Showing papers by "Vanderbilt University published in 1991"

Reduction by Granulocyte Colony-Stimulating Factor of Fever and Neutropenia Induced by Chemotherapy in Patients with Small-Cell Lung Cancer

Abstract: Background. Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Methods. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, <1.0×l09 per liter, with a temperature ≥38.2°C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21 -day cycle. Results. The safety of the study treatment could be evaluated in 207 of the 211 pa...

Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects

Abstract: The role of human cytochrome P-450 IIE1 (P-450 IIE1) in the oxidation of a number of suspect carcinogens was examined by using a variety of approaches, including (1) selective inhibition of catalytic activity in human liver microsomes by diethyldithiocarbamate, which was found to be a selective mechanism-based inactivator of P-450 IIE1, (2) correlation of rates of different catalytic activities with each other and with chlorzoxazone 6-hydroxylation, an indicator of P-450 IIE1, in human liver microsomes, (3) demonstration of catalytic activity in reconstituted systems containing purified human P-450 IIE1, and (4) immunoinhibition of catalytic activity in human liver microsomes with rabbit anti-human P-450 IIE1. The results collectively indicate that P-450 IIE1 is a major catalyst of the oxidation of benzene, styrene, CCl4, CHCl3, CH2Cl2, CH3Cl, CH3CCl3, 1,2-dichloropropane, ethylene dichloride, ethylene dibromide, vinyl chloride, vinyl bromide, acrylonitrile, vinyl carbamate, ethyl carbamate, and trichloroethylene. Levels of P-450 IIE1 can vary considerably among individual humans--the availability of chlorzoxazone as a noninvasive probe of human P-450 IIE1 and of disulfiram (oxidized diethyldithiocarbamate) as an inhibitor may facilitate discernment of the in vivo significance of human P-450 IIE1 as a factor in the bioactivation and detoxication of these cancer suspects. Further, many investigations with diethyldithiocarbamate, disulfiram, and ethanol in humans and experimental animals may be interpreted in light of mechanisms involving P-450 IIE1.

Massive cortical reorganization after sensory deafferentation in adult macaques

Abstract: After limited sensory deafferentations in adult primates, somatosensory cortical maps reorganize over a distance of 1 to 2 millimeters mediolaterally, that is, in the dimension along which different body parts are represented. This amount of reorganization was considered to be an upper limit imposed by the size of the projection zones of individual thalamocortical axons, which typically also extend a mediolateral distance of 1 to 2 millimeters. However, after extensive long-term deafferentations in adult primates, changes in cortical maps were found to be an order of magnitude greater than those previously described. These results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.

Plasticity of sensory and motor maps in adult mammals.

Abstract: This rev iew addresses questions about t he capacity of sensory and motor maps in the brains of adul t mammals to change as a resul t of alterations in the effectiveness of inputs, the availability of effectors, and d irect damage. The issue of the mutabil ity of maps in adults is important because sensory and motor representations occupy much of the brains of mammals, regardless of the complexity and extent of neocortex (e.g. Kaas 1988, Wall 1988, Maunsell & Newsome 1987); behavioral recovery occurs after damage to central representations (e.g. Bor nschlegl & Asanuma 1987, Diirsteler et a11987, Eidelberg & Stein 1974); and such changes may relate to improvements in sensory and motor skills with experience (e.g. Gibson 1953). Tn addition, features of reorganization that are apparent in sensory and motor maps may characterize less easily studied areas of the brain. Specific questions addr essed in this review are as follows:

The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus

Abstract: T-associated maternal effect (Tme) is the only known maternal-effect mutation in the mouse. The defect is nuclear-encoded and embryos that inherit a deletion of the Tme locus from their mother die at day 15 of gestation. There are many genomically imprinted regions known in the mouse genome but so far no imprinted genes have been cloned. The Tme locus is absent in two chromosome-17 deletion mutants, Thp and the tLub2, and its position has been localized using these deletions to a 1-cM region. We report here that the genes for insulin-like growth factor type-2 receptor (Igf2r) and mitochondrial superoxide dismutase-2 (Sod-2) are absent from both deletions. Probes for these genes and for plasminogen (Plg) and T-complex peptide 1 (Tcp-1) were used in pulsed-field gel mapping to show that Tme must lie within a region of 800-1,100 kb. We also demonstrate that embryos express Igf2r only from the maternal chromosome, and that Tcp-1, Plg and Sod-2 are expressed from both chromosomes. Therefore Igf2r is imprinted and closely linked or identical to Tme.

