A spectrum project: preterm birth and small-for-gestational age among infants with birth defects.

OBJECTIVE: The aim of this study is to investigate the association between birth defects (BDs), prematurity and small-for-gestational age (SGA) in a population-based sample. STUDY DESIGN: Participants were singleton live births enrolled in the National Birth Defects Prevention Study, including 18 737 case infants with one or more BD and 7999 controls. Logistic regression models to evaluate associations between BDs, prematurity and fetal growth were computed while adjusting for covariates. RESULT: Cases were significantly more likely to be born prematurely than controls, particularly at 24 to 28 weeks of gestation. The highest odds ratios for preterm birth were found for intestinal atresia, anencephaly, gastroschisis and esophageal atresia. Infants with BDs were also significantly more likely to be SGA than controls (17.2 and 7.8%). CONCLUSION: Infants with BDs are more likely than controls to be born prematurely and SGA. Findings from this study present additional evidence demonstrating a complex interaction between the development of BDs, prematurity and intrauterine growth.

Maternal exposure to water disinfection by-products during gestation and risk of hypospadias.

BACKGROUND: The use of chlorine for water disinfection results in the formation of numerous contaminants called disinfection by-products (DBPs), which may be associated with birth defects, including urinary tract defects. METHODS: We used Arkansas birth records (1998-2002) to conduct a population-based case-control study investigating the relationship between hypospadias and two classes of DBPs, trihalomethanes (THM) and haloacetic acids (HAA). We utilised monitoring data, spline regression and geographical information systems (GIS) to link daily concentrations of these DBPs from 263 water utilities to 320 cases and 614 controls. We calculated ORs for hypospadias and exposure to DBPs between 6 and 16 weeks' gestation, and conducted subset analyses for exposure from ingestion, and metrics incorporating consumption, showering and bathing. RESULTS: We found no increase in risk when women in the highest tertiles of exposure were compared to those in the lowest for any DBP. When ingestion alone was used to assess exposure among a subset of 40 cases and 243 controls, the intermediate tertiles of exposure to total THM and the five most common HAA had ORs of 2.11 (95% CI 0.89 to 5.00) and 2.45 (95% CI 1.06 to 5.67), respectively, compared to women with no exposure. When exposure to total THM from consumption, showering and bathing exposures was evaluated, we found an OR of 1.96 (95% CI 0.65 to 6.42) for the highest tertile of exposure and weak evidence of a dose-response relationship. CONCLUSIONS: Our results provide little evidence for a positive relationship between DBP exposure during gestation and an increased risk of hypospadias but emphasise the necessity of including individual-level data when assessing exposure to DBPs.

A national survey of current admission practices in selected allied health educational programs.

This study investigated the admission practices of selected allied health programs, specifically considering the priorities placed on cognitive and noncognitive factors. The extents to which diversity and a student's desire to work in underserved areas are considered in the selection process were also examined. Of 206 questionnaires mailed to accredited baccalaureate occupational therapy, physical therapy, health information management, and respiratory therapy programs, 144 were returned. The results indicate that allied health programs use combinations of cognitive and noncognitive factors in selecting students for admission. A higher priority is placed on overall grade-point average (GPA) and GPA in foundation courses, whereas lower priorities are placed on the need for diversity and a student's desire to work in underserved areas. The authors discuss the implications of the findings and urge the rethinking of the traditional selection method, which places applicants from ethnic/racial minority backgrounds at a disadvantage.

Oncostatin M-specific receptor expression and function in regulating cell proliferation of normal and malignant mammary epithelial cells.

Oncostatin M (OSM) is a cytokine produced by activated T lymphocytes and macrophages. OSM is structurally and functionally related to leukaemia inhibitory factor (LIF), another cytokine in the interleukin 6 (IL-6) family. The biological activities of OSM are mediated through two types of receptor complexes, the LIF/OSM shared receptor (type I) and OSM-specific receptor (OSM-R, type II), which is composed of gp130 as a binding subunit and a newly identified affinity conversion subunit, OSM-R beta. Previous research conducted in the authors' laboratory has shown that OSM inhibits the growth of several breast cancer cell lines. To investigate whether OSM has a similar effect in primary normal human mammary epithelial (HME) cells, the activity of OSM in HME cells derived from four donors was examined. OSM produced a dose-dependent inhibition of DNA synethesis in these cells. In order to determine the receptor subtypes mediating OSM activity in HME and breast cancer cells, flow cytometry analysis using anti-gp130mAb and anti-OSM-R beta mAb was performed. In these studies, the authors were able to examine expressions of gp130 and OSM-R beta. In addition, quantitative RT-PCR assays were conducted to measure expressions of the mRNAs of the subunits for type I and type II OSM receptor. The results show that HME cells and most breast cancer cell lines express both the type I and the type II OSM receptors. However, type II, OSM-specific receptors are expressed at a higher levels than type I, OSM/LIF shared receptors. Accordingly, we compared the growth regulatory activities of OSM with LIF in HME cells and in breast cancer cells. In contrast to the inhibitory activity of OSM, LIF stimulated the growth of breast cancer cells, whereas it had no effect on normal mammary epithelial cell growth. Together, these data suggest that OSM plays an inhibitory role in normal and malignant mammary epithelial cell growth in vitro. OSM activity is mediated by the OSM-specific receptor (type II), not by the OSM/LIF shared receptor.

