Determination of dead-layer variation in HPGe detectors

The dead-layer uniformity of the top surface of two high purity germanium detectors has been studied using a novel automated scanning set-up that allows a fine-grained topography of a detector's top and lateral surfaces. Comparisons between measurements and Monte Carlo simulations allowed implementation of a dead-layer variation into the detector model, which reproduces the measurements results. The effect of the non-uniform dead-layer on activity determinations based on low-energy γ-rays (i.e. below ~100 keV) has been determined to be of the order of 10% or more.     

Contrasting associations of polymorphisms in FcγRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population

Dengue virus (DENV) causes a spectrum of illness from asymptomatic infection, to a mild febrile illness, to occasional more severe complications including hemorrhage and shock. Dengue is endemic in the state of Morelos, Mexico. Two single nucleotide polymorphisms (SNPs), rs1801274 of FcγRIIa and rs4804803 of DC-SIGN, have been associated with protection from or susceptibility to severe dengue infection. Both of these polymorphisms are located in genes for receptors with important roles in dengue pathogenesis, and their relationship with the clinical presentation of dengue infection in Mexican populations is unknown. In this study, real-time PCR was used to characterize the distribution of rs1801274 and rs4804803 in subjects with asymptomatic dengue infection (n = 145), uncomplicated dengue (n = 67), and severe dengue (n = 36) in Morelos. In contrast with previous studies, the histidine (A) variant of rs1801274 was associated with more mild infection: carrying the histidine allele (either homozygous or heterozygous) was associated with protection from symptomatic infection compared with asymptomatic (OR 0.51, p = 0.038). Histidine homozygotes were also less likely to present severe dengue (OR 0.34, p = 0.05). Logistic regression models confirm this association (OR 0.48, p = 0.04) and also indicate that the G allele of rs4804803 is associated with symptomatic dengue (OR 2.3, p = 0.08), after accounting for other biological factors including history of infection. This variant was rare in this study population, with a frequency of 5.4%. These findings reflect the complexity of influences on the development of severe dengue infection. The inclusion of asymptomatic infections and adjusted case definitions likely do not explain the entire disparity with previous findings. Interactions with other polymorphisms may explain why the association of rs1801274 is reversed in this population compared to others. This study demonstrates the importance of genetic association studies in multiple genetically distinct populations.     

Scintillation proximity assay in lead discovery

Background: Scintillation proximity assay (SPA) is a homogeneous scintillant bead-based platform for the measurement of biological processes and plays an important role in the identification of active chemical entities in drug discovery. Objective: The design and development of solid-phase SPA approaches are examined and compared with alternative non-radiometric fluorescence-based technologies. Methods: This review provides background on the principle of SPA and its application to biomolecular interactions from a variety of biological sources. Conclusion: The SPA approach is well suited to the demands of commercial high volume automation and assay miniaturization for target-based high-throughput screening campaigns on synthetic and natural product libraries as well as for benchtop characterization and confirmation studies. In the near future, innovations in the way SPA and fluorescence-based screening strategies are multiplexed will improve our comprehensive understanding of cellular system biology and dramatically advance the lead discovery process for the treatment of complex target-related disorders.     

Induction of apoptosis by heat and γ-radiation in a human lymphoid cell line; role of mitochondrial changes and caspase activation

Purpose: The aim of the study was to investigate the molecular mechanisms involved in apoptosis of human promyelocytic cells (HL60) induced by hyperthermia and to compare this to radiation-induced apoptosis as a reference model.

Materials and methods: Apoptosis of HL60 cells was induced by heat-treatment (43°C during 1?h) or by γ-radiation (8?Gy) and followed at increasing time periods after treatment with Annexin V binding to phosphatidylserine (PS). The transition of the mitochondrial membrane potential (Δψ_m) was estimated by the extent of mitochondrial JC-1 uptake. Bcl-2 and Bax protein expression levels were monitored using fluorescent-labelled antibodies. Caspase activation was studied using a fluorochrome-labelled pan-caspase inhibitor (FLICA), which also allowed one to study the kinetics of the apoptotic cascade.

