Clinical significance of elevated alpha-fetoprotein in Alaskan Native patients with chronic hepatitis C

The clinical significance of elevated serum alpha-fetoprotein (AFP) in patients with chronic hepatitis C virus (HCV) infection is not well defined. We analysed data from a population-based cohort of patients with HCV infection to assess the prevalence of elevated serum AFP, to determine its association with clinical and virologic parameters and with clinical outcomes. We defined a slightly elevated serum AFP level as 8 to <15 and a high-AFP level as > or =15 microg/L. Among 541 HCV-RNA-positive persons, 61 (11%) had a slightly elevated or high AFP at the time of consent. AFP > or =8 microg/L was associated with the older age, aspartate aminotransferase/alanine aminotransferase ratio >1, and higher alkaline phosphatase levels, but not with heavy alcohol use, IV drug use, genotype, viral load or duration of HCV infection. Among 192 persons with an AFP at liver biopsy, 17% had an AFP > or =8 microg/L. The sensitivity/specificity of an AFP level > or =8 in detecting Ishak 3-6 fibrosis was 39%/95%. Among 372 persons with a minimum of four AFP measurements over 6 years, 5% had persistently elevated AFP >8 microg/L, 19% had both elevated and normal AFP measurements, and 76% had persistently normal AFP. Elevated AFP at consent was associated with hepatocellular carcinoma (HCC) and end-stage liver disease. Over 6 years of follow-up, persistently elevated AFP was associated with the development of HCC; no person with AFP persistently <8 microg/mL developed HCC. Serial AFP measurements appear to be useful in identifying persons with advanced fibrosis and help to determine who needs periodic screening with liver ultrasound to detect HCC.     

Ultrasound: Optimal screening test for pseudotumor detection

Since 1990, metal-on-metal (MOM) hip arthroplasties have been increasingly used. However, there have been concerns lately regarding adverse local tissue reaction to metal ions leading to aseptic masses called pseudotumors. Ultrasound (US), computerized tomography (CT), and magnetic resonance imaging (MRI) have all been suggested to investigate this problem. We have reviewed the use of ultrasound in the detection of pseudotumors and have found it to be equally sensitive and specific, easily accessible, and not as affected by metal artifacts compared to MRI. We recommend that ultrasound be considered as the first line of investigation to rule out a pseudotumor formation in MOM hip arthroplasties.     

结核分枝杆菌特异性蛋白片段Rv3388和6种特异抗原在结核抗体检测中的应用价值

目的 对结核分枝杆菌( MTB) PE家族的所有成员的结构进行分析,预测其抗原表位,截取Rv3388蛋白的优势抗原片段,对重组Rv3388蛋白及其它6种MTB特异性抗原进行评估,探讨不同结核特异性抗原与血清抗体的反应模式,评价血清学检测在结核病诊断中的价值. 方法 利用基因合成技术重叠延伸PCR扩增Rv3388蛋白637~731位的编码基因片段, 原核表达并纯化重组蛋白pET32a/Rv3388637-731 ,将纯化的重组蛋白免疫BALB/c小鼠,采用间接ELISA法对该抗血清进行免疫原性分析. 同时对这7种MTB特异性蛋白的特异性及敏感性进行评价. 结果 重组蛋白pET32a/Rv3388637-731在大肠杆菌中的表达量占全菌蛋白的80%,ELISA显示有较强的免疫原性. 7 种 MTB特异性抗原具有不同的反应模式,单个抗原检测敏感性较差. 结论 对MTB PE家族的蛋白结构分析,表达并纯化重组蛋白pET32a/ Rv3388637-731 ,7种蛋白在血清抗体检测中具有抗原互补性,不同抗原与机体反应存在不同反应模式,提高结核抗体检测敏感性应多种抗原联合检测.     

