bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐dose methylprednisolone is an alternative treatment for adults with autoimmune thrombocytopenic purpura refractory to intravenous immunoglobulins and oral corticosteroids
Authors: Godeau Bertrand , Zini Jean‐Marc , Schaeffer Annette , Bierling Philippe
Published: February 2007

Eight patients with severe chronic autoimmune thrombocytopenic purpura (AITP) refractory to high‐dose intravenous immunoglobulin (IVIgG) and/or oral prednisone were treated with one to three infusions of high‐dose methylprednisolone (HDMP) (15 mg/kg/day). The mean platelet count before treatment was 12 ± 10 × 109/L. HDMP therapy led to a safe platelet count (>50 × 109/L) after 2‐5 days in five patients, and a minimal platelet increase (34 × 109/L) able to stop bleeding in a sixth patient. The effect of HDMP was, however, translent in four of the five responders. No side effects were observed, even in the four patients older than 70 years. HDMP thus appears to be a good alternative in emergency situations or prior to surgery for patients with AITP refractory to conventional therapy.
Oxidized LDL induces serotonin release from blood platelets
Authors: Zhao B. , Dierichs R. , Harrach‐Ruprecht B. , Winterhorff H.
Published: February 2007

Oxidized low‐density lipoprotein (LDL) induces a release of serotonin from morphologically resting platelets and shape changed platelets. This suggests that oxidized LDL, a newly reported weak agonist, contributes to atherogenesis and thrombogenesis by stimulating platelets. © 1995 Wiley‐Liss, Inc.
New variant of type II von willebrand's disease with structural abnormality of plasma von willebrand factor in a patient with very mild bleeding history
Authors: Baillod Peter , Gaucher Christine , Affolter Beat , Mazurier Claudine , Pflugshaupt Rolf
Published: February 2007

A new variant of von Willebrand's disease has been discovered in 2 members of a Macedonian family of 6. The proband, an 8‐year‐old boy, showed a prolonged bleeding episode on 1 occasion. Ristocetin‐induced platelet aggregation and bleeding time were normal. In plasma, ristocetin cofactor activity (RCo) and von Willebrand factor (vWf) antigen were reduced to the same clearly low level. The determination of vWf antigen of platelets resulted in borderline values, while RCo was clearly reduced. Low‐ and intermediate‐resolution agarose gel electrophoresis showed absence of the largest multimers in plasma vWf, and slight reduction in platelet vWf. High‐resolution gels revealed abnormal multimeric structure only in plasma vWf. The smaller multimers could be resolved in a broad central band flanked by 4 fainter satellite bands; however, satellite bands close to the central band were more intense, and more distant ones were fainter, compared to normal plasma. The central band of the fastest‐moving multimer was markedly intensified, and the mobility of the whole quintuplet was slightly reduced. Heredity seems to be autosomal‐dominant. No mutation was found in exon 28 of the vWf gene.

Because there was only 1 mild bleeding episode in the family, this structural variation seems to have only little clinical consequence. We conclude that this vWf abnormality is different from those observed in other type II variants previously described. Based on the revised classification by the International Society on Thrombosis and Haemostasis, we proposed designation type 2A‐Bern for this new subtype. © 1995 Wiley‐Liss, Inc.
Recombinant hirudin (HBW 023): Biological data of ten patients with severe venous thrombo‐embolism
Authors: Bridey F. , Dreyfus M. , Parent F. , Bros A. , Fischer A. M. , Camez A. , Simonneau G. , Duroux P. , Meyera D.
Published: February 2007

This study reports on the biological data of ten patients with acute venous thromboembolism. They were treated for 5 days with continuous intravenous infusion of a fixed dose (0.05 mg/kg/hr) of a recombinant hirudin (r‐H HBW 023 Behringwerke, Germany). The plasma level of r‐H (HBW 023), assessed by an anti‐factor Ila amidolytic activity, was stable after Day 2 and showed considerable individual variations. It correlated with APTT ratio, suggesting that this test is a reliable tool to monitor therapy. In contrast, thrombin time was constantly over 120 sec (control 15 sec) and consequently was not a useful parameter. Prothrombin time showed a slight, but significant, prolongation, which was correlated with the increase of APTT ratio. There was no bleeding time prolongation, platelet count, or ATIII level decrease. Levels of thrombin‐antithrombin III complexes, and D‐dimers, which were high in all patients on admission, decreased during the course of the treatment but remained abnormal on Day 5, showing an ongoing hemostasis and fibrinolysis activation: this is consistent with the delayed, but only slightly decreased thrombin generation evidenced by thrombin generation test performed on Day 3. These results suggest that thrombin inhibition by rH‐hirudin at this dosage is only partial, which allows the generation of traces of thrombin needed for the feed‐back thrombin production generated by factor V and VIII activation. © 1995 Wiley‐Llss, Inc.
Decreased production of TNF and IL‐6 in whole blood of CLL patients
Authors: Oahlke E. , Schlag R. , Langenmayer I. , Frankenberger M. , Käfferlein E. , Subkowski T. , Emmerich B. , Ziegler‐Heitbrock H. W. L.
Published: February 2007

Monocyte derived cytokines, tumor necrosis factor (TNF) and interleukin‐6 (IL‐6), were determined in cell free plasma after stimulation of heparinized whole blood from chronic lymphocytic leukemia (CLL) patients with lipopolysaccharide (LPS) at 1 μg/ml for 6 hr. Compared to control donors (390 U/ml), CLL patients in average had eight‐fold lower levels of TNF bioactivity (50 U/ml). The depressed levels were observed over a wide range of LPS concentrations (0.01 to 10 μg/ml). Furthermore, after stimulation with S. aureus bacteria, CLL samples gave three‐fold lower levels, as well. TNF levels were not decreased because of defective bioactivity of TNF, since strongly reduced levels of TNF protein were also detected in an immunoassay. Finally, interleukin‐6 levels after LPS stimulation were decreased threefold.