Results: After heat-treatment or irradiation of HL60 cells, a decreased Δψ_m as well as PS membrane expression were detectable after 8?h. Bcl-2 and Bax protein expression levels were decreased and increased, respectively, 1?h after heat-treatment or irradiation. The apoptotic rate of HL60 cells, as measured by the FLICA binding, was faster with heat-treatment as compared to γ-irradiation. Addition of a pan-caspase inhibitor prevented PS externalization after heat-treatment but not after irradiation. The presence of a pan-caspase inhibitor did not influence the decrease of Δψ_m both after heat-treatment and γ-irradiation. However, the addition of the specific caspase-2 inhibitor zVDVAD-fmk prevented the mitochondrial breakdown after heat-treatment. Inhibition of caspase-2 had no effect on the γ-irradiation induced apoptosis.

Conclusion: These results suggest that the commitment to apoptosis in HL60 cells after heat-treatment is started by mitochondrial membrane transition involving the Bcl-2 family members and is mainly executed in a caspase-dependent pathway. The results suggest that caspase-2 plays a key role in the heat-induced apoptosis.     

PPARγ在子宫内膜异位症中的作用研究进展

现有的研究已阐明激活PPARγ具有抑制炎症反应、抗血管生成等作用,而炎症反应和血管生成均参与了子宫内膜异位症的发生发展,并且PPARγ在正常子宫内膜组织及异位子宫内膜组织均有表达。PPARγ在子宫内膜异位症中的作用受到越来越多的关注,该文就PPARγ在子宫内膜异位症中的意义作一综述。     

Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease

Introduction: Current treatment of Parkinson’s disease (PD) is limited to symptomatic dopaminergic therapy, while no interventions have been shown to slow down disease progression.

Areas covered: The following article highlights a group of PPAR-γ agonists called thiazolidinediones (TZDs), which are currently being tested for a putative disease-modifying benefit in PD, using pioglitazone as a prototypic compound. PPAR-γ is highly expressed in neurons of the substantia nigra and CNS immune cells. Preclinical data in rodent and primate support an effect of TZDs in preventing and/or arresting neurodegeneration and development of motor symptoms. Although no data on the neuroprotective effect of TZDs is currently available, a clinical trial is ongoing where the primary objective is to assess pioglitazone’s impact on the progression of PD. The trial is also evaluating the drug’s safety concerns.

Expert opinion: The efficacy data from clinical trials must be carefully weighed against the safety concerns. However, given the solid preclinical data, and since the safety data are not yet fully conclusive and limited to the diabetic population, PPAR-γ research in PD can continue with caution. Ideally, drug discovery and development efforts will lead to the identification of new compounds with reduced risk of peripheral side effects.     

泪腺炎患者血清性激素变化及其与γ-IFN、IL-4的相关性

目的 观察泪腺炎患者血清中雌二醇(estradiol,E2)、睾酮(testosterone,T)、泌乳素(prolactin,PRL)水平的变化,并探讨这种变化与血清中γ-干扰素(γ-interferon,γ-IFN)、白细胞介素4(interleukin-4,IL-4)变化的关系.方法 收集42例2013年11月至2014年10月我院确诊为泪腺炎的患者炎症期(炎症期组)与炎症缓解期(缓解期组)的血清,40例同年龄段于我院体检的正常人血清作为正常对照组,采用电化学发光法检测血清中E2、T、PRL的水平,酶联免疫吸附法测定血清中γ-IFN、IL-4水平.结果 泪腺炎患者炎症期组血清E2、PRL水平分别为(64.12±35.92) ng·L-1和(17.63±8.59) μg·L-1,显著高于缓解期组的(43.16 ±26.57)ng·L-1和(10.30±5.59) μg·L-1及正常对照组的(41.92±21.68)ng·L-1和(9.08±2.61) μg·L-1,差异均有统计学意义(均为P＜0.05);炎症期组与缓解期组血清T分别为(0.80±1.36) μg·L-1和(0.79±1.42) μg·L-1,与正常对照组的(1.76±2.49) μg·L-1相比差异均有统计学意义(均为P ＜0.05).炎症期组血清γ-IFN、IL-4水平分别为(353.12±108.36)ng·L-1和(1200.43±314.69)ng·L-1,显著高于缓解期组的(192.68±43.16)ng·L-1和(919.38±227.16)ng·L-1及正常对照组的(190.93±36.40)ng·L-1和(853.37±172.31)ng·L-1,差异均有统计学意义(均为P＜0.05).E2与γ-IFN、IL-4水平呈正相关(均为P＜0.05);T与γ-IFN、IL-4水平呈负相关(均为P＜0.05);PRL与γ-IFN、IL-4水平呈正相关(均为P＜0.05).女性患者炎症期组血清γ-IFN水平为(344.46±112.06)ng·L-1,高于男性的(292.98±71.27)ng·L-1(P＜0.05),E2/T比值为665.36,明显高于男性的13.91(P ＜0.05).结论 泪腺炎患者血清中性激素E2、PRL的升高、T的降低及E2/T比例失调可能介导Th1、Th2细胞免疫通路的平衡紊乱从而致病.女性体内高水平的雌激素可能是导致女性易患自身免疫性疾病的主要原因.     

