The Scientific World Journal: Hematology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate Sun, 21 Jun 2015 12:43:03 +0000 Although Methotrexate (MTX) is an effective drug for the treatment of acute lymphoblastic leukemia (ALL), the toxicity remains a significant problem. In this prospective study, fifty-four patients with ALL were enrolled. 3 g or 5 g MTX/m2 was administered over 24 hours. Serum MTX concentrations were determined in 24, 48, and 96 hours after MTX infusion. Serum creatinine concentrations and creatinine clearance rate (CCR) were determined before and 24 and 48 hours after MTX infusion. A total of 173 courses of MTX infusion were administered. The serum creatinine concentrations did not change much after MTX infusion while the CCR was gradually decreased. MTX clearance status was independently related to CCR decrease, with the risk of 8.07 to develop renal impairment in patients with delayed MTX elimination. Serum creatinine concentration, serum creatinine ratio, CCR, and CCR ratio at 24 hours were all related to MTX elimination delay. Patients with serum creatinine level >35.0 μmol/L, creatinine ratio >1.129, or CCR <100.0 mL/min were more likely to undergo MTX elimination delay. In conclusion, MTX could induce transient renal impairment and compromised renal function will delay MTX clearance. The serum creatinine concentration and the ratio and CCR are useful tools for evaluating MTX elimination status. Shi-Long Yang, Fen-Ying Zhao, Hua Song, Di-Ying Shen, and Xiao-Jun Xu Copyright © 2015 Shi-Long Yang et al. All rights reserved. Morphine for the Treatment of Pain in Sickle Cell Disease Mon, 12 Jan 2015 09:27:30 +0000 Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia. Mihir Gupta, Lilian Msambichaka, Samir K. Ballas, and Kalpna Gupta Copyright © 2015 Mihir Gupta et al. All rights reserved. Haemophilia A: Pharmacoeconomic Review of Prophylaxis Treatment versus On-Demand Mon, 05 Jan 2015 13:44:57 +0000 Objectives. Haemophilia A is a congenital disorder of coagulation that mainly affects males and causes a considerable use of resources, especially when hemophilic patients are treated with prophylaxis. The aim of the present review was to discuss and appraise the methodological aspects and results of published economic evaluations of haemophilia A treatments in the last decade. Methods. The literature search, performed by consulting four engines, covered studies published between 2002 and 2014. Full economic evaluations published in English language were identified and included in the review. A quality assessment of the studies was also carried out based on Drummond’s checklist. Results. After careful evaluations of the identified records, 5 studies were reviewed. Primary and secondary prophylaxis resulted cost-effective compared to on-demand therapy: the ICER of primary prophylaxis ranged from €40.236 to €59.315/QALY gained, while the ICER of secondary prophylaxis was €40.229/QALY gained. Furthermore, 60% were high quality and 40% were medium quality studies. Conclusions. The review underlines the cost-effectiveness of prophylaxis versus on-demand treatment and the different methodological approaches applied. Further economic evaluations are required with models that reflect the clinical reality and consumption of resources in each country. Brigid Unim, Maria Assunta Veneziano, Antonio Boccia, Walter Ricciardi, and Giuseppe La Torre Copyright © 2015 Brigid Unim et al. All rights reserved. The Role of Hibiscus sabdariffa L. (Roselle) in Maintenance of Ex Vivo Murine Bone Marrow-Derived Hematopoietic Stem Cells Tue, 21 Oct 2014 11:20:58 +0000 Hematopoietic stem cells- (HSCs-) based therapy requires ex vivo expansion of HSCs prior to therapeutic use. However, ex vivo culture was reported to promote excessive production of reactive oxygen species (ROS), exposing HSCs to oxidative damage. Efforts to overcome this limitation include the use of antioxidants. In this study, the role of Hibiscus sabdariffa L. (Roselle) in maintenance of cultured murine bone marrow-derived HSCs was investigated. Aqueous extract of Roselle was added at varying concentrations (0–1000 ng/mL) for 24 hours to the freshly isolated murine bone marrow cells (BMCs) cultures. Effects of Roselle on cell viability, reactive oxygen species (ROS) production, glutathione (GSH) level, superoxide dismutase (SOD) activity, and DNA damage were investigated. Roselle enhanced the survival of BMCs at 500 and 1000 ng/mL, increased survival of Sca-1+ cells (HSCs) at 500 ng/mL, and maintained HSCs phenotype as shown from nonremarkable changes of surface marker antigen (Sca-1) expression in all experimental groups. Roselle increased the GSH level and SOD activity but the level of reactive oxygen species (ROS) was unaffected. Moreover, Roselle showed significant cellular genoprotective potency against H2O2-induced DNA damage. Conclusively, Roselle shows novel property as potential supplement and genoprotectant against oxidative damage to cultured HSCs. Zariyantey Abdul Hamid, Winnie Hii Lin Lin, Basma Jibril Abdalla, Ong Bee Yuen, Elda Surhaida Latif, Jamaludin Mohamed, Nor Fadilah Rajab, Chow Paik Wah, Muhd Khairul Akmal Wak Harto, and Siti Balkis Budin Copyright © 2014 Zariyantey Abdul Hamid et al. All rights reserved. Effects of Voltage-Gated K+ Channel on Cell Proliferation in Multiple Myeloma Sun, 08 Jun 2014 00:00:00 +0000 Objective. To study the effects and underlying mechanisms of voltage-gated K+ channels on the proliferation of multiple myeloma cells. Methods. RPMI-8226 MM cell line was used for the experiments. Voltage-gated K+ currents and the resting potential were recorded by whole-cell patch-clamp technique. RT-PCR detected Kv channel mRNA expression. Cell viability was analyzed with MTT assay. Cell counting system was employed to monitor cell proliferation. DNA contents and cell volume were analyzed by flow cytometry. Results. Currents recorded in RPMI-8226 cells were confirmed to be voltage-gated K+ channels. A high level of Kv1.3 mRNA was detected but no Kv3.1 mRNA was detected in RPMI-8226 cells. Voltage-gated K+ channel blocker 4-aminopyridine (4-AP) (2 mM) depolarized the resting potential from −42 ± 1.7 mV to −31.8 ± 2.8 mV . The results of MTT assay showed that there was no significant cytotoxicity to RPMI-8226 cells when the 4-AP concentration was lower than 4 mM. 4-AP arrested cell cycle in G0/G1 phase. Cells were synchronized at the G1/S boundary by treatment of aphidicolin and released from the blockage by replacing the medium with normal culture medium or with culture medium containing 2 mM 4-AP. 4-AP produced no significant inhibitory effect on cell cycle compared with control cells . Conclusions. In RPMI-8226, voltage-gated K+ channels are involved in proliferation and cell cycle progression its influence on the resting potential and cell volume may be responsible for this process; the inhibitory effect of the voltage-gated K+ channel blocker on RPMI-8226 cell proliferation is a phase-specific event. Wei Wang, Yuying Fan, Shuye Wang, Lianjie Wang, Wanting He, Qiu Zhang, and Xiaoxia Li Copyright © 2014 Wei Wang et al. All rights reserved. Overview of Platelet Physiology: Its Hemostatic and Nonhemostatic Role in Disease Pathogenesis Mon, 03 Mar 2014 07:23:09 +0000 Platelets are small anucleate cell fragments