bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous splenic rupture following the administration of intravenous heparin: Case report and retrospective case review
Authors: Ghobrial Michel W. , Karim Mohammad , Mannam Sunitha
Published: November 2002

We report the case of a 40‐year‐old African‐American female who presented to the Emergency Department with unstable angina. The patient, who had multiple risk factors for coronary artery disease, was admitted to the coronary care unit for cardiac work‐up and management. Shortly after the intravenous administration of unfractionated heparin, she suffered the acute onset of upper abdominal pain and shock. A CT scan of the abdomen revealed splenic rupture with hemoperitoneum. The patient, who was managed surgically, had complete recovery before discharge. A review of systems and medical records revealed no obvious risk factors or other potential etiology for this rupture. We herein provide the characteristics of this rarely documented causal relationship between heparin and spontaneous splenic rupture and retrospectively review similar cases in the literature. Am. J. Hematol. 71:314–317, 2002. © 2002 Wiley‐Liss, Inc.
CD5‐Negative, CD10‐Negative small B‐cell leukemia: Variant of chronic lymphocytic leukemia or a distinct entity?
Authors: Sheikh Salwa S. , Kallakury Bhaskar V.S. , Al‐Kuraya Khawla A. , Meck Jeanne , Hartmann Dan P. , Bagg Adam
Published: November 2002

CD5‐ and CD10‐negative chronic lymphocytic leukemias are quite uncommon as compared to the CD5‐positive CLL. We reviewed 250 sequential cases of peripheral blood lymphocytosis to characterize cases of small B‐cell lymphoproliferative disorders, submitted with a clinical diagnosis of chronic lymphocytic leukemia exhibiting a non‐classic immunophenotypic profile. Six cases of CD5‐, CD10‐negative chronic lymphocytic leukemias and no tissue involvement were identified that revealed high‐density surface‐membrane immunoglobulin and CD20 expression, with variable expression of CD11c, CD23, and CD25. Most had a profound leukocytosis (mean WBC 180 × 109/L) with proliferation of mature‐appearing lymphocytes. Subsequent bone marrow biopsies showed diffuse infiltration by neoplastic cells in all evaluated patients. The clinical course appeared indolent, with follow‐up revealing three patients alive (survival time 38–68 months), while two died of unrelated causes and one was lost to follow‐up soon after diagnosis. These cases may represent somewhat unusual chronic lymphoproliferative disorders, with morphologic features and immunophenotypic profile not readily classifiable, but which are certainly atypical for classic chronic lymphocytic leukemia. Some of these features are reminiscent of those seen in marginal‐zone lymphoma. However, it is most unusual for this known to be tissue‐based disease to present primarily as leukemia rather than lymphoma. Am. J. Hematol. 71:306–310, 2002. © 2002 Wiley‐Liss, Inc.
Prevalence of factor V G1691A (factor V‐Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population
Authors: Finan Ramzi R. , Tamim Hala , Ameen Ghada , Sharida Huda E. , Rashid Mooza , Almawi Wassim Y.
Published: November 2002

Factor V G1691A (FV‐Leiden) and prothrombin G20210A mutations are major inherited risk factors for venous thrombosis. Recently, it was suggested that both mutations, through stimulation of venous and placental thrombosis events, were strongly associated with recurrent idiopathic miscarriages, although other studies disputed such a link. The aim of this study was to determine the prevalence of prothrombin G20210A and factor V G1691A (R506Q, FV‐Leiden) mutations in women with recurrent idiopathic abortions and to recommend management for high‐risk mutation carriers. One hundred ten women with two or more consecutive unexplained first‐trimester miscarriages (mean age ± SD, 32.3 ± 5.3) were compared to 67 parous women with uncomplicated pregnancies (mean age ± SD, 33.9 ±7.3) (P = 0.134) from the same ethnic background. The presence or absence of the prothrombin G20210A and FV‐Leiden mutations was assessed by PCR and RFLP analysis, using HindIII and MnlI digestion, respectively. In women with primary habitual abortion, 45 (40.91%) carried the FV‐Leiden mutation, of whom 7 were in the homozygote and 38 were in the heterozygote states, and 15 (13.64%) carried the prothrombin G20210A mutation all as heterozygotes, compared to 16.42% and 2.99% carrier rates among controls, respectively, all of whom were heterozygote carriers. Of the other risk factors analyzed, smoking (OR 1.76; 95% CI = 0.79–3.94) was more prevalent in habitual aborters compared to controls. Both FV‐Leiden and factor II G20210A mutations are major inherited risk factor associated with primary recurrent miscarriages. Women with a family or personal history of thrombosis should be screened before or early in the pregnancy for FV‐Leiden and factor II G20210A mutations. Am. J. Hematol. 71:300–305, 2002. © 2002 Wiley‐Liss, Inc.
Factor XIII deficiency mistaken for battered child syndrome: Case of “correct” test ordering negated by a commonly accepted qualitative test with limited negative predictive value
Authors: Newman Richard S. , Jalili Mehrdad , Kolls Bradley J. , Dietrich Rosalind
Published: November 2002