Familial bipolar disorder: preliminary results from the Otago Familial Bipolar Genetic Study.

OBJECTIVE: This paper outlines the methodologies used, and preliminary descriptive data collected, on a cohort of familial bipolar disorder (BPD) probands and first-degree relatives taking part in a descriptive and genetic study into familial BPD in New Zealand. METHOD: Fifty-five bipolar probands and 67 first-degree relatives were interviewed using the modified Diagnostic Interview for Genetic Studies (DIGS) and Family Interview for Genetic Studies (FIGS). Data was also collated from other sources. Blood samples were taken for DNA genomic analysis. RESULTS: New Zealand families in which BPD segregates proved willing participants in this familial based genetic research. The methodologies used were acceptable. High rates of comorbidity were found in probands (27.3% met DSM-IV criteria for panic disorder/sub-threshold panic disorder; 12.7% for phobic disorder; 1.8% for obsessive-compulsive disorder; 9.1% for alcohol-related disorders and 7.3% for an eating disorder) and relatives (major depression 34.3%; panic disorder/sub-threshold panic disorder 12.0%; phobias 11.9% and alcohol-related disorders 11.9%). The polarity of index BPD illness was related to age of onset and frequency of comorbidity. Suicidal behaviour was common. CONCLUSIONS: Psychiatric genetic research in New Zealand families is highly feasible. Emerging trends in the familial transmission of BPD include high rates of comorbidity, illness patterns based on polarity of index episode and frequent suicidal behaviour. Such trends will be delineated further as numbers accrue, perhaps enabling identification of more homogenous phenotypic subgroups than currently produced by diagnostic schemes.

Influence of subunit combinations on signaling by receptors for oncostatin M, leukemia inhibitory factor, and interleukin-6.

Oncostatin M (OSM), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) induce expression of a similar set of acute phase plasma protein genes in hepatic cells. The redundant action of these cytokines has been ascribed to the involvement of the common signal-transducing receptor subunit, gp130, in combination with cytokine-specific, ligand-binding subunits. To define the specificity of the signal transduction by the LIF/OSM receptor (a heterodimer of gp130 and LIF receptor (LIFR)) and the OSM-specific receptor (a heterodimer of gp130 and OSM receptor (OSMR)), we reconstituted the receptor function by transfection into receptor-negative Hep3B hepatoma cells. Both receptors activate DNA binding activity of STAT1, -3, and -5B and induce gene transcription through IL-6-responsive elements. The signaling-competent cytoplasmic domain regions of OSMR and LIFR were defined by the analysis of progressive carboxyl-terminal deletion constructs. The 36 residue carboxyl-terminal region containing the distal box 3 sequence motif of OSMR is required for signal transduction by the OSM-specific receptor. In contrast, signaling by LIFR did not display the same requirement for receptor domains and was not strictly dependent on the box 3 elements. The signaling by endogenous LIF and OSM receptors differed from that by IL-6R by the prominent activation of STAT5 as shown in the mouse hepatoma cell line, Hepa-1. The data suggest that the signaling specificity of the receptors for the three cytokines is determined by the composition of the cytoplasmic domains associated in the signal-competent receptor complex and that the signaling is not identical among these cytokine receptors.

Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation.

