Treatment of thalassaemia: a review of the new approaches on transfusion safety and the novel therapeutics

Lifetime red cell concentrate (RCC) transfusions still account for significant iron overload‐related morbidity and mortality despite chelation therapy in thalassaemia. The cumulative risk of transfusion‐transmitted infections is substantial for thalassaemia patients. Pathogen reduction technologies for RCC may imply a proactive approach against new/re‐emerging pathogens and may be an ultimate safeguard for transfusion safety in the developing countries. Red cell alloimmunization may become a significant clinical challenge in thalassaemia. The availability of high‐throughput molecular blood group antigen typing in the donors may allow perfect match transfusion, beyond ABO‐D and CEK antigen‐matched transfusions. Allogeneic stem cell transplantation (A‐SCT) is the only available curative therapy in thalassaemia, but carries a substantial risk of serious adverse events and mortality. Gene addition therapy for correction of the α‐globin chain imbalance overcomes the problems of donor availability and immunological complications of A‐SCT. Gene editing by either gene disruption or correction emerged as a potential alternative to gene addition therapy in beta‐thalassaemia. A new era of novel therapeutics targeting α/β imbalance, ineffective erythropoiesis or iron dysregulation is unfolding in thalassaemia management, and a number of those now have agents in preclinical and clinical development. Hydroxyurea (HU) may improve globin chain imbalance and be beneficial for reducing or omitting transfusion requirement. Ruxolitinib has allowed steady decrease in spleen volume that may serve for avoiding splenectomy in beta‐thalassaemia. Luspatercept may restore normal erythroid differentiation and improve anaemia. Hepcidin mimetics or TMPRSS6 inhibitors may modulate ineffective erythropoiesis by iron restriction and improve anaemia and organ iron loading.     

血液胆碱酯酶活力测定方法的进一步研究Ⅰ．红细胞／全血胆碱酯酶活力比例及红细胞计数校正酶活力值的研究

应用硫代乙酰胆碱－联硫代双硝基苯甲酸（ＡＳＣｈ－ＤＴＮＢ）比色测定法，测定了４０名健康者及５名贫血者血样的全血胆碱酯酶（ｂｌ－ＣｈＥ）活力值、红细胞胆碱酯酶（ｅ－ＣｈＥ）活力值及血浆胆碱酯酶（ｐ－ＣｈＥ）活力值，探讨它们之间的比例关系并用红细胞计数值（ＲＢＣ）校正酶活力。结果表明：ｅ－ＣｈＥ与ｂ１－ＣｈＥ之间关系密切（ｒ＝０．９４８，Ｐ＜０．００１），ｅ－ＣｈＥ稳定地占ｂｌ－ＣｈＥ的８４．９７％，在质和量两方面验证了以ｂｌ－ＣｈＥ值表示ｅ－ＣｈＥ值的可靠性和可信程度，血液胆碱酯酶（ｂ１ＣｈＥ）活力主要取决于ｅ－ＣｈＥ活力，ＲＢＣ值的离散对ｅ－ＣｈＥ值有极大影响，故用ＲＢＣ值校正ｅ－ＣｈＥ活力，这样可缩小人群测定值的变异度，得到较难确的群体均值；消除男女之间测定值的差异，建立更合理和通用的临界参比值，极大地方便了使用，使血液胆碱酯酶（ＣＨＥ）活力测定法在防治有机磷农药中毒中的应用，更为敏感和特异。     

Determination of Red Blood Cell Velocity by Video Shuttering and Image Analysis

A novel modification of conventional video imaging techniques has been developed to determine the velocity of red blood cells (RBCs), which offers compatibility with existing video-based methods for determining blood oxygenation and hemoglobin concentration. Traditional frame-by-frame analysis of video recordings limits the maximum velocity that can be measured for individual cells in vivo to about 2 mm/s. We have extended this range to about 20 mm/s, by electronic shuttering of an intensified charge-coupled device camera to produce multiple images of a single RBC in the same video frame. RBCs were labeled with fluorescein isothiocyanate and the labeled cells (FRBCs) were used as probes to determine RBC velocities in microvessels of the hamster retractor muscle. Velocity was computed as the product of the distance between centroids of two consecutive image positions of a FRBC and the shuttering frequency of the camera intensifier. In vitro calibrations of the system using FRBC and Sephadex beads coated onto a rotating disk yielded an average coefficient of variation of about 6%. Flow conservation studies at bifurcations indicated that the maximum diameter of microvessels below which all the FRBCs in the lumen could be detected was 50 m. The technique was used to estimate mean-FRBC velocity distributions in vessels with diameters ranging from 8 to 50 m. The mean-FRBC velocity profiles were found to be blunter than would be expected for Poiseuille flow. Single FRBCs tracked along an unbranched arteriole exhibited significant temporal variations in velocity. © 1999 Biomedical Engineering Society. PAC99: 8719Tt, 8717Jj, 4279Pw, 8780Tq, 8719Ff, 4230Va, 0705Pj     