Flow cytometry analysis with CD14 antibodies demonstrated comparable numbers of monocytes for control donors and CLL patients (698 ± 802 and 427 ± 267, respectively). This suggests that deficient cytokine production was not due to a reduction in monocyte number, but rather to a functional impairment.

The deficiency in cytokine production observed after ex vivo stimulation of whole blood from CLL patients suggests that in vivo during bacterial infection, CLL patients will exhibit an inappropriate response as well. © 1995 witey‐Liss, Inc.
Hb Lepore (Pylos)/Hb S compounds heterozygosity in two Greek families
Authors: Voskaridou E. , Konstantopoulos K. , Kollia P. , Papadakis M. , Loukopoulos D.
Published: February 2007

We have studied three compound heterozygotes for Hb Lepore (“Pylos”)/HbS hemoglobin, a combination quite uncommon in the literature. It is of interest that while two of these cases are clinically similar to those thus far reported, the third one is free of symptoms and the diagnosis was put incidentally. This mild condition may be due to the high level of fetal hemoglobin produced. © 1995 Wiley‐Liss, Inc.
Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: Case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome
Authors: Kouides Peter A. , Bennett John M.
Published: February 2007

If chronic myelomonocytic leukemia (CMML) transforms into an acute leukemic phase, the blast crisis is invariably myeloid. Occasionally, the other subtypes of myelodysplastic syndrome (MDS) (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation) have been noted to transform into acute lymphoblastic leukemia (ALL). We now report a case of CMML that transformed into ALL and we review the literature of 13 other cases of MDS with ALL transformation. Such cases provide suggestive clinical evidence that MDS can involve a pluripotent stem cell. © 1955 Wiley‐Liss, Inc.
Treatment of platelet alloimmunization with intravenous immunoglobulin in a child with aplastic anemia
Authors: Chen Shu‐Huey , Liang Der‐Cherng , Lin Marie
Published: February 2007

A 9‐year‐old girl with severe refractory aplastic anemia had become refractory to platelet transfusion due to platelet alloimmunization. As a result, a huge right parieto‐temporo‐occipital cerebral hematoma and a subarachnoid hemorrhage subsequently occurred. Intravenous immunoglobulin (IVIG) (Green Cross, Taiwan) at a dose of 0.4 g/kg/day for 5 days, followed by another 3 doses during the following 5 days, and combined with large‐dose platelet transfusions effectively controlled the bleeding by elevating the platelet count to above 100 × 103/mm3. The patient soon recovered with only a mild sequela. Two months later, because of multiple caries and a periodontal abscess, dental extraction needed to be performed. IVIG (0.4 g/kg/day × 6 days) enabled surgery to proceed by elevating the platelet count to above 55 × 103/mm3, and no bleeding complications occurred during or after the procedure. The potential benefit of high‐dose IVIG in modulating platelet alloimmunization is a result of increasing the survival of transfused platelets. Thus, this therapy is recommended when patients with platelet alloimmunization have critical bleeding episodes or undergo surgical procedures. © 1995 Wiley‐Liss, Inc.
Adhesion of washed blood platelets in vitro is advanced, accelerated, and enlarged by oxidized low‐density lipoprotein
Authors: Zhao B. , Rickert C. H. , Filler T. J. , Liu B. , Verhallen P. F. J. , Dierichs R.
Published: February 2007

In order to study the influence of oxidized low‐density lipoprotein (Ox‐LDL) on platelet functional morphology at an early activation stage, washed human blood platelets were stimulated by 100 μg/ml Ox‐LDL at 37°C. The settling and spreading process of stimulated and unstimulated platelets on Formvar‐coated glass was observed for approximately 20 min by reflection contrast microscopy (RCM) and quantified by image analysis. Each group consisted of at least 250 platelets. The results show that incubation with Ox‐LDL causes platelet shape change and pseudopodia formation. The sedimentation of stimulated platelets precedes that of unstimulated platelets by approximately 3 min. The increase of the total adhesion area of all Ox‐LDL treated platelets is significantly accelerated in comparison to normal platelets (20.45 μm2/min vs. 15.45 μm2/min;P < 0.01). The mean total adhesion area of Ox‐LDL‐treated platelets was generally larger than that of untreated platelets (189.7 μm2 vs. 144.7 üm2; P < 0.01). The disappearance of intracellular granules after platelet activation, observed by RCM, is supported by transmission electron microscopy. Our results suggest that Ox‐LDL activates platelets and advances and accelerates their adhesion and thereby may contribute to pathological thrombosis and arteriosclerosis.
Idiopathic CD4+ T‐lymphocytopenia in HIV seronegative men with hemophilia and sex partners of HIV seropositive men
Authors: O'Brien Thomas R. , Diamondstone Laura , Fried Michael W. , Aledort Louis M. , Eichinger Sabine , Eyster M. Elaine , Hilgartner Margaret W. , White Gilbert , Di Bisceglie Adrian M. , Goedert James J.
Published: February 2007

