bluuebunny/crossref_metadata_2025 huggingface dataset:
Low‐dose ARA‐C consistently induces hematologic responses in the clinical 5q–syndrome
Authors: Juneja Harinder S. , Jodhani Madhu , Gardner Frank H. , Trevarthen David , Schottstedt Margaret
Published: February 2007

Five patients with the classical clinical syndrome associated with a deletion of the long arm of chromosome 5, i.e., anemia, macrocytosis, and thrombocytosis, or a normal platelet count, were treated successfully with subcutaneous low‐dose cytosine arabinoside (LDARA‐C). Prior therapy with other drugs had failed in four of the five patients. A total of nine complete and one partial hematologic responses were induced in five patients. Duration of the first hematologic response ranged from 3 to 30+ months. Two patients (cases 3 and 4) continue in their first hematologic response at 29 and 30 months. Upon relapse, up to three responses could be reinduced in two patients. Duration of the subsequent hematologic responses in case 1 was 16, 8, and 10 months and case 2 achieved two responses of 15 and 18+ months duration. LDARA‐C therapy was associated with mild to severe neutropenia and moderate to severe thrombocytopenia. Thus, subcutaneous LDARA‐C is highly effective in the treatment of patients with myelodysplasia associated with deletion of the long– arm of chromosome 5 (5q–). © 1994 Wiley‐Liss, Inc.
Molecular analysis of an asymptomatic Ph‐positive CML patient with 27 years of prolonged remission
Authors: Amikam D. , Henig C. , Sharon R. , Tatarsky I. , Ben‐Ishai Z.
Published: February 2007

We describe the results of clinical, cytogenetic, and molecular biological studies of a patient who, after two courses of treatment with Busulphan, has remained free of symptoms of Philadelphia chromosome‐positive chronic myeloid leukemia for 27 years, except for the persistence of a Ph1 chromosome and the presence of its transcribed chimeric mRNA. © 1994 Wiley‐Liss, Inc.
Inhibition by aurintricarboxylic acid of von Willebrand factor binding to platelet GPIb, platelet retention, and thrombus formation in vivo
Authors: Kawasaki T. , Kaku S. , Kohinata T. , Sakai Y. , Taniuchi Y. , Kawamura K. , Yano S. , Takenaka T. , Fujimura Y.
Published: February 2007

Commercial aurintricarboxylic acid (ATA) was separated into molecular‐weight (MW) fractions of <210 to >25,000, using gel permeation chromatography. Fractions with MW >1,300 effectively inhibited both botrocetin‐induced vWF and bovine vWF binding to fixed human platelets. These activities decreased with a MW >17,000. Platelet retention for a human in vitro was reduced by ATA at 150 μ, as was that for rats ex vivo at 3 mg/kg. ATA prolonged tail transection bleeding time in rats but had only a weak effect on buccal mucosal bleeding time in dogs. ATA had no effect on platelet count but markedly prolonged PTT. ATA at 10 mg/kg exhibited antithrombotic activity and caused a marked improvement in patency status following successful thrombolysis by t‐PA in electrically and copper coil‐induced thrombosis models. These results suggest that specific inhibitors of the vWF‐GPIb interaction such as ATA may prove useful as antithrombotic agents. © 1994 Wiley‐Liss, Inc.
Langerhans cell histiocytosis: Lack of a viral etiology
Authors: McClain Kenneth , Jin Hong , Gresik Vicky , Favara Blaise
Published: February 2007

Langerhans cell histiocytosis (LCH) is an enigmatic histiocytic proliferative disorder of unknown etiology that affects children primarily. We have investigated the possibility that viruses are etiological or that they have a “triggering effect” in LCH. Sensitive in situ hybridization and polymerase chain reaction (PCR) techniques were used in 56 cases of LCH. We sought and failed to find evidence of genomes for adenovirus, cytomegalovirus, Epstein‐Barr virus, herpes simplex virus, human herpesvirus type 6, human immunodeficiency virus, human T‐cell leukemia virus types I and II, and parvovfrus. Although some probes hybridized to tissues from several cases, PCR failed to confirm the presence of viral genome in any. We conclude that there is no evidence that these viruses are associated with LCH. © 1994 Wiley‐Liss, Inc.
DNA diagnosis of Hb S and Hb Caribbean (α2β291 Leu→Arg) in a Jamaican family
Authors: Waye John S. , Patterson Margaret , Eng Barry , Chui David H. K. , Sher Graham D. , Olivieri Nancy F.
Published: February 2007

We describe a Canadian infant of Jamaican descent who presented with mild anemia. Hb electrophoresis revealed Hb S and an unknown Hb variant that migrated slightly faster than Hb S on cellulose acetate. Molecular studies of the family indicated that the proband is a compound heterozygote for Hb S and Hb Caribbean. Hb Caribbean has previously been characterized as a mildly unstable hemoglobin with low oxygen affinity, due to a Leu→Arg substitution at amino acid residue 91. The present study establishes the molecular basis for Hb Caribbean (β91, CTG→CGG) and confirms that Hb S/Hb Caribbean syndrome is not associated with serious clinical manifestations. © 1994 Wiley‐Liss, Inc.
Polyethylene glycolated interleukin‐2 as maintenance therapy for acute myelogenous leukemia in second remission
Authors: Wiernik Peter H. , Dutcher Janice P. , Todd Mary , Caliendo Geralyn , Benson Laura
Published: February 2007

