Preclinical PK and PD Studies on 2��-O-Methyl-phosphorothioate RNA Antisense Oligonucleotides in the mdx Mouse Model

Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2′-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (~46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols.     

Recent advances in magnetic resonance imaging of the knee

The examination of the knee has rapidly become the most important non-neurologic application of MR imaging. The widespread availability of high signal-to-noise knee coils has made routine imaging with T2-weighted sequences in both coronal and sagittal planes possible in 30 minutes. The spin-echo sequence remains the most important imaging technique, although many newer sequences have also been applied to the knee, with varying degrees of success. Important pitfalls in diagnosis, such as high signal intensity in the posterior horn of the medial meniscus and the transverse meniscal ligament, displaced buckethandle meniscal tears, and discoid menisci, can be recognized with experience. Common clinical problems that are encountered include meniscal cysts, osteonecrosis, and bone bruises. Detection of subtle injuries of the medial collateral ligament, patellar tendon, and anterior cruciate ligament requires careful observation. Intra-articular loose bodies can be reliably detected with MR imaging, and it should be recognized that localized pigmented villonodular synovitis can sometimes simulate the appearance of a loose body. MR imaging is a valuable noninvasive procedure that is complementary to arthroscopy in the evaluation of diseases of the knee.     

Imaging of the distal radioulnar joint

The distal radioulnar joint can be evaluated by many different imaging techniques, including plain radiography, arthrography, tomography, nuclear medicine bone scanning, computed tomography, and magnetic resonance imaging. Each of these techniques has advantages and disadvantages that must be considered when determining the appropriate diagnostic evaluation for a particular patient.     

儿童腹腔脓肿的CT诊断

目的探讨ＣＴ对儿童腹腔脓肿的诊断价值。方法对２３例经手术和穿刺针吸证实的腹腔脓肿的ＣＴ表现进行分析，急性阑尾炎１３例，升结肠穿孔１例，美克尔憩室炎２例，感染源不明确７例。１９例行平扫与增强检查，４例仅平扫检查。结果脓液ＣＴ值与病程及致病菌种类无关，脓液量与病程呈正相关。５２％脓肿内见到气体影，２２％脓肿内见到小钙化斑。病程１周以上者全部见不均匀厚壁强化的脓肿壁。结论脓肿内见到小钙化斑和气体影像具有特征性，脓腔内较大气液平面提示肠瘘存在，脓肿内无气体影不能排除肠瘘。     

高原地区CT导引经皮腰椎间盘髓核切吸术的临床研究

目的：探讨高原地区CT导引经皮腰椎间盘髓核切吸术（CT-PLD）的临床应用价值。方法：对68例腰椎间盘突出症患者实施了CT-PLD。（1）术前扫描病变椎间盘，筛选病例，并研究手术方案；（2）于即时CT图像上选择最佳的穿刺层面，设计穿刺路径，记录穿刺参数，并于体表标记穿刺点；（3）按既定参数进行穿刺；（4）经CT扫描确认穿刺进入椎间盘，扩张进针路径，进行切吸；（5）术毕CT扫描，观察进针路径有无出血及椎间盘还纳情况。结果：68例共79个椎间盘均穿刺成功。经3-18个月的随访，28例症状完全消失，36例症状明显减轻且能正常工作及生活，椎间盘还纳为1-4mm，显效率为94.12%。结论：CT-PLD安全有效，并发症少，是高原地区腰椎间盘突出症的理想的治疗方法。     

CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples.

We wished to compare the relative reproducibility and validity of cervical intraepithelial neoplasia (CIN) 2 and CIN3 diagnoses. In a population-based cohort study (1993-2001) of human papillomavirus (HPV) and cervical neoplasia in Costa Rica, we compared community pathologists' diagnoses with those of the 2 independent reviewers from the United States (total, n = 357). As measures of validity, we correlated primary and review diagnoses with HPV positivity and cytological interpretations. Two review pathologists agreed with 84% and 81%, respectively, of initial diagnoses of CIN3 compared with 13% and 31% of CIN2. The CIN3 diagnoses made by review pathologists were 94% oncogenic HPV positive, compared with 72% of CIN2 diagnoses. Eighty-one percent of CIN3 diagnoses versus 61% of CIN2 were correlated with high-grade cytological interpretations. The CIN3 is a substantially more reproducible diagnosis that can be validated more frequently with HPV tests and cytological interpretations than CIN2.     

Nitroglycerin and isosorbide dinitrate stimulation of glutathione disulfide efflux from perfused rat liver

Nitroglycerin (GTN) and isosorbide dinitrate (ISD) are metabolized by glutathione S-transferase to nitrite with production of GSSG from GSH. Infusion of organic nitrates into perfused rat liver led to efflux of GSSG in the bile and nitrite in the perfusate. Biliary GSSG increased more rapidly than did nitrite release as GTN infusion rate was increased, indicating that GSSG reducing capacity was being exceeded. Rapid GTN-induced oxidation of GSH may be the mechanism of tissue GSH depletion by GTN and other alkylnitrates. Such depletion of glutathione may reduce nitrite production from organic nitrates and underlie tolerance to these drugs.     

纵隔类癌的CT表现(附6例报道)

目的：分析纵隔类癌的CT表现，探讨CT诊断价值。方法：对1994年一2001年经4所医院病理证实的纵隔类癌6例进行临床、病理、CT对照分析。结果：①临床无特异性表现，极少出现类癌综合征；②CT表现为中上纵隔肿块，位于胸腺区或向其内生长，与心底部大血管及心包关系密切，并有沿血管间隙生长的特点，造影后有轻、中度强化，可发生胸内外转移；③CT表现与病理、预后密切相关。结论：纵隔类癌较罕见，可能来源于胸腺。CT发现以上特点可提示诊断，还可观察肿块大小、位置、范围、内部及与血管心包的关系，帮助确定手术方案及推测预后，但确诊需依靠病理。