Persons with hemophilia or other HIV‐1 risk factors may be more likely to have idiopathic CD4+ T‐lymphocytopenia (ICL). We determined the frequency of ICL in prospectively followed cohorts of HIV‐1 seronegative hemophilic men and seronegative female sex partners of HIV‐1 infected hemophilic men, and examined factors potentially associated with ICL. Seven of 304 (2.3%) seronegative hemophilic men and one of 160 (0.6%) female partners met the ICL definition, but the condition resolved for two of the men and for the sole female partner. All five men with persistent ICL had lymphocytopenia (<1,200 total lymphocytes/ül) and <300 total CD4+ lymphocytes/ü only one had a low CD4+ percent‐ age. On the most recent measurement, 14.5% of the 304 seronegative hemophilic men had lymphoctopenia. Compared with matched hemophilic controls, men with persistent ICL more often had a history of liver disease (3/5 cases, 0/21 controls, P = 0.007) or splenomegaly (3/5 cases, 4/21 controls; P = 0.04), but not severe hemophilia, greater clotting factor concentrate exposure, high alanine aminotransferase levels, hepatitis B virus antigenemia, or detectable hepatitis C virus RNA in plasma. All five cases and 20/21 controls had antibodies to hepatitis C virus present in their serum. In this cohort of hemophilic men, ICL was related to lymphocytopenia associated with liver disease rather than selective loss of CD4+ lymphocytes.
Higher cytotoxic activity and increased levels of IL‐1β, IL‐6, and TNF‐α in patients undergoing cardiopulmonary bypass
Authors: Martí Francesc , Muñoz Joan , Peiró Matilde , Bertran Esther , Ferrán Carme , Octavio Carmen , García Juan , Rueda FÈLix
Published: February 2007

Extracorporeal circulation (EC) by surgical bypass is often associated with a systemic inflammatory response. The purpose of this study was to assess the effect of EC on the serum levels of pro‐inflammatory mediators Interleukin (IL)‐1β, IL‐6, tumor necrosis factor (TNF)‐α, and soluble CD‐23. Peripheral blood lymphocyte subsets and natural killer cell (NK) cytotoxic activity were also analyzed before and after the bypass process. The results from eight patients who underwent cardiac surgery showed a significant increase in the levels of IL‐1β, IL‐6, and TNF‐α, a decrease in CD4+/CD8+ lymphocyte ratio, and an overstimulated NK cytotoxic activity. These changes on serum cytokine levels and cellular immunology parameters could play an important role in the development of adverse effects associated with EC. © 1995 Wiley‐Liss, Inc.
Factor V Leiden (FVQ 506) is common in a Brazilian population
Authors: Arruda Valder R. , Annichino‐Bizzacchi Joyce M. , Costa Fernando F. , Reitsma Pieter H.
Published: February 2007

Resistance to activated protein C (APC) is the most common risk factor in venous thrombosis. A missense mutation in the factor V gene (factor V Leiden) is the molecular basis for this phenotype. Factor V Leiden was previously found in about 20% of unselected patients with thrombosis but also occurred in 3‐5% of healthy Dutch controls. In the present study of Brazilian patients with venous thrombosis we also observed a frequency of 20% for this factor. In addition, in healthy Brazilian controls the frequency of the mutation was 2%. These data suggest that factor V Leiden has a similar distribution worldwide irrespective of the ethnic origin of the population. © 1995 Wiley‐Liss, Inc.
Fetal hemoglobin expression in compound heterozygotes for −117 (G→A) Aγ HPFH and β039 nonsense thalassemia
Authors: Pistidda Paola , Frogheri Laura , Oggiano Lina , Guiso Luciana , Manca Laura , Dore Fausto , Masala Bruno , Gilman John G. , Longinotti Maurizio
Published: February 2007

The‐117(G→A) Aγ hereditary persistence of fetal hemoglobin (Greek HPFH) and β039‐thal mutations are rather frequent in Sardinia so that their interaction is to be expected. Characterization of eight compound heterozygotes for these defects indicated that HPFH was linked to haplotype VII and β039‐thal to haplotype II. Haplotype II β039‐thal chromosome carries the AγT gene which is a useful marker of γ‐gene expression. Since the Hb F level in these compound heterozygotes was significantly higher than in 46 −117 HPFH carriers, the Aγt, and Gγ globin level was determined. AγT was underexpressed while Gγ was significantly increased, which suggests that in −117 Aγ HPFH/β039‐thal healthy subjects the increase in Hb F production is determined only by the −117 mutated Aγ gene and the adjacent Gγ gene. © 1995 Wiley‐Liss, Inc.
Low proteins C and S and activation of fibrinolysis in treated essential thrombocythemia
Authors: Wieczorek Iwona , Macgregor Ian R. , Ludlam Christopher A.
Published: February 2007

The aim of this study was to investigate whether abnormalities in the fibrinolytic system and in the naturally occurring anticoagulant proteins could contribute to the thrombotic risk in essential thrombocythemia. Euglobulin lysis time, fibrin plate lysis area, tissue plasminogen activator antigen, and activity and plasminogen activator inhibitor antigen were measured before and after venous occlusion in a group of 16 patients with essential thrombocythemia and in 16 healthy age and sex matched controls. In addition, resting levels of antithrombin III, D‐dimer, prothrombin fragment 1 + 2, and protein C and S were assessed. The results were related to the presence or absence of a thrombotic history.

The results demonstrated that the patients had a significantly elevated fibrin plate lysis area and significantly decreased plasminogen activator antigen, both at baseline and after venous occlusion. They also had significantly decreased levels of plasma protein C and total protein S. There was a modest, non‐significant elevation in the plasma concentration of D‐Dimer and F 1 + 2. Those patients with a history of thrombosis had significantly lower protein C levels compared with individuals without a thrombotic history.