Seven patients in second complete remission of acute myeloid leukemia (AML) aged 19–65 years were treated with polyethylene glycolated interleukin‐2 (PEG IL‐2), 1 × 106 U/M2 IV weekly as the sole postremission therapy. Second remission duration was in the range of 4–49+ months, and three patients had a second remission duration substantially longer than their first (6,21 +, and 42+ months). The results suggest that PEG IL‐2 may prolong second remission duration in AML and that a prospective randomized study designed to test that idea is warranted. © 1994 Wiley‐Liss, Inc.
Bone marrow necrosis in two patients with acute promyelocytic leukemia during treatment with all‐trans retinoic acid
Authors: Limentani Steven A. , Pretell Judith O. , Potter David , Dubois Jon S. , Daoust Philip R. , Spieler Paul S. , Miller Kenneth B.
Published: February 2007

All‐trans retinoic acid has been used for the treatment of acute promyelocytic leukemia (APL) with encouraging results. However, it has recently been associated with a number of potentially serious complications including the retinoic acid syndrome. We describe two patients with APL who were begun on all‐trans retinoic acid therapy (45 mg/m2), but who developed leukocytosis which was treated with hydroxyurea. Both patients demonstrated clinical and laboratory findings of disseminated intravascular coagulation, massive cell lysis manifested by marked increases in serum lactic dehydrogenase, and rapid clinical deterioration. Both patients developed bone marrow necrosis within viable, non‐infarcted bone trabeculae. We postulate that the development of bone marrow necrosis in these two patients was not a chance occurrence. Rather, the specific combination of cytotoxic and differentiating agents used in these patients (hydroxyurea with all‐trans retinoic acid) caused massive cell lysis and death. The absence of bone marrow necrosis in the setting of induction therapy for APL both with and without all‐trans retinoic acid therapy suggests that the addition of hydroxyurea was critical to the development of marrow necrosis. We, therefore, recommend caution in the use of hydroxyurea and all‐trans retinoic acid in the treatment of APL. © 1994 Wiley‐Liss, Inc.
IL‐5 mRNA expression in blood lymphocytes from patients with Kimura's disease and parasite infection
Authors: Enokihara Hideo , Koike Toshiyuki , Arimura Hironari , Aoyagi Masakuni , Watanabe Kanji , Nakamura Yuichi , Yamashiro Kyoko , Tsuruoka Nobuo , Tsujimoto Masafumi , Saito Kenji , Furusawa Shimpei , Shishido Hideo
Published: February 2007

Blood lymphocytes from patients with eosinophilia are known to produce interleukin‐5 (IL‐5) with appropriate stimulation in vitro. To determine whether blood lymphocytes from these patients produce IL‐5 in vivo, we tested the IL‐5 mRNA expression in blood lymphocytes immediately after separation by reverse‐transcriptase polymerase chain reaction (RT‐PCR) method. We found that lymphocytes from eosinophilic patients expressed IL‐5 mRNA, but lymphocytes from normal volunteers did not express the lymphokine. These findings suggest that in patients with eosinophilia, peripheral blood lymphocytes produce IL‐5 in vivo. © 1994 Wiley‐Liss, Inc.
Improvement of sickle cell anemia by iron‐limited erythropoiesis
Authors: Castro Oswaldo , Poillon William N. , Finke Helga , Massac Etienne
Published: February 2007

We report the hematologic and clinical features of four adult patients (Pts.) with sickle cell anemia and iron‐limited erythropoiesis. Two of the Pts. had spontaneous iron deficiency (chronic Gl bleeding, low‐grade hemoglobinuria). In the other two Pts. iron restriction was induced by periodic RBC aphereses as part of a pilot protocol designed to decrease intracellular HbS polymerization by MCHC reduction. Iron‐limited erythropoiesis was defined by reduction in red cell indices (MCV range 60.4–67 fl) in the presence of low serum ferritin (range <10–20 ng/ml). In these Pts. iron restriction did not cause clinically significant worsening of the anemia (Hb 7.8–9.0 g/dl). In two Pts. the anemia actually improved. Other hematologic effects of iron restriction were: decreased MCHC, reticulocyte count, RDW, and dense cells. A reduced hemolytic rate was suggested by a lowering of serum bilirubin and LDH. In one of the Pts. the 51Cr RBC T1/2 survival increased from 12 to 16 days. The intracellular HbS polymer fractions (fp) were determined at 25% O2 by Csat and with the use of the conservation of mass equation. The baseline fp values ranged from 0.48–0.53. After iron restriction they ranged from 0.33–0.48. The fp decreased even though iron‐limited erythropoiesis also lowered the Hb F concentration in three of our Pts. In one of the two Pts. with induced iron depletion, hospitalization days for pain crises decreased from an average of 4.5 days/month (2 year baseline period) to an average of 0.5 days/month in the 3 year follow‐up after iron depletion. The second patient with induced iron restriction experienced the rapid healing of a leg ulcer. Controlled iron restriction should be explored as a therapeutic strategy in selected SS patients. © 1994 Wiley‐Liss, Inc.
Plasma levels of granulocyte elastase‐α1‐proteinase inhibitor complex in patients with disseminated intravascular coagulation: Pathophysiologic implications
Authors: Okajima Kenji , Fujise Ryuji , Motosato Yuichi , Ushijima Masato , Okabe Hiroaki , Takatsuki Kiyoshi
Published: February 2007