大剂量丙种球蛋白联合纳洛酮治疗乙型脑炎疗效分析

目的：观察大剂量丙种球蛋白联合纳洛酮治疗乙型脑炎的疗效。方法安康市中心医院2012年6月至2014年9月收治的95例乙型脑炎患儿随机分成两组。对照组47例,给予常规综合治疗(抗病毒治疗+营养支持+对症治疗);研究组48例,在常规综合治疗的基础上,给予丙种球蛋白静脉输注1g·kg-1·d-1联合纳洛酮(0.01~0.02)mg/kg治疗。结果研究组患儿平均退热时间、抽搐时间及意识障碍持续时间较对照组明显缩短(t值分别为4.526、3.371、4.487,均P<0.01);研究组较对照组呼吸衰竭发生率明显降低(χ2=14.341,P<0.05);研究组治愈率显著高于对照组(χ2=19.234,P<0.01)。结论丙种球蛋白联合纳洛酮治疗乙型脑炎较单纯综合治疗更为有效,能够显著降低死亡率,提高治愈率,减少后遗症的发生,应在临床治疗中普遍推广及应用。     

哮喘患儿体内EOS、IgE、IL-4及IFN-γ水平的检测及临床意义

目的：探讨哮喘患儿体内嗜酸性粒细胞(eosinophil,EOS)、免疫球蛋白E(IgE)、白介素4(IL-4)及γ干扰素(IFN-γ)水平的检测及临床意义,为临床疾病的诊断和治疗提供依据。方法抽选湖北省鄂州市鄂钢医院2012年11月至2013年6月收治的95例哮喘患儿(哮喘组,其中急性发作期47例、缓解期48例),并抽选同期在本院体检的79例健康患者为对照研究(健康组),采用肺功能仪测定两组的肺功能,并采用痰液诱导、酶联免疫吸附法( ELISA)分别测定患儿痰液中的EOS百分率及血清中IgE、IL-4、IFN-γ水平。结果哮喘组患儿的1秒用力呼气容积(FEV1)/用力肺活量(FVC)的比值(FEV1%)为(69.67±6.63)%,明显低于健康组的(102.27±11.93)%,差异具有统计学意义(t=22.750,P<0.001);哮喘组患儿的FEV1占预计值百分比为(70.45±9.62),明显低于健康组的(90.13±6.34),差异有统计学意义(t=15.582,P<0.001)。哮喘组患儿的痰EOS百分率、血清中IgE、IL-4水平均高于健康组(t值分别为321.962、82.644、76.913,均P<0.05),哮喘组患儿的IFN-γ水平明显低于健康组(t=30.207,P<0.001)。急性发作期哮喘患儿的痰EOS百分率及血清中IgE、IL-4水平均高于缓解期哮喘患儿的(t值分别为15.752、40.762、31.162,均P<0.05),急性发作期哮喘患儿的IFN-γ水平明显低于缓解期哮喘患儿的(t=35.892,P<0.05)。结论血清中IL-4、IgE水平及痰液中EOS百分率升高、血清IFN-γ水平降低,与哮喘的发生、发展密切相关,对其治疗及病情判断具有重要价值。