Showing papers by "Wayne State University published in 2002"

Voriconazole versus Amphotericin B for Primary Therapy of Invasive Aspergillosis

Abstract: Background Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. Methods In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. Results A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematop...

Late-Onset Sepsis in Very Low Birth Weight Neonates: The Experience of the NICHD Neonatal Research Network

Abstract: Objective. Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401–1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998–2000). Methods. The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998. Results. Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%). Conclusions. Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia

Abstract: Background Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. Methods A total of 532 patients with late–chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. Results Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment be...

Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone

Abstract: Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.

Alcohol-related sexual assault: a common problem among college students.

Abstract: Objective: This article summarizes research on the role of alcohol in college students' sexual assault experiences. Sexual assault is extremely common among college students. At least half of these sexual assaults involve alcohol consumption by the perpetrator, the vic- tim or both. Method: Two research literatures were reviewed: the sexual assault literature and the literature that examines alcohol's effects on ag- gressive and sexual behavior. Results: Research suggests that alcohol consumption by the perpetrator and/or the victim increases the likeli- hood of acquaintance sexual assault occurring through multiple path- ways. Alcohol's psychological, cognitive and motor effects contribute to sexual assault. Conclusions: Although existing research addresses some important questions, there are many gaps. Methodological limi- tations of past research are noted, and suggestions are made for future research. In addition, recommendations are made for college prevention programs and policy initiatives. (J. Stud. Alcohol, Supplement No. 14: 118-128, 2002)

Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants.

Abstract: Background It is uncertain whether the rates and causes of early-onset sepsis (that occurring within 72 hours after birth) among very-low-birth-weight infants have changed in recent years, since antibiotics have begun to be used more widely during labor and delivery. Methods We studied 5447 very-low-birth-weight infants (those weighing between 401 and 1500 g) born at centers of the Neonatal Research Network of the National Institute of Child Health and Human Development between 1998 and 2000 who had at least one blood culture in the first three days of life and compared them with 7606 very-low-birth-weight infants born at centers in the network between 1991 and 1993. Results Early-onset sepsis (as confirmed by positive blood cultures) was present in 84 infants in the more recent birth cohort (1.5 percent). As compared with the earlier birth cohort, there was a marked reduction in group B streptococcal sepsis (from 5.9 to 1.7 per 1000 live births of infants weighing 401 to 1500 g, P<0.001) and an increase ...

Evaluation of the biocompatibility of a chitosan scaffold in mice.

Abstract: Chitosan scaffolds appear to be suitable for a variety of tissue engineering applications. This study addressed the biocompatibility of chitosan in a mouse implantation model. Porous chitosan scaffolds were implanted in mice, and animals were sacrificed after 1, 2, 4, 8, or 12 weeks. Macroscopic inspection of the implantation site revealed no pathological inflammatory responses. Histological assessment indicated marked neutrophil accumulation within the implant, which resolved with increasing implantation time. Gram staining and limulus assays revealed no evidence of infection or endotoxin. Collagen was observed within the chitosan pore spaces, indicating that connective tissue matrix was deposited within the implant. Angiogenic activity associated with the external implant surface was also observed. Cellular immune responses were determined by lymphocyte proliferation assays, and antibody responses were measured using ELISA techniques. These assays indicated a very low incidence of chitosan-specific reactions. Although there was a large migration of neutrophils into the implantation area, there were minimal signs of any inflammatory reaction to the material itself. This preliminary study demonstrates that chitosan has a high degree of biocompatibility in this animal model. Overall, the findings suggest that chitosan may be suitable for the development of implantable materials.

Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age.

