bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular basis and hematological characterization of Hb H disease in Southeast Asia
Authors: Liu Ta‐Chih , Chiou Shyh‐Shin , Lin Sheng‐Fung , Chen Tyen‐Po , Tseng Wen‐Ping , Chen Pao‐Huei , Chang Jan‐Gowth
Published: February 2007

We molecularly characterized sixty‐seven cases of Hb H disease by the polymerase chain reaction. The strategy depends on amplifying the α‐thalassemia‐1 (α‐thal‐1) gene by prlmers flanking the breakpoint and sequence differences of the 3′ end of the α‐globin gene and the nonhomologous elements I, II, and III among different types of α‐thala‐2. In the 67 cases studied, all involved α‐thal‐1 of the Southeast Asia type (SEA) In combination with deletional or nondeletional α‐thal‐2. Thirty‐two cases were of the deletion form and 35 cases were of the nondeletion form. In 32 cases of the deletion form, 29 cases were rightward deletion (‐α3.7), and three cases were leftward deletion (‐α4.2). We found that all of the nondeletion forms were α‐thal‐1 of SEA type with Hb CS. After the subtyping of Hb H with ‐α3.7, 26 out of 29 were type I deletion and 3 out of 29 were type II deletion. Comparlsons of clinical data of deletion forms and the nondeletion form showed that there were earlier occurrence of anemic symptoms and a larger erythrocyte volume in the nondeletion form group (P < 0.005). © 1994 Wiley‐Liss, Inc.
Sequential peripheral blood progenitor cell transplantation after mobilization with salvage chemotherapy and G‐CSF in patients with resistant lymphoma
Authors: Sica Simona , Mario Antonella Di , Salutari Prassede , Etuk Benedict , Jovino Michela S. , Pierelli Luca , Marra Roberto , Teofill Luciana , Menichella Giacomo , D'Onofrio Giuseppe , Leone Giuseppe
Published: February 2007

We enrolled 18 patients affected by refractory or relapsed lymphoma (HD, NHL) in a two‐step protocol that included salvage chemotherapy with mitoxantrone, carboplatinum, methylprednisolone, and cytosine arabinoside (MICMA) plus G‐CSF (5 μg/kg/day), peripheral blood progenitor cell (PBPC) collection, and subsequent transplantation after BUCY2 regimen. After MiCMA chemotherapy, four patients (22%) achieved complete response, eight patients (44%) obtained a partial response, and six showed progression of disease (PD). Fourteen out of 18 patients (78%) were considered eligible for PBPC transplantation. Three patients with complete response refused PBPCT; they are currently in continuous complete remission (CCR) at 15, 13, and 15 months, respectively. One patient has been recently transplanted but is too early to be evaluated. Ten patients so far completed the study, eight of whom are currently alive in CR, with a median follow‐up of 7.5 months (range 2–13). Hematologic reconstitution was very rapid with a median time to achieve WBC > 1 × 109/L, PMN > 0.5 × 109/L, platelets > 50 × 109 /L and > 100 × 109/L of 13 (range 9–15), 12(range 9–14), 10(range 0–22), and 14 (range 5–49) days, respectively. Our protocol is highly effective as a salvage treatment, while permitting PBPC collection after G‐CSF administration. Hemopoietic reconstitution after transplantation of PBPCs collected with this procedure is complete, rapid, and sustained. © 1994 Wiley‐Liss, Inc.
Immune and serologic profiles of HIV‐infected and noninfected hemophilic children and adolescents
Authors: Jason Janine , Evatt Bruce , Murphy John , Sleeper Lynn A. , Donfield Sharyne M. , Warrier Indira , Arkin Steven , Gomperts Edward D.
Published: February 2007

Objectives: To assess relationships among the effects of HIV on hemophilic children and adolescents' immunologic parameters and vaccine‐related serology.

Methods: We analyzed data from extensive baseline immunologic evaluations of 207 HIV antibody‐positive (HIV+) and 126 HIV antibody‐negative (HIV−) hemophilic children and adolescents.

Results: HIV+ and HIV‐ participants differed significantly in T‐lymphocyte subpopulation numbers, immunoglobulin levels, and seroprevalence rates for diphtheria toxoid, measles, and mumps antigens. IgG levels, IgM levels, and serologic titers to vaccine antigens showed little correlation with T‐cell parameters. Proportionately more HIV+ participants were nonreactive to each and all of a panel of 7 skin test antigens (71 % vs 28% anerglc, RR 2.6). The odds of anergy increased 1.6 times for every decline of 200 CD4 ± cells/μTl.

Conclusions: HIV had significant, largely independent T‐ and B‐lymphocyte effects on this pediatric cohort. © 1994 Wiley‐Liss, Inc.
Inhibition of leukemic cell proliferation by factor(s) released from irradiated lymphocytes of B‐chronic lymphocytic leukemia patients
Authors: Bessler Hanna , Notti Ida , Cohen Amos M. , Klein Baruch , Djaldetti Meir
Published: February 2007