that circulate in blood playing crucial role in managing vascular integrity and regulating hemostasis. Platelets are also involved in the fundamental biological process of chronic inflammation associated with disease pathology. Platelet indices like mean platelets volume (MPV), platelets distributed width (PDW), and platelet crit (PCT) are useful as cheap noninvasive biomarkers for assessing the diseased states. Dynamic platelets bear distinct morphology, where α and dense granule are actively involved in secretion of molecules like GPIIb , IIIa, fibrinogen, vWf, catecholamines, serotonin, calcium, ATP, ADP, and so forth, which are involved in aggregation. Differential expressions of surface receptors like CD36, CD41, CD61 and so forth have also been quantitated in several diseases. Platelet clinical research faces challenges due to the vulnerable nature of platelet structure functions and lack of accurate assay techniques. But recent advancement in flow cytometry inputs huge progress in the field of platelets study. Platelets activation and dysfunction have been implicated in diabetes, renal diseases, tumorigenesis, Alzheimer’s, and CVD. In conclusion, this paper elucidates that platelets are not that innocent as they keep showing and thus numerous novel platelet biomarkers are upcoming very soon in the field of clinical research which can be important for predicting and diagnosing disease state. Kakali Ghoshal and Maitree Bhattacharyya Copyright © 2014 Kakali Ghoshal and Maitree Bhattacharyya. All rights reserved. Autoimmune Complications after Hematopoietic Stem Cell Transplantation in Children with Nonmalignant Disorders Sun, 19 Jan 2014 10:56:42 +0000 Background. Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for many nonmalignant disorders, such as autoimmune disorders, inborn metabolic disorders, hemoglobinopathies, and immunodeficiency disorders. Autoimmune complications (AICs) after HSCT, such as autoimmune cytopenias, autoimmune hepatitis, primary biliary cirrhosis, and autoimmune cutaneous manifestations, are still neither well defined nor characterized. Patients. Between 2000 and 2012, 92 patients (47 males, 45 females) were treated with HSCT in our hospital, 51 with congenital hemoglobinopathies, 19 with primary immunodeficiency disease, 10 with metabolic disorders, five with Fanconi anemia, three with aplastic anemia, and four with familial hemophagocytic lymphohistiocytosis. Results. Mean age at HSCT was 6.4 years (range, 0.2–32 years) and mean duration of followup after HSCT was 6.81 years (range, 1–11 years). Sixteen (17.4%) patients developed chronic GVHD and five (5.4%) showed sclerodermatous features. Five (5.4%) patients were diagnosed with scleroderma manifestations, six (6.5%) with vitiligo, six (6.5%) with autoimmune hemolytic anemia (AIHA), six (6.5%) with idiopathic thrombocytopenia, three (3.3%) with mild leucopenia, two (2.2%) with aplastic anemia, two (2.2%) (one boy, one girl) with autoimmune thyroid disease, and one (1.1%) with autoimmune hepatitis. Conclusions. It was concluded that AICs are clinically significant complications after HSCT that contribute to morbidity but not to mortality. AICs are more frequent after HSCT for metabolic disorders, and sclerodermatous GVHD is more significant in children who underwent allogeneic HSCT for hemoglobinopathies. The potential to identify risk factors for AICs could lead to less morbidity and mortality and to maintain the patient’s quality of life. Abdalla Khalil, Irena Zaidman, Reuven Bergman, Ronit Elhasid, and Myriam Weyl Ben-Arush Copyright © 2014 Abdalla Khalil et al. All rights reserved. Influence of Febrile Neutropenia Period on Plasma Viscosity at Malignancy Sun, 27 Oct 2013 13:11:50 +0000 Cancer, chemotherapy, and infections all together make changes in blood rheology and may affect the defense mechanisms by changing the thrombocyte function and endothelial cell. We have examined changes of blood rheology on plasma viscosity to put on probable following criteria for starting the treatment of febrile neutropenia immediately. A total of 27 postchemotherapy patients (16 males and 11 females) with febrile neutropenia diagnosed according to international guidelines have been included into the study. The plasma viscosity of the patients whose febrile neutropenia has been successfully treated was also measured to assess the impact of the duration of neutropenia on viscosity. The plasma viscosities of the patients were significantly higher during neutropenic episode than in nonneutropenic state () except for alkaline phosphatase. All study parameters, particularly acute phase reactants, were statistically similar during both states. In the correlation of analysis with study parameters and stages, significant correlation was not observed between plasma viscosity alteration and leukocyte-neutrophil alteration, also other study parameters. We have demonstrated significantly elevated plasma viscosity in our patients during febrile neutropenic episode. Despite normal values of various parameters known to trigger plasma viscosity, particularly fibrinogen, it can be easily argued that the main mechanism may be the endothelial injury during infectious process and immune response mediated microcirculatory blood flow alterations. Ibrahim Tek, Selami Kocak Toprak, Efe Hasdemir, Samed Rahatli, and Aysegül Yesilkaya Copyright © 2013 Ibrahim Tek et al. All rights reserved. The Effect of Reagents Mimicking Oxidative Stress on Fibrinogen Function Mon, 21 Oct 2013 16:20:57 +0000 Fibrinogen is one of the plasma proteins most susceptible to oxidative modification. It has been suggested that modification of fibrinogen may cause thrombotic/bleeding complications associated with many pathophysiological states of organism. We exposed fibrinogen molecules to three different modification reagents—malondialdehyde, sodium hypochlorite, and peroxynitrite—that are presented to various degrees in different stages of oxidative stress. We studied the changes in fibrin network formation and platelet interactions with modified fibrinogens under flow conditions. The fastest modification of fibrinogen was caused by hypochlorite. Fibers from fibrinogen modified with either reagent were thinner in comparison with control fibers. We found that platelet dynamic adhesion was significantly lower on fibrinogen modified with malondialdehyde and significantly higher on fibrinogen modified either with hypochlorite or peroxynitrite reflecting different prothrombotic/antithrombotic properties of oxidatively modified fibrinogens. It seems that, in the complex reactions ongoing in living organisms at conditions of oxidation stress, hypochlorite modifies proteins (e.g., fibrinogen) faster and more preferentially than malondialdehyde. It suggests that the prothrombotic effects of prior fibrinogen modifications may outweigh the antithrombotic effect of malondialdehyde-modified fibrinogen in real living systems. Jana Štikarová, Roman Kotlín, Tomáš Riedel, Jiří Suttnar, Kristýna Pimková, Leona Chrastinová, and Jan E. Dyr Copyright © 2013 Jana Štikarová et al. All rights reserved. Glutathione Redox System in β-Thalassemia/Hb E Patients Mon, 07 Oct 2013 11:38:40 +0000 β-thalassemia/Hb E is known to cause oxidative stress induced by iron overload. The glutathione system is the major