Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes

Isolated thrombocytopenia after bone marrow transplantation was investigated in 65 fully engrafted patients surviving at least 60 days posttransplant. Twenty-four patients (37%) developed this complication, which occurred most frequently in patients receiving pretransplant preparation with total body irradiation or busulfan. Two distinct thrombocytopenic syndromes were identified: (1) transient thrombocytopenia (nine patients), in which a normal platelet count (greater than 100,000/microL) was initially established by day +40 but then diminished to less than 10,000 to 45,000/microL on day +40 to +70, with subsequent resolution of the thrombocytopenia by day +90; (2) chronic thrombocytopenia (15 patients), in which a platelet count greater than 100,000/microL was not achieved at any time during the first four months posttransplant, despite the simultaneous presence of normal granulocyte and reticulocyte counts. Although the transient syndrome did not adversely affect prognosis, the chronic syndrome carried a high mortality (21% actuarial survival at 1,000 days posttransplant compared with 67% survival for all patients, P less than .01) and had a high association with both severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. In three of nine patients with transient thrombocytopenia, a temporal association with trimethoprim-sulfamethoxazole administration was observed, whereas in all other patients, no drug association could be found. Bone marrow biopsies in those patients with drug-associated thrombocytopenia showed decreased numbers of megakaryocytes, whereas biopsies in the remainder of the transiently thrombocytopenic patients demonstrated adequate numbers of platelet precursors, suggesting peripheral platelet destruction or ineffective thrombopoiesis. Biopsies in the chronic thrombocytopenic patients included those with and without adequate numbers of platelet precursors, although the association with chronic GVHD was strongest in patients demonstrating normal numbers of megakaryocytes. We conclude that isolated thrombocytopenia represents a significant complication of bone marrow transplantation, particularly in patients receiving hematopoietic ablative preparatory regimens, and that it is the chronic, not the transient, thrombocytopenic syndrome that is associated with an adverse patient prognosis.     

Early innate immune events induced by prolonged cold ischemia exacerbate allograft vasculopathy

Background  

Ischemia/reperfusion induced innate immune injury is inescapable in solid organ transplantation. Prolonged cold ischemia exacerbates the primary manifestation of late graft rejection, allograft vasculopathy (AV). The relationship between prolonged cold ischemia and late graft events is unclear and the subject of this study.     

Temporal clustering of tropical cyclones and its ecosystem impacts

Tropical cyclones have massive economic, social, and ecological impacts, and models of their occurrence influence many planning activities from setting insurance premiums to conservation planning. Most impact models allow for geographically varying cyclone rates but assume that individual storm events occur randomly with constant rate in time. This study analyzes the statistical properties of Atlantic tropical cyclones and shows that local cyclone counts vary in time, with periods of elevated activity followed by relative quiescence. Such temporal clustering is particularly strong in the Caribbean Sea, along the coasts of Belize, Honduras, Costa Rica, Jamaica, the southwest of Haiti, and in the main hurricane development region in the North Atlantic between Africa and the Caribbean. Failing to recognize this natural nonstationarity in cyclone rates can give inaccurate impact predictions. We demonstrate this by exploring cyclone impacts on coral reefs. For a given cyclone rate, we find that clustered events have a less detrimental impact than independent random events. Predictions using a standard random hurricane model were overly pessimistic, predicting reef degradation more than a decade earlier than that expected under clustered disturbance. The presence of clustering allows coral reefs more time to recover to healthier states, but the impacts of clustering will vary from one ecosystem to another.     

Further genotype – phenotype correlations in neurofibromatosis 2

Selvanathan SK, Shenton A, Ferner R, Wallace AJ, Huson SM, Ramsden RT, Evans DG. Further genotype–phenotype correlations in neurofibromatosis 2. Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype–phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non‐VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.     

In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties

Background and purpose:

The histamine H₄ receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H₄ receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine).

Experimental approach:

We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H₄ receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis.

Key results:

A-940894 potently binds to both human and rat histamine H₄ receptors and exhibits considerably lower affinity for the human histamine H₁, H₂ or H₃ receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D₂ levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice.

Conclusions and Implications:

These data suggest that A-940894 is a potent and selective histamine H₄ receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H₄ receptor pharmacology.     

Early diagnosis of asthma in young children by using non-invasive biomarkers of airway inflammation and early lung function measurements: study protocol of a case-control study

Background  

Asthma is the most common chronic disease in childhood, characterized by chronic airway inflammation. There are problems with the diagnosis of asthma in young children since the majority of the children with recurrent asthma-like symptoms is symptom free at 6 years, and does not have asthma. With the conventional diagnostic tools it is not possible to differentiate between preschool children with transient symptoms and children with asthma. The analysis of biomarkers of airway inflammation in exhaled breath is a non-invasive and promising technique to diagnose asthma and monitor inflammation in young children. Moreover, relatively new lung function tests (airway resistance using the interrupter technique) have become available for young children. The primary objective of the ADEM study (Asthma DEtection and Monitoring study), is to develop a non-invasive instrument for an early asthma diagnosis in young children, using exhaled inflammatory markers and early lung function measurements. In addition, aetiological factors, including gene polymorphisms and gene expression profiles, in relation to the development of asthma are studied.     

