Small nuclear RNA-associated proteins are immunologically related as revealed by mapping of autoimmune reactive B-cell epitopes.

Autoantibodies from a patient with systemic lupus erythematosus, which recognize U1 and U2 small nuclear ribonucleoprotein particles (snRNPs), were used to map B-cell autoepitopes on the U1 snRNP-specific A protein. This protein contains two regions that are highly similar to regions in the U2 snRNP-specific B" protein. A site termed epitope 2 maps in one such region and was found to react with antibodies cross-reactive between A and B". A second site, epitope 1, is situated in a proline-rich region that shows no homology with B". This epitope can bind three different autoantibodies with distinct specificities. Epitope 1-affinity-purified antibodies from different patients react with either (i) the A protein exclusively; (ii) proteins A, B'/B, a synthetic peptide for part of the N polypeptide, and an unidentified protein with a molecular mass of 50 kDa; or (iii) proteins A, B'/B, C, and the N-derived peptide. Comparison of the primary structures of proteins B'/B, N, and C reveals multiple epitope 1-like sequences in all of them. The possibility that these repeating regions act as immunogens in patients with autoimmune disease is discussed.     

Coronary artery assessment by multidetector computed tomography in patients with prosthetic heart valves

Objectives

Patients with prosthetic heart valves may require assessment for coronary artery disease. We assessed whether valve artefacts hamper coronary artery assessment by multidetector CT.

Methods

ECG-gated or -triggered CT angiograms were selected from our PACS archive based on the presence of prosthetic heart valves. The best systolic and diastolic axial reconstructions were selected for coronary assessment. Each present coronary segment was scored for the presence of valve-related artefacts prohibiting coronary artery assessment. Scoring was performed in consensus by two observers.

Results

Eighty-two CT angiograms were performed on a 64-slice (n?=?27) or 256-slice (n?=?55) multidetector CT. Eighty-nine valves and five annuloplasty rings were present. Forty-three out of 1160 (3.7%) present coronary artery segments were non-diagnostic due to valve artefacts (14/82 patients). Valve artefacts were located in right coronary artery (15/43; 35%), left anterior descending artery (2/43; 5%), circumflex artery (14/43; 32%) and marginal obtuse (12/43; 28%) segments. All cobalt-chrome containing valves caused artefacts prohibiting coronary assessment. Biological and titanium-containing valves did not cause artefacts except for three specific valve types.

Conclusions

Most commonly implanted prosthetic heart valves do not hamper coronary assessment on multidetector CT. Cobalt-chrome containing prosthetic heart valves preclude complete coronary artery assessment because of severe valve artefacts.

Key Points

? Most commonly implanted prosthetic heart valves do not hamper coronary artery assessment ? Prosthetic heart valve composition determines the occurrence of prosthetic heart valve-related artefacts ? Bj?rk–Shiley and Sorin tilting disc valves preclude diagnostic coronary artery segment assessment     

Cardiac computed tomography angiography results in diagnostic and therapeutic change in prosthetic heart valve endocarditis

Echocardiography may miss prosthetic heart valve (PHV) endocarditis which advocates for novel imaging techniques to improve diagnostic accuracy and patient outcome. The purpose of this study was to determine the complementary diagnostic value of cardiac computed tomography angiography (CTA) to the clinical routine workup including transthoracic and transesophageal echocardiography (TTE/TEE) in patients with suspected PHV endocarditis and its impact on patient treatment. A diagnostic prospective cross-sectional study was chosen as design. Besides clinical routine workup (including TTE/TEE), CTA was performed to assess its diagnostic accuracy and complementary diagnostic/therapeutic value. For the diagnostic accuracy, the reference standard was surgical findings or clinical follow-up. To determine the complementary diagnostic/therapeutic value an expert-panel was used as reference standard. Twenty-eight patients were included. CTA resulted in a major diagnostic change in six patients (21 %) mainly driven by novel detection of mycotic aneurysms by CTA. Furthermore, treatment changes occurred in seven patients (25 %) compared to clinical routine workup. Diagnostic accuracy of routine clinical workup plus CTA was superior to clinical routine workup alone for the detection of PHV endocarditis in general, vegetations and peri-annular extension. This study demonstrates that CTA and clinical workup including TTE and TEE are complementary in patients with PHV endocarditis. Therefore, CTA imaging has to be considered after clinical routine workup in patients with a high suspicion on PHV endocarditis.     