We conclude that patients with essential thrombocythemia have evidence of activated fibrinolysis in the resting state and after stimulation. This, and the decreased levels of protein C and total protein S, may be secondary to chronic clinically occult thrombosis occurring in myeloproliferative disorders. © 1995 Wiley‐Liss, Inc.
Molecular characterization of a new family with α‐Thalassemia‐1 (——MA mutation)
Authors: Villegas Ana , Sanchez Jesus , Carreno Dolores L. , Ropero Paloma , Gonzalez Fernando A. , Espinos Domingo , Penalver Maria A. , Lozano Matilde
Published: February 2007

A Spanish family with α‐thalassemia‐1 (α‐Thal‐1), deletion (—MA), is described. In addition to the loss of 22 kb of DNA with a deletion of the α1, α2, α1, α2, and Ψζ1 genes, a triplication of the ζ gene cluster in “cis” is produced. The structure of this triplication is formed by the Ψα1, gene, the interzeta region, and, possibly, the insertion of the Ψα2 fragment. © 1995 Wiley‐Liss, Inc.
Discordant morphologic features in bone marrow involvement by malignant lymphomas: Use of gene rearrangement patterns for diagnosis
Authors: Crisan Domnita , Mattson Joan C.
Published: February 2007

Discordant morphology between lymph node or extra‐nodal site and bone marrow (BM) involvement by non‐Hodgkin's malignant lymphoma (NHL) is a common occurrence, causing diagnostic difficulties. Additional diagnostic problems are posed by lymphoid aggregates commonly found in the BM of elderly patients, the age group with the highest incidence of lymphoma. Morphologic features are used to distinguish between benign and malignant lesions but no feature is diagnostic and exceptions are numerous. Immu‐nophenotyping is helpful for detecting B cell monoclonality, but it cannot detect T cell monoclonality. Unique B and T cell gene rearrangement patterns, the molecular “signature” of the lymphoma, can be used to detect monoclonal lymphoid populations. Finding the same rearrangement pattern in the BM as in the primary mass is proof of BM involvement by the same clone of malignant cells. We used B/T and Bcl‐2 gene rearrangements to help diagnose cases with discordant morphology between primary site and BM. One hundred and seventy‐five specimens, obtained from patients undergoing staging or restaging for NHL, were analyzed for B/T cell and Bcl‐2 gene rearrangements by multiple restriction endonuclease digestion and Southern hybridization with 32P labeled JH, JK, CTα, and Bcl‐2 probes. Forty‐two specimens (24%) from 24 patients showed discordant morphology: of 13 specimens with atypical lymphoid aggregates, only one had B cell gene rearrangement; of 15 specimens with morphologically benign lymphoid aggregates, one demonstrated B cell gene rearrangement; and of 14 specimens positive for NHL with different morphology than the lymph node, 13 were positive for B cell gene rearrangements. Molecular analysis can aid in the diagnosis of NHL, can establish a “baseline” for detection of recurrence, and is useful in monitoring therapy. These data suggest that it is also a tool for the pathologist in cases of discordant morphology between the primary tumor and BM, and should be strongly considered for each site. © 1995 Wiley‐Liss, Inc.
Immune mediated agranulocytosis and anemia associated with thymoma
Authors: Postiglione Kathy , Ferris Richard , Jaffe Jeffrry P. , Stroncek David
Published: February 2007

Thymoma has been associated with a variety of autoimmune disorders. We report a case of agranulocytosis and anemia in a 68‐year‐old woman with a spindle cell thymoma. She was unresponsive to treatment with antibiotics, granulocyte‐colony stimulating factor (G‐CSF), prednisone, and high‐dose intravenous immunoglobulin. Serial bone marrow examinations on this therapy showed progression from a cellular marrow with mild my‐eloid and erythroid hyperplasia and lymphocytosis, to granulocyte aplasia and severe erythroid hypoplasia. Her serum contained granulocyte‐specific antibodies and inhibited the growth in culture of her own marrow cells and marrow cells from a normal donor. An IgG fraction from her serum also inhibited the growth of marrow cells.

Although the patient's spindle cell thymoma was surgically removed, she remained neutropenic. She was treated with six plasma exchanges followed by 1,000 milligrams of intravenous cyclophosphamide 2 days after the final plasma exchange and daily G‐CSF. Three weeks later her peripheral blood showed marked leukocytosis with pronounced neutrophilia and a left shift. Although her agranulocytosis resolved, she died of fungal sepsis.

This case demonstrates that aggressive plasma exchange and immunosuppressive therapy may benefit patients with agranulocytosis associated with thymoma. © 1995 Wiley‐Liss, Inc.
Expression of the intestinal T‐lymphocyte‐associated‐molecule recognized by the HML‐1 antibody on mononuclear cells from HTLV‐I‐infected subjects
Authors: Otsuka Maki , Hanada Shuichi , Utsunomiya Atae , Ishitsuka Kenji , Uozumi Kimiharu , Arima Terukatsu
Published: February 2007

We investigated the expression of a monoclonal antibody (HML‐1) defined antigen that appears on human intestinal T‐lymphocytes in HTLV‐I‐related disease. We studied 25 ATL, and 24 healthy HTLV‐I carriers. Patients with acute ATL showed a variety of the expression of the HML‐1 antigen (range 0.4–74.8%). HML‐1 expression on mononuclear cells (MNCs) in blood from patients with chronic ATL ranged from 1.7–43.6% (mean 13.5%). This level of expression was less than that of patients with acute ATL, but not significantly. In patients with smoldering ATL, the degree of patients with acute ATL, but not significantly. In patients with smoldering ATL, the degree of expression ranged from 1.6–13.3% (mean 8.0%). In contrast to patients wtih acute ATL, MNCs from patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and B‐cell type chronic lymphocytic leukemia (B‐CLL) did not express the HML‐1 antigen, except for the 2 patients with ALL. Healthy HTLV‐I carriers and healthy controls also were negative for HML‐1 reactivity. In acute ATL, patients with gastrointestinal tract infiltration tended to have high expression of the HML‐1 epitope. After stimulation with phytohemagglutinin (PHA), healthy HTLV‐I carriers showed significantly increased expression of the HML‐1 epitope (P< 0.05).