We report herein a case of Factor XIII deficiency that remained undiagnosed until 2 years of age. Part of the delay in diagnosis was a consequence of testing that was performed on a blood sample obtained after plasma transfusion therapy for a life‐threatening bleeding episode. Due to insufficient family follow‐up after discharge from the hospital, the diagnosis was delayed 1 year until the child was rehospitalized and a pre‐transfusion plasma sample was tested. The commonly accepted approach of using only a qualitative test for the diagnosis of factor XIII deficiency is challenged by this case report. Am. J. Hematol. 71:328–330, 2002. © 2002 Wiley‐Liss, Inc.
Chronic lymphocytic leukemia presenting in association with aplastic anemia
Authors: Zonder Jeffrey A. , Keating Michael , Schiffer Charles A.
Published: November 2002

An unusual case of chronic lymphocytic leukemia presenting in association with aplastic anemia is discussed, along with a review of the few previously reported cases. Possible humoral and cellular autoimmune mechanisms are examined as possible causes of marrow aplasia in this setting. Am. J. Hematol. 71:323–327, 2002. © 2002 Wiley‐Liss, Inc.
Additional chromosomal abnormalities and variability of BCR breakpoints in Philadelphia chromosome/BCR‐ABL‐positive acute lymphoblastic leukemia in Taiwan
Authors: Ko Bor‐Sheng , Tang Jih‐Lu , Lee Fen‐Yu , Liu Ming‐Chi , Tsai Woei , Chen Yao‐Chang , Wang Chiu‐Hwa , Sheng Ming‐Chin , Lin Dong‐Tsam , Lin Kai‐Hsin , Tien Hwei‐Fang
Published: November 2002

From 1986 to 1998, 26 (23%) of 114 adult acute lymphoblastic leukemia (ALL) patients and 11 (4%) of 328 pediatric patients were found to have Philadelphia (Ph) chromosome. In the 30 patients with available data at diagnosis, 18 (60%) had extra‐chromosomal abnormalities. They included 1q duplication (5/18, 28%), supernumerary Ph chromosome (4/18, 22%), 9p abnormalities (3/18, 17%), 7q deletion/monosomy 7 (3/18, 17%), trisomy 19 (1/18, 6%), and trisomy 8 (1/18, 6%). Excluding those with specific cytogenetic changes, only one patient had hyperdiploid karyotype with more than 50 chromosomes. The incidence of 1q duplication was higher and that of hyperdiploidy was lower in this study than has been previously reported. There was no prognostic implication of these additional cytogenetic abnormalities. With fluorescence in situ hybridization (FISH) and reverse transcription‐polymerase chain reaction (RT‐PCR), 14 (27%) of 53 unselected adult ALL patients and 2 (5%) of 38 unselected pediatric patients were BCR‐ABL‐positive, including one adult and two children without Ph chromosome. The BCR‐ABL fusion genes/transcripts were also present in all other 16 selected Ph‐positive ALL patients. The BCR‐ABL fusion subtypes were determined in all these 32 patients: 91% (11/12) childhood cases showed m‐type fusion gene while 45% (9/20) adult ones did so (P = 0.0083). The clinical outcome was similar between the two groups of patients with m‐type and M‐type BCR‐ABL. In conclusion, both cytogenetic and molecular studies are very helpful for identifying the subgroup of ALL patients with Ph/BCR‐ABL. The additional cytogenetic abnormalities and subtypes of BCR‐ABL fusion genes/transcripts had no significant implications in this group of patients. Am. J. Hematol. 71:291–299, 2002. © 2002 Wiley‐Liss, Inc.
Successful treatment of a young infant who developed high‐titer inhibitors against VWF‐cleaving protease (ADAMTS‐13): Important discrimination from Upshaw‐Schulman syndrome
Authors: Ashida Akira , Nakamura Hyogo , Yoden Atsushi , Tamai Hiroshi , Ishizashi Hiromichi , Yagi Hideo , Matsumoto Masanori , Fujimura Yoshihiro
Published: November 2002

We report herein the case of a 9‐month‐old female infant with acquired thrombotic thrombocytopenic purpura (TTP), which was initially suspected to be either Upshaw‐Schulman syndrome (USS or a congenital TTP) or hemolytic uremic syndrome (HUS) because of onset of clinical signs in infancy and accompanying diarrhea. She received combination therapy of plasma exchange, steroid pulse, and high‐dose intravenous immunoglobulin infusion that was initiated before the definitive diagnosis, which resulted in excellent clinical improvement. The retrograde analysis of plasma ADAMTS‐13 activity and its inhibitor showed a lack of this enzyme activity and the presence of a high‐titer IgG inhibitor (200–320 Bethesda units/mL) to this enzyme activity. From our experience, it was suggested that we should recognize the possibility of the patient with acquired TTP in infancy and the importance of plasma exchange therapy for management of its clinical symptoms. Am. J. Hematol. 71:318–322, 2002. © 2002 Wiley‐Liss, Inc.
Prospective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism
Authors: Folsom Aaron R. , Cushman Mary , Tsai Michael Y. , Heckbert Susan R. , Aleksic Nena
Published: November 2002