endogenous antioxidant that protects animal cells from oxidative damage. This study aimed to determine the effect of disease state and splenectomy on redox status expressed by whole blood glutathione (GSH)/glutathione disulfide (GSSG) and also to evaluate glutathione-related responses to oxidation in β-thalassemia/Hb E patients. Twenty-seven normal subjects and 25 β-thalassemia/Hb E patients were recruited and blood was collected. The GSH/GSSG ratio, activities of glutathione-related enzymes, hematological parameters, and serum ferritin levels were determined in individuals. Patients had high iron-induced oxidative stress, shown as significantly increased serum ferritin, a decreased GSH/GSSG ratio, and increased activities of glutathione-related enzymes. Splenectomy increased serum ferritin levels and decreased GSH levels concomitant with unchanged glutathione-related enzyme activities. The redox ratio had a positive correlation with hemoglobin levels and negative correlation with levels of serum ferritin. The glutathione system may be the body’s first-line defense used against oxidative stress and to maintain redox homeostasis in thalassemic patients based on the significant correlations between the GSH/GSSH ratio and degree of anemia or body iron stores. Ruchaneekorn W. Kalpravidh, Thongchai Tangjaidee, Suneerat Hatairaktham, Ratiya Charoensakdi, Narumol Panichkul, Noppadol Siritanaratkul, and Suthat Fucharoen Copyright © 2013 Ruchaneekorn W. Kalpravidh et al. All rights reserved. Updates in Hemoglobinopathies Thu, 03 Oct 2013 17:49:59 +0000 Youssef Al-Tonbary, Fernando Tricta, Amal El-Beshlawy, Mohamed Ahmed Badr, and Ahmed Mansour Copyright © 2013 Youssef Al-Tonbary et al. All rights reserved. Sickle Cell Disease: New Opportunities and Challenges in Africa Thu, 19 Sep 2013 13:41:02 +0000 Sickle cell disease (SCD) is one of the most common genetic causes of illness and death in the world. This is a review of SCD in Africa, which bears the highest burden of disease. The first section provides an introduction to the molecular basis of SCD and the pathophysiological mechanism of selected clinical events. The second section discusses the epidemiology of the disease (prevalence, morbidity, and mortality), at global level and within Africa. The third section discusses the laboratory diagnosis and management of SCD, emphasizing strategies that been have proven to be effective in areas with limited resources. Throughout the review, specific activities that require evidence to guide healthcare in Africa, as well as strategic areas for further research, will be highlighted. J. Makani, S. F. Ofori-Acquah, O. Nnodu, A. Wonkam, and K. Ohene-Frempong Copyright © 2013 J. Makani et al. All rights reserved. Three-Dimensional Gait Analysis Can Shed New Light on Walking in Patients with Haemophilia Mon, 13 May 2013 16:53:22 +0000 In patients with haemophilia (PWH) (from Greek “blood love”), the long-term consequences of repeated haemarthrosis include cartilage damage and irreversible arthropathy, resulting in severe impairments in locomotion. Quantifying the extent of joint damage is therefore important in order to prevent disease progression and compare the efficacy of treatment strategies. Musculoskeletal impairments in PWH may stem from structural and functional abnormalities, which have traditionally been evaluated radiologically or clinically. However, these examinations are performed in a supine position (i.e., non-weight-bearing condition). We therefore suggest three-dimensional gait analysis (3DGA) as an innovative approach designed to focus on the functional component of the joint during the act of walking. This is of the utmost importance, as pain induced by weight-bearing activities influences the functional performance of the arthropathic joints significantly. This review endeavors to improve our knowledge of the biomechanical consequences of multiple arthropathies on gait pattern in adult patients with haemophilia using 3DGA. In PWH with arthropathy, the more the joint function was altered, the more the metabolic energy was consumed. 3DGA analysis could highlight the effect of an orthopedic disorder in PWH during walking. Indeed, mechanical and metabolic impairments were correlated to the progressive loss of active mobility into the joints. Sébastien Lobet, Christine Detrembleur, Firas Massaad, and Cedric Hermans Copyright © 2013 Sébastien Lobet et al. All rights reserved. Ineffective Erythropoiesis in β-Thalassemia Thu, 28 Mar 2013 18:35:44 +0000 In humans, β-thalassemia dyserythropoiesis is characterized by expansion of early erythroid precursors and erythroid progenitors and then ineffective erythropoiesis. This ineffective erythropoiesis is defined as a suboptimal production of mature erythrocytes originating from a proliferating pool of immature erythroblasts. It is characterized by (1) accelerated erythroid differentiation, (2) maturation blockade at the polychromatophilic stage, and (3) death of erythroid precursors. Despite extensive knowledge of molecular defects causing β-thalassemia, less is known about the mechanisms responsible for ineffective erythropoiesis. In this paper, we will focus on the underlying mechanisms leading to premature death of thalassemic erythroid precursors in the bone marrow. Jean-Antoine Ribeil, Jean-Benoit Arlet, Michael Dussiot, Ivan Cruz Moura, Geneviève Courtois, and Olivier Hermine Copyright © 2013 Jean-Antoine Ribeil et al. All rights reserved. Biologic Complexity in Sickle Cell Disease: Implications for Developing Targeted Therapeutics Mon, 25 Mar 2013 11:41:00 +0000 Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstrated in vivo before investing in expensive and labor-intensive clinical trials. Beatrice E. Gee Copyright © 2013 Beatrice E. Gee. All rights reserved. The Impact of Migrations on the Health Services for Rare Diseases in Europe: The Example of Haemoglobin Disorders Mon, 18 Mar 2013 09:48:13 +0000 Migration from different parts of the world to several European countries leads to the introduction of haemoglobinopathy genes into the population, which creates several demanding needs for prevention and treatment services for Hb disorders. In this paper we examined the degree to which European health services have responded to such challenges and in particular to health services necessary to address the needs of patients with thalassaemia and sickle cell disease (SCD). Information on available services was obtained from international organizations, collaborated European project, and the Thalassaemia International Federation (TIF) Databases, which include information from published surveys, registries, field trips, and delegation visits to countries and regions by expert advisors, local associations, and other collaborators’ reports. Results show that countries with traditional strong prevention and treatment programs are well prepared to face the above challenges, while others are urgently needed to address these problems in a systematic way. The Thalassaemia International Federation (TIF) is committed to monitor the progress, raise awareness, and support the promotion of more immigrant-oriented health policies to ensure their integration in society and their access to appropriate, adequate, and timely health services. Michalis Angastiniotis, Joan-Lluis Vives