An attempt was made to clarify the mechanism by which splenic irradiation in patients with B‐chronic lymphocytic leukemia (B‐CLL) can induce a reduction in lymph node size. For this purpose peripheral blood lymphocytes from B‐CLL patients were exposed to cobalt irradiation and were cultured for 1–8 days. The effect of the supernatants on the proliferation capacity of normal and malignant human cells was examined. A suppression of phytohemagglutinin (PHA)‐induced proliferation of autologous and heterologous B‐CLL lymphocytes was observed, whereas there was no effect on the proliferation of lymphocytes obtained from healthy volunteers. in addition, supernatants of irradiated B‐CLL lymphocytes inhibited thymidine incorporation into blasts derived from patients with acute leukemia and the lymphoblastoid cell line Daudi, but they did not exert any effect on normal cells obtained from human embryonic liver. These results suggest the secretion of some factor(s) by irradiated B‐CLL lymphocytes, which may inhibit the proliferation of malignant cells but has no effect on normal cells. © 1994 Wiley‐Liss, Inc.
Allogeneic bone marrow transplantation for leukemia following piperazinedione and fractionated total body irradiation
Authors: Dimopoulos Meletios A. , Yau Jonathan C. , Huan Susan D. , Jagannath Sundar , Spitzer Gary , Spinolo Jorge A. , Zagars Gunar K. , Lemaistre Charles F. , Dicke Karel A. , Zander Axel R.
Published: February 2007

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty‐one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno‐occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI. © 1994 Wiley‐Liss, Inc.
Low fetal morbidity in pregnancy associated with acute and chronic idiopathic thrombocytopenic purpura
Authors: Sharon Rivka , Tatarsky Ilana
Published: February 2007

Forty‐six mothers with immune thrombocytopenic purpura (ITP) gave birth to 72 babies. Sixty‐two babies were delivered vaginally and 10 babies by cesarean section. There was no mortality among mothers or babies. Eighteen infants were born thrombocytopenic (PLT < 100 ± 109/l). Eleven infants had a platelet count of less than 50 ± 109/l. All the severely thrombocytopenic babies (except 1) were born to post splenectomy thrombocytopenic mothers, regardless of steroid treatment during pregnancy. Five babies had clinical manifestations of bleeding; 3 had mild purpura, 1 severe gastrointestinal bleeding, and 1 intracranial bleeding. The latter 2 babies were born prematurely to the same mother who was severely thrombocytopenic despite splenectomy in childhood. In view of very low morbidity in babies of ITP mothers, we suggest that they be delivered vaginally. Cesarean delivery should be performed in selected cases where the mother is severely thrombocytopenic despite splenectomy or where prematurity or obstetrical complications are encountered. © 1994 Wiley‐Liss, Inc.
Use of alveolar carbon monoxide measurements to assess red blood cell survival in hemodialysis patients
Authors: Medina Angela , Ellis Carol , Levitt Michael D.
Published: February 2007

We recently described a simple technique for measuring RBC survival based on measurements of the concentration of carbon monoxide (CO) in alveolar air, corrected for environmental CO using a device that equilibrates with atmospheric CO at the same rate as does the patient. The purpose of the present report is to demonstrate the clinical utility of this method via measurements of RBC turnover in hemodialysis patients. Prior to dialysis, the mean RBC survival of 9 chronic dialysis patients was 70 ± 9 days, about 50% shorter than that of 32 healthy subjects. During the dialysis, the endogenous Pco increased by 14% (P < 0.05) while subjects not undergoing dialysis had a 6% fall in endogenous Pco over this same time period. Thus, this technique demonstrated that the hemodialysis procedure resulted in about a 20% increase in RBC destruction. This increased RBC destruction has not been detectable with previous methodologies (including conventional measurements of CO production) due to the insensitivity and lack of reproducibility of conventional techniques. We conclude that the simple, non‐invasive measurement of endogenous Pco provides the most accurate available means of assessing the influence of a variety of acute manipulations on RBC survival. © 1994 Wiley‐Liss, Inc.
Mortality in immune thrombocytopenic purpura: Report of seven cases and consideration of prognostic indicators
Authors: Schattner Elaine , Bussel James
Published: February 2007

ITP (Immune thrombocytopenic purpura) is generally considered a benign disease. Despite what may be severe thrombocytopenia, most patients with ITP do not suffer significant bleeding episodes. Mortality is rare, and the majority of cases are managed successfully with conventional treatments. For patients who maintain a platelet count of > 20,000/μl, aggressive immunosuppressive therapy is usually unwarranted.

There are some patients with ITP who are at increased risk of serious morbidity and mortality from their disease. Fatal cases of ITP are rarely mentioned in published reports. In this study we review the incidence of mortality and describe the deaths of seven patients with ITP, with the aim of identifying and improving management of high‐risk cases.

Based on our review of the literature and analysis of cases at our institution, fatal cases of ITP fall into three groups: death from intracranial hemorrhage with severe thrombocytopenia, death after splenectomy, and death due to infection after cytotoxic treatments. Patients who appear to carry increased risk include: 1) older patients; 2) chronic, refractory patients with a history of hemorrhage; and 3) patients with concomitant bleeding diatheses such as uremia and hemophilia. © 1994 Wiley‐Liss, Inc.
Systematic use of automated fluorescence‐based sequence analysis of amplified genomic DNA for rapid detection of point mutations
Authors: Tamary H. , Surrey S. , Kirschmann H. , Shalmon L. , Zaizov R. , Schwartz E. , Rappaport E. F.
Published: February 2007

