Dubin-Johnson-like black liver with normal bilirubin level

Black liver is a common finding in Dubin-Johnson syndrome (DJS), which is caused by the lack of multidrug resistance-associated protein 2 (MRP2). Impaired excretion of epinephrine metabolites is believed to be a cause of black liver in DJS. Recently, we experienced a patient with black liver whose serum bilirubin level was normal. Coarse brown granules were observed in the hepatocytes, and this finding closely resembled that observed in DJS. However, the granules were negative for Schmorl staining. The MRP2 gene did not show any mutation. Immunostaining study demonstrated MRP2 protein expression in the liver, and it was localized in the canalicular membranes of hepatocytes. This case illustrates for the first time that DJS is not the only cause of black liver.     

Changes in cyclic nucleotide phosphodiesterase activity and calmodulin concentration in heart muscle of cardiomyopathic hamsters

Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered in the cardiac muscle of cardiomyopathic heart failure, and PDE inhibitors improve the abnormal muscle condition through changing the cyclic nucleotide concentration. These observations prompted us to investigate the role of calmodulin (CaM) in the regulation of cyclic nucleotide PDE activities, and moreover to study the modulation of the PDE isozymes in heart failure, using cardiac muscles of cardiomyopathic hamster. The CaM concentrations in the heart muscle of the normal control and cardiomyopathic hamsters (each of three to four hamsters) varied with cell fraction and with the age of the animal. The CaM concentrations in the soluble fraction obtained from cardiomyopathic hamster tissue were significantly increased at 25 and 32 weeks of age (2.02 +/- 0.62 microg/mg protein (mean +/- S.E.), and 3.21 +/- 0.95) compared with that obtained from the control (0.60 +/- 0.04) or cardiomyopathic (0.95 +/- 0.12) hamsters at 8 weeks of age. The solubilized PDE isolated from the hamster heart muscle (three or four hamsters in each age) by column chromatography on diethylaminoethyl (DEAE)-cellulose revealed three peaks of activity, which may correspond to the isozymes of PDE classified recently, namely PDE I, II, and III. These three peaks of activity, particularly peak III, seen in the soluble fraction of cardiomyopathic hamster heart declined in proportion to the age of the animal compared with that of the control hamster heart. In the cGMP-PDE assay system, the concentration of CaM inhibitor W-7 required for 50% inhibition (IC(50)) of PDE I, II, and III peak activities was 140, 29, and 46 microM, respectively, suggesting that PDE II is more sensitive to W-7. These results suggest that alteration in these isozyme activities accompanied with changes of CaM concentration may influence the cardiac muscle contractility in cardiomyopathic hamster via changes of cyclic nucleotide concentration.     

Impaired virus-specific T cell responses in patients with myeloproliferative neoplasms treated with ruxolitinib

Ruxolitinib is effective in myeloproliferative neoplasms (MPN) but can cause reactivation of silent infections. We aimed at evaluating viral load and T-cell responses to human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in a cohort of 25 MPN patients treated with ruxolitinib. EBV-DNA and HCMV-DNA were quantified monthly using real-time polimerase chain reaction (PCR) on peripheral blood samples, and T-cell subsets were analyzed by flowcytometry. HCMV and EBV-directed T-cell responses were evaluated using the IFN-γ ELISPOT assay. Most patients had CD4+ and/or CD8+ T-cells below the normal range; these reductions were related to the duration of ruxolitinib treatment. In fact, reduced T-lymphocytes' subsets were found in 93% of patients treated for ≥5 years and in 45% of those treated for <5 years (P = .021). The former also had lower median numbers of CD4+ and CD8+ cells. Subclinical reactivation of EBV and HCMV occurred in 76% and 8% of patients. We observed a trend to an inverse relationship between EBV and CMV-specific CD4+ and CD8+ T-cell responses and viral load, and a trend to an inverse correlation with ruxolitinib dose. Therefore, our data suggest that the ruxolitinib treatment may interfere with immunosurveillance against EBV and HCMV.     

Tissue Doppler imaging and strain Doppler imaging as modalities for predicting clinical improvement in patients receiving biventricular pacing.

BACKGROUND: The purpose of this study was to determine the utility and efficacy of tissue Doppler imaging (TDI) and strain Doppler imaging (SDI) for evaluating ventricular synchrony and function, and for predicting the long-term clinical improvement in patients undergoing biventricular pacing (BVP). METHODS AND RESULTS: TDI and SDI were performed before and <1 month after initiating BVP in 17 patients with advanced heart failure. An intraventricular conduction delay between the left ventricular (LV) septal and lateral walls was measured by TDI. The average LV strain (LV-strain) was calculated from data obtained at the center of 6 regions of the LV (base and mid-point between the basal and apical portions, and the mid-point between these 2 points on the septal and lateral walls). During a 23+/-7 month follow-up period, 12 patients improved clinically and did not require re-hospitalization for heart failure (responder group), but the remaining 5 did not improve (nonresponder group). Before BVP, the intraventricular conduction delay was greater in the responder group than in the nonresponder group (p<0.01), but after BVP, it did not differ between the 2 groups. LV-strain improved after BVP in the responder group but not in the nonresponder group (p<0.05). CONCLUSION: A high intraventricular conduction delay before BVP and decreased strain shortly after BVP may predict long-term clinical improvement in patients undergoing this treatment.     