Corrons, Elpidoforos S. Soteriades, and Androulla Eleftheriou Copyright © 2013 Michalis Angastiniotis et al. All rights reserved. Phytomedicines and Nutraceuticals: Alternative Therapeutics for Sickle Cell Anemia Thu, 14 Feb 2013 17:25:27 +0000 Sickle cell anemia is a genetically inherited disease in which the “SS” individual possesses an abnormal beta globin gene. A single base substitution in the gene encoding the human β-globin subunit results in replacement of β6 glutamic acid by valine, leading to the devastating clinical manifestations of sickle cell disease. This substitution causes drastic reduction in the solubility of sickle cell hemoglobin (HbS) when deoxygenated. Under these conditions, the HbS molecules polymerize to form long crystalline intracellular mass of fibers which are responsible for the deformation of the biconcave disc shaped erythrocyte into a sickle shape. First-line clinical management of sickle cell anemia include, use of hydroxyurea, folic acid, amino acids supplementation, penicillinprophylaxis, and antimalarial prophylaxis to manage the condition and blood transfusions to stabilize the patient's hemoglobin level. These are quite expensive and have attendant risk factors. However, a bright ray of hope involving research into antisickling properties of medicinal plants has been rewarding. This alternative therapy using phytomedicines has proven to not only reduce crisis but also reverse sickling (in vitro). The immense benefits of phytomedicines and nutraceuticals used in the management of sickle cell anemia are discussed in this paper. Ngozi Awa Imaga Copyright © 2013 Ngozi Awa Imaga. All rights reserved. Erratum to “Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management” Thu, 14 Feb 2013 15:53:14 +0000 Samir K. Ballas, Muge R. Kesen, Morton F. Goldberg, Gerard A. Lutty, Carlton Dampier, Ifeyinwa Osunkwo, Winfred C. Wang, Carolyn Hoppe, Ward Hagar, Deepika S. Darbari, and Punam Malik Copyright © 2013 Samir K. Ballas et al. All rights reserved. Does Thrombocyte Size Give Us an Idea about Thrombocytosis Etiology? Mon, 10 Sep 2012 14:13:49 +0000 In the presence of a pathogenetic mutation in JAK2 or MPL, a differential diagnosis of essential thrombocythemia (ET) from reactive causes is relatively simple. However, in patients with suspected ET who lack JAK2 and MPL mutations, the exclusion of secondary causes is especially important. The study was aimed to explore the clinical application of particularly mean platelet volume (MPV), hemoglobin, red blood cell indices, white blood cell, serum iron profile, and C-reactive protein level in the differential diagnosis of thrombocytosis. Medical records of 49 patients, consisting of reactive thrombocytosis (RT) and ET were retrospectively reviewed. The mean MPV level in RT group was 7.49 fL, and in ET group was 8.80 fL (). A cutoff point of <8.33 fL was found to have significant predictive value according to ROC curve analysis. This cutoff was associated with 83% positive predictive value (PPV) and 74% negative predictive value (NPV) in the diagnosis of ET and had a sensitivity of 65% and specificity of 89% for ET. Investigation of MPV is cheap, quick, and noninvasive, and may serve as a predictor of primary thrombocytosis. High sensitivity, specificity, PPV, and NPV enable this test an important tool and a possible surrogate marker in clinical practice. Selami Kocak Toprak, Betul Erismis, Sema Karakus, Nazmiye Kursun, Aysegul Haberal, and Mustafa Gurhan Ulusoy Copyright © 2012 Selami Kocak Toprak et al. All rights reserved. Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management Wed, 01 Aug 2012 11:15:18 +0000 The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes. Samir K. Ballas, Muge R. Kesen, Morton F. Goldberg, Gerard A. Lutty, Carlton Dampier, Ifeyinwa Osunkwo, Winfred C. Wang, Carolyn Hoppe, Ward Hagar, Deepika S. Darbari, and Punam Malik Copyright © 2012 Samir K. Ballas et al. All rights reserved. Prognostic Assessment in Patients with Indolent B-Cell Lymphomas Tue, 31 Jul 2012 10:26:10 +0000 Follicular lymphoma (FL) is an indolent lymphoma with long median survival. Many studies have been performed to build up prognostic scores potentially useful to identify patients with poorer outcome. In 2004, an international consortium coordinated by the International Follicular Lymphoma Prognostic Factor project was established and a new prognostic study was launched (FLIPI2) using progression-free survival (PFS) as main endpoint and integrating all the modern parameters prospectively collected. Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Each entity is characterized by unique clinicobiologic features. Some studies have been focused on prognostic factors in single lymphoma subtypes, with the development of specific-entity scores based on retrospective series, for instance splenic marginal zone lymphoma (SMZL). A widely accepted prognostic tool for clinical usage for indolent non-follicular B-cell lymphomas is largely awaited. In this paper we summarized the current evidence regarding prognostic assessment of indolent follicular and non-follicular lymphomas. Luca Arcaini, Sara Rattotti, Manuel Gotti, and Stefano Luminari Copyright © 2012 Luca Arcaini et al. All rights reserved. The Expanding Family of Bone Marrow Homing Factors for Hematopoietic Stem Cells: Stromal Derived Factor 1 Is Not the Only Player in the Game Mon, 04 Jun 2012 15:52:48 +0000 The α-chemokine stromal derived factor 1 (SDF-1), which binds to the CXCR4 and CXCR7 receptors, directs migration and homing of CXCR4+ hematopoietic stem/progenitor cells (HSPCs) to bone marrow (BM) and plays a crucial role in retention of these cells in stem cell niches. However, this unique role of SDF-1 has been recently challenged by several observations supporting SDF-1-CXCR4-independent BM homing. Specifically, it has been demonstrated that HSPCs respond robustly to some bioactive lipids, such as sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), and migrate in response to gradients of certain extracellular nucleotides, including uridine triphosphate (UTP) and adenosine triphosphate (ATP). Moreover, the responsiveness of HSPCs to an SDF-1 gradient is enhanced by some elements of innate immunity (e.g., C3 complement cascade cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL-37 or β2-defensin) as well as prostaglandin E2 (PGE2). Since all these factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors supporting, and in some situations even replacing, the SDF-1-CXCR4 axis. Mariusz Z. Ratajczak, ChiHwa Kim, Anna Janowska-Wieczorek, and Janina Ratajczak Copyright © 2012 Mariusz Z. Ratajczak et al. All rights reserved. Ferrous versus Ferric Oral Iron Formulations for the Treatment of Iron Deficiency: A Clinical Overview Wed, 02 May 2012 13:35:52 +0000 Iron deficiency anaemia represents a major public health problem, particularly in infants, young children, pregnant women, and females with heavy menses. Oral iron supplementation is a cheap, safe, and effective means of increasing haemoglobin levels and restoring iron stores to prevent and correct iron deficiency. Many preparations are available, varying widely in dosage, formulation (quick or prolonged release), and chemical state (ferrous or ferric form). The debate over the advantages of ferrous versus ferric