珊瑚涂层人工骨的制备及溶血实验研究

目的根据生物工程及化工等原理,制备珊瑚人工骨,并检测此珊瑚(Coral)复合人工骨的血液相容性。方法将制备的珊瑚复合人工骨、按照国际标准化组织和我国国家标准规定要求,采用将珊瑚复合人工骨及其浸提液与抗凝稀释兔血直接接触,测定红细胞释放的血红蛋白量(OD值),将测得的OD值换算为溶血率。结果珊瑚复合人工骨材料浸提液组的溶血率为1．81％,材料与血液直接接触组溶血率为1．41％,阴性对照组和阳性对照组溶血率分别为0％、100％。结论珊瑚复合人工骨材料无溶血作用,血液相容性良好。     

RBC膜铁蛋白的免疫检测及在CRF中的初步研究

本文应用免疫印迹法,观察到CRF患者红细胞膜上有铁蛋白。铁蛋白的RIA测定结果表明:CRF组红细胞膜上铁蛋白含量明显高于对照组(P<0.001),而且与Hb呈负相关(r=-0.637);与血清Cr和BUN呈正相关(r=0.535和r=0.712)。提示患者RBC膜铁蛋白含量的改变,具有一定的临床意义。     

In vitro biosynthesis and core glycosylation of the histidine-rich protein of Plasmodium lophurae

We have characterized the early biosynthetic forms of the histidine-rich protein (HisRP), a major, granule-bound protein (Mr 58 000) of the avian malarial parasite Plasmodium lophurae. We have translated poly(A)-containing, size-selected parasite mRNA in the wheat germ cell-free system in the presence of [3H]histidine. HisRP was synthesized as a larger precursor (Mr 63 000). When dog pancreas microsomal membranes were present in the cell-free system during translation, a still larger form of HisRP (Mr 66 000) was detected. This larger form was segregated into the dog pancreas microsomal vesicles and was core glycosylated. Presumably, it corresponds to an intermediate form located in the parasite rough endoplasmic reticulum (RER). The difference in the Mr of approx. 8 000 between this RER associated 'pro' form and the granule-bound, mature form of HisRP suggests that proteolytic processing occurs upon transport from the RER to the granule. Segregation and core glycosylation were strictly coupled to translation and were not observed upon posttranslational addition of microsomal membranes. Thus, the early events in the biosynthesis of HisRP are similar to those established for secretory and lysosomal proteins.     

Three Kinds of Foamy Cells in the Spleen: Comparative Histochemical and Ultrastructural Studies

By light and electron microscopy, we observed foamy cells in the spleens from a patient with hemolytic anemia due to red cell adenosine deaminase (ADA) overproduction, a patient with rheumatoid arthritis (RA) treated with gold, and patients with idiopathic thrombocytopenic purpura (ITP)

The foamy cells associated with red cell ADA overproduction were essentially similar to Gaucher-like cells described in patients with thalassemia, and it was suggested that the accelerated destruction of red cells was one of the factors responsible for the development of foamy cells. Foamy cells in ITP and RA were closely associated with an increased destruction of platelets in the spleen. Morphologic transitions between phagocytosed platelets and myelinlike materials were traced in these disorders. In RA, however, foamy cells were heterogeneous from an ultrastructural standpoint, with different cytoplasmic inclusions. In addition to myelinlike materials, dense bodies, vacuoles with flocculent materials, and gold were noted in most of foamy cells. As gold compounds are known to inhibit lysosomal enzymes, we surmise that an acquired disturbance in lysosomal digestion is partially responsible for the accumulation of intermediate metabolites.

In the pathogenesis of foamy cells associated with blood cell dyscrasia, the accelerated destruction of blood cells and/or acquired disorders in catabolic pathways within the macrophages are suggested to be the underlying mechanism of an intralysosomal accumulation of incompletely degraded cellular debris.     

基于暗视场荧光图像分析的大鼠微血管流速测量系统的建立

将荧光标记的自身红细胞注入SD大鼠体内,在荧光显微镜下观测标记红细胞在大鼠微血管中的流动情况,并通过显微摄像系统将整个过程以视频信号的形式存贮。使用视频采集卡将流速变化过程回放采样,得到暗视场下的荧光图像。然后利用帧图像分离出奇偶场的图像分析方法测定血流速度。在该系统下测量流动小室中荧光小球的流速,得到的测量值与实际值之间的误差小于7%,两者没明显的差异(P>0.05),流速测量的上限为9.6mm/s。并在大鼠微循环障碍研究中,应用此系统得到了血流速度随时间变化的情况。