Case–control studies have indicated increased risk of venous thrombosis associated with the prothrombin gene G20210A polymorphism and with elevated plasma prothrombin levels. We sought to confirm these results in a prospective population‐based study of 21,690 persons. We measured G20210A and prothrombin antigen on pre‐event blood samples of 302 participants who developed venous thromboembolism (VTE) and 626 participants who remained free of VTE. Approximately 4.0% of cases and 2.4% of controls carried the G20210A polymorphism, but only one of 137 African Americans did. The odds ratio in whites was 1.87 (95% CI = 0.85, 4.11)—higher for those who reported a prior history of VTE (OR = 5.44) than those reporting no VTE history (OR = 1.41) and in those with idiopathic VTE (OR = 2.51) than those with secondary VTE (OR = 1.38). There was no association between venous thromboembolism and plasma prothrombin antigen level. We estimated that the G20210A polymorphism may account for approximately 2.5% of venous thromboembolism events in United States whites. Am. J. Hematol. 71:285–290, 2002. © 2002 Wiley‐Liss, Inc.
Novel nonsense mutation in the platelet glycoprotein Ibβ gene associated with Bernard‐Soulier syndrome
Authors: Kunishima Shinji , Matsushita Tadashi , Ito Takahiko , Kamiya Tadashi , Saito Hidehiko
Published: November 2002

Bernard‐Soulier syndrome (BSS) is an autosomal recessive bleeding disorder caused by quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIbα, GPIbβ, GPIX, and GPV, and the coordinated assembly of GPIbα, GPIbβ, and GPIX is required for the efficient surface expression of a functional complex. We report here a novel nonsense mutation of the GPIbβ gene associated with BSS. Flow cytometric analysis of the patient's platelets showed markedly reduced GPIbα and absent GPIX surface expression. Immunoblot analysis of solubilized platelets showed that a small amount of GPIbα was detected; however, GPIbβ and GPIX were undetectable. DNA sequencing analysis revealed a novel nonsense mutation of the GPIbβ gene that converts Trp (TGG) to a stop codon (TAG) at residue 123. Transient transfection studies revealed that the mutant GPIbβ polypeptide was not detected in the transfected 293T cells, suggesting that null expression of the mutant GPIbβ impairs expression of the GPIbα and GPIX subunits and results in a BSS phenotype in the patient. Am. J. Hematol. 71:279–284, 2002. © 2002 Wiley‐Liss, Inc.
Serum α‐fetoprotein level in Fanconi's anemia: Evaluation of 33 Turkish patients
Authors: Aslan Deniz , Gümrük Fatma , Alikaşifoğlu Mehmet , Altay Çiğdem
Published: November 2002

Recently, measurement of serum α‐fetoprotein (sAFP) was introduced as a preliminary test for diagnosis of Fanconi's anemia (FA). In the present study, sAFP levels were measured in order to determine its sensitivity and specificity in 33 Turkish FA patients (17 males and 16 females) with a mean age of 11.6 ± 7.7 (1.0–28.0) (median 10.0). Complementation groups were available in 12 patients. Nineteen age‐matched healthy children, 17 patients with bone marrow failure syndromes, 37 FA heterozygotes, and 37 children with acute leukemia served as negative control groups. The sAFP was measured by particle immunoassay. The level of sAFP was found to be higher than the cut‐off value, 8 IU/mL in 46% and was within normal limits in 54% of the FA patients. The AFP values were within normal limits in all of the subjects belonging to the control groups. This method provided 46% sensitivity and 100% specificity in the diagnosis of FA. The sAFP values were high in 4 of 17 (24%) FA patients who did not receive any androgen therapy, while the sAFP level was high in 7 of 9 (78%) patients who received such a therapy. The statistical analysis of incidence of a high sAFP level between these two groups indicated a significant difference (P = 0.014), suggesting that androgen therapy might be a contributing factor for elevation of sAFP. The comparison of several clinical and laboratory parameters between FA patients with high and normal levels of AFP revealed no statistically significant differences. The level of sAFP was elevated in only 5 of the 11 patients with complementation group A; in addition, variable levels of sAFP were noted among the affected members in 4 families, indicating that complementation groups, type of mutation, or familial factors were not responsible for elevation of sAFP. Am. J. Hematol. 71:275–278, 2002. © 2002 Wiley‐Liss, Inc.
Aplastic anemia in Brazil: Incidence and risk factors
Authors: Maluf Eliane M.C.P. , Pasquini Ricardo , Eluf Jose N. , Kelly Judith , Kaufman David W.
Published: November 2002

This study is the first large‐scale epidemiological investigation of acquired aplastic anemia (AAA) in South America. The objective was to estimate the incidence and to identify risk factors for AAA in Brazil. A national case–control study was conducted to investigate the risk factors for the disease. One hundred twenty‐five cases and 129 controls were included. Multiple logistic regression was used in the estimation of odds ratios (OR) to control confounding. The size of Brazil made it unfeasible to estimate the incidence of AAA in the whole country, and we limited the calculation to the state of Parana. The annual incidence of AAA in Parana was 2.4 cases/106 inhabitants. There was no positive association between chloramphenicol use and AAA (OR 0.4; 95% CI: 0.1–2.9). The OR of AAA associated with household pesticides that include organophosphates in their composition was 2.7 (1.0–8.4). The OR for the usage of unspecified thinner and/or acetone for at least 7 days was 3.0 (1.2–7.3). Cases of AAA in Brazil seem to be associated with some factors traditionally related to this disease, such as certain solvents and the incidence is similar to what has been reported from Europe. Am. J. Hematol. 71:268–274, 2002. © 2002 Wiley‐Liss, Inc.
Urokinase could increase the yield of progenitor cells during red cell depletion in elapsed and anticoagulated cord blood
Authors: Lee Young‐Ho , Han Jin‐Yeong , Seo Su‐Yeong , Kim Kyeong‐Hee , Lee Young‐Ah , Lee Hyung‐Sik , Hur Woo‐Joo , Han Hun , Kwon Hyuk‐Chan , Kim Jae‐Seok , Kim Hyo‐Jin
Published: November 2002

