Showing papers by "Case Western Reserve University published in 1995"

The need to belong: Desire for interpersonal attachments as a fundamental human motivation.

Abstract: A hypothesized need to form and maintain strong, stable interpersonal relationships is evaluated in light of the empirical literature. The need is for frequent, nonaversive interactions within an ongoing relational bond. Consistent with the belongingness hypothesis, people form social attachments readily under most conditions and resist the dissolution of existing bonds. Belongingness appears to have multiple and strong effects on emotional patterns and on cognitive processes. Lack of attachments is linked to a variety of ill effects on health, adjustment, and well-being. Other evidence, such as that concerning satiation, substitution, and behavioral consequences, is likewise consistent with the hypothesized motivation. Several seeming counterexamples turned out not to disconfirm the hypothesis. Existing evidence supports the hypothesis that the need to belong is a powerful, fundamental, and extremely pervasive motivation.

Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability

Abstract: Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.

Perspective Making and Perspective Taking in Communities of Knowing

Abstract: Knowledge-intensive firms are composed of multiple communities with specialized expertise, and are often characterized by lateral rather than hierarchical organizational forms. We argue that producing knowledge to create innovative products and processes in such firms requires the ability to make strong perspectives within a community, as well as the ability to take the perspective of another into account. We present models of language, communication and cognition that can assist in the design of electronic communication systems for perspective making and perspective taking. By appreciating how communication is both like a language game played in a local community and also like a transmission of messages through a conduit, and by appreciating how cognition includes a capacity to narrativize our experience as well as a capacity to process information, we identify some guidelines for designing electronic communication systems to support knowledge work. The communication systems we propose emphasize that narratives can help construct strong perspectives within a community of knowing, and that reflecting upon and representing that perspective can create boundary objects which allow for perspective taking between communities. We conclude by describing our vision of an idealized knowledge intensive firm with a strong culture of perspective making and perspective taking, and by identifying some elements of the electronic communication systems we would expect to see in such a firm.

Targeted Disruption of Mouse EGF Receptor: Effect of Genetic Background on Mutant Phenotype

Abstract: Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.

T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years

Abstract: In 1990, a clinical trial was started using retroviral-mediated transfer of the adenosine deaminase (ADA) gene into the T cells of two children with severe combined immunodeficiency (ADA- SCID). The number of blood T cells normalized as did many cellular and humoral immune responses. Gene treatment ended after 2 years, but integrated vector and ADA gene expression in T cells persisted. Although many components remain to be perfected, it is concluded here that gene therapy can be a safe and effective addition to treatment for some patients with this severe immunodeficiency disease.

Neurological Deficit and Extent of Neuronal Necrosis Attributable to Middle Cerebral Artery Occlusion in Rats Statistical Validation

Abstract: Background and Purpose Occluding a large intracranial artery in rats produces a brain lesion that grows in terms of an increase in both surface area and number of necrotic neurons. The present study investigated whether reperfusing the ischemic territory 30 to 60 minutes after the arterial occlusion would have a beneficial effect on either the clinical or the histological outcome of the lesion. Methods One hundred four adult rats (including appropriate controls) were used; 97 had a middle cerebral artery occluded by inserting a nylon monofilament via the right external carotid artery. The arterial occlusion was transient in two groups and permanent in another; survival times were comparable for all groups. Control animals were subjected to a sham operation during which the artery was occluded for less than 1 minute. The outcome was evaluated by measuring the extent of the neurological deficit and the severity of the histological injury. Results Mean neurological score and mean number of necrotic neurons i...

Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5‐azacytidine

Abstract: The compound 5-azacytidine has been previously shown to convert cells of the rat embryonic fibroblastic cell line, C3H/10T1/2, into myoblasts, adipocytes, and chondrocytes. Rare, resident cells of bone marrow and periosteum, referred to as mesenchymal stem cells, have been shown to differentiate into a number of mesenchymal phenotypes including bone, cartilage, and adipocytes. Rat bone marrow-derived mesenchymal stem cells were exposed to 5-azacytidine beginning 24 h after seeding twice-passaged cells into culture dishes. After an exposure of 24 h, long, multinucleated myotubes were observed in some of the dishes 7-11 days later. Cells containing Sudan black-positive droplets in their cytoplasm were also observed. Thus, culture-propagated rat bone marrow mesenchymal stem cells appear to have the capacity to be induced to differentiate in vitro into myogenic and adipocytic phenotypes, although nonmesenchymal cells (rat brain fibroblasts) cannot be so induced. Taken together, these observations provide support for the suggestion that mesenchymal stem cells in the bone marrow of postnatal organisms may provide a source for myoprogenitor cells which could function in clinically relevant myogenic regeneration.