神经胶质瘤生物治疗的研究现状与进展

脑胶质瘤是颅内最常见的肿瘤。近年来关于神经胶质瘤的生物学研究取得了一定进展。首先是脑肿瘤干细胞的发现,其次是开展了肿瘤全基因组测序,这对于发现新的分子标记物是非常有用的,这些标记物(如IDH1基因突变)的发现甚至导致了基于分化和间质转化状况对神经胶质瘤的重新分类。此外,利用1p/19q标记及O6-甲基鸟嘌呤-DNA甲基转移酶基因(MGMT)是否被甲基化能为胶质瘤患者选择疗法和进行个性化药物治疗提供有意义的指导。作为治疗策略,替莫唑胺几年前已被确定为治疗脑胶质瘤的标准药物。最近在临床上贝伐单抗已开始用于脑胶质瘤的治疗。其他一些疗法目前还处于临床前开发和临床试验阶段,比如癌症疫苗、溶瘤腺病毒的研究等,这些潜在的疗法将来有可能成为胶质瘤治疗的手段或辅助手段。这些研究不仅揭示了神经胶质瘤的细胞起源,也为胶质瘤的诊断、治疗和预后判断提供了有用的信息和参考。     

Retroviral transduction and expression of the human alkyltransferase cDNA provides nitrosourea resistance to hematopoietic cells

Myelosuppression is the dose-limiting toxicity for nitrosourea chemotherapy. This toxicity predominantly involves modification of the O6 position of guanine with an alkyl moiety. The enzyme responsible for repair of O6-alkylguanine adducts, O6-alkylguanine-DNA alkyltransferase (alkyltransferase), is expressed at low levels in bone marrow (BM) cells. High alkyltransferase expression prevents the cytotoxicity and carcinogenicity of nitrosoureas in several transgenic and in vitro gene transfer models. We used gene transfer using a novel myeloproliferative sarcoma virus (MPSV) based retrovirus (vM5MGMT) to express the human alkyltransferase cDNA (MGMT) in human and murine hematopoietic cells. Transduced K562 cells had very high levels of alkyltransferase expression and significantly increased resistance to 1,3-bis (2- chloroethyl) nitrosourea (BCNU) as compared with untransduced K562 cells. Primary murine BM progenitors showed a high transduction efficiency with vM5MGMT and have increased BCNU resistance in vitro. After BM transplantation with vM5MGMT-transduced BM cells and BCNU treatment of these mice, BM, spleen and thymus had a 10- to 40-fold increase in alkyltransferase expression that persisted for at least 23 weeks posttransplantation. Progenitor cells procured from mice expressing high levels of alkyltransferase also had increased resistance to BCNU. Thus, an MPSV-based retroviral vector transduces mouse and human hematopoietic cells at high efficiency and results in high levels of gene expression both in vitro and in vivo. Overexpression of the alkyltransferase protein may protect hematopoietic progenitors from nitrosourea-induced myelosuppression.     

Regulatory modules in the developing heart

Fragments of regulatory DNA of cardiac genes drive reporter gene expression in sometimes unexpected subdomains of the heart. These patterns have revealed that the regulatory DNA of genes consists of distinct subfragments (regulatory modules) that are active in different regions of the developing heart. In this review we give an overview of the activity of regulatory modules in vivo. Furthermore, we investigated the relationship between the activity domains of the regulatory modules, the building blocks of the heart and the developmental patterning of the myocardium. Most of the regulatory modules show a domain of activity broader than the morphological boundary of a cardiac compartment and seem to respond to a patterning program along the antero-posterior axis.