formulations is ongoing. In this literature review, the tolerability and efficacy of ferrous versus ferric iron formulations are evaluated. We focused on studies comparing ferrous sulphate preparations with ferric iron polymaltose complex preparations, the two predominant forms of iron used. Current data show that slow-release ferrous sulphate preparations remain the established and standard treatment of iron deficiency, irrespective of the indication, given their good bioavailability, efficacy, and acceptable tolerability demonstrated in several large clinical studies. Palacios Santiago Copyright © 2012 Palacios Santiago. All rights reserved. CD4+CD25highCD127low Regulatory T Cells in Peripheral Blood Are Not an Independent Factor for Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Tue, 01 May 2012 16:01:11 +0000 Background. The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (HSCT) largely relies on the graft-versus-leukemia (GVL) effect. Uncontrolled graft-versus-host disease (GVHD) is a feared complication of HSCT. Regulatory T cells (Treg) are a subset of CD4+ T-helper cells believed to maintain tolerance after HSCT. It remains unclear whether low peripheral blood Treg have an impact on the risk for acute (aGVHD) and chronic GVHD (cGVHD). Methods. In this paper we enumerated the CD4+CD25highCD127low Treg in the peripheral blood of 84 patients after at least 150 days from HSCT and in 20 healthy age-matched controls. Results. Although similar mean lymphocyte counts were found in patients and controls, CD3+CD4+ T-cell counts were significantly lower in patients. Patients also had significantly lower Treg percentages among lymphocytes as compared to controls. Patients with cGVHD had even higher percentages of Treg if compared to patients without cGVHD. In multivariate analysis, Treg percentages were not an independent factor for cGVHD. Conclusions. This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity. Jolanta B. Perz, Selma Gürel, Stefan O. Schonland, Ute Hegenbart, Anthony D. Ho, and Peter Dreger Copyright © 2012 Jolanta B. Perz et al. All rights reserved. LDL-Apheresis: Technical and Clinical Aspects Mon, 30 Apr 2012 11:40:54 +0000 The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) levels, and coronary heart disease refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are five different LDL-apheresis systems available: cascade filtration or lipid filtration, immunoadsorption, heparin-induced LDL precipitation, dextran sulfate LDL adsorption, and the LDL hemoperfusion. There is a strong correlation between hyperlipidemia and atherosclerosis. Besides the elimination of other risk factors, in severe hyperlipidemia therapeutic strategies should focus on a drastic reduction of serum lipoproteins. Despite maximum conventional therapy with a combination of different kinds of lipid-lowering drugs, sometimes the goal of therapy cannot be reached. Hence, in such patients, treatment with LDL-apheresis is indicated. Technical and clinical aspects of these five different LDL-apheresis methods are shown here. There were no significant differences with respect to or concerning all cholesterols, or triglycerides observed. With respect to elevated lipoprotein (a) levels, however, the immunoadsorption method seems to be most effective. The different published data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe hyperlipidemia refractory to maximum conservative therapy is effective and safe in long-term application. Rolf Bambauer, Carolin Bambauer, Boris Lehmann, Reinhard Latza, and Ralf Schiel Copyright © 2012 Rolf Bambauer et al. All rights reserved. Prognostic Value of Hepatocyte Growth Factor, Syndecan-1, and Osteopontin in Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance Thu, 26 Apr 2012 15:43:56 +0000 Our aim was to compare serum levels of selected biological parameters in different phases of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) to determine their diagnostic and prognostic potential. A cohort of 234 individuals was assessed for serum levels of hepatocyte growth factor (HGF), syndecan-1/CD138 (SYN), and osteopontin (OPN). The patients with MM (𝑁=156) were divided into 3 groups: at the time of diagnosis (𝑁=45), in relapse/progression (𝑁=56), and in remission (𝑁=50). The analysis revealed significant differences of all three parameters in comparison of active and remission phase MM. Moreover, the parameters in active myeloma were significantly higher than in MGUS. Within the comparison of active disease (newly diagnosed and relapsing), there was no significant difference. Similar results were in remission phase MM and MGUS. There was no relationship of pretreatment levels of the parameters to therapeutic response. We conclude that serum levels of HGF, OPN, and SYN correspond to the activity of MM and might become useful in differentiation of MGUS, asymptomatic MM, and overt/symptomatic form of MM. The levels of all three parameters behave accordingly with MM activity. Pretreatment measurement without the assessment of their kinetics, however, has no relationship to therapeutic response. Jiri Minarik, Tomas Pika, Jaroslav Bacovsky, Pavla Petrova, Katerina Langova, and Vlastimil Scudla Copyright © 2012 Jiri Minarik et al. All rights reserved. Progress towards Mechanism-Based Treatment for Diamond-Blackfan Anemia Tue, 24 Apr 2012 08:37:27 +0000 Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplastic anemia, characterized by macrocytic anemia, reticulocytopenia, and severely reduced numbers of erythroid precursors in the bone marrow. For more than fifty years, glucocorticoids have remained the main option for pharmacological treatment of DBA. While continuous glucocorticoid administration increases hemoglobin levels in a majority of DBA patients, it also causes severe side effects. There is therefore a great need for more specific and effective treatments to boost or replace the use of glucocorticoids. Over the years, many alternative therapies have been tried out, but most of them have shown to be ineffective. Here we review previous and current attempts to develop such alternative therapies for DBA. We further discuss how emerging knowledge regarding the pathological mechanism in DBA and the therapeutic mechanism of glucocorticoids treatment may reveal novel drug targets for DBA treatment. Sara E. Sjögren and Johan Flygare Copyright © 2012 Sara E. Sjögren and Johan Flygare. All rights reserved. Pure Red Cell Aplasia and Lymphoproliferative Disorders: An Infrequent Association Thu, 19 Apr 2012 13:46:48 +0000 Pure red cell aplasia (PRCA) is a rare bone marrow failure syndrome defined by a progressive normocytic anaemia and reticulocytopenia without leukocytopenia and thrombocytopenia. Secondary PRCA can be associated with various haematological disorders, such as chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma (NHL). The aim of the present review is to investigate the infrequent association between PRCA and lymphoproliferative disorders. PRCA might precede the appearance of lymphoma, may present simultaneously with the lymphoid neoplastic disease, or might appear following the lymphomatic disorder. Possible pathophysiological molecular mechanisms to explain the rare association between PRCA and lymphoproliferative disorders are reported. Most cases of