To Investigate the role of neutrophil activation in the pathophysiology and sequelae of disseminated intravascular coagulation (DIC), we measured plasma levels of granulocyte elastase‐α1‐proteinase inhibitor complex (GEPIC) in 41 patients with DIC and 27 patients with similar underlying conditions but without DIC. Mean GEPIC levels were significantly higher in patients with DIC (421.0 ± 45.6 ng/ml) than in patients without DIC (246.1 ± 41.9 ng/ml, P < 0.01). Significant differences were also noted in DIC patients with or without infection (474.7 ± 61.2 ng/ml vs. 302.4 ± 48.9 ng/ml, P < 0.04), with or without organ dysfunction (546.6 ± 72.7 ng/ml vs. 305.6 ± 42 ng/ml, P < 0.01), and with or without respiratory failure (640.0 ± 91.2 ng/ml vs. 328.1 ± 55.1 ng/ml, P < 0.01). No significant difference was found in mean GEPIC levels in DIC patients with or without renal failure, heart failure, hepatic failure, or gastrointestinal bleeding. The frequency of respiratory failure correlated with rising plasma levels of GEPIC. Mortality was higher in patients with GEPIC levels >500 ng/ml (53.8%) than in patients with GEPIC levels <500 ng/ml (28.6%). This correlation was particularly strong in patients with DIC, infection, and respiratory failure. Based on these data, we suggest that neutrophil activation, triggered by the coagulation cascade and perhaps augmented by endotoxin or cytokine release with infection, significantly contributes to respiratory failure and mortality in patients with DIC. © 1994 Wiley‐Liss, Inc.
Clinical relevance of gestational thrombocytopenia of <100,000/μl
Authors: Anteby Eyal , Shalev Oded
Published: February 2007

We identified 22 women with thrombocytopenia of <100,000/μl found incidentally during pregnancy and prospectively monitored their platelet count and clinical outcome for a minimum of 6 months postpartum. During the study period, four women became pregnant twice, accounting for a total of 26 pregnancies. The lowest platelet count during pregnancy was 65,600/μl ± 19,400 (mean ± SD), and at delivery 84,500/μl ± 32,300 (P < 0.02). The thrombocytopenia was virtually asymptomatic in all patients during the pregnancy and delivery, whether vaginal or surgical. Neonatal platelet counts (n = 18) were normal (270,700/μl ± 69,900), and none of the newborns (n = 24) had a bleeding diathesis. Normalization of the platelet count (i.e., >150,000/μl) was documented in 18 patients within 1 month postpartum, in five within 3 months postpartum, and in two as late as 5 months after delivery. One woman did not recover from the thrombocytopenia and eventually developed other stigmata of an autoimmune disease. Long‐term follow‐up showed recurrence of thrombocytopenia in four patients: three in the context of a subsequent pregnancy and one who developed idiopathic thrombocytopenic purpura. Retrospective analysis of blood counts obtained from 12 previous pregnancies demonstrated thrombocytopenia of a similar degree to the index pregnancy. We conclude that gestational thrombocytopenia of <100,000/μl is clinically a benign phenomenon that can recur in subsequent pregnancies and is not accompanied by neonatal thrombocytopenia. In some cases, however, pregnancy‐associated thrombocytopenia may be a manifestation of an autoimmune disease with its attendant implications for the neonate. Since the differential diagnosis between the two conditions may be difficult to establish when first encountered during pregnancy, a conservative approach emphasizing careful surveillance and guarded reassurance is justified as long as the platelet counts are >50,000/μl. © 1994 Wiley‐Liss, Inc.
CD8‐positive adult T‐cell leukemia cells with an integrated defective HTLV‐I genome show a paracrine growth to IL‐2
Authors: Matsushita Kakushi , Arima Naomichi , Hidaka Shiroh , Ohtsubo Hideo , Fujiwara Hiroshi , Fukumori Junko , Tanaka Hiromitsu
Published: February 2007

We describe a 50‐year‐old man with adult T‐cell leukemia complicated by laryngeal tuberculosis whose tumor cells proliferate in response to IL‐2 in a paracrine manner. On admission, the patient's white blood cell count was 17,900/mm3; 73% were abnormal lymphocytes with convoluted nuclel. FACS analysis showed that the tumor cells were CD4‐negative, CD8‐positive T cells. Southern blot analysis of tumor cells revealed integration of a defective HTLV‐I genome lacking gag and pol genes. He was diagnosed with chronic ATL complicated by laryngeal tuberculosis. The primary leukemic cells expressed IL‐2Rα and IL‐2Rβ detected by FACS and Northern blot analysis and showed marked growth in response to exogenously added recombinant IL‐2 in short‐term cultures. Northern blot analysis did not show any IL‐2 mRNA. We have previously demonstrated that primary leukemic cells from some ATL patients grow in response to IL‐2 in an autocrine or paracrine manner. These results suggest that in CD8 ATL, IL‐2 may beinvolved in a paracrine manner. © 1994 Wiley‐Liss, Inc.
Fresh frozen plasma has no beneficial effect on the hemostatic system in children receiving L‐asparaginase
Authors: Halton Jacqueline M. , Mitchell Lesley G. , Vegh Patsy , Eves Marilyn , Andrew Maureen E.
Published: February 2007

L‐Asparaginase (ASP), a chemotherapeutic agent used in the treatment of children with acute lymphoblastic leukaemia (ALL), is linked to thromboembolic complications secondary to an acquired deficiency of antithrombin III (ATIII). Fresh frozen plasma (FFP) is used to prevent and/or treat thrombotic complications in these children. However, the effect of FFP on plasma concentrations of ATIII and biochemical markers of activation of coagulation has never been tested. In this study, FFP (20 ml/kg) was administered to eight children with ALL receiving ASP in the consolidation phase of their treatment. Plasma samples were drawn pre‐infusion, and following infusion at 1, 24, and 48 hr. Prior to the FFP infusions, plasma concentrations of prothrombin, fibrinogen, α2‐macroglobulin, heparin cofactor II, protein C, and protein S were similar to levels in healthy children. Only plasma concentrations of ATIII were significantly decreased (0.55 U/ml). Following FFP infusions, there was no statistical or clinically important increase in plasma concentrations of any coagulation protein at any time point. Pre‐infusion plasma concentrations of markers of endogenous thrombin generation (thrombin‐antithrombin III complexes (TAT)) and activation of the fibrinolytic system in response to activation of the coagulation system (D‐dimer levels) were significantly increased. However, FFP had no statistical or clinically important effect on concentrations of these markers. We conclude that FFP administration for the prevention and treatment of acquired ATIII deficiency secondary to ASP has no demonstrable benefit on plasma levels of coagulation proteins and is unlikely to be of clinical benefit. © 1994 Wiley‐Liss, Inc.
HLA‐DR53 protects against thrombotic thrombocytopenic purpura/adult hemolytic uremic syndrome
Authors: Joseph Geetha , Smith Kenneth J. , Hadley Terence J. , Djulbegovic Benjamin , Troup Gary M. , Oldfather John , Barker Robert L.
Published: February 2007