On merging identity theory and stress research

Abstract: In this paper I develop and discuss the concept of «identity-relevant stressors.» Identities refer to individuals' conceptions of themselves in terms of the social roles that they enact (e.g., spouse, parent, worker, churchgoer, friend). An identity-relevant experience is one that threatens or, alternatively, enhances an identity that the individual values highly; identity-irrelevant experiences occur in roles that the individual does not value highly. This concept can help solve a problem in the stress literature, namely the inability of stress theory to account parsimoniously for social status differences in psychological distress

Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor

Abstract: Angiotensin II elicits different responses which affect cardiovascular, neuronal and electrolyte transport regulation. To understand the mechanisms responsible for its various actions, the receptor for angiotensin II has long been sought, but numerous attempts to purify the receptor have been unsuccessful owing to its instability and low concentration. We report here the expression cloning of a complementary DNA encoding a bovine angiotensin II receptor to overcome these difficulties. The receptor cDNA encodes a protein of 359 amino-acid residues with a transmembrane topology similar to that of other G protein-coupled receptors. COS-7 cells transfected with the cDNA expressed specific and high-affinity binding sites for angiotensin II, angiotensin II antagonist and a non-peptide specific antagonist for type-1 receptor. Dithiothreitol inhibited ligand binding. The concentration of intracellular Ca2+ and of inositol-1,4,5-trisphosphate increased in the transfected COS-7 cells in response to angiotensin II or angiotensin III, indicating that this receptor is the type-1 receptor for angiotensin II. Northern blot analysis revealed that the messenger RNA for this receptor is expressed in bovine adrenal medulla, cortex and kidney.

Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.

Abstract: Objective To evaluate the relative risk for peptic ulcer disease that is associated with the use of nonaspirin nonsteroidal anti-inflammatory drugs Design Nested case-control study Setting Tennessee Medicaid program Participants Medicaid enrollees 65 years of age or older were included in the study The 1415 case patients had been hospitalized for confirmed peptic ulcer disease at some point from 1984 through 1986 The 7063 control persons represented a stratified random sample of other Medicaid enrollees Measurements and main results The estimated relative risk for the development of peptic ulcer disease among current users of nonaspirin nonsteroidal anti-inflammatory drugs, compared with that among nonusers, was 41 (95% CI, 35 to 47) For current users, the risk increased with increasing dose, from a relative risk of 28 (CI, 18 to 43) for the lowest to a relative risk of 80 (CI, 44 to 148) for the highest dose category The risk was greatest in the first month of use (relative risk, 72; CI, 49 to 105) If the association is fully causal, 29% of peptic ulcers in the study sample resulted from the use of these drugs, and the excess risk associated with such use was 174 hospitalizations for ulcer disease per 1000 person-years of exposure Conclusions These data support other findings indicating that a clinically significant risk for serious ulcer disease is associated with the use of nonaspirin nonsteroidal anti-inflammatory drugs The data show that this risk increases with dose and recency of use and that use of these drugs may be responsible for a large proportion of peptic ulcer disease among elderly persons

The Functional Disability Inventory: Measuring a Neglected Dimension of Child Health Status

Abstract: Described the development and validation of the Functional Disability Inventory (FDI) for school-age children and adolescents. Results provide support for construct, concurrent, and predictive validity. FDI scores also demonstrated stability over a 3-month period in patients with a chronic condition, and the instrument was sensitive to changes in patient status subsequent to medical treatment. There was some evidence that gender played a role in disability, particularly in adolescence. The instrument may be used (a) in studying individual differences in pediatric disability, (b) in examining the relation of disability to psychosocial functioning in the child and other family members, or (c) as an outcome measure in assessing the impact of interventions on patient functioning.