Oncostatin M (OSM) is a cytokine whose structural and functional features are similar to other members of the interleukin (IL)-6 family of cytokines (IL-6, IL-11, leukemia inhibitory factor (LIF), granulocyte colonystimulating factor, ciliary neurotrophic factor, and cardiotrophin-1), many of which utilize gp130 as a common receptor subunit. A biologically active OSM receptor has been previously described that consists of a heterodimer of leukemia inhibitory factor receptor (LIFR) and gp130. This LIFR.gp130 complex is also a functional receptor for LIF. We have cloned and characterized an alternative subunit (OSMRbeta) for an OSM receptor complex (a heterodimer of gp130 and OSMRbeta) that is activated by OSM but not by LIF. The signaling capability of specific receptor subunit combinations was analyzed by independent assays measuring cell proliferation or induction of acute phase protein synthesis. Our results demonstrate that both LIF and OSM cause tyrosine phosphorylation and activation of the gp130.LIFR combination, but the gp130.OSMRbeta complex is activated by OSM only. OSM-induced cellular responses, initiated through low affinity binding to gp130, are mediated by two heterodimeric receptor complexes that utilize alternative signal transducing subunits that confer different cytokine specificities to the receptor complex.

Proliferative responses and binding properties of hematopoietic cells transfected with low-affinity receptors for leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor.

Specific low-affinity receptors for leukemia inhibitory factor (LIF), oncostatin M (OSM; gp130), and ciliary neurotrophic factor (CNTF; receptor alpha, CNTFR alpha) may be utilized in various combinations to generate high-affinity binding sites and signal transduction. We have tested the ability of combinations of these receptors to transduce a proliferative signal in BAF-B03 cells. Coexpression of the LIF receptor and gp130 in these cells conferred high-affinity LIF and OSM binding and responsiveness to LIF and OSM. These cells also responded to CNTF in the absence of detectable binding. The further addition of CNTFR alpha conferred high-affinity CNTF binding and enhanced responsiveness to CNTF but did not modify responses to LIF or OSM. Coexpression of LIF receptor and CNTFR alpha resulted in a nonfunctional high-affinity binding site. These data are consistent with a role for the CNTFR alpha in enhancing CNTF action but the CNTFR alpha is not absolutely required for CNTF action and suggest a wider range of targets for CNTF.

Reconstitution of the response to leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in hepatoma cells.

Ciliary neurotrophic factor (CNTF) has been described as a neuro-active cytokine that shares functional similarities with the leukemia inhibitory factor (LIF). We demonstrate here that, like LIF, CNTF stimulates expression of acute phase plasma proteins in rat H-35 hepatoma cells. Transfection of the LIF receptor into Hep3B hepatoma cells reconstituted LIF and oncostatin M regulation of acute phase plasma protein genes. Co-expression of the LIF receptor and the CNTF receptor, but not expression of either subunit alone, generated CNTF responsiveness in Hep3B cells, suggesting cooperativity of these receptor subunits. Evidence is presented for direct interaction of the LIF receptor with the intracellular signal transduction machinery.

Distinct regions of the human granulocyte-colony-stimulating factor receptor cytoplasmic domain are required for proliferation and gene induction.

Using two different cell systems, we show that the cytoplasmic domain of the granulocyte-colony-stimulating factor receptor (G-CSFR) may be composed of at least two functional regions. The first, within the membrane-proximal 57 amino acids, is absolutely required to deliver a proliferative signal. This region contains two sequence motifs conserved between members of the hematopoietin receptor family. The second functional region resides between amino acids 57 and 96. This region is required for the induction of acute-phase plasma protein gene expression when the G-CSFR is transfected into human hepatoma cell lines. The G-CSFR-transfected hepatoma cells respond to G-CSF by increasing the production of the same set of plasma proteins as stimulated by interleukin-6, suggesting that the two cytokines share a common signal transduction pathway.

Molecular cloning of the interleukin-1 beta converting enzyme.

Interleukin-1 beta (IL-1 beta) mediates a wide range of immune and inflammatory responses. The active cytokine is generated by proteolytic cleavage of an inactive precursor. A complementary DNA encoding a protease that carries out this cleavage has been cloned. Recombinant expression in COS-7 cells enabled the cells to process precursor IL-1 beta to the mature form. Sequence analysis indicated that the enzyme itself may undergo proteolytic processing. The gene encoding the protease was mapped to chromosomal band 11q23, a site frequently involved in rearrangement in human cancers.

The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor.

Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are multifunctional cytokines with many similar activities. LIF is structurally and functionally related to another cytokine, Oncostatin M (OSM), that binds to the high-affinity LIF receptor but not to the low-affinity LIF receptor. A complementary DNA was isolated that encodes the high-affinity converting subunit of the LIF receptor. The converter conferred high-affinity binding of both LIF and OSM when expressed with the low-affinity LIF receptor and is identical to the signal transducing subunit of the IL-6 receptor, gp130. The gp130 subunit alone confers low-affinity binding of OSM when expressed in COS-7 cells. This receptor system resembles the high-affinity receptors for granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5, which share a common subunit.