We assessed whether the urokinase could increase the yield of progenitor cells during processing in elapsed, anticoagulated cord blood (CB) after collection, and we also determined the optimal dose of urokinase. The total nucleated cell (TNC) counts after red cell depletion in 48‐hr‐elapsed CB were significantly higher in samples treated with 10,000 and 50,000 IU of urokinase/mL than in untreated samples or treated with 5,000 IU of urokinase/mL. The CD34+ cell counts were significantly higher in samples treated with 10,000 IU of urokinase/mL than in untreated samples and in samples treated with 5,000 or 50,000 IU of urokinase/mL. In 6‐, 12‐, and 24‐hr‐elapsed CB, however, there were no significant differences of TNC, CD34+ cells, or CFU‐GM counts between untreated samples and samples treated with 10,000 IU of urokinase/mL. These findings suggest that the addition of 10,000 IU of urokinase/mL before red cell depletion in 48‐hr‐elapsed, anticoagulated CB could increase the yield of progenitor cells. However, there are no advantages in using urokinase for processing CB prior to 24 hr after collection. Am. J. Hematol. 71:336–339, 2002. © 2002 Wiley‐Liss, Inc.
Randomized trial of fluconazole versus low‐dose amphotericin B in prophylaxis against fungal infections in patients undergoing hematopoietic stem cell transplantation
Authors: Koh L.P. , Kurup A. , Goh Y.T. , Fook‐Chong S.M.C. , Tan P.H.C.
Published: November 2002

Over the past decade, invasive fungal infections have become an increasingly important problem in patients undergoing hematopoietic stem cell transplantation (HSCT). The optimal approach for prophylactic antifungal therapy has yet to be determined. To resolve this issue, we performed a prospective randomized study to compare the efficacy of fluconazole (FL) versus low‐dose amphotericin B (AmB) in preventing fungal infections during the first 100 days after HSCT. Patients undergoing allogenic or autologous HSCT were randomized to receive fluconazole 200 mg/day PO or amphotericin B 0.2 mg/kg/day IV beginning 1 day prior to commencement of conditioning regimen and continuing until engraftment, drug‐associated toxicity was suspected, or systemic fungal infection was suspected or proven. High‐dose amphotericin B (0.5–1.0 mg/kg/day) was started for patients with suspected or proven fungal infections. From January 1993 to December 1998, a total of 186 patients were enrolled into the trial, with 100 receiving FL and 86 receiving AmB. Eighty (43%) patients were removed from prophylaxis for persistent fever despite broad‐spectrum antibacterial therapy or suspected fungal infections (FL 46 vs. AmB 34, P > 0.05). The incidence of proven fungal infections (FL 12% vs. AmB 12.8%), suspected fungal infections (FL 4% vs. AmB 2.3%), superficial fungal infections (FL 1% vs. AmB 4.6%) did not show any significant difference. The survival at 100 days post transplant was similar between the 2 groups (FL 78% vs. AmB 70%, P = 0.254). Death attributable to fungal infections was similar in both groups (6% vs. 7%, P > 0.05). We conclude that fluconazole is as effective as low‐dose amphotericin B in prophylaxis against fungal infections in patients undergoing hematopoietic cell transplantation. Am. J. Hematol. 71:260–267, 2002. © 2002 Wiley‐Liss, Inc.
Conservative treatment for patients over 80 years with acute myelogenous leukemia
Authors: Latagliata Roberto , Alimena Giuliana , Carmosino Ida , Breccia Massimo , Borza Paola Anticoli , Bongarzoni Velia , Copia Carolina , Spadea Antonio , Pinazzi Beatrice , Frattarelli Natalia , Ferrara Felicetto , Petti Maria Concetta , Mandelli Franco
Published: November 2002

In order to evaluate the best treatment of very elderly patients with AML, we have retrospectively analyzed 60 cases of patients aged more than 80 years, with a diagnosis of AML and observed from January 1988 to December 1998. Six of these patients were subsequently referred to other centers; of the remaining 54 patients, 20 (37%) received only supportive care, whereas 34 (63%) required palliative chemotherapy to control leukocytosis, after a median time from diagnosis of 9 days (range 0–253). Median overall survival was 13 weeks (range 1–105): 21 (39%) and 6 (11%) patients survived more than 6 and 12 months, respectively. Twenty‐eight patients (51.8%) died from progressive disease, 19 (35.1%) died from AML‐related or unrelated causes in the phase of stable disease, while in 7 patients the cause of death was unknown. In univariate analysis, PS > 2 and WBC > 50 × 109/L had an adverse prognostic significance on survival. Our results, as compared with those reported in the literature for patients over 80 years treated with intensive chemotherapy, support the idea that intensive chemotherapy is usually not indicated in very elderly patients with AML, and that conservative treatment and the primary strategy of “watch‐and‐wait” presently seems to be the best choice. Am. J. Hematol. 71:256–259, 2002. © 2002 Wiley‐Liss, Inc.
Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th‐generation cephalosporin + aminoglycosides: Comparative study
Authors: Tamura K. , Matsuoka H. , Tsukada J. , Masuda M. , Ikeda S. , Matsuishi E. , Kawano F. , Izumi Y. , Uike N. , Utsunomiya A. , Saburi Y. , Shibuya T. , Imamura Y. , Hanada S. , Okamura S. , Gondoh H.
Published: November 2002