Abstract: ContextChildhood asthma is strongly associated with allergic sensitization. Studies have suggested that animal exposure during infancy reduces subsequent allergic sensitization.ObjectiveTo evaluate the relationship between dog and cat exposure in the first year of life and allergic sensitization at 6 to 7 years of age.Design, Setting, and SubjectsProspective birth cohort study of healthy, full-term infants enrolled in a health maintenance organization in suburban Detroit, Mich, who were born between April 15, 1987, and August 31, 1989, and followed up yearly to a mean age of 6.7 years. Of 835 children initially in the study at birth, 474 (57%) completed follow-up evaluations at age 6 to 7 years.Main Outcome MeasuresAtopy, defined as any skin prick test positivity to 6 common aeroallergens (dust mites [Dermatophagoides farinae, D pteronyssinus], dog, cat, short ragweed [Ambrosia artemisiifolia], and blue grass [Poa pratensis]); seroatopy, defined as any positive allergen-specific IgE test result for the same 6 allergens or for Alternaria species.ResultsThe prevalence of any skin prick test positivity (atopy) at age 6 to 7 years was 33.6% with no dog or cat exposure in the first year of life, 34.3% with exposure to 1 dog or cat, and 15.4% with exposure to 2 or more dogs or cats (P = .005). The prevalence of any positive allergen-specific IgE test result (seroatopy) was 38.5% with no dog or cat exposure, 41.2% with exposure to 1 dog or cat, and 17.9% with exposure to 2 or more dogs or cats (P = .003). After adjustment for cord serum IgE concentration, sex, older siblings, parental smoking, parental asthma, bedroom dust mite allergen levels at 2 years, and current dog and cat ownership, exposure to 2 or more dogs or cats in the first year of life was associated with a significantly lower risk of atopy (adjusted odds ratio, 0.23; 95% confidence interval, 0.09-0.60) and seroatopy (adjusted odds ratio, 0.33; 95% confidence interval, 0.13-0.83).ConclusionExposure to 2 or more dogs or cats in the first year of life may reduce subsequent risk of allergic sensitization to multiple allergens during childhood.

Microbial arsenic: from geocycles to genes and enzymes.

Abstract: Arsenic compounds have been abundant at near toxic levels in the environment since the origin of life. In response, microbes have evolved mechanisms for arsenic resistance and enzymes that oxidize As(III) to As(V) or reduce As(V) to As(III). Formation and degradation of organoarsenicals, for example methylarsenic compounds, occur. There is a global arsenic geocycle, where microbial metabolism and mobilization (or immobilization) are important processes. Recent progress in studies of the ars operon (conferring resistance to As(III) and As(V)) in many bacterial types (and related systems in Archaea and yeast) and new understanding of arsenite oxidation and arsenate reduction by respiratory-chain-linked enzyme complexes has been substantial. The DNA sequencing and protein crystal structures have established the convergent evolution of three classes of arsenate reductases (that is classes of arsenate reductases are not of common evolutionary origin). Proposed reaction mechanisms in each case involve three cysteine thiols and S–As bond intermediates, so convergent evolution to similar mechanisms has taken place.

Toward a contextual theory of leadership

Abstract: We propose moving leadership theory and research to another level—one that recognizes that current leadership scholarship is not invalid but incomplete. Such scholarship needs to be looked at in different ways and with various approaches relevant for different circumstances. Macro views need increasing recognition, but to supplement rather than replace currently emphasized meso/micro perspectives. Also, human agency is not to be replaced with mechanistic prescription, but leadership scholars are in a position to contribute to the strategy and organization theory research that currently minimizes leader influence. This philosophy is illustrated through the interplay of leadership with the four contexts of: stability, crisis, dynamic equilibrium, and edge of chaos; the latter operationalized through a complexity theory/dynamic systems perspective. We discuss each context and leadership, in terms of patterning of attention and network leadership, and conclude with a brief measurement treatment. These contexts encourage researchers to reconsider temporality, causal relations, units of analysis, and dependent variables consistent with the social construction of human agency within the given context, to develop more robust models and leadership understanding.

Enhancement of hippocampal neurogenesis by lithium.

Abstract: Increasing evidence suggests that mood disorders are associated with a reduction in regional CNS volume and neuronal and glial cell atrophy or loss. Lithium, a mainstay in the treatment of mood disorders, has recently been demonstrated to robustly increase the levels of the cytoprotective B-cell lymphoma protein-2 (bcl-2) in areas of rodent brain and in cultured cells. In view of bcl-2's antiapoptotic and neurotrophic effects, the present study was undertaken to determine if lithium affects neurogenesis in the adult rodent hippocampus. Mice were chronically treated with lithium, and 5-bromo-2-deoxyuridine (BrdU) labeling of dividing cells was conducted over 12 days. Immunohistochemical analysis was undertaken 1 day after the last injection, and three-dimensional stereological cell counting revealed that lithium produced a significant 25% increase in the BrdU-labeled cells in the dentate gyrus. Double-labeling immunofluorescence studies were undertaken to co-localize BrdU-positive cells with neuron-specific nuclear protein and showed that approximately 65% of the cells were double-labeled. These results add to the growing body of evidence suggesting that mood stabilizers and antidepressants exert neurotrophic effects and may therefore be of use in the long-term treatment of other neuropsychiatric disorders.