Peptide vaccination for patients with melanoma and other types of cancer based on pre-existing peptide-specific ctotoxic T-lymphocyte precursors in the periphery

Identification of antigenic peptides expressed on cancer cells enables us to treat cancer patients with peptide-based immunotherapy. Although optimal protocols for peptide-based vaccines have not yet been elucidated, boosting the immune system could be a better approach than priming the immune system to elicit prompt and potent peptide-specific T-cell responses in cancer patients. With this possibility in mind, the authors undertook a clinical trial in which cancer patients were vaccinated with peptides (maximum 4) after confirmation of pre-existing peptide-specific cytotoxic T-lymphocyte (CTL) precursors in the periphery. Fourteen patients (seven with melanoma and seven with other types of cancer) positive for either HLA-A24 or HLA-A2 were enrolled in this study. Fourteen and 16 peptides were used to screen for HLA-A24+ and HLA-A2+ patients, respectively. The vaccination was well tolerated, and the only adverse effects were local pain and fever. Kinetic analysis revealed that peptide-reactive CTLs increased after peptide vaccination in 7 of 14 patients. Immunoglobulin G (IgG) reactive to the administered peptides was detected in 2 patients before vaccination, although it became detectable in 8 of the other 12 patients after the peptide vaccination. Stable disease for more than 6 months was observed in five patients (one with melanoma and four with other types of cancer); all of these patients showed increased levels of peptide-specific IgG. These results indicate that peptide vaccination of patients showing evidence of pre-existing peptide-specific CTL precursors can be applied in further clinical trials aimed at the treatment of melanoma and other types of cancer.     

放射外科组织病理改变(附4例报告)

目的:探讨放射外科治疗的放射生物学效应。方法:报告4例放射外科治疗的手术病理改变,与影像改变及治疗计划等对照研究,结合文献复习,探讨放射生物机理。结果:4例出现不同程度变性、坏死、组织吸收及水肿反应,有剂量及时间依赖性。结论:放射外科治疗后病灶早期改变是血脑屏障紊乱和靶细胞超微结构改变,逐步出现水肿期、坏死期、吸收期及瘢痕期。在坏死期及吸收早期,从治疗体积中心向外依次为坏死区、变性与反应区、水肿区,分别与计算机体层摄影(CT)或磁共振成像(MRI)的中央无强化区、强化环、周围低密度或长T_1长T_2水肿样信号区相对应,水肿样改变主要与灶周剂量较高有关。坏死是靶细胞辐射损伤与血管闭塞相结合的结果,后者为管壁增厚和血栓形成所致。糖皮质激素对灶周水肿的疗效与血管壁损伤程度有关。     

中枢神经细胞瘤5例报告及文献复习

目的探讨提高中枢神经细胞瘤诊疗水平的策略和方法。方法回顾分析2004年8月至2006年4月我院收治的5例中枢神经细胞瘤，总结其临床表现、影像学表现、病理学特征及显微外科手术治疗效果。结果肿瘤位于侧脑室前部或室间孔附近，呈宽基底与侧脑室壁或透明隔相连。肿瘤边缘及内部可见多发囊泡，常见钙化，MRI检查T1WI、T2WI相均表现为等或略高信号，增强后呈轻至中度强化。免疫组织化学染色均显示神经突触素阳性。显微外科手术治疗5例，其中全切除4例，次全切除1例，1例死于术后并发症，4例随访至今未复发。结论中枢神经细胞瘤影像学表现具有一定特征，是术前诊断的重要参考。显微手术切除肿瘤是最佳的治疗手段，预后良好。     

脑出血大鼠锥体束显微和超微结构改变

目的研究脑出血大鼠锥体束病理变化规律及特点。方法使用Ⅳ型胶原酶．肝素诱导大鼠基底节脑出血,采用劳克坚牢蓝（LFB）染色、神经丝蛋白（NF）免疫组化和电镜对内囊后肢进行观察。结果Ⅳ型胶原酶-肝素能成功建立具有典型神经功能缺损的大鼠脑出血模型。光镜发现锥体束髓鞘损伤在脑出血1～3d逐渐加重,7d开始再生修复,1～7d轴突损伤持续加重,14d轴突光度值（0．09±0．01）有所增加,但与7d（0．10±0．02）相比无显著性差异（P〉0．05）。电镜显示脑出血1d锥体束髓鞘松解,轴突水肿,部分无髓轴突崩解坏死消失,3d髓鞘松解、空泡样变性,局部髓鞘消失、厚薄不均,轴突水肿严重,甚至坏死崩解。结论大鼠脑出血后1w内锥体束损伤呈进行性加重,提示应早期和超早期予以干预治疗以减轻损伤和促进修复。