Closely related antibody receptors exploit fundamentally different strategies for steroid recognition

Molecular recognition by the adaptive immune system relies on specific high-affinity antibody receptors that are generated from a restricted set of starting sequences through homologous recombination and somatic mutation. The steroid binding antibody DB3 and the catalytic Diels–Alderase antibody 1E9 derive from the same germ line sequences but exhibit very distinct specificities and functions. However, mutation of only two of the 36 sequence differences in the variable domains, Leu^H47Trp and Arg^H100Trp, converts 1E9 into a high-affinity steroid receptor with a ligand recognition profile similar to DB3. To understand how these changes switch binding specificity and function, we determined the crystal structures of the 1E9 Leu^H47Trp/Arg^H100Trp double mutant (1E9dm) as an unliganded Fab at 2.05 Å resolution and in complex with two configurationally distinct steroids at 2.40 and 2.85 Å. Surprisingly, despite the functional mimicry of DB3, 1E9dm employs a distinct steroid binding mechanism. Extensive structural rearrangements occur in the combining site, where residue H47 acts as a specificity switch and H100 adapts to different ligands. Unlike DB3, 1E9dm does not use alternative binding pockets or different sets of hydrogen-bonding interactions to bind configurationally distinct steroids. Rather, the different steroids are inserted more deeply into the 1E9dm combining site, creating more hydrophobic contacts that energetically compensate for the lack of hydrogen bonds. These findings demonstrate how subtle mutations within an existing molecular scaffold can dramatically modulate the function of immune receptors by inducing unanticipated, but compensating, mechanisms of ligand interaction.     

钆塞酸二钠在肝脏MRI增强扫描应用中的护理

目的：探讨肝胆特异性对比剂钆塞酸二钠(Gd-EOB-DTPA)在肝脏MRI增强扫描应用中的护理措施。方法针对Gd-EOB-DTPA的使用注意事项和MRI增强检查的特殊要求,对288例应用该对比剂行肝脏MRI增强扫描的患者从心理护理、检查前准备、检查中配合、检查后不良反应处理等方面进行护理干预。结果4例(1.4%)患者呼吸配合欠佳,其中1例图像伪影较多,影响观察及诊断,3例图像伪影较小,对图像质量的影响不大,其余284例患者(98.6%)患者顺利完成检查,取得高质量的图像效果。288例患者中,1例患者检查后出现颜面部潮红,2例患者出现恶心,无呕吐,其余患者在检查过程中及检查后均无不适。结论 Gd-EOB-DTPA应用于肝脏MRI增强扫描中具有安全、有效的优点,提高图像质量、实施综合护理措施是检查成功的重要因素。     

Molecular modeling of salsolinol,a full Gi protein agonist of the μ‐opioid receptor,within the receptor binding site

(R/S)‐Salsolinol is a full agonist of the μ‐opioid receptor (μOR) G_i protein pathway via its (S)‐enantiomer and is functionally selective as it does not promote β‐arrestin recruitment. Compared to (S)‐salsolinol, the (R)‐enantiomer is a less potent agonist of the G_i protein pathway. We have now studied the interactions of the salsolinol enantiomers docked in the binding pocket of the μOR to determine the molecular interactions that promote enantiomeric specificity and functional selectivity of (R/S)‐salsolinol. Molecular dynamics simulations showed that (S)‐salsolinol interacted with 8 of the 11 residues of the μOR binding site, enough to stabilize the molecule. (R)‐Salsolinol showed higher mobility with fewer prevalent bonds. Hence, the methyl group bound to the (S)‐stereogenic center promoted more favorable interactions in the μOR binding site than in the (R)‐orientation. Because (S)‐salsolinol is a small molecule (179.2 Da), it did not interact with residues implicated in the binding of larger morphinan agonists that are located toward the extracellular portion of the binding pocket: W318^7.35, I322^7.39, and Y326^7.43. Our results suggest that contact with residues which (S)‐salsolinol interacts with are enough to elicit G_i protein activation, and possibly define a minimum set required by μOR ligands to promote activation of the G_i protein pathway.