Recently, the β7 integrin family has been found to play a specific role in mucosal localization or adhesion, and HML‐1 protein was found to match the deduced β7 N‐terminal sequence. We propose that the cellular gene responsible for HML‐1 epitope expression may, like IL‐2, IL‐2R, etc., be transactivated by infection with HTLV‐I, and that HML‐1 antigen gene expression by HTLV‐I infection may lead to infiltration of ATL cells with highly expressed HML‐1 epitope into the gut mucosa.
Flow cytometric evaluation of platelet activation in blood collected into EDTA vs. Diatube‐H, a sodium citrate solution supplemented with theophylline, adenosine, and dipyridamole
Authors: Kühne Thomas , Hornstein Adriana , Semple John , Chang Wilda , Blanchette Victor , Freedman John
Published: February 2007

With platelet activation, there is modulation of platelet surface molecule expression. In flow cytometric analyses of in vivo platelet activation, results are often confounded by activation induced in vitro by the preparative procedures. It is particularly important therefore to prevent or retard platelet activation as soon as possible after withdrawal of the blood sample. Taking blood into paraformaldehyde, or fixing the cells with paraformaldehyde as soon as possible after withdrawal, has been employed to prevent platelet activation in vitro, but paraformaldehyde‐fixed platelets cannot be further used in functional studies. We investigated the efficacy of Diatube‐H, a commercially available combination of platelet antagonists (theophylline, adenosine, and dipyridamole), in preventing or retarding platelet activation in vitro, along with its effects on modulation of platelet membrane glycoproteins (GP) and adhesion molecules. In contrast to blood taken into EDTA, blood taken into Diatube‐H vacutainer tubes could be stored at room temperature for up to 4 hr prior to paraformaldehyde fixation without significant in vitro platelet activation, as measured by CD62P, CD63 and modulation of GPIb and GPIIbIIIa surface expression. Hence, paraformaldehyde fixation could be deferred for several hours, permitting transport of samples from distant sites. Studies of thrombin‐induced platelet activation indicated that platelets taken into Diatube‐H remained functional i.e. were able to be activated. Expression of the CD29, CD49b and CD31 adhesion molecules on the platelet surface was unaffected by storage in Diatube‐H. The results suggest that Diatube‐H may be a useful reagent for flow cytometric studies of platelets when the samples cannot be processed immediately.
Sickle cell anemia, right atrial thrombosis, and the antiphospholipid antibody
Authors: Yeghen T. , Benjamin S. , Boyd O. , Pumphrey C. , Bevan D. H.
Published: February 2007

We report a patient with sickle cell anemia (homozygous Hb SS) and typical features of sickle chest syndrome but with no response to exchange transfusion. A right atrial thrombus was found, and antiphospholipid antibodies were detected in his blood. He responded to thrombolytic therapy. The relationship between right atrial thrombus and massive pulmonary embolus, and the implications of an additional thrombophilic state in sickle cell disease are discussed.
Autologous bone marrrow transplantation versus chemotherapy in relapsed/refractory non‐hodgkin's lymphoma: Estimates of long‐term survival from the recent literatur
Authors: Meehan Kenneth R. , Pritchard Robert S. , Leichter Joshua W. , Littenberg Benjamin , Gilbert Welch H.
Published: February 2007

Long‐term survival following chemotherapy or autologous bone marrow transplantation in adults with relapsed/refractory non‐Hodgkin's lymphoma was evaluated. English language articles published from January 1, 1988 to September 1, 1993 were obtained from a broad‐based MEDLINE search retrieving 3,854 citations regarding therapy for lymphomas.

Citations were evaluated using both computer‐based evaluation and manual review. Articles were included if they addressed the disease of interest (non‐Hodgkin's lymphoma, Working Formulation D‐H), the population of interest (adults with either relapsed or refractory disease), and the therapies of interest (chemotherapy or autologous bone marrow transplantation). Articles were excluded if they did not provide convincing information on long‐term survival (as evidenced by either survival analysis or individual patient data) or if they reported a small number of patients (N < 15).

No randomized trials of the two therapies were found. Nine case series were found reporting on 444 eligible patients receiving chemotherapy; eight were found reporting on 256 patients undergoing autologous marrow transplantation. After weighting by sample size, the mean 3‐year survival rate was 25% (95% Cl, 20–30%) following chemotherapy and 40% (95% Cl, 33–47%) following marrow transplantation. The reporting of potentially relevant prognostic factors was inconsistent among articles.

Despite our comprehensive synthesis and evaluation of currently available data, the survival advantage of marrow transplantation in relapsed/refractory non‐Hodgkin's lymphoma that we report must be viewed as tentative, given the limitations of the case series data. In addition, establishing the comparability of patients treated with these therapies is made more difficult by the inconsistent reporting of potentially relevant prognostic factors. The results of an international randomized trial of these two therapies is forthcoming and may address some of these shortcomings.
Recognition of unusual presentation of natural killer cell leukemia
Authors: Gardiner C. M. , Reen D. J. , O'Meara A.
Published: February 2007