PRCA are presumed to be autoimmune mediated by antibodies against either erythroblasts or erythropoietin, by T-cells secreting factors selectively inhibiting erythroid colonies in the bone marrow or by NK cells directly lysing erythroblasts. Finally, focus is given to the therapeutical approach, as several treatment regimens have failed for PRCA. Immunosuppressive therapy and/or chemotherapy are effective for improving anaemia in the majority of patients with lymphoma-associated PRCA. Further investigation is required to define the pathophysiology of PRCA at a molecular level and to provide convincing evidence why it might appear as a rare complication of lymphoproliferative disorders. Efthymia Vlachaki, Michael D. Diamantidis, Philippos Klonizakis, Styliani Haralambidou-Vranitsa, Elizabeth Ioannidou-Papagiannaki, and Ioannis Klonizakis Copyright © 2012 Efthymia Vlachaki et al. All rights reserved. Expression and Clinical Significance of Antiapoptotic Gene (Survivin) in NB4 and Acute Promyelocytic Leukemia Cells Sun, 01 Apr 2012 08:54:07 +0000 To study survivin gene expression in APL cells and to explore its correlation with clinical manifestations. PML/RARα and survivin mRNA expression were analysed using RT-PCR. By treatment of ATRA, the survivin mRNA expression in NB4 cells gradually decreased with time and was almost undetectable in the 72th hour. Survivin was expressed in 67% of the 36 APL cases (de novo and relapse patients) with PML/RARα fusion gene expression. However, in 22 cases of remission stage patients without PML/RARα fusion gene expression, survivin was expressed in 36%. The survivin mRNA expression positive rate in de novo and relapse groups, and PML/RARα fusion gene L-type positive groups, was obviously higher than those in remission period groups and was significantly lower than those in acute leukemia groups. In 36 cases of de novo and relapse APL patients, all cases could obtain complete remission, irrespective of the survivin expression. APL patients expressed with survivin mRNA had DIC and serious infection (one patient died). The clinical symptom included slight skin or mucosa bleeding, fever, and asthenic for patients without the survivin mRNA expression. Later, two cases of APL patients with the survivin mRNA expression were treated by ATRA, induction differentiation sign in their peripheral blood and bone marrow figure was not obvious. It was concluded that the survive gene expression was lower in APL than those in any other types of leukemia, thus closely associated with clinical manifestation. Jun Xue, Xiao-Jing Xie, and Mao-Fang Lin Copyright © 2012 Jun Xue et al. All rights reserved. Dependence of Acute Myeloid Leukemia on Adhesion within the Bone Marrow Microenvironment Wed, 04 Jan 2012 11:00:13 +0000 Acute myeloid leukemia (AML) cells home to the endosteal region of the bone marrow. They interact with bone marrow stromal components including extracellular matrix proteins, glycosaminoglycans, and stromal cells, by which they derive proliferative and growth inhibitory signals. Furthermore, adhesion to marrow stroma confers chemotherapy drug resistance and thereby promotes leukemia survival. A subpopulation of the leukemic blasts, known as leukemia stem cells, that are capable of propagating the leukemia, remain sheltered in the bone marrow microenvironment, exhibit resistance to chemotherapy, and serve as the origin of relapse after a variable period of remission. Detachment of these cells from the bone marrow in combination with chemotherapy may improve the outcome of therapy for AML. Pamela S. Becker Copyright © 2012 Pamela S. Becker. All rights reserved. Stem Cell Heterogeneity of Mononucleated Cells from Murine Peripheral Blood: Molecular Analysis Thu, 03 Nov 2011 00:00:00 +0000 The main purpose of this paper was to determine the heterogeneity of primary isolated mononucleated cells that originated from the peripheral blood system by observing molecular markers. The isolated cells were cultured in complete medium for 4 to 7 days prior to the separation of different cell types, that is, adherent and suspension. Following a total culture time of 14 days, adherent cells activated the Cd105 gene while suspension cells activated the Sca-1 gene. Both progenitor markers, Cbfa-1 and Ostf-1, were inactivated in both suspension and adherent cells after 14-day culture compared to cells cultured 3 days in designated differentiation medium. In conclusion, molecular analyses showed that primary mononucleated cells are heterogeneous, consisting of hematopoietic stem cells (suspension) and mesenchymal stem cells (adherent) while both cells contained no progenitor cells. Muhammad Dain Yazid, Shahrul Hisham Zainal Ariffin, Sahidan Senafi, Zaidah Zainal Ariffin, and Rohaya Megat Abdul Wahab Copyright © 2011 Muhammad Dain Yazid et al. All rights reserved. Human Leukocyte Antigen Class I and II Alleles and Overall Survival in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma Tue, 01 Nov 2011 00:00:00 +0000 Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01–3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24–4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02–0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20–0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation. Yani Lu, Amr M. Abdou, James R. Cerhan, Lindsay M. Morton, Richard K. Severson, Scott Davis, Wendy Cozen, Nathaniel Rothman, Leslie Bernstein, Stephen Chanock, Patricia Hartge, and Sophia S. Wang Copyright © 2011 Yani Lu et al. All rights reserved. Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside Tue, 25 Oct 2011 00:00:00 +0000 Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβ pathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting. Jacopo Olivieri, Sabrina Coluzzi, Imma Attolico, and Attilio Olivieri Copyright © 2011 Jacopo Olivieri et al. All rights reserved. The Role of T Cells in Hematopoietic Stem Cell Engraftment Mon, 01 Jan 1900 00:00:00 +0000 Much attention has focused on the immune recovery of donor T cells following hematopoietic stem cell transplantation (HSCT). Termed immune reconstitution, a better understanding of the dynamics of the functional recovery of immune cells following HSCT has important implications both for fighting infections and, in the allogeneic setting, for providing antitumor activity while controlling graft-vs.