内皮前体细胞自体移植促进缺血心肌血管的新生

目的:观察内皮前体细胞自体移植后能否促进血管新生、改善心肌灌注、进而改善心脏功能。方法:实验于2004-01/05在解放军总医院心内科实验室完成。①实验分组:雄性新西兰白兔32只,体质量3.0～3.5kg,随机分为治疗组和对照组,每组16只。②实验方法:治疗组自骨髓获取内皮前体细胞培养扩增。结扎动物冠状动脉前降支根部。心电图检测至少5个胸前导联出现ST段显著抬高作为模型制作成功标志。2.5g/L胰蛋白酶消化细胞,洗涤干净后5mL磷酸盐缓冲液悬浮细胞,结扎前降支2h后将细胞悬液从耳静脉注入动物体内,移植细胞数量为(9.8±2.9)×106个/只。对照组注射磷酸盐缓冲液5mL。饲养5周。③实验评估:分别行超声心动图检查和左心室压力曲线检测心脏功能和心肌组织的梗死情况以及通过免疫组织化学检测观察血管密度。结果:纳入新西兰白兔共32只,因前降支细小排除2只。对照组因心功能衰竭和腹泻各死亡1只。治疗组结扎前降支后突发室性心律失常死亡1只。最终27只进入实验。①体外培养的内皮前体细胞生长迅速,能够在2～3周达到预定移植细胞数量。②内皮前体细胞移植5周后,超声心动图检测显示治疗组动物心肌功能指数显著降低(P<0.01),左心室射血分数显著高于对照组(P<0.01),左心室舒张末压明显低于对照组(P<0.05),而等容收缩期左室压力最大上升速率显著升高(P<0.05)。③治疗组心肌梗死面积显著减小(P<0.01),而血管密度明显高于对照组(P<0.01)。④标记细胞主要位于梗死心肌组织,大部分整合至毛细血管中,参与血管新生。结论:内皮前体细胞自体移植能促进缺血心肌血管新生,有效改善缺血心肌的灌注,进而改善心脏功能。     

血管内皮生长因子对梗阻性肾病中肾小管周围毛细血管的调节作用

目的:观察刚断乳雄性SD大鼠单侧输尿管完全梗阻模型中血管内皮生长因子对肾小管周围毛细血管形态学变化的调节作用,探讨血管内皮生长因子在肾病进展中的生物活性作用。方法:实验于2005-03/2006-05在苏州大学儿科研究所完成。①实验材料:30只清洁级刚断乳雄性SD大鼠,体质量50～70g。②实验过程:结扎SD大鼠左侧输尿管建立单侧输尿管完全梗阻模型。于术后0,1,7,14,28d,分别随机选择6只模型大鼠,收获肾脏标本。③实验评估:采用苏木精-伊红染色观察肾积水的严重程度;Masson染色观察肾小管间质纤维化程度;PAS染色观察肾小管萎缩程度;免疫组织化学方法检测肾小管周围毛细血管的密度和血管内皮生长因子的表达水平;原位末端标记法对肾小管周围毛细血管和肾小管上皮细胞进行原位凋亡测定;透射电镜显示超微结构变化;血管内皮生长因子蛋白的表达强度和间质纤维化程度采用Leica图像分析系统检测。结果:①梗阻第1周,肾小管上皮细胞胞浆里的血管内皮生长因子染色在局部有增强,胎肝激酶1阳性肾小管周围毛细血管数量变化不显著,肾小管上皮细胞凋亡很少见,间质纤维化轻。第2,4周,血管内皮生长因子表达逐渐下降,直至在一些肾小管内完全消失。与此同时,胎肝激酶1阳性的肾小管周围毛细血管数量减少,肾小管扩张或萎缩明显,间质纤维化严重。②电镜显示肾小管上皮细胞、肾小管周围毛细血管内皮细胞的死亡形式主要为凋亡。③原位末端标记法显示肾小管上皮细胞凋亡在第14天达到高峰,然后迅速下降。④在梗阻第2周时,原位末端标记法阳性的肾小管周围毛细血管内皮细胞数与血管内皮生长因子表达面积百分比负相关(r=-0.668,P<0.05);肾小管周围毛细血管密度与血管内皮生长因子表达面积百分比正相关(r=0.707,P<0.05),而与肾小管上皮细胞凋亡负相关(r=-0.863,P<0.01)。结论:肾小管周围毛细血管减少与肾小管上皮细胞内血管内皮生长因子的表达不足相关,并与肾小管上皮细胞凋亡相关。