Several approaches are now available for screening populations for known mutations in a given gene. However, for detection of multiple mutations in a population that has not been characterized or for detection of new mutations, the value and efficiency of these screening procedures decreases. Although more than 100 different β‐thalassemia mutations have so far been described, the spectrum of mutations in the Eastern Mediterranean and Israel has not been defined in detail. We have used automated fluorescence‐based DNA sequence analysis of PCR‐amplified genomic DNA employing a cycle‐sequencing strategy coupled with advanced analysis software to rapidly detect β‐thalassemia mutations in Israeli patients. This method enabled rapid identification of eight different mutations in 10 patients, including two rare mutations, one of which has never been described in this geographic region. Our results show that automated fluorescence‐based DNA sequence analysis of amplified genomic DNA is a rapid and reliable method for detection of point mutations and small deletions or insertions in both heterozygous and homozygous states. This approach is particularly effective for a relatively small gene such as β‐globin, but it can also be used for rapid detection of mutations in large genes by first sequencing clusters of exons and intron/exon borders. © 1994 Wiley‐Liss, Inc.
Rapid improvement of coagulopathy by all‐trans retinoic acid in acute promyelocytic leukemia
Authors: Kawai Yohko , Watanabe Kiyoaki , Kizaki Masahiro , Murata Mitsuru , Kamata Tetsuji , Uchida Hideo , Moriki Takanori , Yokoyama Kenji , Tokuhira Michihide , Nakajima Hideaki , Handa Makoto , Ikeda Yasuo
Published: February 2007

Treatment of acute promyelocytic leukemia (APL) patients with all‐trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment‐E), cross‐linked fibrin degradation product (D‐dimer fragment), thrombin‐antithrombin III complex and plasmin‐α2‐plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (A TIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near‐normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low‐dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells. © 1994 Wiley‐Liss, Inc.
Congenital coagulopathies and pregnancy: Report of four pregnancies in a factor X‐deficient woman
Authors: Kumar Manjusha , Mehta Paulette
Published: February 2007

Pregnancy in women with congenital coagulation factor deficiencies has been associated with adverse fetal outcomes. Recurrent spontaneous abortions, placental abruptions, and premature births are reported, the exact reasons for which are not clear, and management of such patients continues to be a challenge. We reviewed the outcome of four pregnancies in a patient with factor X deficiency, and looked at the effect of factor replacement therapy on pregnancy. Her first two pregnancies resulted in the birth of extremely premature babies at 21 and 25 weeks of gestation, both of which died in the neonatal period. The patient was treated with fresh frozen plasma for acute bleeding episodes during these pregnancies. In addition during her second conception she was given factor IX complex [Konyne] prophylactically, but only in the latter half of her pregnancy. During her next two pregnancies she was treated early on during pregnancy, with prophylactic replacement of factor X. She delivered healthy babies at 34 and 32 weeks of gestation, and they are both doing well. We therefore suggest possible mechanisms by which aggressive prophylactic factor support in a female with severe congenital coagulopathy, may improve on fetal outcome. © 1994 Wiley‐Liss, Inc.
Analysis of p53 gene mutations in acute myeloid leukemia
Authors: Trecca Dino , Longo Letizia , Biondi Andrea , Cro Lilla , Calori Rossella , Grignani Fausto , Maiolo Anna Teresa , Pelicci Pier Giuseppe , Neri Antonino
Published: February 2007

We have previously reported the absence of mutations within exons 5–9 of the p53 gene in a panel of 30 cases of acute promyelocytic leukemia (APL), which represent the M3 FAB type of acute myeloid leukemia (AML). In the present report, we extend our analysis of p53 gene mutations to 70 cases of AML representative of the other FAB types of the disease, including M1 (16 cases), M2 (20 cases), M4 (17 cases), M5 (12 cases), and M6 (5 cases). DNAs were analyzed for p53 gene mutations in exons 5 to 9 by polymerase chain reaction (PCR), single‐strand conformation polymorphism (SSCP), and direct sequencing of PCR‐ amplified products. Mutant p53 alleles were detected in 5 of 70 cases; 1 case in exon 5, 2 cases in exon 6, and 2 cases in exon 7. The alterations of the p53 gene were represented by point mutation leading to an amino acid substitution in four cases, and deletion in the remaining case. In four of the five cases, direct sequencing indicated the loss of the normal p53 allele; in the remaining case, two mutations were detected, presumably involving both p53 alleles. Three cases showed mutations at diagnosis; in the remaining two, the mutations were observed in clinical relapse but not at diagnosis. Our results confirm the relatively low incidence of p53 mutations in AML and further support the evidence that p53 plays a role in leukemogenesis through a recessive mechanism (two‐hit model) of inactivation of tumor suppressor activity. © 1994 Wiley‐Liss, Inc.
Cefotetan‐induced hemolytic anemia causing severe hypophosphatemia
Authors: Mohammed Suneel , Knoll Sandra , Van Amburg Albert , Mennes Paul A.
Published: February 2007

Phosphorus is a major component of proteins, phospholipids, and nucleotides. The increased uptake of phosphorus by cells during erythropoiesis can result in severe hypophosphatemia. A case of severe hypophosphatemia due to accelerated erythropoiesis in response to Cefotetan‐induced hemolytic anemia is described. The hypophosphatemia seen during hemolysis may be the result, rather than the cause, of the hemolysis. © 1994 Wiley‐Liss, Inc.
Concurrent RhGM‐CSF does not offset myelosuppression from intensive chemotherapy: Randomized placebo‐controlled study in childhood acute lymphoblastic leukemia
Authors: Calderwood Stan , Romeyer Françoise , Blanchette Victor , Chan Helen , Doyle John , Greenberg Mark , Lorenzana Adonis , Malkin David , Saunders Fred , Weitzman Sheila , Zipursky Alvin , Freedman Melvin H.
Published: February 2007