-host disease (GVHD). The immune cells involved in immune reconstitution include antigen-presenting cells, B lymphocytes, natural killer cells, and, in particular, T lymphocytes, the immune cell that will be the subject of this review. In addition, T cells can play an important role in the process of engraftment of hematopoietic stem cells. The evidence for a T cell tropic effect on hematopoietic engraftment is both direct and indirect, and comes from the clinic as well as the research lab. Animal models have provided useful clues, but the molecular mechanisms that govern the interaction between donor stem cells, donor T cells, the host immune system, and the stem cell niche remain obscure. This review will describe the current published clinical and basic evidence related to T cells and stem cell engraftment, and will identify future directions for translational research in this area. Elizabeth Hexner Copyright © 2006 Elizabeth Hexner. All rights reserved. Advances in Hemophagocytic Lymphohistiocytosis: Pathogenesis, Early Diagnosis/Differential Diagnosis, and Treatment Mon, 01 Jan 1900 00:00:00 +0000 Hemophagocytic lymphohistiocytosis (HLH) is a histiocytic disorder characterized by a highly stimulated, but ineffective, immune response to antigens, which results in life-threatening cytokine storm and inflammatory reaction. Considerable progress has been made during the past 2 decades. Detection of molecular genetic abnormalities in genes involved in immune response pathways, such as PRF1, STX11, UNC13D, STXBP2, RAB27A, LYST, AP3B1, SH2D1A, and BIRC4, is confirmatory for the diagnosis. Clinical diagnosis is largely made according to HLH-2004 criteria. However, a new finding of the Th1/Th2 cytokine pattern (significant increase of IFN-γ and IL-10 with slightly increased or normal level of IL-6) is a useful biomarker for the early diagnosis, differential diagnosis, and the monitoring of the disease. Intensive immunosuppressive therapy is generally accepted as treatment for the relief of clinical symptoms/signs, while allogeneic hematopoietic stem cell transplantation is currently the only potentially curative therapy option for severe familial forms of HLH. Yong-Min Tang and Xiao-Jun Xu Copyright © 2011 Yong-Min Tang and Xiao-Jun Xu. All rights reserved. Influence of Natural Honey on Biochemical and Hematological Variables in AIDS: A case study Mon, 01 Jan 1900 00:00:00 +0000 Honey lowers prostaglandins and elevates nitric oxide (NO) in various biological fluids in normal persons. NO and prostaglandin play a role in pathogenesis of AIDS. The study was designed to assess the effect of natural honey on prostaglandins and NO levels, blood indices and biochemical tests in a 40 year-old woman with AIDS. This presentation is a case story of a 40 year-old women with a long history of AIDS treated with 80g of natural honey. Plasma and urinary prostaglandin F2 alpha and thromboxane B2 levels, plasma, urine and saliva content of NO-end product (total nitrite) and hematological tests were estimated before and 3 hours after oral consumption of 80g of natural honey. These variables, in addition to biochemical tests, were re-estimated after 21 days of daily consumption of 80g of natural honey. Results showed that prostaglandins level compared with normal subjects were elevated in patient with AIDS. Natural honey decreased prostaglandins levels, and elevated NO-end product, percentage of lymphocytes, platelet count, and serum protein, albumin and copper levels. It might be concluded that natural honey decreased prostaglandins level, elevated NO production and improved hematological and biochemical tests in a patient with a long history of AIDS. Noori S. Al-Waili, Thia N. Al-Waili, Ali N. Al-Waili, and Khelod S. Saloom Copyright © 2006 Noori S. Al-Waili et al. All rights reserved. Treating Imatinib-Resistant Leukemia: The Next Generation Targeted Therapies Mon, 01 Jan 1900 00:00:00 +0000 Imatinib (Gleevec/STI-571/CGP57148B, Novartis) is a small-molecule, tyrosine kinase inhibitor developed to target BCR-ABL, c-Kit, and PDGF-R. Through inhibition of these oncogenic kinases, imatinib is effective in the treatment of BCR-ABL–positive leukemia, gastrointestinal stromal tumor, and hypereosinophilic syndrome, respectively. However, clinical success of imatinib is hampered by acquired resistance that may occur through several mechanisms including kinase domain mutation, target amplification, and activation of alternate signaling pathways. Strategies to overcome resistance have included targeting BCR-ABL stability and downstream signaling pathways important for tumor growth. Additional work has shown that new BCR-ABL kinase inhibitors with increased potency or alternate conformation-binding properties can target imatinib resistance. This review focuses on the mechanisms of imatinib resistance and the strategies currently being developed to overcome clinical resistance. Michael R. Burgess and Charles L. Sawyers Copyright © 2006 Michael R. Burgess and Charles L. Sawyers. All rights reserved. Spinal Cord Blood Flow after Ischemic Preconditioning in a Rat Model of Spinal Cord Ischemia Mon, 01 Jan 1900 00:00:00 +0000 Spinal cord blood flow after ischemic preconditioning is poorly characterized. This study is designed to evaluate spinal cord blood flow patterns in animals after acute ischemic preconditioning. Experiment 1: After a laminectomy and placement of a laser Doppler probe over the lumbar spinal cord to measure spinal cord blood flow, 16 male Sprague-Dawley rats were randomized into two groups: ischemic preconditioning (IPC, n = 8), and control (CTRL, n = 8). Rats in the CTRL and the IPC groups were subjected to 12 min of ischemia directly followed by 60 min of reperfusion. IPC rats received 3 min of IPC and 30 min of reperfusion prior to the 12-min insult period. Experiment 2: After instrumentation, the rats were randomized into three groups: control (CTRL, n = 7), ischemic preconditioning (IPC, n = 7), and time control (TC, n = 4). Rats in the CTRL and the IPC groups were subjected to the same ischemia and reperfusion protocol as above. The TC group was anesthetized for the same time period as the CTRL and the IPC groups, but had no ischemic intervention. Microspheres were injected at baseline and at 15 and 60 min into the final reperfusion. All rats were euthanized and tissue harvested for spinal cord blood flow analysis. In Experiment 1, there was a slight, significant difference in spinal cord blood flow during the ischemic period; however, this difference soon disappeared during reperfusion. In experiment 2, there was no difference in blood flow at any experimental time. The results of these experiments demonstrate that IPC slightly enhances blood flow to the spinal cord during ischemia; however, this effect is not sustained during the reperfusion period. David Zvara, James M. Zboyovski, Dwight D. Deal, Jason C. Vernon, and David M. Colonna Copyright © 2004 David Zvara et al. All rights reserved. Ascorbic Acid Augments Arsenic-Mediated Cell Death in Multiple Myeloma (MM) Cells Mon, 01 Jan 1900 00:00:00 +0000 Jennifer M. Grad, Nizar J. Bahlis, and Lawrence H. Boise Copyright © 2001 Jennifer M. Grad et al. All rights reserved. Role of Transforming Growth Factor 1 in Lymphocyte Development and Death Mon, 01 Jan 1900 00:00:00 +0000 Ramireddy Bommireddy, Ilona Ormsby, Moying Yin, and Thomas C. Doetschman Copyright © 2001 Ramireddy Bommireddy et al. All rights reserved. Urothelial Carcinoma of the Bladder Metastatic to Bone Marrow Presenting as Isolated Thrombocytopenia Mon, 01 Jan 1900 00:00:00 +0000 The skeletal system is a frequent site for metastases of urothelial carcinoma (UC) of the bladder (22–37%). Of those cases involving bone, the marrow is infiltrated in 27% of patients. Imaging modalities, such as X-ray and CT, will detect gross skeletal lesions in the vast majority of these patients with bone marrow involvement, however, most patients with bone involvement are symptomatic at presentation. Additionally, there have been few reports in the literature of bone marrow metastases from UC presenting with isolated thrombocytopenia. Robert C. Chan, Greg L. Hundemer, Amy Tatsas, and Michael S. Cookson Copyright © 2007 Robert C. Chan et al. All rights reserved. Defining the