Acid-doped polybenzimidazoles : a new polymer electrolyte

Abstract: Polybenzimidazole films doped with phosphoric acid are being investigated as potential polymer electrolytes for use in hydrogen/air and direct methanol fuel cells. In this paper, we present experimental findings on the proton conductivity, water content, and methanol vapor permeability of this material, as well as preliminary fuel cell results. The low methanol vapor permeability of these electrolytes significantly reduces the adverse effects of methanol crossover typically observed in direct methanol polymer electrolyte membrane fuel cells.

Category Theory For Computing Science

Abstract: Preliminaries. Categories. Functors. Diagrams. Naturality and Sketches. Products and Sums. Catesian Closed Categories. Finite Discrete Sketches. Limits and Colimits. More About Sketches. Fibrations. Adjoints. Algebras for Endofunctors. Toposes.

Guidelines for the medical management of osteoarthritis

Abstract: Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.

p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts

Abstract: Increased expression of wild-type p53 in response to DNA damage arrests cells late in the G1 stage of the cell cycle by stimulating the synthesis of inhibitors of cyclin-dependent kinases, such as p21/WAF1. To study the effects of p53 without the complication of DNA damage, we used tetracycline to regulate its expression in MDAH041 human fibroblasts that lack endogenous p53. When p53 is expressed at a level comparable to that induced by DNA damage in other cells, most MDAH041 cells arrested in G1, but a significant fraction also arrested in G2/M. Cells released from a mimosine block early in S phase stopped predominantly in G2/M in the presence of p53, confirming that p53 can mediate arrest at this stage, as well as in G1. In these cells, there was appreciable induction of p21/WAF1. MDAH041 cells arrested by tetracycline-regulated p53 for as long as 20 days resumed growth when the p53 level was lowered, in striking contrast to the irreversible arrest mediated by DNA damage. Therefore, irreversible arrest must involve processes other than or in addition to the interaction of p53-induced p21/WAF1 with G1 and G2 cyclin-dependent kinases.

Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability

Abstract: Microsatellite instability has been observed in both sporadic and hereditary forms of colorectal cancer. In the hereditary form, this instability is generally due to germline mutations in mismatch repair (MMR) genes. However, only one in ten patients with sporadic tumours exhibiting microsatellite instability had a detectable germline mutation. Moreover, only three of seven sporadic tumour cell lines with microsatellite instability had mutations in a MMR gene, and these mutations could occur somatically. These results demonstrate that tumours can acquire somatic mutations that presumably do not directly affect cell growth but result only in genetic instability. They also suggest that many sporadic tumours with microsatellite instability have alterations in genes other than the four now known to participate in MMR.

A Randomized Trial of Care in a Hospital Medical Unit Especially Designed to Improve the Functional Outcomes of Acutely Ill Older Patients

Abstract: Background Older persons who are hospitalized for acute illnesses often lose their independence and are discharged to institutions for long-term care. Methods We studied 651 patients 70 years of age or older who were admitted for general medical care at a teaching hospital; these patients were randomly assigned to receive usual care or to be cared for in a special unit designed to help older persons maintain or achieve independence in self-care activities. The key elements of this program were a specially prepared environment (with, for example, uncluttered hallways, large clocks and calendars, and handrails); patient-centered care emphasizing independence, including specific protocols for prevention of disability and for rehabilitation; discharge planning with the goal of returning the patient to his or her home; and intensive review of medical care to minimize the adverse effects of procedures and medications. The main outcome we measured was the change from admission to discharge in the number of five ...