To determine whether recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF) can offset the myelosuppressive effects of intensive chemotherapy, we carried out a double‐blind placebo‐controlled trial in which 40 patients with acute lympho‐blastic leukemia (ALL) were randomized into two groups of 20 each. One group received rhGM‐CSF (5.5 μg/kg SC) coadministered with chemotherapy and the other, placebo coadministered with chemotherapy from day 5 to day 11 and from day 19 to day 25 of the 28‐day intensification phase of our institutional high‐risk protocol for childhood ALL. The results indicate that, at the dose and schedule used, rhGM‐CSF did not prevent neutrope‐nia or shorten the number of days required to complete this phase of therapy. In addition, the treated and placebo groups showed no significant difference in absolute neutrophil counts, number of days with neutropenia, number of days with fever, number of days spent in hospital, or number of days on antibiotics during the 28‐day study period. There was also no difference between the two groups in the number, type, or severity of Infectious episodes. Two of 20 patients in the treatment group have relapsed, whereas none of the patients in the placebo group has yet relapsed (follow‐up: 3–37 months), but these events were not statistically significant We conclude that treatment with rhGM‐CSF at the dose and schedule employed is not clinically beneficial. © 1994 Wiley‐Liss, Inc.
Serum lactate dehydrogenase and platelet count predict survival in thrombotic thrombocytopenic purpura
Authors: Patton Jeffrey F. , Manning Kenneth R. , Case Douglas , Owen John
Published: February 2007

A significant number (some 20%) of patients with thrombotic thrombocytopenic purpura do not respond to standard therapy and die. We reasoned that early identification of those who are likely to fail standard therapy would allow the rational introduction of other treatment modalities. To this end we prospectively evaluated 27 consecutive patients, examining serum LDH levels and platelet counts as markers of disease activity and as predictors of outcome. All patients were treated, according to a written protocol, with high volume plasma exchange (35 ml/kg), prednisone, aspirin, and persantine. Twenty‐one of the 27 patients (78%) are alive following therapy. Initial LDH and platelet values did not distinguish between the survivors and nonsurvivors. However, by day 3 of therapy both LDH levels and platelet counts differed significantly between the two groups. Mean day 3 LDH level for survivors was 364 units/L, and for nonsurvivors, 891 units/L (P < 0.005). Mean day 3 platelet count for survivors was 119,000/μL, and for nonsurvivors, 46,000/μL (P < 0.005). Receiver Operator Characteristic curves were constructed and assessed by calculating the area under the curve. This analysis showed that LDH is able to discriminate survivorship one day earlier than platelet count. Both LDH level and platelet count are excellent predictors of survival, under standard therapy, after 3 days of treatment. Early identification of those at greatest risk will facilitate the early institution and evaluation of alternative methods of treatment, such as splenectomy, intravenous Ig, or Vincristine. © 1994 Wiley‐Liss, Inc.
Results of secondary prophylaxis in children with severe hemophilia
Authors: Manco‐Johnson Marilyn J. , Nuss Rachelle , Geraghty Susan , Funk Sharon , Kilcoyne Ray
Published: February 2007

In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0–12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8–127) in the year prior to prophylaxis, of which a mean of 24 (range 5–46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII‐deficient boys and for the one factor IX‐deficient boy. Two of three factor VIII‐deficient boys responded to an increase to 30 U/kg prior to the 3‐day interval. The dose frequency was increased to three times a week for the factor IX‐deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII‐deficient boys plus seven other factor VIII‐deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of >1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one‐half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted. © 1994 Wiley‐Liss, Inc.
Characterization of apocytochrome C binding to human erythrocytes
Authors: Krishnan Gomathi , MacGregor Roderick D. , Shohet Stephen B. , Hunt C. Anthony
Published: February 2007

The binding of 125I‐labeled apocytochrome c to human erythrocytes was determined for free apocytochrome c concentrations at 10−10‐10−6 M. At about 2 × 10−9 M, maximum cell 22°C have three classes of apocytochrome c binding sites: one high‐affinity noncooperative site (n1 = 728 per cell, Kd1 = 1.5 × 10−9 M) and two positively cooperative sites (n2 = 3.7 × 104 per cell, Kd2 = 1.2 × 10−7 M, α2 = 2.0, and n3 = 2.5 × 105 per cell, Kd3 = 7.1 × 10−7 M, α3 = 12). Erythrocytes at 37°C, and erythrocyte ghosts at 22°C, also have three classes of apocytochrome c binding sites, and most sites are positively cooperative. © 1994 Wiley‐Liss, Inc.
Optimal blood stem cell mobilization using 10 μg/kg granulocyte colony‐stimulating factor (G‐CSF) alone for high‐dose melphalan intensification in multiple myeloma: An intrapatient controlled study
Authors: Feremans W. , Le Moine F. , Ravoet C. , Lambermont M. , Bastin G. , Delville J. P. , Pradier O. , Dupont E. , Capel P.
Published: February 2007

A recent randomized multicentric French study has shown that intensification with stem cell rescue improves the response rate and progression‐free survival in multiple myeloma. Transplantation with primed peripheral blood stem cells (PBSC) displays a faster hematological recovery, especially for platelets, as compared with a bone marrow stem cell graft. In multiple myeloma, the optimal mobilization method for PBSC is unknown. The present study compares mobilization with cyclophosphamide 4 g/m2 + G‐CSF 5 μg/kg versus G‐CSF 5 μg/kg alone versus G‐CSF 10 μg/kg alone in two cases of multiple myeloma, using an intrapatient controlled evaluation of the amount of CD34‐positive cells obtained during each leukapheresis. In both cases, the highest CD34‐positive cells yield was obtained with G‐CSF at 10 μg/kg. Despite the low number of cases, this method, devoid of life‐threatening toxicity, might be of greatest interest in multiple myeloma. © 1994 Wiley‐Liss, Inc.
Anthracycline‐based therapy of de novo acute myeloid leukemia in adults: Failure of first‐cyde cytoreduction to predict second‐cycle outcome
Authors: Hammerschmidt Dale E. , Crea Mary T. Wild
Published: February 2007

During 1971–1988, 194 adults with de novo acute myeloid leukemia (AML) received initial therapy at the University of Minnesota with an anthracycline‐based regimen. Seventy‐two of the 194 required further chemotherapy and received a second cycle of the same or similar therapy; 63 of these 72 were evaluable.