1998, a consensus meeting was held in Miyazaki, Japan, to develop an approach to management of febrile neutropenia (FN). The K‐HOT study group decided to examine whether this proposal was applicable to clinical practice in a multicenter study. Patients who developed fever with neutrophil counts <1,000/μL were randomized to receive either a single antibiotic, cefepime or one of the carbapenems, or a combination of cefepime and an aminoglycoside. Patients who became afebrile within the first 3 days were continued on the same treatment. Patients who remained febrile were switched to a combination regimen if they were randomized to receive a single agent, and patients on combination medication were changed from cefepime to another cephalosporin. A total of 165 patients were entered into the trial. One hundred fifty‐three patients were evaluable for response. The average age was 52 years, and 70% of the patients had acute leukemia. Severe neutropenia, defined as <100/μL at the time of FN, was seen in 62% of the patients on entry and during the course of treatment 71% of patients experienced neutrophil counts of <100/μL. Microbiologically documented infection was seen in 6.5% for monotherapy, and 10.5% for a combination treatment, and fever of unknown origin occurred in 75.3% and 59.2% of the patients in each regimen, respectively. Excellent to good response was seen in two‐thirds of the patients in all treatment groups. Adverse events were minimal, and three early deaths were observed at days 9, 16, and 16 among patients treated with a single antibiotic and three in the combination regimen group at days 14, 15, and 20. These results indicate that cefepime or a carbapenem alone is as effective as a combination of cefepime and an aminoglycoside for treating FN. Am. J. Hematol. 71:248–255, 2002. © 2002 Wiley‐Liss, Inc.
Lymphocyte‐specific murine deubiquitinating enzymes induced by cytokines
Authors: Baek Kwang‐Hyun
Published: November 2002

It is becoming clear that a number of proteins regulating cellular mechanisms for homeostasis in all eukaryotes are controlled not only by phosphorylation and dephosphorylation but also by ubiquitination and deubiquitination. This includes most of oncoproteins and signaling components involved in receptor tyrosine kinase (RTK)‐mediated signal transduction pathways. Like protein phosphorylation and dephosphorylation regulated by kinases and phosphatases, respectively, protein ubiquitination and deubiquitination are very dynamic and are regulated by ubiquitin conjugating enzymes and deubiquitinating (DUB) enzymes. A number of deubiquitinating enzymes have been isolated even though little is known about their biological functions. This review concentrates on recent findings and new insights into DUB enzyme subfamily members in lymphocytes. Am. J. Hematol. 71:340–345, 2002. © 2002 Wiley‐Liss, Inc.
Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early‐onset, major depression
Authors: Zubenko George S. , Hughes Hugh B. , Maher Brion S. , Stiffler J. Scott , Zubenko Wendy N. , Marazita Mary L.
Published: December 2002

This report describes the results of a model‐free linkage analysis of six polymorphic markers, located in a 15 cM region of chromosome 2q33‐35, and unipolar Mood Disorders in 81 families identified by probands with Recurrent, Early‐Onset Major Depressive Disorder (RE‐MDD), a severe and familial form of clinical depression. Our findings reveal significant evidence of linkage of unipolar Mood Disorders to a 451 Kb region of 2q33‐34 flanked by D2S2321 and D2S2208 in these families. Increasing peak LOD scores were observed in both the single point and multipoint analyses for Mood Disorder phenotypes whose definitions embodied progressively less stringent severity criteria for inclusion in the affected group. The sex‐dependent multipoint linkage analysis of any Major or Minor Mood Disorders produced LOD scores that reached 6.331 and 6.866 at D2S2321 and D2S2208, respectively. Linkage of Mood Disorders to this region was observed exclusively among female affected relative pairs; no suggestion of linkage was observed when male affected relative pairs were analyzed. These observations imply that a sex‐specific susceptibility gene in this region contributes to the vulnerability of women in these families to the development of unipolar Mood Disorders that ranged in severity from minor to severe at the time of clinical assessment. The region between the markers that yielded the peak LOD score includes the CREB1 gene, which encodes a cAMP‐responsive element‐binding protein (CREB) that is a member of the bZIP family of transcription factors. Based on considerable clinical and preclinical evidence, CREB1 is an attractive candidate for a susceptibility gene for unipolar Mood Disorders. The sex‐specificity of the susceptibility locus identified by our study may result from reported synergistic interactions of CREB with nuclear estrogen receptors. © 2002 Wiley‐Liss, Inc.
Alcohol and genetics: New models
Authors: Crabbe John C.
Published: December 2002