Activation of the beta 1 isozyme of phospholipase C by alpha subunits of the Gq class of G proteins.

Abstract: MANY hormones, neurotransmitters and growth factors, on binding to G protein-coupled receptors or receptors possessing tyrosine kinase activity, increase intracellular levels of the second messengers inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. This is due to activation of phosphoinositide-specific phospho-lipase(s) C (PLC), the isozymes of which are classified into groups, α, β, γ and δ (refs 1, 2). The β, γ and δ groups themselves contain PLC isozymes which have both common and unique structural domains3. Only the γl isozyme has been implicated in a signal transduction mechanism4. This involves association with, and tyrosine phosporylation by, the ligand-bound epidermal growth factor and platelet-derived growth factor receptors5–7, probably by means of the PLC-γl-specific src homology (SH2) domain8. Because EGF receptor-mediated tyrosine phosphorylation of PLC-γ1 stimulates catalytic activity in vitro9 and G proteins have been implicated in the activation of PLC10, we investigated which PLC isozymes are subject to G protein regulation. We have purified11 an activated G protein α subunit that stimulates partially purified phospholipase C and now report that this G protein specifically activates the β1 isozyme, but not the γ1 and δ1 isozymes of phospholipase C. We also show that this protein is related to the Gq class of G protein α subunits12.

Involvement of Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse

Abstract: Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 are members of the TGF-beta gene family most closely related to the Drosophila Decapentaplegic and Xenopus Vg-1 genes. Members of this gene family have been implicated in diverse processes during embryogenesis including epithelial-mesenchymal interactions. Here, we use in situ hybridization to localize BMP-4 and Vgr-1 transcripts during murine development. BMP-4 mRNA is found in a variety of tissues. In the 8.5 days p.c. embryo, transcripts are localized to the mesoderm posterior to the last somite. Later gestation embryos show expression in developing limbs, the embryonic heart, the facial processes and condensed mesenchymal cells associated with early whisker follicle formation. In the developing central nervous system (CNS), BMP-4 expression is restricted to the floor of the diencephalon associated with pituitary development. In contrast, Vgr-1 transcripts are found along the anteroposterior axis of the CNS, in cells immediately adjacent to the floor plate and in the roof plate extending to the forebrain. Together, the data support the hypothesis that polypeptide growth factors of the TGF-beta superfamily play key roles in the initial stages of neurogenesis and organogenesis during murine development.

Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development

Abstract: Isoform-specific antibodies to TGF beta 1, TGF beta 2, and TGF beta 3 proteins were generated and have been used to examine the expression of these factors in the developing mouse embryo from 12.5-18.5 d post coitum (d.p.c.). These studies demonstrate the initial characterization of both TGF beta 2 and beta 3 in mammalian embryogenesis and are compared with TGF beta 1. Expression of one or all three TGF beta proteins was observed in many tissues, e.g., cartilage, bone, teeth, muscle, heart, blood vessels, lung, kidney, gut, liver, eye, ear, skin, and nervous tissue. Furthermore, all three TGF beta proteins demonstrated discrete cell-specific patterns of expression at various stages of development and the wide variety of tissues expressing TGF beta proteins represent all three primary embryonic germ layers. For example, specific localization of TGF beta 1 was observed in the lens fibers of the eye (ectoderm), TGF beta 2 in the cortex of the adrenal gland (mesoderm), and TGF beta 3 in the cochlear epithelium of the inner ear (endoderm). Compared to the expression of TGF beta mRNA transcripts in a given embryonic tissue, TGF beta proteins were frequently colocalized within the same cell type as the mRNA, but in some cases were observed to localize to different cells than the mRNA, thereby indicating that a complex pattern of transcription, translation, and secretion for TGF beta s 1-3 exists in the mouse embryo. This also indicates that TGF beta 1, beta 2, and beta 3 act through both paracrine and autocrine mechanisms during mammalian embryogenesis.

