B cell lymphoma and myeloma in murine Gaucher's disease

Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin‐secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long‐term development of B cell malignancies in an authentic model of non‐neuronopathic Gaucher's disease in mice: selective deficiency of β‐glucocerebrosidase in haematopoietic cells [Gba^{tm1Karl/tm1Karl}Tg(Mx1‐cre)1Cgn/0, with excision of exons 9–11 of the murine GBA1 gene, is induced by poly[I:C]. Mice with Gaucher's disease showed visceral storage of β‐glucosylceramide and greatly elevated plasma β‐glucosylsphingosine [median 57.9 (range 19.8–159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04–1.38) nm; n = 29] (p < 0.0001). Sporadic fatal B cell lymphomas developed in 11 of 21 GD mice (6–24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed monoclonal gammopathy, but in the control group only one animal of 25 had clonal immunoglobulin abnormalities. Seven of 10 of the B cell lymphomas were found to secrete a monoclonal paraprotein and the lymphomas stained intensely for pan‐B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138⁺ plasma cells frequently surrounded splenic macrophages engorged with glycosphingolipid. Our strain of mice, with inducible deficiency of β‐glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell malignancies, faithfully recapitulates human Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive sphingolipids in the control of B cell proliferation and the pathogenesis of myelomatosis—the most prevalent human cancer associated with this disorder. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High lipoprotein(a) levels with predominance of high molecular weight apo(a) isoforms in patients with pulmonary embolism

Abstract. Lipoprotein(a) (Lp(a)) may interact with the cellular components and protein co-factors of fibrino-lysis. To evaluate the effect of Lp(a) in thromboem-bolic diseases of the venous system, we measured serum levels and the isoform distribution of apo(a) in 25 patients with pulmonary embolism (18 men, 7 women, aged 21—77 years). The control group was adjusted for sex and age ( P = 0.189). Serum Lp(a) concentration was significantly higher in the study group (median: 9.3 vs. 4.3 mg dL^-1). As the distribution of high and low molecular weight subtypes of apo(a) did not show any differences ( P = 0.127) between the two groups, the elevated Lp(a) levels in patients with pulmonary embolism could not be attributed to the investigated kringle-4 polymorphism of the apo(a) gene and therefore other genetic or non-genetic implications are indicated.     

Duodenal Injuries: A Review

Abstract Duodenal injuries are uncommon injuries but are associated with significant morbidity and mortality from a delayed diagnosis in the case of blunt trauma and associated major vascular injuries in penetrating trauma. A simplistic approach with primary repair or resection and anastomosis is ideal for the vast majority. Complex procedures such as pyloric exclusion with or without gastrojejunostomy may be indicated for delayed treatment or severe, high-grade combined pancreato-duodenal injuries. A high index of suspicion and a judicious treatment plan based on a careful consideration of all the available options are crucial for optimal outcome.     

The effect of anemia and blood transfusions on mortality in closed head injury patients

BACKGROUND: The purpose of this study was to determine if anemia in isolated head trauma patients results in a higher mortality rate that would justify a more liberal use of blood transfusions. METHODS: A retrospective review of isolated blunt head trauma patients was performed between January 2001 and December 2006. Comparisons were made between survivors and nonsurvivors regarding demographics, laboratory values, transfusions received, and lengths of stay. RESULTS: There were 788 patients with 735 survivors who were significantly younger (46.3 y +/- 21.5 survivors versus 68.9 y +/- 18.8 nonsurvivors, P < 0.0001) and less injured [(ISS: 14.7 +/- 5.2 survivors versus 23.2 +/- 4.7 nonsurvivors, P < 0.0001), (head abbreviated injury severity: 3.7 +/- 0.7 survivors versus 4.7 +/- 0.5 nonsurvivors, P < 0.0001)] than those who died (n = 53). The survivors also had shorter lengths of stay (days) [(ICU: 2.4 +/- 4.2 versus 5.6 +/- 11.7, P = 0.03), (hospital: 6.3 +/- 9.8 versus 7.8 +/- 14.8, P = 0.02)]. Multivariate logistic regression showed age (OR 1.063, CI 1.042-1.084), ISS (OR 1.376, CI 1.270-1.491), minimum hemoglobin (OR 0.855, CI 0.732-1.000), and total blood products transfused (OR 1.073, CI 1.008-1.142) to be independent predictors of mortality with an ROC of 0.942. Outcome was independent of the operative procedures, hematocrit and packed red blood cells transfused at 24, 48, and 72 h. Hemoglobin levels of <8 mg/dL were more predictive of death than >8 mg/dL (P = 0.01). CONCLUSIONS: This study supports the need to balance mild anemia with judicious blood product use in the head trauma patient. Given the risk with blood product use, each transfusion should be carefully considered and the patient re-evaluated regularly to determine the need for further intervention.     