For each marrow, a tumor burden index (TBI) was calculated, as the product of the marrow cellularity and the proportion of malignant cells. For each patient, the decrement in TBI between the initial and day ≈14 marrows was recorded. Patients who achieved second‐cycle CR were comparable to those who did not in general descriptors; there was no difference between second‐cycle CR achievers and nonachievers in the cytoreduction efleeted by the Initial cycle of therapy (74.9% ± 4.5% [σ] versus 71.9% = 5.9%).

We then stratified patients according to the first‐cycle cytoreduction, asking if we could find a level that was reliably predictive of increased or decreased likelihood of achieving CR with cycle 2. We could not, despite testing at many centite cuts. Patients achieving a very “poor” degree of cytoreduction In cycle 1 were as likely to achieve CR with cycle 2 as were patients having a very “good” initial cytoreduction.

We conclude that (1) first‐cycle response is not a useful predictor of second‐cycle outcome in anthracycline‐based therapy of de novo adult AML; and (2) a “poor” response to cycle 1 does not therefore a priori indicate a change to a different regimen for cycle 2. © 1994 Wiley‐Liss, Inc.
Effect of desferrioxamine and hydroxypyridones on hemopoietic progenitors and neuroectodermal tumor cells
Authors: Timeus Fabio , Valle Paola , Crescenzio Nicoletta , Ruggieri Luciano , Rosso Paolo , Pagliardi Giovanni Luca , di Montezemolo Luca Cordero , Gabutti Vilma , Ramenghi Ugo
Published: February 2007

The iron chelator desferrioxamine (DFO) has been shown to inhibit the proliferation of hemopoietic progenitors and several tumor cell lines. We have compared the in viro hemopoietic inhibitory effect of desferrioxamine (DFO) and hydroxypyridones (HPOs) on hemopoietic progenitors and two human neuroectodermal (NE) tumor cell lines, NB 100 and SKNMC. Both DFO and HPOs showed a direct dose‐related inhibitory effect on BFU‐E and CFU‐GM obtained from purified human non‐T MNAC (T‐Iymphocyte‐depleted nonadherent mononuclear cells) and CD34+ cells. DFO and HPOs displayed both an inhibitory and a cytotoxic effect on NE cell lines. We calculated the ratio between NE cell and hemopoietic cell growth inhibition for a range of concentrations of chelators. DFO showed the most satisfactory ratio. This suggests that DFO is still the most preferable chelating agent for the treatment of neuroblastoma, since it combines the highest antineuroblastoma effect with the lowest hematopoietic toxicity. © 1994 Wiley‐Liss, Inc.
Capacity of the store‐regulator in maintaining iron balance
Authors: Sayers Merlyn H. , English Genia , Finch Clement
Published: February 2007

There is evidence that iron stores alter iron absorption to meet body iron needs. In this study, quantitative aspects of this regulation of iron balance are examined. Two male subjects, one with low and one with average iron stores, were given additional dietary iron over 500 days. Changes in iron stores were monitored by plasma ferritin measurements, and the ferritin estimate of stores was validated at the end of the study by bleeding to the point of iron deficiency. The subject with low iron stores increased his ferritin by 39 μg/L or 0.8 mg/day, whereas the subject with average iron stores had no significant change. It is concluded that the mechanism by which stores regulate food iron absorption has a capacity of about 1 mg/day, sufficient to meet usual physiological needs, with the exception of pregnancy, as well as the ability to resist increase in stores above normal despite an iron rich diet. © 1994 Wiley‐Liss, Inc.
Compound heterozygosity for two α‐globin gene defects, Hb taybe (α1; 38 or 39 minus thr) and a poly a mutation (α2; AATAAA → AATAAG), results in a severe hemolytic anemia
Authors: Pobedimskaya D. D. , Molchanova T. P. , Streichman S. , Huisman T. H. J.
Published: February 2007

We have identified two α‐globin gene variations in an Arabian male with severe hemolytic disease through sequencing of amplified DNA of his α2‐ and α1‐globin genes. One of the abnormalities involves a CAC (ACC or CCA) deletion between codons 36 and 41 of the α1‐globin gene. This leads to the synthesis of an abnormal α chain with one instead of two threonine residues at positions 38–39 and to the formation of the unstable Hb Taybe. The second variation is a mutation located in the poly A site of the α2‐globin gene (AATAAA → AATAAG) which is common among Arabian people. Family studies have shown that the two variations are located on opposite chromosomes. The hemolytic disease in this man, resembling Hb H disease, is likely the result of a severe downregulation of both α‐globin genes on the chromosome with the α2 poly A mutation, and the instability of the α‐Taybe chain being the product of an α 1‐globin gene; this leaves only one α2‐globin gene normally active. © 1994 Wiley‐Liss, Inc.
Molecular characterisation of red cell glucose‐6‐phosphate dehydrogenase deficiency in Singapore Chinese
Authors: Saha S. , Saha N. , Tay J. S. H. , Jeyaseelan K. , Basair J. B. , Chew S. E.
Published: February 2007