Cell-Cell Interactions in the Testis

Abstract: THE ability of cells to interact and communicate is a biological phenomenon that developed with the evolution of multicellular organisms. The cell-cell interactions that have evolved are essential for the survival of both simple organisms such as dictyostelium and complex organisms such as mammals. These cellular associations allow an organism to develop capacities that are greater than the simple sum of their individual parts. As early as 1878, Claude Bernard proposed that the “milieu interieur” (i.e. internally produced fluid environment) and a cybernetic-like control system (i.e. cell-cell interactions and communication) in multicellular organisms are needed to adaptively regulate the growth, development, and maintenance of normal tissue function (1, 2). The experimental analysis of cellular interactions was initiated with the investigation of cell aggregation in simple organisms such as sponges (3, 4) and progressed into the areas of embryology (5) and cell biology (6, 7). Analysis of cell biology on ...

Eukaryotic start and stop translation sites

Abstract: Sequences flanking translational initiation and termination sites have been compiled and statistically analyzed for various eukaryotic taxonomic groups. A few key similarities between taxonomic groups support conserved mechanisms of initiation and termination. However, a high degree of sequence variation at these sites within and between various eukaryotic groups suggest that translation may be modulated for many mRNAs. Multipositional analysis of di-, tri-, and quadrinucleotide sequences flanking start/stop sites indicate significant biases. In particular, strong tri-nucleotide biases are observed at the -3, -2, and -1 positions upstream of the start codon. These biases and the interspecific variation in nucleotide preferences at these three positions have lead us to propose a revised model of the interaction of the 18S ribosomal RNA with the mRNA at the site of translation initiation. Unusually strong biases against the CG dinucleotide immediately downstream of termination codons suggest that they may lead to faulty termination and/or failure of the ribosome to disassociate from the mRNA.

Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment.

Abstract: Platelets metabolize arachidonic acid to thromboxane A2, a potent platelet aggregator and vasoconstrictor compound. The first step of this transformation is catalyzed by prostaglandin (PG) G/H synthase, a target site for nonsteroidal antiinflammatory drugs. We have isolated the cDNA for both human platelet and human erythroleukemia cell PGG/H synthase using the polymerase chain reaction and conventional screening procedures. The cDNA encoding the full-length protein was expressed in COS-M6 cells. Microsomal fractions from transfected cells produced prostaglandin endoperoxide-derived products which were inhibited by indomethacin and aspirin. Mutagenesis of the serine residue at position 529, the putative aspirin acetylation site, to an asparagine reduced cyclooxygenase activity to barely detectable levels, an effect observed previously with the expressed sheep vesicular gland enzyme. Platelet-derived growth factor and phorbol ester differentially regulated the expression of PGG/H synthase mRNA levels in th...

Corticosteroid Use and Peptic Ulcer Disease: Role of Nonsteroidal Anti-inflammatory Drugs

Abstract: Objective: To estimate the relative risk for peptic ulcer disease that is associated with the use of oral corticosteroids. Design: A nested case-control study. Setting: Tennessee Medicaid program. ...

The Epidemiology of Helicobacter pylori Infection

Abstract: The evidence that H. pylori causes gastritis in humans comes from both primary and secondary observations. The most important primary observations are the human volunteer studies, the animal models, and the treatment studies with antimicrobial agents. Supporting information comes from studies showing the specific association of H. pylori infection with type B gastritis and with gastric (but not intestinal) epithelial cells; the specific ultrastructural lesions, including adherence pedestals; the ubiquity and stability of the immune response; the response to bismuth treatment; and the association with epidemic gastritis and hypochlorhydria. It is important to note that all of Koch's postulates have been fulfilled, and despite nearly universal initial skepticism, no evidence exists against the hypothesis that H. pylori plays an etiologic role in type B gastritis. Therefore, it is reasonable to conclude that H. pylori is a pathogen in humans. The known features of H. pylori infection are listed in. Infection is chronic and common throughout the world, with a higher prevalence in developing countries than in developed countries. The prevalence of H. pylori infection increases with age in parallel with that of gastritis. Acquisition of H. pylori infection does not appear to have any seasonality, and infection is equally common among men and women. Without a significant animal or environmental reservoir for human strains of H. pylori, person-to-person contact appears to be the most likely mode of transmission. Exactly how the organism is transmitted from the stomach of one person to that of another remains unclear. Also unknown are the factors which determine who becomes ill after infection; why one person has gastritis alone while another person develops a duodenal ulcer; and how the traditional risk factors for ulcer disease, such as smoking, aspirin, and alcohol, interact with H. pylori infection. Finally, the long term neoplastic consequences of infection must be understood. Further elucidation of the natural history of H. pylori and the consequences of H. pylori infection is the most important goal for future study.