Class I and Class II HLA antigens were tested in patients treated for thrombotic thrombocytopenic purpura or hemolytic uremic syndrome (TTP/HUS) to determine whether there is a disease association. Based on the results of a pilot trial, retrospective HLA‐typing of 18 patients with a diagnosis of TTP/HUS and prospective typing of 12 newly diagnosed patients with TTP/HUS were performed. Twenty‐one patients were non‐Hispanic Caucasians, 7 were African‐Americans, and 2 were Hispanic‐Caucasians. Of 30 patients tested, 28 were positive for DR52 (chi‐squared = 5.14, P<0.05), and only two were positive for DR53 compared to 57% of controls (chi‐squared = 18.5, P<0.0005). Diverse DR52 subtypes (DRB3*0101, DRB3*02, and DRB3*0301) were found by oligonucleotide testing in 15 patients, suggesting the association was not with DR52 but with absence of the DR53 antigen. The 2 patients with DR53 were not homozygous. This study suggests that the supertypic antigen, DR53, may govern susceptibility to TTP/HUS, since the relative risk of this disease among DR53 positives is reduced at 0.09 (95% confidence interval, 0.01–0.28). This finding indicates a possible immunogenetic component in the pathogenesis of TTP. © 1994 Wiley‐Liss, Inc.
Effect of low‐dose granulocyte‐macrophage colony‐stimulating factor (LD‐GM‐CSF) on platelet transfusion‐dependent thrombocytopenia
Authors: Vesole David H. , Jagannath Sundar , Glenn Luther D. , Barlogie Bart
Published: February 2007

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is a hematopoietic growth factor known to promote the proliferation and differentiation of precursors of granulocytes and monocytes. GM‐CSF at standard doses (125–500 μg/m2) alleviates neutropenia secondary to cytotoxic chemotherapy, myelodysplastic syndromes, and aplastic anemia, but has minimal effect on anemia or thrombocytopenia. GM‐CSF at doses <30 μg/m2 has been reported to improve platelet counts in some patients exhibiting cytopenia related to hematologic disorders such as aplastic anemia and myelodysplastic syndrome. Lowdose GM‐CSF (10–20 μg/m2) was evaluated in 20 patients with transfusion‐dependent thrombocytopenia persisting after myeloablative cytotoxic chemotherapy or with disease‐related cytopenia. Seven patients (35%) responded as defined by a reduction in the platelet transfusion requirements by at least 75%. Low‐dose GM‐CSF did not significantly increase neutrophil counts or decrease red blood cell transfusion requirements. These results indicate that low‐dose GM‐CSF has a thrombopoietic effect in about one‐third of patients with platelet transfusion‐dependent thrombocytopenia which has not been observed at higher doses. © 1994 Wiley‐Liss, Inc.
Inhibitors in hemophilia patients: Current status and management
Authors: Aledort Louis
Published: February 2007

The development of inhibitor antibodies is a long‐standing, well‐documented complication of coagulation factor replacement therapy and is difficult to treat. Previous estimates of 5–15% of patients developing inhibitors may be low, since newer data suggest a wider range of occurrence. Factors that appear to affect inhibitor development include the severity of hemophilia, age, genetics, and, possibly, the type of replacement therapy administered. Recent studies raise the concern that recombinant factor therapies may be associated with more rapid development and higher levels of inhibitors in previously untreated patients. However, results of different studies are often difficult to compare owing to differences in methodology and populations studied. Further studies standardized in design and methods are clearly needed.

Management of patients with inhibitors involves control of acute bleeding episodes and, over the long term, Induction of immune tolerance for the coagulation replacement therapy. Many with low or moderate levels of inhibitors may be treated simply by administering higher doses of dotting factor. Other therapies appropriate for those with high levels of inhibitors include porcine F VIII and factor VIII “bypassing” agents, such as recombinant factor VIIa. Long‐term immune tolerance has been achieved through the high‐dose “Bonn” regimen and immunosuppressive regimens such as the “Malmö” method.

Although management of inhibitor patients has improved, it still represents a major challenge. Further research is needed to identify which patients will develop inhibitors and tolerance, as well as to develop better methods to manage, reduce, or eliminate inhibitors from these patients. © 1994 Wiley‐Liss, Inc.
Hb E/Hb LeporeHollandia in a family from Bangladesh
Authors: Waye John S. , Eng Barry , Patterson Margaret , Chui David H. K. , Chang Lebe S. , Cogionis Bessie , Poon Annette O. , Olivieri Nancy F.
Published: February 2007

We describe a family from Bangladesh in which three children are compound heterozy‐gotes for Hb E (α2β2, β26Glu Lys) and Hb Lepore (δ‐β fusion gene). PCR amplification and direct nucleotide sequencing established that the fusion gene is Hb LeporeHollandia, with the cross‐over localized to a 40 bp window between codon 22 and IVS‐1 nt 16 of the δ‐ and β‐globin genes. This unusual combination of mutations is associated with a relatively mild clinical phenotype, with all three affected siblings having microcytic anemia of moderate severity without the need for transfusions. © 1994 Wiley‐Liss, Inc.
Acute megakaryoblastic leukemia following transient myeloproliferative disorder in a patient without down syndrome
Authors: Brissette Mark D. , Duval‐Arnould Bertrand J. , Gordon Bruce G. , Cotelingam James D.
Published: February 2007