Expansion of the natural killer (NK) subset of lymphocytes represents a rare leukemia phenotype with variations in clinical presentation, morphology, surface phenotype, and effector function. This paper reports on a 5‐year‐old male patient who had an unusual presentation of an NK cell leukemia that was initially diagnosed as neuroblastoma. A bone marrow (BM) aspirate showed clumps of undifferentiated cells with the following phenotype: CD56bright+, CD33dim+, CD45‐, CD2‐, CD19‐, CD16‐, and CD57‐. Cytochemistry was noncontributory. The patient, having failed to respond to conventional neuroblastoma chemotherapy, was subsequently diagnosed as having NK cell leukemia based on functional in vitro assays. The patient responded to acute lymphoblastic leukemia (ALL) chemotherapy but relapsed 4 weeks into treatment and eventually died 25 weeks after initial presentation. The cell surface phenotype observed is consistent with a rare NK cell subset, the biology of which has not been well defined. Freshly isolated BM cells killed K562 cells in a conventional 51Cr‐release assay. Both interleukin‐2 (IL‐2) and interferon‐α (IFN‐α) induced LAK activity against the Daudi cell line. IL‐2 induced proliferation of the leukemic cells. TNF‐α, IFN‐γ, IL‐6, IL‐1ra, and TGF‐β levels were assessed and found to be concentrated in BM, in contrast to plasma samples. TNF‐α was present at a high concentration in BM (150.9 pg/ml), probably a reflection of the associated disease pathology of severe bone pain and pyrexia. In summary, this paper details clinical and laboratory investigations of a leukemia of a rare NK cell subset.
Reticulated platelets in uremic patients: Effect of hemodialysis and continuous ambulatory peritoneal dialysis
Authors: Tassies Dolors , Reverter Joan‐Carles , Cases Aleix , Escolar Ginés , Villamor Neus , López‐Pedret José , Castillo Ricardo , Ordinas Antoni
Published: February 2007

Platelet RNA content can be detected by flow cytometry using thiazole orange staining to identify platelets recently released into the circulation. We studied platelet RNA content and platelet function in uremic patients under different treatment regimens. Four groups were studied: (I) 15 end‐stage renal disease (ESRD) patients (10M/5F) on maintenance hemodialysis (HD); (II) 11 ESRD patients (6M/5F) on continuous ambulatory peritoneal dialysis (CAPD); (III) 8 patients with chronic renal failure managed conservatively (5M/3F); and (IV) 34 controls (20M/14F). A double color labeling technique using a phycoerythrin‐tagged antibody against glycoprotein lb (CD42b) and RNA labeling by thiazole orange was performed and read by flow cytometry. Aggregation studies were made in platelet‐rich plasma using ADP, epinephrine, collagen, arachidonic acid, and ristocetin. In group I, samples were also obtained after HD. Platelet counts did not differ among the groups. Aggregation studies showed a lower response to ADP and ristocetin in the HD patients, but not in the CAPD or in the chronic renal failure patients. The percentage of platelets with high RNA content in group I was significantly lower than in controls (3.72 ± 1.72% vs. 9.05 ± 3.53%, P < 0.01), but was also lower than in the remaining groups (I vs. II P < 0.01, and I vs. III P < 0.01). No differences were seen in platelet RNA content among groups II (8.67 ± 2.73%), III (9.14 ± 3.04%) and IV. In group I, the percentage of reticulated platelets decreased further after HD (2.14 ± 1.09%, P < 0.01). Aggregation studies showed a significantly lower response to ADP and ristocetin in group I (P < 0.05), but not in groups II or III in comparison with controls. Aggregation response to ADP and ristocetin decreased after HD (P < 0.05). In conclusion, HD may decrease the percentage of RNA‐rich platelets through elimination of the younger and more active platelets and worsen the thrombopathy present in uremic patients.
Monoclonal antibodies in the management of acute leukemia
Authors: Wang Jean C. Y. , Beauregard Patrice , Soamboonsrup Praniti , Neame Peter B.
Published: February 2007

This report reviews the diagnostic significance of immune markers, their relationship to patient outcome, and the therapeutic uses of monoclonal antibodies (MoAbs) in acute leukemia. Immunophenotyping allows for rapid and reproducible diagnosis in the majority of cases of acute leukemia. It is of particular importance in recognizing the major immunologic subclasses of acute lymphoblastic leukemia (ALL), and in identifying subtypes of acute myeloblastic leukemia (AML) which cannot be differentiated by morphology and cytochemistry alone, such as FAB M0 or M7. Immune marker analysis has been used to detect minimal residual disease in patients' bone marrow and CSF after treatment. However, the presence of leukemia‐associated phenotypes on small numbers of normal ceils may reduce the sensitivity of detection in some cases. The prognostic value of immune markers in AML is limited. In ALL, the prognostic significance of the different immunophenotypic subtypes has been lessened by modern treatment protocols. The relationship of mixed‐lineage or biphenotypic antigen expression to patient outcome in both AML and ALL is unclear. Therapeutic applications of MoAbs in acute leukemia include immunologic techniques for purging malignant cells from autografts prior to transplantation, T‐lymphocyte depletion from allografts as a strategy to reduce graft‐versus‐host disease, and the use of flow cytometry to monitor the timing and extent of leukapheresis in peripheral stem cell transplantation. MoAbs have also enabled the recent development of transplantation protocols using positively‐selected CD34 + stem cells.
Dysfibrinogenemia: A case with thrombosis (fibrinogen richfield) and an overview of the clinical and laboratory spectrum
Authors: Schorer Anna E. , Singh Jasbir , Basara Michael L.
Published: February 2007

Fibrinogen Richfield exemplifies a dysfibrinogen associated with a life‐long thrombotic tendency. The evaluation of this novel case indicates that, like similar thrombotic dysfibrinogenemias, the abnormal protein polymerizes abnormally and demonstrates impaired clot dissolution. A survey of other cases of dysfibrinogenemia indicates that the relatively common abnormalities of Fibrinopeptide A release are generally asymptomatic or associated with bleeding, polymerization abnormalities are likely to be asymptomatic or associated with thrombosis (or occasionally bleeding), and complex abnormalities or additional, independent hemostatic defects are rather common. Thrombin and Reptilase clotting times are not helpful in distinguishing between the subsets, but clinical history, fibrinopeptide release, and polymerization studies may be useful. Abnormalities of fibrinogen function tend to correlate with changes in molecular domains related to binding and hydrolysis.
Hemostatic abnormalities and increased vascular endothelial cell markers in patients with red cell fragmentation syndrome induced by mitomycin C
Authors: Nagaya Shozaburo , Wada Hideo , Oka Kouzi , Tanigawa Motoaki , Tamaki Shigehisa , Tsuzi Kouta , Miyanishi Eiki , Wakita Yoshihiro , Minami Nobuyuki , Deguchi Katsumi , Suzuki Kozi , Nakano Takeshi , Shiku Hiroshi
Published: February 2007