Thrombotic Risk in Patients with Myeloproliferative Neoplasms Mon, 01 Jan 1900 00:00:00 +0000 Polycythemia vera (PV) and essential thrombocythemia (ET) are two Philadelphia-negative myeloproliferative neoplasms (MPN) associated with an acquired mutation in the JAK2 tyrosine kinase gene. There is a rare incidence of progression to myelofibrosis and myeloid metaplasia in both disorders, which may or may not precede transformation to acute myeloid leukemia, but thrombosis is the main cause of morbidity and mortality. The pathophysiology of thrombosis in patients with MPN is complex. Traditionally, abnormalities of platelet number and function have been claimed as the main players, but increased dynamic interactions between platelets, leukocytes, and the endothelium do probably represent a fundamental interplay in generating a thrombophilic state. In addition, endothelial dysfunction, a well-known risk factor for vascular disease, may play a role in the thrombotic risk of patients with PV and ET. The identification of plasma markers translating the hemostatic imbalance in patients with PV and ET would be extremely helpful in order to define the subgroup of patients with a significant clinical risk of thrombosis. Fabrizio Vianello, Anna Battisti, Giuseppe Cella, Marina Marchetti, and Anna Falanga Copyright © 2011 Fabrizio Vianello et al. All rights reserved. A Case of Acute Tuberculous Pleuropneumonia in a Patient with Acute Lymphoblastic Leukemia Mon, 01 Jan 1900 00:00:00 +0000 Respiratory system infections are the most common complications in immunocompromised cancer patients. We here report a 14-year-old male who was admitted to the hospital because of acute pneumonia, who had been diagnosed with acute lymphoblastic leukemia (ALL) when he was 12 years old. A diagnosis of acute tuberculous pleuropneumonia was made based on clinical and radiographical findings, and Mycobacterium tuberculosis was identified by Ziehl-Neelson acid-fast stain and culture on Löwenstein-Jensen medium. Twenty months before pneumonia onset, the patient had been treated with immunosupressive therapy (ALL IC-BFM 2002 protocol). Snezana Zivanovic, Ljiljana Saranac, Gordana Kostic, Vesna Bogicevic, and Danijela Jovancic Copyright © 2010 Snezana Zivanovic et al. All rights reserved. Plasmablastic Lymphoma: A Systematic Review Mon, 01 Jan 1900 00:00:00 +0000 Plasmablastic lymphoma (PBL) is a very aggressive variant of diffuse large B-cell lymphoma initially described in the oral cavity of HIV-infected individuals. PBL represents a diagnostic challenge given its characteristic morphology and lack of CD20 expression, and also a therapeutic challenge, with early responses to therapy, but with high relapse rates and poor prognosis. In recent years, our understanding and clinical experience with PBL has increased in both HIV-positive and -negative settings. However, given its rarity, most of the data available rely on case reports and case series. The main goal of this article is to systematically review the most recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and prognosis in patients with PBL. Specific covered topics include new pathological markers for diagnosis, its association with Epstein-Barr virus, and the need of more intensive therapies. Jorge J. Castillo and John L. Reagan Copyright © 2011 Jorge J. Castillo and John L. Reagan. All rights reserved. Hematology-Aims and Scope and a Call for Papers Mon, 01 Jan 1900 00:00:00 +0000 Edward Benz Copyright © 2005 Edward Benz. All rights reserved. ABO Blood Group. Related Investigations and Their Association with Defined Pathologies Mon, 01 Jan 1900 00:00:00 +0000 The ABO blood group system was discovered by Karl Landsteiner in 1901. Since then, scientists have speculated on an association between different pathologies and the ABO blood group system. The aim of this pilot study was to determine the significance between different blood types of the ABO blood group system and certain pathologies. We included 237 patients with known diagnosis, blood group, sex, and age in the study. As a statistical method, the Chi-square test was chosen. In some cases, a significant association between the blood groups and defined diseases could be determined. Carriers of blood group O suffered from ulcus ventriculi and gastritis (X21 = 78.629, p <0.001), colitis ulcerosa and duodenitis (X21 = 5.846, p < 0.016), whereas male patients carrying blood group A tended to contract different types of tumours. In patients with intestinal tumours, females with blood group A were more likely to develop the pathology, whereas in males, the blood group O dominated. The development of cholelithiasis was found, above all, in patients with blood group O, which differed from other research where a correlation between this pathology and blood group A was found. Ursula Jesch, P. Christian Endler, Beatrix Wulkersdorfer, and Heinz Spranger Copyright © 2007 Ursula Jesch et al. All rights reserved. Risk-Reduction Strategies for Platelet Transfusion in the United States Mon, 01 Jan 1900 00:00:00 +0000 Despite bacterial culture of platelets, transfusion-associated bacteremia/sepsis (TABS) may occur with a frequency of approximately 1/60,000 platelet transfusions, while an emerging transfusion-transmitted infection (TTI) could reproduce the epidemic of transfusion-transmitted human immunodeficiency virus (HIV) in the future. As platelet pathogen-reduction (PR) systems licensed in Europe may eventually become licensed in the U.S., three alternative strategies for reducing the residual risks of TTIs and TABS may become available in the U.S. in the future: (1) transfusion of (already-available) non–pathogen-reduced single-donor (as opposed to pooled whole-blood-derived [PWBD]) platelets, (2) transfusion of pathogen-reduced single-donor platelets, or (3) transfusion of pathogen-reduced PWBD platelets (if trials of this component are conducted in the U.S. in the future). PR of platelets will increase the risk of mild and moderate (albeit perhaps not severe) bleeding complications and it cannot protect from all pathogens. Compared to PWBD platelets, single-donor platelets can reduce, by at least twofold, the risk of all known and emerging TTIs, as well as the risk of TABS, without incurring any risk. The fewer donor exposures secured by the use of single-donor platelets – especially if combined with collection of red blood cells and/or plasma from the same donation for transfusion to the same recipient through the use of multicomponent apheresis – may also reduce the risk of transfusion-related acute lung injury. To choose between pathogen-reduced and non–pathogen-reduced single-donor platelets, the increased risks of bleeding complications as well as other possible adverse events secondary to PR need to be quantified precisely and weighed against the competing risks of TABS and emerging TTIs. Eleftherios C. Vamvakas Copyright © 2011 Eleftherios C. Vamvakas. All rights reserved. Pyrrolo-1,5-Benzoxazepines Induce Apoptosis in Chronic Myeloid Leukemia (CML) Cells by Bypassing the Apoptotic Suppressor BCR-ABL Mon, 01 Jan 1900 00:00:00 +0000 Margaret M. Mc Gee, Giuseppe Campiani, Anna Ramunno, Caterina Fattorusso, Vito Nacci, Mark Lawler, D. Clive Williams, and Daniela M. Zisterer Copyright © 2001 Margaret M. Mc Gee et al. All rights reserved.