A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder.

Abstract: Background. In carcinoma of the bladder, both intravesical chemotherapy and immunotherapy can induce tumor regression and reduce the rate of recurrence, but the relative merits of these two therapies are unclear. We conducted a multi-institutional study to address this question. Methods. Patients with rapidly recurrent (stage Ta or T1) or in situ transitional-cell carcinoma of the bladder were randomly assigned to receive either doxorubicin administered intravesically or bacille Calmette–Guerin (BCG) administered both intravesically and percutaneously. The 262 eligible patients were followed for a median of 65 months. Complete responses to treatment of carcinoma in situ were confirmed by biopsy and cytologic analysis of the urine. Results. For patients with Ta and T1 tumors without carcinoma in situ, the estimated probability of being disease free at five years was 17 percent after doxorubicin, as compared with 37 percent after immunotherapy with BCG (P = 0.015). The median times to treatment fai...

Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice.

Abstract: The role of CD4+ and CD8+ T lymphocytes in terminating respiratory syncytial virus (RSV) replication, causing disease, and protecting from reinfection was investigated using a BALB/c mouse model in which CD4+ or CD8+ lymphocytes or both were depleted by injections of Mab directed against the respective mouse lymphocyte determinants. Kinetics of RSV replication, illness, and pathology were assessed after primary infection and rechallenge. Both CD4+ and CD8+ lymphocyte subsets were involved in terminating RSV replication after primary infection. When both T lymphocyte subsets were depleted RSV replication was markedly prolonged, yet no illness was evident, suggesting that host immune response rather than viral cytocidal effect was the primary determinant of disease in mice. Both CD4+ and CD8+ lymphocytes contributed to illness, although CD8+ lymphocytes appeared to play the dominant role in this particular system. Analysis of histological responses suggested that CD4+ lymphocytes were required for the appearance of peribronchovascular lymphocytic aggregates seen in normal mice after rechallenge, and that the presence of alveolar lymphocytes was correlated with illness. It is postulated that antibody is an illness-sparing mechanism for protecting mice from RSV infection, and that T lymphocytes are an important determinant of illness. Further delineation of RSV-induced immunopathogenesis in primary infection and reinfection will provide important information for the development of vaccine strategies.

Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture

Abstract: Despite the importance of germ cells to the survival of species, surprisingly little is known about their embryological origin, proliferation, migration and entry into mitotic arrest or meiosis. Mutations in the murine Dominant White Spotting (W) and Steel genes, which respectively encode the c-kit tyrosine kinase receptor and the c-kit ligand (or Steel factor), impair the development of primordial germ cells (PGCs) in vivo, as well as haematopoietic stem cells and neural crest-derived melanoblasts. Here we use a monoclonal antibody against c-kit tyrosine kinase receptor and recombinant Steel factor to study the c-kit receptor-ligand system in cultured PGCs. In addition, we show that leukaemia inhibitory factor (also known as differentiation inhibitory activity), a factor secreted by STO fibroblasts, can stimulate proliferation of primordial germ cells in vitro.

Paradigmatic Distinctions between Instructionally Relevant Measurement Models

Abstract: In this article, we delineate essential commonalities and distinctions between two approaches to measurement for instructional decision making. Specific subskill mastery measurement is explained using a case study, and salient features of this predominant model are described. Then, a major contrasting approach, the general outcome measurement model, is explained; a curriculum-based measurement case study is provided to illustrate general outcome measurement; and the essential features of this alternative model are reviewed. Finally, we describe how general outcome measurement represents an innovative approach to assessment by bridging traditional and contemporary paradigms.