妇进行自我管理教育。分别在干预前和干预后评估两组孕妇的自我管理认知和行为;两组孕妇空腹血糖及餐后2 h血糖值的比较。结果实验组干预后自我管理认知和行为改变显著优于对照组(P0.01或P0.05);两组孕妇空腹血糖值差异无统计学意义(P0.05);实验组餐后2 h血糖值低于对照组(P0.01)。结论对糖耐量异常孕妇实施团队干预,进行自我管理教育,可有效降低血糖,提高自我管理能力。     

A new optical imaging probe targeting αVβ3 integrin in glioblastoma xenografts

α_Vβ₃ Integrins are a widely recognized target for in vivo molecular imaging of pathological conditions such as inflammation, cancer and rheumatoid arthritis. We have evaluated the sensitivity of a new, near‐infrared fluorescence (NIRF), RGD cyclic probe (DA364) in noninvasive detection of α_Vβ₃ integrin‐overexpressing tumors. DA364's binding affinity for α_Vβ₃ integrin was first evaluated in vitro. Human α_Vβ₃ integrin‐positive, U‐87 MG glioblastoma cells were then xenografted in nude mice, and DA364 was injected intravenously (i.v.) to evaluate its in vivo distribution, specificity and sensitivity in comparison with a commercially available probe. DA364 bound α_Vβ₃ integrin on U‐87 MG cells with high affinity and specificity, both in vitro and in vivo. This binding specificity was corroborated by the strong inhibition of its tumor uptake induced by nonfluorescent, cyclic‐RGD peptides. Ex vivo analysis showed that DA364 accumulated at the tumor site, whereas very low levels were detected in liver and spleen. In conclusion, DA364 allows sensitive and specific detection of transplantable glioblastoma by NIRF imaging, and is thus a promising candidate for the elaboration of imaging and therapeutic probes for α_Vβ₃ integrin‐overexpressing tumors. Copyright © 2011 John Wiley & Sons, Ltd.     

Integrin Ligands with α/β‐Hybrid Peptide Structure: Design,Bioactivity, and Conformational Aspects

Integrins are cell surface receptors for proteins of the extracellular matrix and plasma‐borne adhesive proteins. Their involvement in diverse pathologies prompted medicinal chemists to develop small‐molecule antagonists, and very often such molecules are peptidomimetics designed on the basis of the short native ligand‐integrin recognition motifs. This review deals with peptidomimetic integrin ligands composed of α‐ and β‐amino acids. The roles exerted by the β‐amino acid components are discussed in terms of biological activity, bioavailability, and selectivity. Special attention is paid to the synthetic accessibility and efficiency of conformationally constrained heterocyclic scaffolds incorporating α/β‐amino acid span.     

Improvements in endotoxemic syndromes using a disintegrin,rhodostomin, through integrin αvβ3‐dependent pathway

Summary. Background and objectives: Septic shock is a major cause of morbidity and mortality in intensive care units, but there is still no effective therapy for the patients. We evaluated the effects of rhodostomin (Rn), an Arg‐Gly‐Asp‐containing snake venom disintegrin, on lipopolysaccharide (LPS)‐activated phagocytes in vitro and LPS‐induced endotoxemia in vivo. Methods and results: Rn inhibited adhesion, migration, cytokine production and mitogen‐activated protein kinase (MAPK) activation of macrophage induced by LPS. Flow cytometric analysis revealed that Rn specifically blocked anti‐αv mAb binding to RAW264.7. Besides inhibiting MAPK activation of THP‐1, Rn bound to LPS‐activated THP‐1 and specifically blocked anti‐αvβ3 mAb binding to THP‐1. Binding assays proved that integrin αvβ3 was the binding site for rhodostomin on phagocytes. Rn reversed the enhancement of fibronectin and vitronectin on LPS‐induced monocyte adhesion and cytokine release. Transfection of integrin αv siRNA also inhibited LPS‐induced activation of monocyte, and Rn exerted no further inhibitory effect. Furthermore, Rn significantly decreased the production of tumor necrosis factor‐α (TNF‐a), interleukin (IL)‐6, ‐1β and ‐10 and attenuated cardiovascular dysfunction, including blood pressure and heart pulse, and thrombocytopenia in LPS‐induced endotoxemic mice. Rn also protected against tissue inflammation as evidenced by histological examination. Conclusions: Rn may interact with αvβ3 integrin of monocytes/macrophages leading to interfere with the activation of phagocytes triggered by LPS. These results suggest that the protective function of Rn in LPS‐induced endotoxemia may be attributed to its anti‐inflammation activities in vivo.     

糖尿病肾病患者转铁蛋白与β2-微球蛋白和微量清蛋白的关系

目的探讨糖尿病肾病患者尿转铁蛋白（UTRF）与β2-微球蛋白（β2-MG）及尿微量清蛋白（mALB）的关系。方法采用免疫比浊法检测尿β2-MG、mALB和UTRF。结果mALB与β2-MG呈正相关（F=0．215，P〈0．01），mALB与UTRF呈正相关（F=-0．327，P〈0．01），UTRF和β2-MG呈正相关（F=0．161，P〈0．05）；单因素线性回归分析发现UTRF是mALB和β2-MG的相关因子（P〈0．05）。结论UTRF升高的糖尿病肾病患者mALB和β2-MG均增加，UTRF、mALB和β2-MG测定可作为糖尿病肾病患者早期肾损伤一个理想的反映肾小球滤过功能的敏感指标。     

Effects of variation in the human α2A‐ and α2C‐adrenoceptor genes on cognitive tasks and pain perception

Background: The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. α_2C‐ and α_2A‐adrenergic receptors regulate noradrenergic activity and are important mediators of pain perception and analgesia. We hypothesized that common genetic variants in these genes, particularly the ADRA2C 322–325 deletion variant, affect pain perception or cognitive responses. Methods: We studied 73 healthy subjects (37 Caucasians and 36 African–Americans) aged 25.4 ± 4.6 years. Pain response to a cold pressor test was measured using a 10 cm visual analog scale and again on the next day, after three infusions of the selective α₂‐agonist dexmedetomidine. Standardized cognitive tests were administered at baseline and after each infusion. The contribution of ADRA2C deletion genotype, dexmedetomidine concentration, and other covariates to pain perception and cognitive responses was determined using multiple linear regression models. Secondary analysis examined the effects of ADRA2A and other ADRA2C variants on pain perception. Results: ADRA2C Del homozygotes had higher pain scores in response to cold at baseline (6.3 ± 1.8 cm) and after dexmedetomidine (5.6 ± 2.2 cm) than insertion allele carriers (4.6 ± 2.1 cm [baseline] and 3.8 ± 1.9 cm [after dexmedetomidine]; adjusted P‐values = 0.019 and 0.004, respectively). Cognitive responses were unrelated to ADRA2C Ins/Del genotype. None of the other ADRA2A and ADRA2C variants was significantly related to cold pain sensitivity before dexmedetomidine; after dexmedetomidine, ADRA2A rs1800038 was marginally associated (P = 0.03). Conclusion: The common ADRA2C del322–325 variant affected pain perception before and after dexmedetomidine but did not affect other cognitive responses, suggesting that it contributes to interindividual variability in pain perception.