Transient myeloproliferative disorder (TMD) and subsequent acute myeloid leukemia (AML) occur with increased frequency in infants and children with Down syndrome. TMD can also occur in phenotypically normal newborns. We describe the second case of a non‐Down syndrome child with TMD who subsequently developed AML. Trisomy 21 karyotype was restricted to hematopoietic cells in the blood and bone marrow. No other karyotypic abnormalities were found. Leukemic blasts showed megakaryoblastic features with immunophenotyping. This case shows that TMD in a child without Down syndrome may not be entirely benign. Close follow‐up is warranted. © 1994 Wiley‐Liss, Inc.
Antithrombin III kumamoto II; A single mutation at Arg393‐his increased the affinity of antithrombin III for heparin
Authors: Okajima Kenji , Abe Hiroki , Wagatsuma Masako , Okabe Hiroaki , Takatsuki Kiyoshi
Published: February 2007

Abnormal antithrombin III (AT III) was found in a 30‐year‐old woman who suffered from recurrent thrombosis during pregnancy and the postpartum period. Among her family members, only her father had recurrent episodes of deep vein thrombosis of the lower extremities, from his youth. The antithrombin and antifactor Xa heparin cofactor activities of the proposita's plasma were 61% and 42% of normal, respectively. The progressive antithrombin and antifactor Xa activities were also decreased to 55% and 58% of normal, respectively. The immunoreactive level of AT III was within the normal range (23.1 mg/dl). Analysis of the proposita's plasma by crossed immunoelectrophoresis in the presence or absence of heparin and by affinity chromatography on heparin‐Sepharose revealed that the proposita's AT III had apparently normal affinity for heparin. Nucleotide sequencing of 7 exons of the proposita's AT III gene amplified by polymerase chain reaction (PCR) disclosed that the second base of codon 393 comprised both G and A, indicating Arg393‐His conversion. The base sequences of exons 1,2,3a, 3b, 4, and 5 were normal, excluding any other mutation. These findings indicated that the proposita's AT III was a variant of AT III at the thrombin binding site and that the proposita was a heterozygote for the abnormality. Heparin affinity of purified abnormal AT III from the proposita's plasma was demonstrated to be increased upon affinity chromatography using heparin‐Sepharose, suggesting that the mutation (Arg393‐His) per se could possibly increase the affinity of antithrombin III for heparin.

For this variant AT III (Arg393‐His), the name AT III Kumamoto II is proposed. ©1995 Wiley‐Liss, Inc.
Sickle cell rheology is determined by polymer fraction–not cell morphology
Authors: Hiruma Hiroyuki , Noguchi Constance Tom , Uyesaka Nobuhiro , Hasegawa Setsuo , Blanchette‐Mackie E. Joan , Schechter Alan N. , Rodgers Griffin P.
Published: February 2007

Sickle cell disease pathophysiology is mediated by acute and chronic impairment of cell flexibility due to the formation of intracellular sickle hemoglobin (Hb S) polymer as cells are partially deoxygenated in the microcirculation. We have recently developed a method to measure the relationship between the formation of intracellular polymerized Hb S and cell filtration. In this study, we have used this method to examine whether sickle cell morphology, independent of Hb S polymer fraction, had an effect on cell rheology. We primarily use sickle trait (AS) and Hb S‐β+‐thalassemia (S‐β+‐thal) erythrocytes with low hemoglobin F levels, which have normal membranes and few or no dense cells, to remove these confounding effects. We find that the relationship between filtration and the percentages of each “type” of morphological deformation of AS erythrocytes was different from that of the S‐β+‐thal erythrocytes. In addition, we find that while the filtration of AS erythrocytes as a function of oxygen saturation was similar, whether measured during deoxygenation or reoxygenation, the relationship between the percentages of each type of deformed erythrocyte and oxygen saturation demonstrated hysteresis during oxygenation‐deoxygenation experiments. Transmission electron microscopy, for both elongated and irregularly shaped cells, showed that similarly distorted cells could have very different amounts and alignment of polymer. These results suggests that cell morphology per se is not strongly related to filtration, whereas calculated intracellular Hb S polymer fraction predicts loss of filtration of AS and S‐β+‐thal erythrocytes well. Measured or calculated polymer fraction values would appear to be a better parameter for the study of sickle cell disease pathophysiology and response to treatment than cell morphology studies. ©1995 Wiley‐Liss, Inc.
Unexpected hepatotoxicity after priming and treatment with molgramostim (rhGM‐CSF) in acute myeloid leukemia during induction chemotherapy
Authors: Hansen Per Boye , Johnsen Hans E. , Lund Jens Otto , Hansen Mogens Sandbjerg , Hansen Niels Ebbe
Published: February 2007

The effect of supplementing induction chemotherapy with recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF) was studied in a randomized trial of 18 patients with acute myeloid leukemia (AML). Ten patients received rhGM‐CSF, starting on day one to three before chemotherapy and continued for a maximum of 21 days after the start of induction treatment. Unexpected adverse effects of rhGM‐CSF and chemotherapy combination included a transient decline in plasma coagulation factors II, VII, and X (5 of 5 patients) and an increased transcapillary escape rate of albumin (in 3 of 3 patients tested). The decline in coagulation factors was prevented in subsequent patients by prophylactic treatment with vitamin K. Although the small number of patients studied may not allow a definite conclusion, caution with regard to liver function should be shown in combining rhGM‐CSF with intensive chemotherapy. ©1995 Wiley‐Liss, Inc.
Role of interferon alpha‐2a in the treatment of polycythemia vera
Authors: Foa Paolo , Massaro Paolo , Ribera Sonia , Lurlo Alessandra , Mezzanotte Carmen , Giandalia Daniela , Maiolo Anna Teresa
Published: February 2007