Acquiring Knowledge by Foreign Partners from International Joint Ventures in a Transition Economy: Learning-by-Doing and Learning Myopia

Abstract: This paper proposes and tests a model of how firms acquire knowledge from their international joint venturing experience. Based on survey responses from 73 Singapore and 89 Hong Kong firms with respect to their joint ventures set up in China, the results indicate that both overseeing effort and management involvement are significant channels of knowledge acquisition. The former channel is more important for firms with a great deal of operational experience in China and for parents of older joint ventures. This finding indicates that firms improve their skills of knowledge acquisition through learning-by-doing. Moreover, the strategic importance of the venture concerned, instead of the learning intent of the parent, is the driving force behind the allocation of resources to the two channels. This implies that firms mainly learn through managing their key joint ventures. Since a venture that provides novel and fruitful learning experience may not, and need not, be an operation of great strategic importance, this finding suggests the existence of learning myopia. Copyright © 2002 John Wiley & Sons, Ltd.

Engineering tolerance and hyperaccumulation of arsenic in plants by combining arsenate reductase and gamma-glutamylcysteine synthetase expression.

Abstract: We have developed a genetics-based phytoremediation strategy for arsenic in which the oxyanion arsenate is transported aboveground, reduced to arsenite, and sequestered in thiol-peptide complexes. The Escherichia coli arsC gene encodes arsenate reductase (ArsC), which catalyzes the glutathione (GSH)-coupled electrochemical reduction of arsenate to the more toxic arsenite. Arabidopsis thaliana plants transformed with the arsC gene expressed from a light-induced soybean rubisco promoter (SRS1p) strongly express ArsC protein in leaves, but not roots, and were consequently hypersensitive to arsenate. Arabidopsis plants expressing the E. coli gene encoding gamma-glutamylcysteine synthetase (gamma-ECS) from a strong constitutive actin promoter (ACT2p) were moderately tolerant to arsenic compared with wild type. However, plants expressing SRS1p/ArsC and ACT2p/gamma-ECS together showed substantially greater arsenic tolerance than gamma-ECS or wild-type plants. When grown on arsenic, these plants accumulated 4- to 17-fold greater fresh shoot weight and accumulated 2- to 3-fold more arsenic per gram of tissue than wild type or plants expressing gamma-ECS or ArsC alone. This arsenic remediation strategy should be applicable to a wide variety of plant species.

Culturally Sensitive Research Approaches: An African-American Perspective

Abstract: This article contributes to discussions about culturally sensitive research approaches in qualitative research. The author argues that the use of culturally sensitive research approaches in research focusing on African Americans can use the cultural knowledge and experiences of researchers and their participants in the design of the research as well as in the collection and interpretation of data. The author presents a rationale for the use of culturally sensitive research approaches for African Americans, a theoretical framework for culturally sensitive research approaches, and a discussion of culturally sensitive research in practice. This article concludes by discussing some implications for teaching and practice in educational research.

Oral Contraceptives and the Risk of Breast Cancer

Abstract: Background It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case–control study to determine the risk of breast cancer among former and current users of oral contraceptives. Methods We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. Results The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women...

Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9

Abstract: Much is known about the transport of arsenite and antimonite into microbes, but the identities of mammalian transport proteins are unknown. The Saccharomyces cerevisiae FPS1 gene encodes a membrane protein homologous to the bacterial aquaglyceroporin GlpF and to mammalian aquaglyceroporins AQP7 and AQP9. Fps1p mediates glycerol uptake and glycerol efflux in response to hypoosmotic shock. Fps1p has been shown to facilitate uptake of the metalloids arsenite and antimonite, and the Escherichia coli homolog, GlpF, facilitates the uptake and sensitivity to metalloid salts. In this study, the ability of mammalian aquaglyceroporins AQP7 and AQP9 to substitute for the yeast Fps1p was examined. The fps1Δ strain of S. cerevisiae exhibits increased tolerance to arsenite and antimonite compared to a wild-type strain. Introduction of a plasmid containing AQP9 reverses the metalloid tolerance of the deletion strain. AQP7 was not expressed in yeast. The fps1Δ cells exhibit reduced transport of 73As(III) or 125Sb(III), but uptake is enhanced by expression of AQP9. Xenopus laevis oocytes microinjected with either AQP7 or AQP9 cRNA exhibited increased transport of 73As(III). These results suggest that AQP9 and AQP7 may be a major routes of arsenite uptake into mammalian cells, an observation potentially of large importance for understanding the action of arsenite as a human toxin and carcinogen, as well as its efficacy as a chemotherapeutic agent for acute promyelocytic leukemia.