家兔主动脉粥样斑块内血管内皮生长因子表达与煦少火胶囊的干预

目的:根据《素问·阴阳应象大论》"少火之气壮"的理论研制的"煦少火"复方中药在冠心病的治疗中虽取得较好的效果,但其作用途径需深入探讨。实验观察了其对家兔动脉粥样斑块血管内皮生长因子表达的影响,以验证作用机制。方法:实验于2005-01/2007-05在河北医科大学中西医结合基础实验室完成。①材料:清洁级健康新西兰纯种雄性大白兔64只,体质量(2.5±0.5)kg;煦少火胶囊(由附子、西洋参、石菖蒲、丹参、枳壳等组成);通心络胶囊(石家庄以岭药业股份有限公司),辛伐他汀(北京万生药业有限公司)。②分组:将兔随机分成5组:空白对照组、高脂造模组、辛伐他汀组、通心络组、煦少火胶囊组,每组各12只。③给药:空白对照组喂正常饲料,其余各组均喂高脂肪饲料8周,构建实验性家兔主动脉粥样硬化模型。辛伐他汀组喂服辛伐他汀药液[2.5mg/(kg·d)];通心络组喂服通心络药液[1.0g/(kg·d)];煦少火胶囊组喂服煦少火药液[1.0g/(kg·d)],继续喂养4周。④评估:观察各组血清低密度脂蛋白胆固醇,一氧化氮,乳酸脱氢酶及血管形态学的变化;采用免疫组织化学,反转录聚合酶链式反应及WesternBlot蛋白印迹方法,从不同水平观察煦少火胶囊、通心络及辛伐他汀对动脉粥样斑块血管内皮生长因子表达的影响。结果:4只兔验证模型是否成功。60只家兔进入结果分析。①与空白对照组比较,高脂模型组的血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇增高,高密度脂蛋白胆固醇降低(均P<0.01);血清乳酸脱氢酶增高,一氧化氮降低(均P<0.01);光镜下观察家兔整条主动脉内膜粗糙不平,有大量粥样硬化斑块形成;血管内皮生长因子免疫组织化学染色为强阳性表达(P<0.01),反转录-聚合酶链反应分析呈现强亮度条带(P<0.05),Westernblot蛋白印迹分析增高(P<0.01)。②与高脂模型组比较,煦少火组、通心络组、辛伐他汀组的血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇降低,(均P<0.01);血清乳酸脱氢酶降低,一氧化氮升高(均P<0.01);主动脉内膜粥样硬化斑块较少、程度轻,主要限于主动脉弓段和分叉处(P<0.01);血管内皮生长因子免疫组织化学染色为弱阳性表达(P<0.01),反转录-聚合酶链反应分析可见模糊条带;Western blot蛋白印迹分析降低(均P<0.01)。结论:"煦少火胶囊"减少动脉粥样斑块血管内皮生长因子表达,降低血清低密度脂蛋白胆固醇及乳酸脱氢酶的浓度,升高一氧化氮浓度;其可通过降低血管内皮生长因子在粥样斑块中的表达,实现稳定粥样斑块,延缓动脉粥样硬化进程的作用。     