Sixty‐two G6PD deficient Chinese males have been investigated for the presence of seven mutations of the coding region of the G6PD gene by natural and artifically created amplified restriction sites. The results show that the G to T substitution at nucleotide (nt) 1376 and G to A substitution at nt 1388 represent 24% and 21% of G6PD deficiency, respectively, in the Singapore Chinese; 37% of the sample could not be characterised. The remaining samples were identified as follows: 10% C→T at nt 563, 5% A→G at nt 95, and 3% C→T at nt 1024. The G to A substitution (nt 487) and the substitution A→G (nt 493) were not present in this sample. None of the subjects with the Mediterranean mutation (563 C→T) had the silent mutation at 1311 (C→T). This study confirms the extreme molecular heterogeneity of the G6PD gene in the Chinese. © 1994 Wiley‐Liss, Inc.
Quinine‐induced immune thrombocytopenia with hemolytic uremic syndrome: Clinical and serological findings in nine patients and review of literature
Authors: Gottschall Jerome L. , Neahring Betsy , McFarland Janice G. , Wu Guo‐Guang , Weitekamp Lee Ann , Aster Richard H.
Published: February 2007

Quinine‐induced immune thrombocytopenia with hemolytic uremic syndrome (HUS) is a recently defined clinical entity. In this paper we have attempted to characterize the natural history and laboratory abnormalities typical of quinine‐induced immune thrombocytopenia associated with hemolytic uremic syndrome in nine patients experiencing ten episodes of the disease. In addition, review of other reported cases of probable quinine‐induced HUS is presented. The disease was characterized by the onset of chills, diapheresis, nausea and vomiting, abdominal pain, decreased urine output, and petechiae following quinine exposure. All patients experience significant anemia, severe thrombocytopenia, increased lactate dehydrogenase, elevated serum creatinine, and oliguria. Quinine‐dependent platelet‐reactive antibodies were identified in eight of nine using flow cytometry. Unexpectedly, drug‐dependent antibodies reactive with red cells and granulocytes were identified in four and eight patients, respectively. All patients were treated with plasma exchange (range 1–12 procedures), and seven required hemodialysis. All survive without residual abnormality. Our experience with nine patients with quinine‐induced HUS and the nine additional cases reported by others and reviewed in this paper establishes this condition as a distinct clinical entity. Adult patients presenting with HUS should routinely be asked about exposure to quinine in the form of medication or beverages. The mechanism by which quinine‐dependent antibodies produce renal failure is uncertain, but preliminary studies (described elsewhere) suggest that drug‐induced antibodies reactive with endothelial cells and possibly margination of granulocytes in renal glomeruli may be responsible for this complication. The prognosis in quinine‐induced HUS is better than in other forms of adult HUS. © 1994 Wiley‐Liss, Inc.
Sensitivity of myeloid progenitors to NK‐cell depletion
Authors: Fardoun‐Joalland D. , Texeira‐Lebrun G. , Jouan‐Beades F. , Lenormand B. , Dzondo‐Gadet M. , Vannier J. P.
Published: February 2007

To gain additional informations on the role played by Natural Killer cells (NK) in the differentiation of human hematopoietic precursors, we have studied the effect of NK‐cell depletion on the in vitro proliferation of hematopoietic cells. NK cells were depleted from blood mononuclear cells by FACS using anti CD3 and anti CD56 monoclonal antibodies. Depletion of NK cells suppressed CFU‐GM up to 69% (P < 0,01), while no significant effect on either BFU‐E and CFU‐Mix growth was observed. To define the threshold of CD56+ cells required to support CFU‐GM formation, NK cells were added to NK‐depleted cells in a titrated fashion. Enhancement of CFU‐GM colony growth was observed at NK/NK ‐ depleted cells ratio of 0.15/1. A dose dependent suppression of CFU growth was observed at ratios ranging from 0.25/1 to 0.5/1. Addition of neutralizing antibodies against IL3 and GM‐CSF abrogate the stimulating effect of NK cells.

Our results suggest that cells with LGL morphology and NK markers play an important role in differentiation of myeloid precursors and exert a moderate influence on erythroid progenitors. The modulatory effect on hematopietic progenitors depend on the number of NK cells present in the mixed culture. © 1994 Wiley‐Liss, Inc.
Apoptosis induction with three nucleoside analogs on freshly isolated B‐chronic lymphocytic leukemia cells
Authors: Zinzani P. L. , Tosi P. , Visani G. , Martinelli G. , Farabegoli P. , Buzzi M. , Ottaviani E. , Salvucci M. , Bendandi M. , Zaccaria A. , Tura S.
Published: February 2007

