Immunomodulation by hyperimmunoglobulins after solid organ transplantation: Beyond prevention of viral infection

Hyperimmunoglobulins are pharmaceutical formulations of human IgG which contain high titers of antibodies against specific viruses. They have been successfully used in solid organ transplantation (SOT) to prevent Cytomegalovirus (CMV) and Hepatitis B Virus (HBV) infection. The introduction of effective and cheaper antiviral drugs has resulted in decreasing usage of hyperimmunoglobulins in SOT. However, it may still be attractive to combine antiviral drug therapy with hyperimmunoglobulins after SOT, as there is some evidence that hyperimmunoglobulins, similar to high doses of intravenous immunoglobulins (IVIgs), might exert anti-inflammatory activity and thereby prevent immunological graft damage and improve graft and patient survival. In this review we discuss the existing clinical evidence for beneficial anti-inflammatory effects of hyperimmunoglobulins after cardiac, lung, kidney, and liver transplantation. Only a limited number of studies have addressed this issue, and these studies often included small patient cohorts and showed considerable variations in the type, intensity and duration of treatment regimens. Due to these limitations, it is difficult to draw firm conclusions. Retrospective studies consistently demonstrated that addition of CMV hyperimmunoglobulin (CMV-Ig) to antiviral drug prophylaxis after lung transplantation is associated with reduced rates of CMV disease and bronchiolitis obliterans syndrome (BOS), and improved patient survival. The doses of CMV-Ig administered after SOT are much lower than the minimal effective dose of IVIg used for anti-inflammatory therapy in auto-immune diseases. Therefore, it is questionable whether the reduced incidence of BOS is the result of ‘direct’ anti-inflammatory effects of CMV-Ig or is caused by a reduction of CMV infection, which is a risk factor for BOS. No or very limited evidence for better prevention of immunological graft damage by anti-CMV combination therapy is available for heart, kidney and liver transplant patients. In liver transplantation published evidence suggests that the high-doses of Hepatitis B virus hyperimmunoglobulin (HBIg) administered to prevent HBV-infection may reduce the risk of acute rejection, while combination therapy of HBIg and antiviral drugs in HBV-infected patients is consistently associated with better graft and patient survival compared to antiviral monotherapy. Well-designed prospective randomized studies with larger patient cohorts are needed to substantiate the current limited evidence for anti-inflammatory benefits of hyperimmunoglobulins besides prevention of CMV and HBV infection after SOT.     

先天性神经母细胞瘤发病机制与临床特点的研究进展CSCD

神经母细胞瘤是儿童最常见的颅外实体肿瘤,来源于肾上腺髓质或交感神经节。先天性神经母细胞瘤约占神经母细胞瘤患儿总数的5%,大多数患儿于出生后1个月内确诊。与1岁以上神经母细胞瘤患儿相比,新生儿神经母细胞瘤有其独特的病程。本文就先天性神经母细胞瘤的发病机制、临床表现、治疗方法以及预测患儿长期预后的生物学因素进行综述。     

Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary arteriography

Angiographic evidence of coronary artery disease (CAD) was correlated with leukocyte count (WBC), red cell count (RBC), cigarette smoking, age, sex, and cholesterol and triglyceride concentrations in 573 patients who underwent coronary arteriography and who did not have evidence of infection or recent myocardial infarction. Smokers had a higher WBC (7,449 ± 1,964leukocytes/mm³ vs 6,533 ± 1,557, p = 0.0001) and RBC (4.921 × 10⁶ ± 0.491 × 10⁶ erythrocytes/mm³ vs 4.753 × 10⁶ ± 0.480 × 10⁶ p = 0.0001) than nonsmokers. Patients with CAD had a higher WBC (7,280 ± 1,926 vs 6,664 ± 1,700, p = 0.0005) and RBC (4.903 × 10⁶ ± 0.488 vs 4.777 × 10⁶ ± 0.485 × 10⁶, p = 0.0062) than those with normal coronary arteriograms. A positive correlation between WBC and the severity of CAD (sum of arterial diameter narrowing) was noted (r = 0.16, p = 0.0001). Multiple regression showed an independent contribution of WBC in predicting severity of CAD (F = 9.26, p = 0.0025), after accounting for the effects of age, sex, serum cholesterol and triglyceride levels. When smoking was entered into the equation, the contribution of WBC in predicting the severity of angiographic CAD became weaker (F = 4.46, p = 0.035). Similar relations were seen when only smokers were analyzed and when patients with history of remote myocardial infarction were excluded. In nonsmokers these associations became either insignificant or much weaker. Thus, the relation of WBC, and RBC with CAD is mainly due to the elevation of WBC and RBC and the increase of CAD risk induced by cigarette smoking.     

早期治疗肺动脉狭窄型法洛四联症临床分析

目的总结早期治疗婴幼儿肺动脉狭窄型法洛四联症（TOF）的临床经验。方法2007年7月至2009年7月，本院共收治肺动脉狭窄型TOF患儿144例，年龄2．36个月，中位数8．2个月，体重4．5～13b，平均（8．7±2．8）kg。140例患儿接受一期根治手术，术中经右心室切口修补室间隔缺损及疏通右室流出道，其中52例患儿肺动脉及瓣环发育欠佳，行双片法跨瓣环补片治疗，4例患儿行分流手术治疗。结果本组围手术期死亡3例（2．1％），其余恢复顺利，痊愈出院。获门诊随访128例，随访时间3～24个月，患儿有心功能良好，无右室流出道梗阻。结论TOF患儿应在1岁以内治疗，经有心室路径矫治便于操作，术后右室功能良好，应用双片法进行跨环补片修补，疗效满意。     