Alcoholism is a complex genetic trait; susceptibility is influenced by multiple genes of small effect. To pursue mechanistic studies, genetic animal models have been used. These models are partial, each addressing one or more of the contributing traits rather than the disease as a whole. Animal studies have modeled alcohol's rewarding effects, the development of tolerance, the pathological consequences to brain systems, and the dependence on alcohol inferred from the presence of withdrawal symptoms when the drug is removed. The classical genetic methods of inbred strain analysis and development and studies of selectively bred lines have been employed for more than 40 years. Recently, such studies have shown that a genetic tendency to experience severe withdrawal is associated with a tendency to avoid self‐administration of alcohol. Also recently, attempts to identify the specific genes conferring risk or protection from alcohol's effects have been undertaken. These studies have used mapping techniques based on gene sequence polymorphisms, studies of gene expression differences, and the use of candidate gene targeting such as creation of null mutants. Studies reviewed here have mapped quantitative trait loci (QTL) for many genes affecting alcohol sensitivity, tolerance, reward, and withdrawal severity. The furthest progress in gene mapping has been made toward one withdrawal QTL on mouse chromosome 4. Using multiple congenic strains, the gene conferring increased withdrawal severity has been isolated to a region of less than 1 centiMorgan, containing fewer than 20 genes. A strong candidate gene, coding for a multiple PS095/DLG/Z0‐1 (PDZ) binding domain zinc finger protein, cannot be excluded. Although many more such genes will be identified in the near future, their contribution to the mapped phenotype will be shown to be dependent on epistatic interactions with other risk genes, as well as genes in the animal's background. Progress in gene identification will also depend crucially on the precise description of the phenotypes being mapped so that their pleiotropic range of influence on the multi‐behavioral phenotypic syndrome can be determined. © 2002 Wiley‐Liss, Inc.
Markovian models for the developmental study of social behavior
Authors: Berchtold André , Sackett Gene
Published: December 2002

Behavioral development involves changes in the probabilities of both social and nonsocial activities and the sequential pattern of activities over time. A number of methods have been offered for the analysis of these patterns of behavioral sequences. However, there continue to be problematic issues, including the analysis of nonstationary data; accommodation of changes in patterns within an observation period, or over repeated observations or age; and identification of differences in pattern changes between individuals or groups, and the factors responsible for these differences. In this work, we analyze data from 15 young monkeys (Macaca nemestrina) using classification and Markovian methods, including a new approach to nonstationary data called the double‐chain Markov model (DCCM). These methods allowed us to identify differences in behavior patterns that differentiate between normal subjects and those presenting developmental anomalies. Am. J. Primatol. 58:149–167, 2002. © 2002 Wiley‐Liss, Inc.
Brain alkaline intracellular pH after neonatal encephalopathy
Authors: Robertson Nicola J. , Cowan Frances M. , Cox I. Jane , Edwards A. David
Published: December 2002

Experimental studies demonstrate an alkaline shift in brain intracellular pH (pHi) after hypoxia‐ischemia (HI). In infants with neonatal encephalopathy after HI, our aims were to assess (1) brain pHi during the first 2 weeks after birth in infants categorized according to magnetic resonance imaging (MRI) during the first 2 weeks after birth and at more than 3 months of age, and neurodevelopmental outcome at 1 year; (2) the relationship between brain pHi and lactate/creatine; and (3) duration of alkaline brain pHi. Seventy‐eight term infants with neonatal encephalopathy were studied using MR techniques. One hundred and fifty‐one studies were performed throughout the first year including 56 studies of 50 infants during the first 2 weeks after birth. pHi was calculated using phosphorus‐31 MR spectroscopy and lactate/creatine was measured using proton MRS. The mean (standard deviation [SD]) brain pHi during the first 2 weeks after birth in infants with severely abnormal versus normal MRI was 7.24 (SD, 0.17) versus 7.04 (SD, 0.05; p < 0.001); in infants who subsequently developed cerebral atrophy versus those who did not: 7.23 (SD, 0.17) versus 7.06 (SD, 0.06; p < 0.05); in infants who died or had a severe neurodevelopmental impairment versus normal outcome: 7.28 (SD, 0.15) versus 7.11 (SD, 0.09; p < 0.05). Brain alkalosis was associated with increased brain lactate/creatine (p < 0.001). pHi remained more alkaline in the severe outcome group up to 20 weeks after birth (p < 0.05). Ann Neurol 2002;52:000–000
Loss of myostatin attenuates severity of muscular dystrophy in mdx mice
Authors: Wagner Kathryn R. , McPherron Alexandra C. , Winik Nicole , Lee Se‐Jin
Published: December 2002

Myostatin, a transforming growth factor–β family member, is a negative regulator of skeletal muscle growth. To explore the therapeutic potential of targeting myostatin in settings of muscle degeneration, we crossed myostatin null mutant mice with mdx mice, a model for Duchenne and Becker muscular dystrophy. Mdx mice lacking myostatin were stronger and more muscular than their mdx counterparts. Diaphragm muscle showed less fibrosis and fatty remodeling, suggesting improved muscle regeneration.
Primary dystonia: Is abnormal functional brain architecture linked to genotype?
Authors: Tros̆t Maja , Carbon Maren , Edwards Christine , Ma Yilong , Raymond Deborah , Mentis Marc J. , Moeller James R. , Bressman Susan B. , Eidelberg David
Published: December 2002

The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.
Modeling stability in neuron and network function: the role of activity in homeostasis
Authors: Marder Eve , Prinz Astrid A.
Published: November 2002