乙型肝炎病毒疫苗免疫现状及存在的问题

自实行乙型肝炎病毒(HBV)疫苗免疫以来,世界范围内的新生儿和此间出生的儿童乙型肝炎(HB)患病率、HBV携带率平均下降约80％,部分地区下降90％以上．HBV疫苗联合HB免疫球蛋白对阻断母婴传播亦收到较好效果．目前,一些国家HBV疫苗接种范围已扩大到新生儿以外人群．一些新疫苗已经或正在研制并用于HB免疫．但不同国家、地区HB免疫进展并不平衡,国内一些地区对新生儿尚未做到及时全程免疫．现用的HBV疫苗、标准接种方案有其局限性,对含有高危人群的流动人口、囚犯、性乱等人群的HB免疫从管理到系统接种尚未系统实施;对所发现的新老HB患者及HBsAg携带者除疫卡报告和数字统计外,对其本人、家族成员及密切接触者未作系统卫情调查和免疫等处理．HB免疫的任务依然艰巨．     

Common large partial VWF gene deletion does not cause alloantibody formation in the Hungarian type 3 von Willebrand disease population

Summary. Background: Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWF gene and show high variability among different populations. Methods: Twenty‐five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWF gene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Results: Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1‐3) of the 5′‐region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730–10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. Conclusion: We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.     

补肾方药归经与实验性骨质疏松靶器官信号转导分子Smad2的表达

目的:观察补肾方药归经与实验性骨质疏松靶器官信号转导分子Smad2的基因表达,从基因水平研究中医归经理论,为靶向给药提供依据。方法:实验于2004-06/2006-11在河北医科大学中西医结合基础实验室完成。实验分组:选择3个月龄健康雌性SD大鼠(未曾交配)90只,体质量(300±20)g。常规喂养1周后,随机数字表法分成7组:正常对照组、骨质疏松模型组、补肾方药口服组、肾经外贴组、膀胱经外贴组、依普拉封口服组、非经非穴位外贴组,其中正常对照组和骨质疏松模型组每组20只,其余每组各10只。实验处理:除正常对照组喂正常饲料,自由饮水外,其余各组均喂食低钙饲料,饮用蒸馏水,每周2次在大鼠大腿内侧肌肉注射地塞米松1mg/kg体质量,5周后建立骨质疏松模型。实验评估:造模后,用抗骨松穴位贴剂分别外贴肾经和膀胱经穴位、非经非穴位、并与口服补肾方药比较治疗骨质疏松,以双能X线骨密度仪检测连续给药16周后大鼠离体股骨骨密度,采用逆转录-聚合酶链反应、蛋白免疫印迹杂交方法分别检测Smad2的mRNA、蛋白表达,观察其治疗效果。结果:纳入90只大鼠,在实验第5周时,正常对照组、骨质疏松模型组分别取10只,用于验证造模成功,70只进入结果分析。①给药16周后,与骨质疏松模型组比较,补肾方药口服组、肾经外贴组、膀胱经外贴组、依普拉封口服组的股骨骨密度明显增加[(0.161±0.016),(0.206±0.028),(0.196±0.023),(0.202±0.015),(0.205±0.023)g/cm2,P均<0.01]。②应用补肾中药防治16周后,与骨质疏松模型组比较,补肾方药口服组、肾经外贴组、膀胱经外贴组、依普拉封口服组Smad2mRNA的表达明显上调(0.517±0.031,0.524±0.033,0.596±0.033,0.592±0.021,0.583±0.032,P<0.01);Smad2蛋白表达亦明显增强,差异显著(50.901±2.205,71.802±2.100,72.352±2.306,74.012±2.145,73.802±2.203,P<0.01)。结论:①补肾方药通过口服和外贴穴位两种不同途径均发挥“归经”作用,引起靶器官骨组织上调Smad2的表达而有效改善骨密度。②Smad2mRNA表达及蛋白水平的下调可能是原发性骨质疏松症发生的重要机制之一。