Summary Statement From a Workshop on Asymptomatic Primary Hyperparathyroidism: A Perspective for the 21st Century

Abstract: Department of Medicine, Columbia University College of Physicians and Surgeons (J.P.B., S.J.S.), New York, New York 10032; Department of Medicine, Massachusetts General Hospital, Harvard Medical School (J.T.P., R.N.), Boston, Massachusetts 02114; American University of Beirut Medical Center (G.E.-H.F.), Beirut, Lebanon; Department of Medicine, Wayne State University School of Medicine (M.K.), Detroit, Michigan 48201; Department of Medicine, Indiana University School of Medicine (M.P.), Indianapolis, Indiana 46202; Department of Surgery, University Hospital (J.R.), Uppsala, Sweden; Department of Surgery, Yale-New Haven Hospital, Yale University School of Medicine (R.U.), New Haven, Connecticut 06520; and Department of Surgery, Duke University Medical Center (S.A.W.), Durham, North Carolina 27710

On the physical origin of blue-shifted hydrogen bonds.

Abstract: For blue-shifted hydrogen-bonded systems, the hydrogen stretching frequency increases rather than decreases on complexation. In computations at various levels of theory, the blue-shift in the archetypical system, F3C−H···FH, is reproduced at the Hartree−Fock level, indicating that electron correlation is not the primary cause. Calculations also demonstrate that a blue-shift does not require either a carbon center or the absence of a lone pair on the proton donor, because F3Si−H···OH2, F2NH···FH, F2PH···NH3, and F2PH···OH2 have substantial blue-shifts. Orbital interactions are shown to lengthen the X−H bond and lower its vibrational frequency, and thus cannot be the source of the blue-shift. In the F3CH···FH system, the charge redistribution in F3CH can be reproduced very well by replacing the FH with a simple dipole, which suggests that the interactions are predominantly electrostatic. When modeled with a point charge for the proton acceptor, attractive electrostatic interactions elongate the F3C−H, while...

The yeast DHHC cysteine-rich domain protein Akr1p is a palmitoyl transferase

Abstract: Protein palmitoylation has been long appreciated for its role in tethering proteins to membranes, yet the enzymes responsible for this modification have eluded identification. Here, experiments in vivo and in vitro demonstrate that Akr1p, a polytopic membrane protein containing a DHHC cysteine-rich domain (CRD), is a palmitoyl transferase (PTase). In vivo, we find that the casein kinase Yck2p is palmitoylated and that Akr1p function is required for this modification. Akr1p, purified to near homogeneity from yeast membranes, catalyzes Yck2p palmitoylation in vitro, indicating that Akr1p is itself a PTase. Palmitoylation is stimulated by added ATP. Furthermore, during the reaction, Akr1p is itself palmitoylated, suggesting a role for a palmitoyl-Akr1p intermediate in the overall reaction mechanism. Mutations introduced into the Akr1p DHHC-CRD eliminate both the trans- and autopalmitoylation activities, indicating a central participation of this conserved sequence in the enzymatic reaction. Finally, our results indicate that palmitoylation within the yeast cell is controlled by multiple PTase specificities. The conserved DHHC-CRD sequence, we propose, is the signature feature of an evolutionarily widespread PTase family.

Centrality dependence of high-pt hadron suppression in Au + Au collisions at √SNN = 130 GeV

Abstract: Inclusive transverse momentum distributions of charged hadrons within 0.2 < p T < 6.0 GeV/c have been measured over a broad range of centrality for Au + Au collisions at S N N = 130 GeV. Hadron yields are suppressed at high PT in central collisions relative to peripheral collisions and to a nucleon-nucleon reference scaled for collision geometry. Peripheral collisions are not suppressed relative to the nucleon-nucleon reference. The suppression varies continuously at intermediate centralities. The results indicate significant nuclear medium effects on high-p T hadron production in heavy-ion collisions at high energy.

Inhibition of Human Cancer Cell Growth and Metastasis in Nude Mice by Oral Intake of Modified Citrus Pectin

Abstract: Background: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro. Methods: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student’s t test or Fisher’s protected least-significant-difference test. Results: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 µg/mL) to HUVECs by 72.1% (P = .038) and 95.8% (P = .025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 µg/mL) to HUVECs by 100% (P = .032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner. Conclusions: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/ or treatment of cancer. [J Natl Cancer Inst 2002;94:1854–62]