We studied the effects of recombinant interferon alpha‐2a (IFN‐alpha) in 36 patients with polycythemia vera (PV) previously treated with phlebotomy and/or conventional cytostatic agents. In each patient, after at least 2 months of discontinuation of any cytotoxic therapy, the hematocrit (Hmt) was first brought to normal value by phlebotomy; IFN‐alpha treatment was then begun at a starting dose of 3,000,000 IU s. c. three times a week. Response to treatment, which was assessed monthly, was defined as persistent normalization of Hmt without concomitant phlebotomy; in non‐responsive patients the initial IFN‐alpha weekly dosage was progressively increased. Twenty patients were responsive with a median duration of response of 7 months (range 2‐25+ months); out of these, 7 patients are still under treatment and responsive at 13+, 17+, 20+, 22+, 23+, 25+, 25+ months. These findings indicate that a cohort, although small, of patients with PV (19.4%) are persistently sensitive to IFN‐alpha; in this subset of patients, this cytokine can therefore provide a useful treatment option, since, contrary to conventional therapeutic approaches such as radioactive phosphorus, cytostatic agents, or phlebotomy, IFN‐alpha is devoid of harmful side effects. ©1995 Wiley‐Liss, Inc.
Initiation codon mutation (ATG → ATA) of the β‐globin gene causing β‐thalassemia in a Swedish family
Authors: Landin Britta , Rudolphi Olle , Ek BÖRje
Published: February 2007

An initiation codon mutation ATG → ATA of the β‐globin gene was found in seven members of three generations of a family living in northern Sweden. This mutation, which has not previously been described, changes the initiation codon for methionine into a codon for isoleucine and will then result in a β°‐thalassemic phenotype. The affected family members all present hematological findings typical for β‐thalassemic trait, with slight anemia, marked microcytosis, and increased levels of Hb A2. ©1995 Wiley‐Liss, Inc.
Fibrinogen/fibrin degradation products and D‐dimer in clinical practice: Interpretation of discrepant results
Authors: Sato Naoaki , Takahashi Hoyu , Shibata Akria
Published: February 2007

In clinical practice, occasionally some patients show dissociated values of fibrinogen / fibrin degradation products (FDP) and D‐dimer (cross‐linked fibrin degradation products). In an attempt to assess the frequency, clinical backgrounds, and hemostatic states of these cases, FDP and D‐dimer were simultaneously measured together with other hemostatic parameters in 371 samples from patients with various diseases. As a whole, FDP values were positively correlated with D‐dimer values (r = 0.871, P < 0.0001), and both were elevated in parallel with the progress of activation of blood coagulation and fibrinolysis. However, in patients with elevated FDP and/or D‐dimer, 11.5% of samples showed relatively lower D‐dimer values than those expected from FDP levels, and these were regarded as an apparently dissociated group. In the dissociated group, activation of coagulation and fibrinolysis occurred to a lesser extent than others. Analysis of these samples suggested that the possible reasons for the dissociation bet ween FDP and D‐dimer values were accelerated fibrinogenolysis with or without secondary fibrinolysis, accelerated fibrinogenolysis by non‐plasmic proteinases, elevated soluble fibrin, and possibly false‐positive FDP levels due to unclottable fibrinogen remaining in the serum samples. In practice, simultaneous measurements of FDP and D‐dimer are useful for more accurate estimation of hyperfibrinolytic states. ©1995 Wiley‐Liss, Inc.
Morphological, ultrastructural, and genetic characterization of an unusual T‐cell lymphoma in a patient with sinus histiocytosis with massive lymphadenopathy
Authors: Koduru P. R. K. , Susin M. , Kolitz J. E. , Sonl M. , Teichberg S. , Siques M. J. , Sun T. , Amorosi E. , Budman D. R.
Published: February 2007

Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare benign disease of unknown etiology. It is rarely associated with malignant lymphoma. This report documents the first case of a T‐cell lymphoma, which developed in a patient with a 10‐year history of SHML. The disease was complicated by hypereosinophilia and massive retroperitoneal lymphadenopathy. Histological examination of a cervical lymph node biopsy during the terminal phase identified a lymphoma composed of cells with morphological plasmacytoid features. Ultrastructurally, the tumor cells showed poorly developed cytoplasm, nuclei with peripheral chromatin clumping, and inconspicuous nucleoli. Cytogenetic studies showed two related clones. On immunohistochemical staining tumor cells were positive with monoclonal antibodies (mAb) CD3 and CD45RO. Southern blotting analysis identified clonal rearrangements in the T‐cell receptor (TCR) alpha, beta and gamma genes. Thus, T‐cell lineage of the tumor cells was established. In situ hybridization of interleukin‐2 (IL‐2) and interleukin‐5 (IL‐5) cDNA probes on tissue sections identified the synthesis of IL‐5 by the eosinophils, suggesting an autocrine pathway of eosinophilopoiesis leading to hypereosinophilia in this patient. ©1995 Wiley‐Liss, Inc.
Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator inhibitor, high lipoprotein(a), and therapy with stanozolol
Authors: Glueck Charles J. , Freiberg Richard , Glueck Helen I. , Tracy Trent , Stroop Davis , Wang Ying
Published: February 2007