Individual neurons display characteristic firing patterns determined by the number and kind of ion channels in their membranes. We describe experimental and computational studies that suggest that neurons use activity sensors to regulate the number and kind of ion channels and receptors in their membrane to maintain a stable pattern of activity and to compensate for ongoing processes of degradation, synthesis and insertion of ion channels and receptors. We show that similar neuronal and network outputs can be produced by a number of different combinations of ion channels and synapse strengths. This suggests that individual neurons of the same class may each have found an acceptable solution to a genetically determined pattern of activity, and that networks of neurons in different animals may produce similar output patterns by somewhat variable underlying mechanisms. BioEssays 24:1145–1154, 2002. © 2002 Wiley Periodicals, Inc.
Modelling the heart: insights, failures and progress
Authors: Noble Denis
Published: November 2002

Mathematical models of the heart have developed over a period of about 40 years. Cell types in all regions of the heart have been modelled and they are now being incorporated into anatomically detailed models of the whole organ. This combination is leading to the creation of the first ‘virtual organ,’ which is being used in drug discovery and testing, and in simulating the action of devices, such as cardiac defibrillators. Simulation is a necessary tool of analysis in attempting to understand biological complexity. We often learn as much from the failures as from the successes of mathematical models. It is the iterative interaction between experiment and simulation that is important. Examples are given where this process has been instrumental in some of the major advances in the field. BioEssays 24:1155–1163, 2002. © 2002 Wiley‐Periodicals, Inc.
Modeling transcriptional regulatory networks
Authors: Bolouri Hamid , Davidson Eric H.
Published: November 2002

Developmental processes in complex animals are directed by a hardwired genomic regulatory code, the ultimate function of which is to set up a progression of transcriptional regulatory states in space and time. The code specifies the gene regulatory networks (GRNs) that underlie all major developmental events. Models of GRNs are required for analysis, for experimental manipulation and, most fundamentally, for comprehension of how GRNs work. To model GRNs requires knowledge of both their overall structure, which depends upon linkage amongst regulatory genes, and the modular building blocks of which GRNs are heirarchically constructed. The building blocks consist of basic transcriptional control processes executed by one or a few functionally linked genes. We show how the functions of several such building blocks can be considered in mathematical terms, and discuss resolution of GRNs by both “top down” and “bottom up” approaches. BioEssays 24:1118–1129, 2002. © 2002 Wiley‐Periodicals, Inc.
Modelling ‘evo‐devo’ with RNA
Authors: Fontana Walter
Published: November 2002

The folding of RNA sequences into secondary structures is a simple yet biophysically grounded model of a genotype–phenotype map. Its computational and mathematical analysis has uncovered a surprisingly rich statistical structure characterized by shape space covering, neutral networks and plastogenetic congruence. I review these concepts and discuss their evolutionary implications. BioEssays 24:1164–1177, 2002. © 2002 Wiley‐Periodicals, Inc.
The dynamics of cell cycle regulation
Authors: Tyson John J. , Csikasz‐Nagy Attila , Novak Bela
Published: November 2002

Major events of the cell cycle—DNA synthesis, mitosis and cell division—are regulated by a complex network of protein interactions that control the activities of cyclin‐dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological properties of cell replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast. BioEssays 24:1095–1109, 2002. © 2002 Wiley‐Periodicals, Inc.
What is complexity?
Authors: Adami Christoph
Published: November 2002

Arguments for or against a trend in the evolution of complexity are weakened by the lack of an unambiguous definition of complexity. Such definitions abound for both dynamical systems and biological organisms, but have drawbacks of either a conceptual or a practical nature. Physical complexity, a measure based on automata theory and information theory, is a simple and intuitive measure of the amount of information that an organism stores, in its genome, about the environment in which it evolves. It is argued that physical complexity must increase in molecular evolution of asexual organisms in a single niche if the environment does not change, due to natural selection. It is possible that complexity decreases in co‐evolving systems as well as at high mutation rates, in sexual populations, and in time‐dependent landscapes. However, it is reasoned that these factors usually help, rather than hinder, the evolution of complexity, and that a theory of physical complexity for co‐evolving species will reveal an overall trend towards higher complexity in biological evolution. BioEssays 24:1085–1094, 2002. © 2002 Wiley‐Periodicals, Inc.
Complexity of calcium signaling in synaptic spines
Authors: Franks Kevin M. , Sejnowski Terrence J.
Published: November 2002

Long‐term potentiation and long‐term depression are thought to be cellular mechanisms contributing to learning and memory. Although the physiological phenomena have been well characterized, little consensus of their underlying molecular mechanisms has emerged. One reason for this may be the under‐appreciated complexity of the signaling pathways that can arise if key signaling molecules are discretely localized within the synapse. Recent findings suggest an unanticipated degree of structural organization at the synapse, and improved methods in cellular imaging of living tissue have provided much‐needed information about the intracellular dynamics of Ca2+, thought to be critical for both LTP and LTD. In this review, we briefly summarize some of these developments, and show that a more complete understanding of cellular signaling depends on the successful integration of traditional biochemistry and molecular biology with the spatial and temporal details of synaptic ultrastructure. Biophysically realistic computer simulations can have an important role in bridging these disciplines. BioEssays 24:1130–1144, 2002. © 2002 Wiley‐Periodicals, Inc.
Mathematical models of HIV pathogenesis and treatment
Authors: Wodarz Dominik , Nowak Martin A.
Published: November 2002