The cytotoxic effects and the induction of programmed cell death (apoptosis) by Fludarabine (FLU), 2‐chlorodeoxyadenosine (2‐CdA), and deoxycoformycin (DCF) with/without α‐interferon (α‐IFN) were evaluated in vitro against freshly isolated B‐chronic lymphocytic leukemia (B‐CLL) cells. Cytotoxicity was evaluated according to the soluble tetrazolium/formazan assay. Regarding the cytotoxicity, FLU, 2‐CdA, and DCF showed a mean antitumor activity of 45% ± 3.39 (mean ± S.D.), 55% ± 4.72, and 20% ± 3.16, respectively. α‐IFN alone showed a mean cytotoxic activity of 10% ± 2.72. The cytotoxicity of these purine analogues in combination with α‐IFN was 52% ± 2.97, 75% ± 3.41, and 26% ± 7.09, respectively. We observed a statistically significant increase of cytotoxicity compared to controls in FLU alone (P < 0.05), 2‐CdA (P < 0.05), and their combination with α‐IFN (P < 0.05). Apoptosis was evaluated by electrophoresis gel of DNA oligonucleosomal fragments and by a cytofluorimetric method. Only FLU and 2‐CdA activated the apoptosis and DCF showed a minor apoptotic pathway amount. These apoptosis data were confirmed by both gel electrophoresis of DNA and by propidium iodide cytofluorimetric method. FLU and 2‐CdA show activity in B‐CLL cells by direct cytotoxic action and the induction of cell death by apoptosis; in the future, it would be interesting to utilize these in vitro assays in monitoring chemosensitivity and predicting response for the clinical use. © 1994 Wiley‐Liss, Inc.
Acute promyelocytic leukaemia (M3): Relapse with acute myeloblastic leukaemia (M2) and dic(5;17) (q11; p11)
Authors: Hatzis Theodore , Standen Graham R. , Howell Rodney T. , Savill Catherine , Wagstaff Michael , Scott Geoffrey L.
Published: February 2007

Secondary leukaemia following treatment of M3 acute promyelocytic leukaemia (APL) is a rare event. We describe a patient in remission following chemotherapy for APL who relapsed with M2 acute non‐lymphoblastic leukaemia (ANLL). The original t(15;17) (q22; q21) chromosome translocation was lost and replaced by a clone containing a dic(5;17) (q11; p11) abnormality. Southern genomic analysis demonstrated re‐arrangements of the retinoic acid receptor α (RARα) and PML genes in the APL blasts at presentation but not in the M2 ANLL marrow at relapse. The significance of unbalanced 5;17 translocations as markers for therapy‐related secondary leukaemia is discussed. ©1995 Wiley‐Liss, Inc.
α‐2a interferon therapy and antibody formation in patients with essential thrombocythemia and polycythemia vera with thrombocytosis
Authors: Törnebohm‐Roche E. , Merup M. , Lockner D. , Paul C.
Published: February 2007

In ten patients with essential thrombocythemia and polycythemia Vera with thrombocytosis we have investigated the therapeutic effect of recombinant α‐2a interferon (Roceron A®) given subcutaneously in a maintenance dosage of 3 million units three times weekly. The aim was to normalize the platelet count (⩽ 400 × 109/L). One of the secondary aims was to study platelet activity measured as β‐thromboglobulin (β‐TG) in urine.

All but one patient could administer the injections and in all patients a significant reduction in platelet values was seen. The treatment was discontinued in three patients due to side effects of interferon, two because of hair loss (one with irreversible alopecia), and one because of depression. Three patients developed antibodies to α‐2a interferon and a concomitant rise in the platelet level; in one patient therapy was switched to leukocyte α‐interferon with an excellent response. The initial levels of β‐TG were elevated in 9/10 patients and were significantly reduced at 6 months in 4/5 patients not developing antibodies. Six patient are still on α‐interferon therapy with a long‐term follow‐up of 3‐3.5 years. We conclude that α‐interferon therapy may be an alternative in patients with thrombocytosis and/or complications necessitating treatment. ©1995 Wiley‐Liss, Inc.
Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia
Authors: Steinberg M. H. , Hsu H. , Nagel R. L. , Milner P. F. , Adams J. G. , Benjamin L. , Fryd S. , Gillette P. , Gilman J. , Josifovska O. , Hellman‐Erlingsson S. , Safaya S. , Huey L. , Rieder R. F.
Published: February 2007

In Africa, the β‐globin gene cluster haplotype may be associated with variation of Hb F levels in subjects with sickle cell anemia (SS). These observations have not yet been conclusively confirmed in SS out of Africa, perhaps because of small sample sizes, the predominance of haplotype heterozygotes, and diverse influences, including gender, upon Hb F levels.

We studied 384 adult African‐American SS patients (mean age, 31 years) and explored the relationship of gender, β‐globin gene cluster haplotype, and α thalassemia to hematological values and Hb F levels. Both haplotype and gender influenced Hb F concentration. In the total sample, Hb F was higher in females than in males (8.2 vs. 6.5%). In 35 males who were either homozygous for the Senegal chromosome or had the Senegal/Benin haplotype, the mean percent Hb F (8.0%) was equivalent to the Hb F level in females with Benin and Bantu haplotypes (‐7.5%). Both females and males homozygous for the Senegal haplotype chromosome or with the Senegal/Benin combination had a significant increase in Hb F compared to other groups. In 44 Senegal/Senegal or Senegal/Benin females the Hb F was 10.9%, or 1.0 g/dl, the highest value observed in all primary analysis groups. Preliminary analyses suggested that the presence of a Bantu chromosome blunted the gender‐associated difference in Hb F, but Hb F differences between females with the Senegal/Benin haplotype (11.2%) and the Senegal/Bantu haplotype (8.8%) were not statistically significant. Hemoglobin concentrations were higher in males than in females except in subjects with at least one Senegal haplotype chromosome, where hemoglobin levels were equal. As expected, α thalassemia reduced the MCV, increased hemoglobin concentration, and lowered reticulocyte counts, regardless of haplotype. Hb F levels were not affected by the presence of α thalassemia in any group.