In five patients with idiopathic osteonecrosis (ON) of the hip, four having hypofibrinolysis mediated by high plasminogen activator inhibitor (PAI‐Fx), and one with high Lp(a), our specific aim was to determine whether therapy (Rx) with the anabolic‐androgenic steroid, Stanozolol(6 mg/day), would normalize PAI‐Fx and Lp(a) and thus potentially ameliorate ON. Prior to Rx, none of the four patients with high PAI‐Fx could normally elevate tissue plasminogen activator (tPA‐Fx) after 10 min venous occlusion at 100 mm Hg. After 12‐18 weeks on Rx, PAI‐Fx and stimulated tPA‐Fx normalized in all four patients. Prior to Rx, mean (SD) stimulated tPA‐Fx was low, 0.4 ± 0.3 IU/ml (lower limit of normal 2.28 IU/ml). On Rx, stimulated tPA‐Fx normalized, rising to 2.83 ± 1.9 IU/ml, P = 0.004. Prior to Rx, mean (SD) basal PAI‐Fx was high, 99 ± 68 (upper limit of normal 26.9 U/ml), and fell on Rx to 22.5 ± 22, P = 0.004. In two of the five patients normalization of hypofibrinolysis or high Lp(a) was accompanied by major symptomatic improvement. Prior to Rx, and 2 years after onset of unilateral hip pain, one of the four patients with high PAI‐Fx and low stimulated tPA‐Fx could walk only one block painfully. After 8 weeks on Stanozolol Rx, and continuing through 54 weeks on Rx, he walked 2 miles per day without pain, despite radiographic progression of ON. In three of the four patients with high PAI and with osteonecrosis present 0.3, 2, and 6 years prior to Stanozolol Rx, there was no clinical improvement after 14‐156 weeks of Rx despite normalization of stimulated tPA‐Fx and PAI‐Fx. The fifth patient, 1 month after onset of disabling hip pain, had normal PAI‐Fx but high Lp(a) (27 mg/dl), and MRI evidence of bone marrow edema (“transient osteoporosis”). After 3 weeks on Rx, Lp(a) normalized (14 mg/dl) and there was marked amelioration of symptoms. For the subsequent 11 weeks on Rx, this patient's Lp(a) was 5 mg/dl, and he became totally asymptomatic and remains asymptomatic 14 months later. We speculate that when ON is diagnosed prior to segmental collapse of the femoral head, it may be possible to reverse hypofibrinolysis, and/or to arrest the progression of ON. We postulate that high PAI or high Lp(a) lead to inadequate lysis of venous thrombi in bone, impaired bone venous circulation, venous hypertension of bone, and subsequent, potentially reversible development of ON. © 1995 Wiley‐Liss, Inc.
Treatment of acute myelogenous leukemia in patients over 50 years of age with V‐TAD: A southwest oncology group study
Authors: Bigelow Carolyn L. , Kopecky Kenneth , Files Joe C. , Head David , Lipschitz David A. , Grever Michael , Appelbaum Frederick R.
Published: February 2007

Acute myelogenous leukemia (AML) in the elderly continues to have a poor prognosis and new treatment approaches are needed. This Phase II trial was undertaken to evaluate the complete remission rate and toxicity of a chemotherapeutic regimen including etoposide and 6‐thioguanine, combined with reduced doses of cytosine arabinoside and daunorubicin (V‐TAD) in individuals greater than 50 years of age with AML.

Thirty‐five patients, ranging in age from 51 to 80 years (median, 66 years), were registered onto the study. Twenty‐nine patients were entered at the first dose level (daunomycin 20 mg/m2 days 1 and 2, ara‐C 75 mg/m2 days 1‐5, 6‐thioguanine 75 mg/m2 every 12 hr days 1‐5, and etoposide 50 mg/m2 days 1, 2, and 3) and six patients underwent therapy at the second dose level (ara‐C 75 mg/m2 days 1‐7 with the remainder of the regimen unchanged). After achieving a complete remission, patients underwent two to three consolidation cycles of chemotherapy.

Thirty‐one patients were evaluable for response. Thirteen patients (ten of twenty‐five at the first dose level and three of six at the second dose level) achieved a complete remission (42%). Median remission duration was 6 months (range 1‐21 months).

The current regimen, while tolerated, did not result in improved survival compared with prior treatment regimens because of a high incidence of resistant and recurrent leukemia. © 1995 Wiley‐Liss, Inc.
Characterization of two cases of acquired transitory von willebrand syndrome with ciprofloxacin: Evidence for heightened proteolysis of von willebrand factor
Authors: Castaman Giancarlo , Lattuada Antonella , Mannucci Pier Mannuccio , Rodeghiero Francesco
Published: February 2007

We characterized the cause of two cases of transitory acquired von Willebrand syndrome associated with the administration of ciprofloxacin. Purified lg from the two patients did not inhibit Ristocetin Cofactor activity or binding to collagen of normal plasma, ruling out the possibility of an inhibitor. The analysis of multimeric pattern of plasma von Willebrand Factor (vWF) showed the lack of larger multimers in both patients, with a relative decrease of all the remaining forms in the first patient. The subunit composition of plasma vWF showed a marked reduction of the native 225 Kd subunit (31.9% and 32.9%; normal range 74‐46%) and an increased proportion of the 189, 176, and 140 Kd fragments. These abnormalities disappeared during the follow‐up, without any specific therapy. In conclusion, a common pathophysiological basis is demonstrated in both patients, with a heightened proteolysis of plasma vWF by an unknown mechanism. © 1995 Wiley‐Liss, Inc.
Serum antibodies to distinct epitopes of the tissue‐type plasminogen activator (t‐PA) in patients with systemic lupus erythematosus
Authors: Ruiz‐Arguelles Alejandro , Angles‐Cano Eduardo , Perez‐Romano Beatriz , Ruiz‐Arguelles Guillermo J. , Deleze Margarita , Alarcon‐Segovia Donato , Gaussem Pascale
Published: February 2007