We review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long‐term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long‐term non‐progression. BioEssays 24:1178–1187, 2002. © 2002 Wiley‐Periodicals, Inc.
Stability of expanded beds during the application of crude feedstock
Authors: Lin Dong‐Qiang , Kula Maria‐Regina , Liten Alisa , Thömmes Jörg
Published: November 2002

Expanded bed adsorption is an integrated technology that allows the introduction of a particle containing feedstock without the risk of blocking the bed. Provided a perfectly classified fluidized bed (termed expanded bed) is formed in the crude feed, a sorption performance comparable to packed beds is found. During the application of biomass containing samples to stable expanded beds an increase in bed expansion due to the higher density and viscosity of the feed is encountered. In this article it is investigated whether the expanded bed condition is also fulfilled during the transition in bed expansion from lower to higher density (i.e., from an equilibration buffer to a biomass containing feedstock). Residence time distribution analyses were performed by using model systems and a yeast suspension during this transition phase. It is shown that in systems in which the biomass does not interact with the fluidized stationary phase, the perfectly classified fluidization is maintained also during this transition phase regardless of the type of feedstock. Additional bed expansion takes place in an “ordered” manner without compromising bed stability. In case of biomass/adsorbent interactions, a deterioration in bed stability is found directly when the crude feed is loaded. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 21‐26, 2003,
Endoplasmic reticulum signaling as a determinant of recombinant protein expression
Authors: Cudna Renata E. , Dickson Alan J.
Published: November 2002

Generation of functional recombinant proteins requires efficient and undisturbed functioning of the ER–Golgi secretory pathway in host cells. In large‐scale production, where target proteins are highly overexpressed, this pathway can be easily congested with unfolded or misfolded proteins. Accumulating evidence suggests that, in addition to responsibility for protein processing, ER is also an important signaling compartment and a sensor of cellular stress. Two ER responses have been described to arise from the overaccumulation of proteins: unfolded protein response (UPR) and ER overload response (EOR). UPR and EOR employ various mechanisms at the transcriptional and the translational levels to deal efficiently and appropriately with encountered stress. This review will outline the molecular bases of ER functioning and stress response, highlight the relevance of ER signaling to the large‐scale cell culture productivity and discuss possible approaches to the improvement of the secretion capacities of recombinant cells. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 56–65, 2003.
Thermally triggered purification and immobilization of elastin–OPH fusions
Authors: Shimazu Mark , Mulchandani Ashok , Chen Wilfred
Published: November 2002

A bifunctional fusion protein consisting of organophosphorus hydrolase (OPH) and elastin‐like polypeptide (ELP) was synthesized for the detoxification of organophosphorus compounds. ELPs undergo a reversible phase transition upon an increase in temperature, forming hydrophobic aggregates. This thermally triggered property of phase transition allows for a simple and rapid means of purifying the fusion protein. Over 1,300‐fold purification was achieved after only 2 cycles of inverse phase transition. The purified fusion protein showed identical kinetic properties as the native OPH with only a modest 10% increase in Km and a 5% decrease of Kcat. The ability of the ELP domain to form collapsed aggregates also improved long‐term stability of the fusion enzyme. Aggregated ELP–OPH retained nearly 100% activity over a span of three weeks. In addition to facilitating purification and stability, the ELP moiety served as a hydrophobic tag for one‐step immobilization of the fusion protein onto hydrophobic surfaces. The ELP–OPH was capable of rapidly degrading paraoxon while immobilized. The protein also retained ELP functionality of reversible phase transition thereby allowing for the regeneration of the treated surface. This technology offers a swift and convenient means for purification, immobilization, and regeneration of OPH onto a variety of hydrophobic surfaces by simple environmental triggers. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 74–79, 2003.
Unveiling steady‐state multiplicity in hybridoma cultures: The cybernetic approach
Authors: Namjoshi Abhijit Anand , Hu Wei‐Shou , Ramkrishna Doraiswami
Published: November 2002

Mammalian cells grown in suspension produce waste metabolites such as lactate, alanine, and ammonia, which reduce the yield of cell mass and the desired product on the nutrients supplied. Previous studies (Cruz et al., 1999; Europa et al., 2000; Follstad et al., 1999) have shown that the cells can be made to alter their metabolism by starving them on their nutrients in continuous cultures at low dilution rates or starting the culture as a fed‐batch. This leads to multiple steady states in continuous reactors, with some states being more favorable than others. Mathematical models that take into account the metabolic regulation that leads to these multiple steady states are invaluable tools for bioreactor control. In this article we present a cybernetic modeling strategy in which Metabolic Flux Analysis (MFA) is used to guide the cybernetic formulation. The hybridoma model presented as a result of this strategy considers the partially substitutable, partially complementary nature of glucose and glutamine. The choice of competitions within the network is guided by MFA and the model is successful in explaining the three multiple steady states observed. The cybernetic model though identified for the hybridoma experiments of Hu and others (Europa et al., 2000) seem generally applicable to mammalian systems as it captures the pathways that are common to mammalian cells grown in suspension. The model presented here could be used for start‐up strategies for continuous reactors and model‐based feedback control for maintaining high productivity of the reactor. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 80–91, 2003.