Reconstitution of high affinity leukaemia inhibitory factor (LIF) receptors in haemopoietic cells transfected with the cloned human LIF receptor.

cDNA clones encoding the human leukaemia inhibitory factor (hLIF) receptor were isolated by screening a placental cDNA expression library in COS-7 cells with 125I-hLIF. The cloned LIF receptor is a member of the haemopoietin receptor family and comprises a signal sequence (44 amino acids), an extracellular region of two haemopoietin receptor domains and three fibronectin type III domains (789 amino acids), a transmembrane domain (26 amino acids) and a cytoplasmic domain (238 amino acids). The LIF receptor is expressed in COS-7 cells as a 190 kDa glycoprotein that specifically binds human LIF with low affinity, but does not bind mouse LIF. Clones encoding a soluble form of the homologous mouse LIF receptor have been isolated, suggesting complex interactions between the various forms of LIF ligand and receptor in vivo. The LIF receptor is most related to the gp130 signal-transducing component of the IL-6 receptor, a feature that may provide a molecular basis for the intertwined biologies of LIF and IL-6 in the absence of obvious structural similarly between the ligands. Mouse B9 plasmacytoma cells transfected with the human LIF receptor display novel high affinity LIF receptors that are presumed to consist of transfected receptors in association with endogenous mouse high affinity-converting subunits. Unlike the low affinity human LIF receptor, the mixed species high affinity receptor is capable of binding mouse LIF.

A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types.

cDNA clones corresponding to an Mr approximately 80,000 receptor (type I receptor) for interleukin-1 (IL-1) have been isolated previously by mammalian expression. Here, we report the use of an improved expression cloning method to isolate human and murine cDNA clones encoding a second type (Mr approximately 60,000) of IL-1 receptor (type II receptor). The mature type II IL-1 receptor consists of (i) a ligand binding portion comprised of three immunoglobulin-like domains; (ii) a single transmembrane region; and (iii) a short cytoplasmic domain of 29 amino acids. This last contrasts with the approximately 215 amino acid cytoplasmic domain of the type I receptor, and suggests that the two IL-1 receptors may interact with different signal transduction pathways. The type II receptor is expressed in a number of different tissues, including both B and T lymphocytes, and can be induced in several cell types by treatment with phorbol ester. Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location. Like the type I receptor, the human type II IL-1 receptor can bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1ra). Vaccinia virus contains an open reading frame bearing strong resemblance to the type II IL-1 receptor.

On the accuracy and reliability of predictions by control-system theory.

In three experiments we used control-system theory (CST) to predict the results of tracking tasks on which people held a handle to keep a cursor even with a target on a computer screen. 10 people completed a total of 104 replications of the task. In each experiment, there were two conditions: in one, only the handle affected the position of the cursor; in the other, a random disturbance also affected the cursor. From a person's performance during Condition 1, we derived constants used in the CST model to predict the results of Condition 2. In two experiments, predictions occurred a few minutes before Condition 2; in one experiment, the delay was 1 yr. During a 1-min. experimental run, the positions of handle and cursor, produced by the person, were each sampled 1800 times, once every 1/30 sec. During a modeling run, the model predicted the positions of the handle and target for each of the 1800 intervals sampled in the experimental run. In 104 replications, the mean correlation between predicted and actual positions of the handle was .996; SD = .002.

Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen.

The prostate cancer detection rate from screening by digital rectal examination and tactilely guided prostate biopsy is approximately 1.7%. Among 1,807 men a detection rate of 14.6% was achieved in a clinical urological practice by physician-conducted prostate ultrasonography, digital rectal examination and determination of serum prostate specific antigen. Results are presented in 5-year increments as well as for the group as a whole. The possible benefit to be derived from an improved detection rate is undetermined. Recommendations are made regarding the clinical use of these diagnostic modalities.

Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily.

IL-4, a pleiotropic cytokine produced by T lymphocytes, plays an important role in immune responsiveness by regulating proliferation and differentiation of a variety of lymphoid and myeloid cells via binding to high affinity receptors. In this report we describe the isolation and functional expression of a human IL-4-R cDNA. When transfected into COS-7 cells, the cDNA encodes a 140-kD cell-surface protein. After transfection into a murine T cell line, the cDNA encodes a protein that binds human IL-4 with high affinity and can confer responsiveness to human IL-4. The predicted extracellular domain of the IL-4-R exhibits significant amino acid sequence homology with the beta subunit of the IL-2-R (p75), and the receptors for IL-6, erythropoietin, and prolactin. These receptors comprise a novel superfamily with extracellular domains characterized by four conserved cysteine residues and a double tryptophan-serine (WSXWS) motif located proximal to the transmembrane region.