We examined red cell fragmentation syndrome (RCFS) induced by mitomycin C (MMC) (13 patients), by thrombotic thrombocytopenic purpura (TTP) (17 patients), and by disseminated intravascular coagulation (DIC) (15 patients). Plasma cytokine levels were increased in the TTP and DIC patients, but not in those whose RCFS was induced by MMC, suggesting that the activation of the immune system plays an important role in the pathogenesis of RCFS due to TTP and DIC but did not in RCFS due to MMC. Plasma thrombomodulin, tissue type plasminogen activator, and plasminogen activator inhibitor‐I levels were increased in all RCFS patients, suggesting that RCFS, whether MMC induced, or due to TTP or DIC, might be associated with vascular endothelial cell injury. In TTP, von Willebrand factor (vWF) antigen and high molecular weight vWF multimer levels were reduced, possibly as a result of microthrombus consumption. The hemostatic data in this study showed that the TTP patients were in a hypercoagulable state without hyperfibrinolysis, and that DIC patients were in both a hypercoagulable and a hyperfibrinolytic state, whereas hemostatic abnormalities were slight in patients with MMC induced RCFS. These findings suggest that vascular endothelial cell injuries might be associated with RCFS, and that those injuries in MMC‐induced RCFS might not be related to microthrombi or an activated immune system.
Phenotypic and functional analysis of lymphocytes in paroxysmal nocturnal hemoglobinuria
Authors: Tseng Jennifer E. , Hall Sharon E. , Howard Thad A. , Ware Russell E.
Published: February 2007

The hematologic disorder paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation within the Piga gene important for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. The PNH defect has been identified in all cells of the myeloerythroid lineage, but involvement of the lymphoid lineage in PNH is more controversial. We therefore analyzed lymphocytes from 22 patients with PNH to characterize phenotypically the GPI‐deficient population, and to investigate the functional consequences of GPI deficiency. GPI‐deficient T lymphocytes, B lymphocytes, and NK cells were identified, but at a lower percentage than granulocytes and erythrocytes. CD8+ lymphocytes were significantly more affected than CD4+ T cells, and CD45RA+ lymphocytes were significantly more affected than CD45RO+ cells. Proliferation assays demonstrated that lymphocytes from PNH patients, either unfractionated or purified GPI‐deficient cells, responded normally to in vitro stimuli. When stimulated with phytohemagglutinin (PHA), naive CD45RA+ GPI‐deficient T lymphocytes acquired the memory CD45RO+ phenotype. In addition, GPI‐deficient T lymphocytes had a relative growth advantage as compared to normal T cells. The results demonstrate that PNH involves the lymphoid as well as the myeloerythroid lineage, and therefore arises from a totipotent bone marrow stem cell. The in vitro growth advantage of GPI‐deficient lymphocytes in PNH may have important implications for the pathogenesis of some puzzling clinical aspects of PNH, including predominance of the PNH clone, defective hematopoiesis, and leukemogenesis.
Treatment of chronic neutropenia associated with large granular lymphocytosis with cyclosporine a and filgrastim
Authors: Jakubowski Ann , Winton Elliott F. , Gencarelli Alison , Gabrilove Janice
Published: February 2007

A patient with neutropenia and life‐threatening infections secondary to T‐γ lymphoproliferative disease, who did not respond to treatment with recombinant human G‐CSF (filgrastim), was treated with filgrastim plus cyclosporine A (CyA). The patient achieved a good response in the absolute neutrophil count and subsequently required a dose reduction in the filgrastim. The patient was eventually discontinued from the CyA but continues on filgrastim alone. While on therapy, the large granular lymphocytes disappeared from the circulation and the beta‐TCR rearrangement, which was present prior to beginning therapy, became undetectable. The patient had no significant toxicity to the CyA or the filgrastim and he has not experienced any serious infections or required hospitalization. Filgrastim has proven to be relatively nontoxic and of some benefit to patients with this disease and should probably be utilized first when treatment is necessary. However, if improvement is not observed, these findings suggest that a trial of the combination of CyA plus filgrastim may be beneficial.
Improved survival of patients with chronic myelogenous leukemia undergoing allogeneic bone marrow transplantation
Authors: Moreb Jan , Johnson Thomas , Kubilis Paul , Myers Lesley , Oblon David , Miller Alan , Elfenbein Gerald , Weiner Roy
Published: February 2007

A total of 28 patients with chronic myelogenous leukemia (CML) in chronic phase (CP) received bone marrow allografts from HLA‐matched siblings at the University of Florida between August 1984‐July 1992. The present study compares the disease‐free survival (DFS) for those patients who were transplanted before or after August 1988 using the same conditioning regimen. The analysis shows significant difference in 3‐year DFS for those patients transplanted post‐ vs. pre‐August 1988 (69.6% vs. 20%, respectively; P = 0.006). A decrease in pneumonitis due to different etiologies from pre‐August 1988 (6/13, 46%) to post‐August 1988 (1/15, 7%) was statistically significant (P = 0.029). A decrease, although statistically insignificant, in the overall incidence and severity of acute and chronic graft vs. host disease (GVHD) after August 1988 was also noticed. This study indicates significantly improved outcome for patients with CML in CP who have been treated in the University of Florida after August 1988. Better supportive care and prophylaxis for GVHD most likely contributed to such improvement.
From new screens to discovered genes: The successful past and promising present of single gene disorders
Authors: Roe Anne Marie , Shur Natasha
Published: February 2007