We conclude that gender and β‐globin gene cluster haplotype interact significantly in the modulation of Hb F and anemia in adults with SS. ©1995 Wiley‐Liss, Inc.
A new myeloproliferative syndrome
Authors: Schofield Jill R. , Robinson William A.
Published: February 2007

We report here two cases of a previously undescribed myeloprollferative disorder. Both were young adult males who presented with generalized lymphadenopathy, splenomegaly, leukocytosis, polycythemia, and persistent thrombocytopenia. The leukocyte alkaline phosphatase (LAP) score was low in both cases, and the bone marrow was hypercellular without dysplasia or fibrosis, but lacked the Philadelphia chromosome, BCR gene rearrangement, or other karyotypic abnormalities. The clinical course was indolent in each case. One patient died from an unusual ‘blast crisis’ after 12 years, while the second patient remains in a complete hematologic remission on hydroxyurea and alpha interferon 4 years from diagnosis. Interestingly, changes in therapy in this patient have consistently resulted in precise and concerted fluctuations in his blood counts, with the red and white cells cycling together and the platelets and mean corpuscular volume (MCV) changing concomitantly but in the opposite direction. This unique myeloproliferative disorder is distinguishable from all previously described forms of chronic myeloid leukemia and other myeloproliferative syndromes. ©1995 Wiley‐Liss, Inc.
Bone marrow biopsy imprints (touch preparations) for assessment of iron stores
Authors: Pasquale Donald , Chikkappa G.
Published: February 2007

Noninvasive evaluation for iron deficiency is compromised in many individuals due to the presence of chronic inflammatory processes and/or malignancy, thus necessitating bone marrow examination for definitive diagnosis. However, bone marrow aspiration is not obtainable or is inadequate for interpretation (dry tap) in some individuals, and decalcified bone marrow biopsies require 24‐48 hr to prepare, and may falsely indicate absence of iron. We evaluated the accuracy of bone marrow biopsy imprints (touch preparations) compared with aspirate particle smears for semiquantitation of bone marrow iron stores. Results indicate that Prussian blue‐stained bone marrow biopsy imprints accurately reflect the quantity of iron, compared with bone marrow aspirate particle smears, allowing for rapid determination of iron stores in individuals in whom a bone marrow aspirate cannot be obtained. © 1995 Wiley‐Liss, Inc.
Biochemical indices of vitamin B12 nutrition in pregnant patients with subnormal serum vitamin B12 levels
Authors: Metz Jack , McGrath Katherine , Bennett Michael , Hyland Keith , Bottiglieri Teodoro
Published: February 2007

To determine the significance of the commonly observed fall in serum vitamin B12 levels during pregnancy, serum levels of the B12 metabolites methylmalonic acid (MMA) and homocysteine (Hcy) were measured in a group of 50 pregnant patients with subnormal serum B12 (range 45‐199 pg/ml) and the results compared with those of 25 pregnant controls (serum B12208‐580 pg/ml). Mean values for serum MMA and total Hcy in the subnormal B12 group were 445.4 nmol/L and 7.03 μmol/L, respectively, which were not significantly different from the mean MMA of 440.5 nmol/L and Hcy of 6.88 nmol/L in the controls. For the total group of patients, neither serum MMA nor serum Hcy levels correlated with serum B12. One‐third of pregnant patients showed elevated serum MMA values, independent of B12 status. Significant elevation of serum Hcy was detected in only two patients, both with subnormal serum B12 and hematological evidence of B12 deficiency. We conclude that the usual fall in serum B12 concentration in pregnancy does not reflect B12 deficiency at the biochemical level. In establishing true B12 deficiency in pregnancy, the serum Hcy level (in the absence of folate deficiency) but not serum MMA, is of value. © 1995 Wiley‐Liss, Inc.
Bone marrow transplantation in a young child with sickle cell anemia
Authors: Kalinyak Karen A. , Morris Christopher , Ball William S. , Ris M. Douglas , Harris Richard , Rucknagel Donald
Published: February 2007

Bone marrow transplantation (BMT) is the only curative therapy available for hemoglobinopathies. BMT was performed on a young child with sickle cell anemia (SCA) after approximately 9 months of transfuslon therapy following her initial stroke. The patient received a matched sibling donor (sickle trait) BMT. The conditioning regimen consisted of busulfan 4 mg/kg/day × 4, cyclophosphamide 50 mg/kg/day × 4. Graft vs. host disease prophylaxis was daily cyclosporine for 6 months. There were no significant complications during BMT. Engraftment occurred on day + 17 and the patient was transfusion independent since day +45. Pre‐BMT cerebral arteriography showed multiple stenotic cerebral vessels and a moya‐moya pattern. Perfusion MRI demonstrated reduced capillary perfusion. Approximately 170 days after BMT the patient experienced episodes of transient left‐sided weakness and speech problems. Neuroimaging revealed progression of large vessel pathology by angiography despite significant improvement in cortical perfusion (MR perfusion scan). Molecular analysis by PCR and DNA fingerprinting confirmed absence of mixed mosaicism. Rheologic evaluation showed normal corrected bulk viscosity. It is possible that progression of large vessel pathology and return of clinical symptoms in the face of normal rheologic parameters may be due to worsening of the already damaged cerebral vessels by the BMT conditioning regimen. Further evaluations of patients with SCA undergoing BMT after a stroke are needed to answer this question. © 1995 Wiley‐Liss, Inc.