Photodynamic therapy targeting neuropilin-1: Interest of pseudopeptides with improved stability properties

The general strategy developed aims to favor the vascular effect of photodynamic therapy by targeting tumor vasculature. Since angiogenic endothelial cells represent an interesting target to potentiate this vascular effect, we previously described the conjugation of a photosensitizer to a peptide targeting neuropilins (NRPs) over-expressed specially in tumor angiogenic vessels and we recently characterized the mechanism of photosensitization-induced thrombogenic events. Nevertheless, in glioma-bearing nude mice, we demonstrated that the peptide moiety was degraded to various rates according to time after intravenous administration. In this study, new peptidases-resistant pseudopeptides were tested, demonstrating a molecular affinity for NRP-1 and NRP-2 recombinant chimeric proteins and devoid of affinity for VEGF receptor type 1 (Flt-1). To argue the involvement of NRP-1, MDA-MB-231 breast cancer cells were used, strongly over-expressing NRP-1 receptor. We evidenced a statistically significant decrease of the different peptides-conjugated photosensitizers uptake after RNA interference-mediated silencing of NRP-1. Peptides-conjugated photosensitizers allowed a selective accumulation into cells. In mice, no degradation was observed in plasma in vivo 4 h after intravenous injection by MALDI-TOF mass spectrometry. This study draws attention to this potential problem with peptides, especially in the case of targeting strategies, and provides useful information for the future design of more stable molecules.     

从心肝论治心脏神经官能症

心脏神经官能症(cardiac neurosis,CN)可与器质性心脏病同时发生,为"双心疾病"之一。"心主血脉""心主神明",脾胃之气衰败,气血生化无源或思虑过度,暗耗心血,致心血亏虚,无以充养心神,发为CN。心血亏虚,心神失养是CN发病之本。肝与心为相生关系,肝主疏泄,调畅气机,气行则血行。气畅达,气血调和则心得安;肝气郁滞则心不安。肝主疏泄功能失常,致心神失养是CN发病的重要条件。治疗可以从中医形神一体观出发,疏肝解郁以养其神,益气养血以护其形,以达到同时治疗"血脉之心"和"神明之心"的效果。     

先天性十二指肠梗阻91例临床分析

目的总结先天性十二指肠梗阻的临床表现、手术方法和围手术期处理。方法回顾性分析91例年龄1h至4个月的十二指肠梗阻病例,其中先天性肠旋转不良57例,环状胰腺22例,十二指肠膜式闭锁9例,其他型十二指肠闭锁2例,异常索带1例。8例(8.8%)存在2种原因的梗阻。本组行Ladd's术57例,十二指肠前壁菱形吻合术27例,隔膜切除、十二指肠纵切横缝5例,十二指肠端端吻合术1例,索带松解术1例。结果88例治愈,1例合并肠坏死自动出院,1例术后并发坏死性小肠结肠炎、肠穿孔放弃治疗,1例术后发现合并食道闭锁,放弃治疗。结论先天性十二指肠梗阻的主要病因是肠旋转不良、环状胰腺、十二指肠膜式闭锁,早期诊断、合理选择手术方法、避免漏诊、加强围手术期处理是提高治愈率的关键。     

Ethanol dependence in the rat: role of extrapyramidal motor systems in the withdrawal reaction

Rats were implanted with chronic recording electrodes in the caudate nucleus, substantia nigra, red nucleus, and pontine reticular formation and thereafter maintained on ethanol-containing liquid diets for 18 to 22 days. The removal of ethanol resulted in the time-dependent appearance of epileptiform abnormalities in each of the explored brain regions. The abnormalities characteristically began with increases in EEG synchrony and amplitude coupled with the appearance of epileptiform spike activity, which increased in amplitude and frequency during the latter stages of withdrawal. Quantification of preconvulsive epileptiform spike activity revealed major differences in the temporal sequence of development of spiking in the caudate nucleus and substantia nigra compared to the red nucleus and pontine reticular formation. However, a significant equipotentiality existed among these regions as initiation sites for seizure discharge during spontaneous behavioral convulsion. It was concluded that these brain sites, which have previously been considered to serve significant motor functions, play an active, but as yet unspecifiable, role in the genesis of the ethanol withdrawal reaction. It was further hypothesized that an important aspect of the development of epileptiform activity during the ethanol withdrawal reaction may involve interaction of the caudate nucleus, substantia nigra, and red nucleus with existing thalamocortical synchronizing systems in the midline and nonspecific thalamic nuclei.     

Lack of carcinogenicity of mediumviscosity liquid paraffin given in the diet to F344 rats

The carcinogenicity of medium-viscosity liquid paraffin was examined in Fischer 344 rats. Groups of 50 males and 50 females were given the material at dietary doses of 0 (control), 2.5 or 5% for 104 wk. Slight increases in food consumption and body weight were observed in both sexes of the 5% group. However, no significant differences between the control and treated groups were noted with regard to clinical signs, mortality and haematology findings. A variety of tumours developed in all groups, including the control group, but all the neoplastic lesions were histologically similar to those known to occur spontaneously in F344 rats, and no statistically significant increase in the incidence of any tumour type was found for either sex in the treated groups. Granulomatous inflammation in the mesenteric lymph nodes, considered to be a reaction to paraffin absorption, was observed with similar incidence and severity in both sexes of the 2.5 and 5% groups. Thus, it is concluded that under the present experimental conditions, the high dose, about 2000–200000 times higher than the current temporary acceptable daily intake, does not have any carcinogenic potential in F344 rats. Furthermore, granulomatous inflammation observed in mesenteric lymph nodes were not associated with any development of neoplastic lesions.