Prenatal screening for single gene disorders, which include over 10,000 diverse diseases, presents a great challenge. The major approach to identifying high‐risk groups for diseases, from Tay Sachs Disease to sickle cell disease, has historically centered on ethnic‐based screening. A major concern in an ethnic‐based approach is that carriers belonging to less‐traditionally considered populations will be missed. In the United States, the paradigm for a more modern pan‐ethnic approach has become exemplified by cystic fibrosis (CF), although considerable debate about future directions remains. CF screening brings several additional issues to the forefront, including that the largest molecular prenatal genetic screening program is based on a single gene disorder that is not necessarily severely disabling. On the other hand, several devastating disorders where screening is indeed available remain relatively inaccessible to prenatal patients in the general population. Future candidates to consider for broad‐based screening programs include spinal muscular atrophy (SMA), fragile X, and inborn errors of metabolism. As prenatal screening for single gene disorders expands, issues to consider include inclusion criteria and risk versus benefit. © 2007 Wiley‐Liss, Inc.
DNA single‐strand break repair is impaired in aprataxin‐related ataxia
Authors: Hirano Makito , Yamamoto Aya , Mori Toshio , Lan Li , Iwamoto Taka‐Aki , Aoki Masashi , Shimada Keiji , Furiya Yoshiko , Kariya Shingo , Asai Hirohide , Yasui Akira , Nishiwaki Tomohisa , Imoto Kyoko , Kobayashi Nobuhiko , Kiriyama Takao , Nagata Tetsuya , Konishi Noboru , Itoyama Yasuto , Ueno Satoshi
Published: February 2007

Objective

Early‐onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive form of cerebellar ataxia. The causative protein for EAOH/AOA1, aprataxin (APTX), interacts with X‐ray repair cross‐complementing 1 (XRCC1), a scaffold DNA repair protein for single‐strand breaks (SSBs). The goal of this study was to prove the functional involvement of APTX in SSB repair (SSBR).

Methods

We visualized the SSBR process with a recently developed laser irradiation system that allows real‐time observation of SSBR proteins and with a local ultraviolet‐irradiation system using a XPA‐UVDE cell line that repairs DNA lesions exclusively via SSBR. APTX was knocked down using small interference RNA in the cells. Oxidative stress–induced DNA damage and cell death were assessed in EAOH fibroblasts and cerebellum.

Results

Our systems showed the XRCC1‐dependent recruitment of APTX to SSBs. SSBR was impaired in APTX‐knocked‐down cells. Oxidative stress in EAOH fibroblasts readily induced SSBs and cell death, which were blocked by antioxidants. Accumulated oxidative DNA damage was confirmed in EAOH cerebellum.

Interpretation

This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment. Ann Neurol 2007;61:162–174
Model of infantile spasms induced by N‐methyl‐D‐aspartic acid in prenatally impaired brain
Authors: Velíšek Libor , Jehle Kamran , Asche Samantha , Velíšková Jana
Published: February 2007

Objective

Infantile spasms (a catastrophic epileptic syndrome of childhood) are insensitive to classic antiepileptic drugs. New therapies are limited by lack of animal models. Here we develop a new model of flexion spasms based on prenatal exposure to betamethasone combined with postnatal administration of N‐methyl‐D‐aspartic acid (NMDA) and determine brain structures involved in the induction of flexion spasms.

Methods

Pregnant rats received two doses of betamethasone on day 15 of gestation. Offspring was injected with NMDA on postnatal day 15. Effects of adrenocorticotropin therapy on the development of age‐specific flexion spasms were determined and electroencephalographic correlates recorded. C‐fos immunohistochemistry and [14C]2‐deoxyglucose imaging identified brain structures involved in the development of flexion spasms.

Results

Prenatal betamethasone exposure sensitizes rats to development of NMDA‐induced spasms and, most importantly, renders the spasms sensitive to adrenocorticotropin therapy. Ictal electroencephalogram results correspond to human infantile spasms: electrodecrement or afterdischarges were observed. Imaging studies defined three principal regions involved in NMDA spasms: limbic areas (except the dorsal hippocampus), hypothalamus, and the brainstem.

Interpretation

Despite certain limitations, our new model correlates well with current infantile spasm hypotheses and opens an opportunity for development and testing of new effective drugs. Ann Neurol 2007;61:109–119
Automated criminal link analysis based on domain knowledge
Authors: Schroeder Jennifer , Xu Jennifer , Chen Hsinchun , Chau Michael
Published: February 2007

Link (association) analysis has been used in the criminal justice domain to search large datasets for associations between crime entities in order to facilitate crime investigations. However, link analysis still faces many challenging problems, such as information overload, high search complexity, and heavy reliance on domain knowledge. To address these challenges, this article proposes several techniques for automated, effective, and efficient link analysis. These techniques include the co‐occurrence analysis, the shortest path algorithm, and a heuristic approach to identifying associations and determining their importance. We developed a prototype system called CrimeLink Explorer based on the proposed techniques. Results of a user study with 10 crime investigators from the Tucson Police Department showed that our system could help subjects conduct link analysis more efficiently than traditional single‐level link analysis tools. Moreover, subjects believed that association paths found based on the heuristic approach were more accurate than those found based solely on the co‐occurrence analysis and that the automated link analysis system would be of great help in crime investigations.