Defective fibrinolysis due to decreased tissue‐type plasminogen activator (t‐PA) activity is a well‐established finding in patients with systemic lupus erythematosus (SLE). The possibility that this decrease in t‐PA activity may be related to the presence of autoantibodies directed against t‐PA, and the possible role of these autoantibodies in the patho‐physiology of fibrinolysis in SLE, were investigated. Serum samples from 115 SLE patients and 63 normal volunteers were analyzed for the presence of such antibodies. The search for antibodies to t‐PA was performed by means of several systems, allowing for the identification of epitopes presented in different conformational physical states of t‐PA: free or associated to its inhibitor (PAI‐1) in plasma, specifically bound to fibrin surface, or passively adsorbed to solid supports. Antibodies in variable amounts were detected by all systems used; however, t‐PA activity was not inhibited by the IgG fraction of the positive sera in a fibrin‐agar fibrinolysis system. Moreover, the demonstration of serum anti‐t‐PA antibodies was not associated with clinical or laboratory abnormalities related to vasoocclusive episodes. These results indicate that, as in the case of other autoantibodies, their detection in serum does not imply their direct participation in the pathophysiology of thrombosis in SLE. © 1995 Wiley‐Liss, Inc.
Peripheral blood neutrophil morphology reflects bone marrow dysplasia in myelodysplastic syndromes
Authors: Widell S. , Hellström‐Lindberg E. , Kock Y. , Lindberg M. , Öst Å. , Hast R.
Published: February 2007

Dysplastic features of cells in peripheral blood and bone marrow were studied in 51 patients with myelodysplastic syndromes (MDS) to evaluate the significance of the degree of neutrophil granulation (G‐score) and the percentage of pelgeroid polymorphs (ppp) in the peripheral blood, as indices of dysplastic changes in the bone marrow. There was a good correlation between peripheral blood and bone marrow findings, both for G‐score figures (r = 0.92, P < 0.01) and ppp (r = 0.82, P < 0.01). Significantly lower G‐score figures were found among patients with an increased percentage of bone marrow blasts (P < 0.05), while high ppp correlated with the presence of ring sideroblasts, the degree of bone marrow fibrosis, and findings of complex chromosomal abnormalities. Patients with a high degree of bone marrow dysplasia had significantly lower G‐score (P < 0.01) and significantly higher ppp (P < 0.05) figures, than those with less pronounced myelodysplasia. In addition, extreme hypogranulation (G‐score <150) or very high ppp (≥20%) was generally a sign of bi‐ and tri‐lineage dysplasia in the bone marrow. The results thus show that quantitative estimation of peripheral blood polymorph dysplasia by G‐score figures and ppp seems to reflect the total degree of bone marrow dysplasia in MDS and may serve as a complement to bone marrow evaluation when the diagnosis of MDS is difficult. © 1995 Wiley‐Liss, Inc.
Comparative study of multidrug resistance evaluated by means of the quantitative immunohistochemical detection of p‐glycoprotein and the functional release of rhodamine 123
Authors: Delville Jean‐Pierre , Pradier Olivier , Pauwels Olivier , Van Onderbergen Anne , Kiss Robert , Feremans Walter , Capel Paul
Published: February 2007

The immunological detection of P‐Glycoprotein (P‐GP) and the functional release of Rhodamine 123 (R123) have been compared in a number of human and murine cancer cell lines, in chemo‐and/or radiotherapy‐resistant subclones, and in clinical specimens from patients. The chemoresistance level was established from the viability index (IC50) in the presence of doxorubicin. Cytocentrifuge preparations were immunostained with JSB‐1 monoclonal antibody followed by the alkaline phosphatase anti‐alkaline phosphatase technique. The strength of the reaction was quantified by a digital image analyser. The kinetic incorporation and release of Rhodamine 123 were evaluated by flow cytometry. The parent cell lines and radiotherapy resistant subclones showed a low IC50, were JSB‐1 negative and retained R123 during the whole experiment, while the chemoresistant and radio‐chemoresistant cell line mutants had a high IC50, were JSB‐1 positive, and actively pumped the R123 out of the cells. Good correlations were obtained between the IC50, the digital image analysis, and flow cytometry. The kinetic profile of the R123 release allowed the distinction between typical and atypical multidrug resistance phenotypes. These findings were confirmed in clincal specimens from patients. We conclude that antigenic and functional studies are complementary and are useful in experimental and clinical approaches to multidrug resistance.
Establishment and characteristics of a gastric cancer cell line (HuGC‐OOHIRA) producing high levels of G‐CSF, GM‐CSF, and IL‐6: The presence of autocrine growth control by G‐CSF
Authors: Baba Masaru , Hasegawa Hiroshi , Nakayabu Masahiro , Shimizu Noriko , Suzuki Shiro , Kamada Nanao , Tani Kenzaburo
Published: February 2007

We successfully established a human gastric cancer cell line, HuGC‐OOHIRA, from the ascites of a 60‐year‐old patient with advanced gastric cancer (poorly differentiated adenocarcinoma) complicated by peritonitis carcinomatosa and leukocytosis of unknown origin. Morphologically, the cells were polygonal and adhered weakly to the culture flask. They tended to pile up upon reaching confluence. Chromosome analysis revealed that the cell line has two modes of chromosome number, namely near diploidy and tetraploidy. Double minutes (DMs) were present in abundance in each cell. The doubling time was 25‐30 hr. The cell line was successfully transplanted into nude mice, and their peripheral leukocyte counts increased in proportion to the growth of the tumors. At 2 weeks after the transplantation, the serum rG‐CSF level was elevated to 2,893 üg/ml. The concentration of human G‐CSF in the culture supernatants was an extraordinary high level of 145,380 pg/ml/day. Secretion of GM‐CSF and IL‐6 was also detected. The intracellular localization of the G‐CSF was identified for the first time by immunofluorescence. Moreover, Northern blot analysis detected G‐CSF mRNA in this cell line. Anti‐recombinant human G‐CSF serum suppressed the propagation of HuGC‐OOHIRA cell line. Therefore, it is likely that the autocrine growth loop by G‐CSF is present in this cell line. This cell line would be very useful for understanding both the cellular and molecular basis for the production of various cytokines such as G‐CSF as well as cytokine‐dependent tumor proliferation.