Stochastic choice of basis functions in adaptive function approximation and the functional-link net

Abstract: A theoretical justification for the random vector version of the functional-link (RVFL) net is presented in this paper, based on a general approach to adaptive function approximation The approach consists of formulating a limit-integral representation of the function to be approximated and subsequently evaluating that integral with the Monte-Carlo method Two main results are: (1) the RVFL is a universal approximator for continuous functions on bounded finite dimensional sets, and (2) the RVFL is an efficient universal approximator with the rate of approximation error convergence to zero of order O(C//spl radic/n), where n is number of basis functions and with C independent of n Similar results are also obtained for neural nets with hidden nodes implemented as products of univariate functions or radial basis functions Some possible ways of enhancing the accuracy of multivariate function approximations are discussed >

Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer

Abstract: The TGF beta type II receptor (RII) was found to be mutated within a polyadenine tract in 100 of 111 (90%) colorectal cancers with microsatellite instability Other polyadenine tracts of similar length were mutated in these samples but not as frequently as RII In most cases, the polyadenine tract mutations affected both alleles of RII, and in four tumors heterozygous for the polyadenine mutations, three had additional mutations that were expected to inactivate the other RII allele These genetic data support the idea that RII behaves like a tumor suppressor during CR cancer development and is a critical target of inactivation in mismatch repair-deficient tumors

Adolescents' exposure to violence and associated symptoms of psychological trauma

Abstract: Objective. —To examine the extent to which adolescents are exposed to various types of violence as either victims or witnesses, and the association of such exposure with trauma symptoms; specifically, the hypotheses that exposure to violence will have a positive and significant association with depression, anger, anxiety, dissociation, posttraumatic stress, and total trauma symptoms. Design and Setting. —The study employed a survey design using an anonymous self-report questionnaire administered to students (grades 9 through 12) in six public high schools during the 1992-1993 school year. Participants. —Sixty-eight percent of the students attending the participating schools during the survey participated in the study (N=3735). Ages ranged from 14 to 19 years; 52% were female; and 35% were African American, 33% white, and 23% Hispanic. Results. —All hypotheses were supported. Multiple regression analyses of the total sample revealed that violence exposure variables (and to a lesser extent, demographic variables) explained a significant portion of variance in all trauma symptom scores, including depression (R2=.31), anger (R2=.30), anxiety (R2=.30), dissociation (R2=.23), posttraumatic stress (R2=.31), and total trauma (R2=.37). Conclusions. —A significant and consistent association was demonstrated linking violence exposure to trauma symptoms within a diverse sample of high school students. Our findings give evidence of the need to identify and provide trauma-related services for adolescents who have been exposed to violence. (JAMA. 1995;273:477-482)

Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate : implications for gene-specific therapy

Abstract: Background The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. Methods and Results Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QTc were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QTc from 535±32 to 445±31 ms, P<.005) but not among LQT2 patients (QTc from 530±79 to 503±60 ms, P=NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P<.05; data e...

Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.

Abstract: Platelets have a key role in atherosclerosis, thrombosis, and acute coronary syndromes. Therapeutic manipulation of platelet function has focused principally on the use of aspirin, which has proved...

Determinants of mortality for necrotizing soft-tissue infections.

Abstract: OBJECTIVE: The authors determined the risk factors of mortality in patients with necrotizing soft-tissue infections (NSTIs) and examined the incidence and mortality from NSTI secondary to Streptococcus pyogenes. METHODS: All patients with NSTIs who were treated between January 1989 and June 1994 were analyzed for presentation, etiology, factors important in pathogenesis and treatment, and mortality. RESULTS: Sixty-five patients were identified with NSTIs secondary to postoperative wound complications (18), trauma (15), cutaneous disease (15), idiopathic causes (10), perirectal abscesses (3), strangulated hernias (2), and subcutaneous injections (2). Necrotizing soft-tissue infections were polymicrobial in 45 patients (69%). S. pyogenes was isolated in only 17% of the NSTIs, but accounted for 53% of monomicrobial infections. Eight of ten idiopathic infections were caused by a single bacterium (p = 0.0005), whereas 82% of postoperative infections were polymicrobial. An average of 3.3 operative debridements per patient and amputation in 12 patients were necessary to control infection. The overall mortality was 29%; mortality from S. pyogenes infection was only 18%. The average time from admission to operation was 90 hours in nonsurvivors versus 25 hours in survivors (p = 0.0002). Other risk factors previously associated with the development of NSTIs did not affect mortality. CONCLUSIONS: Early debridement of NSTI was associated with a significant decrease in mortality. S. pyogenes infection was the most common cause of monomicrobial NSTI, but was not associated with an increased mortality.

Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use.

Abstract: We report a phase I trial to determine the feasibility of collection, ex vivo culture-expansion and intravneous infusion of human bone marrow-derived progenitor stromal cells (mesenchymal progenitor cells (MPCs)). Ten milliliter bone marrow samples were obtained from 23 patients with hematologic malignancies in complete remission. Bone marrow mononuclear cells were separated and adherent cells were culture-expanded in vitro for 4-7 weeks. Autologous MPCs were reinfused intravenously and a bone marrow examination repeated 2 weeks later for histologic assessment and in vitro hematopoietic cultures. Patient age ranged from 18 to 68 years and 12 subjects previously had undergone an autologous or syngeneic bone marrow transplant 4-52 months prior to collection of MPCs. A median of 364 x 10(6) nucleated bone marrow cells (range: 103 to 1004 x 10(6)) were used for ex vivo expansion. Median number of MPCs which were obtained after ex vivo culture expansion was 59.0 (range: 1.1 to 347 x 10(6)) representing a median cell doubling of 16,000-fold (13 doublings). Fifteen of 23 patients completed the ex vivo expansion and underwent MPC infusion. Time to infusion of MPCs after collection ranged from 28 to 49 days. Five patients in each of three groups were given 1, 10 and 50 x 10(6) MPCs. No adverse reactions were observed with the infusion of the MPCs. MPCs obtained from cancer patients can be collected, expanded in vitro and infused intravenously without toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term developmental outcomes of low birth weight infants.

Abstract: Advances in neonatal medicine have resulted in the increased survival of infants at lower and lower birth weight. While these medical success stories highlight the power of medical technology to save many of the tiniest infants at birth, serious questions remain about how these infants will develop and whether they will have normal, productive lives. Low birth weight children can be born at term or before term and have varying degrees of social and medical risk. Because low birth weight children are not a homogeneous group, they have a broad spectrum of growth, health, and developmental outcomes. While the vast majority of low birth weight children have normal outcomes, as a group they generally have higher rates of subnormal growth, illnesses, and neurodevelopmental problems. These problems increase as the child's birth weight decreases. With the exception of a small minority of low birth weight children with mental retardation and/or cerebral palsy, the developmental sequelae for most low birth weight infants include mild problems in cognition, attention, and neuromotor functioning. Long-term follow-up studies conducted on children born in the 1960s indicated that the adverse consequences of being born low birth weight were still apparent in adolescence. Adverse sociodemographic factors negatively affect developmental outcomes across the continuum of low birth weight and appear to have far greater effects on long-term cognitive outcomes than most of the biological risk factors. In addition, the cognitive defects associated with social or environmental risks become more pronounced as the child ages. Enrichment programs for low birth weight children seem to be most effective for the moderately low birth weight child who comes from a lower socioeconomic group. Continued research and attempts to decrease the rate of low birth weight and associated perinatal medical sequelae are of primary importance. Ongoing documentation of the long-term outcome of low birth weight children needs to be mandated, as does the implementation of environmental enrichment programs to help ameliorate the long-term consequences for infants who are born low birth weight.

Effect of high-dose ibuprofen in patients with cystic fibrosis.

Abstract: Background Since the inflammatory response to chronic infection contributes to lung destruction in patients with cystic fibrosis, we hypothesized that antiinflammatory therapy might slow the progression of lung disease. Methods In a double-blind trial, 85 patients, 5 to 39 years of age, with mild lung disease (forced expiratory volume in one second [FEV1], >60 percent of the predicted value) were randomly assigned to receive ibuprofen or placebo orally twice daily for four years. Doses were adjusted individually to achieve peak plasma concentrations of 50 to 100 μg per milliliter. Changes in pulmonary function, the percentage of ideal body weight, the chest-radiograph score, and the frequency of hospitalization were assessed. Results Patients randomly assigned to ibuprofen had a slower annual rate of change in FEV1 than the patients assigned to placebo (mean [±SE] slope, -2.17±0.57 percent vs. -3.60±0.55 percent in the placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was better ...

Inflammatory cytokines in cystic fibrosis lungs.

Abstract: Chronic pulmonary infection with Pseudomonas aeruginosa continues to be the major cause of morbidity and mortality in cystic fibrosis (CF). Several characteristics of CF, including the excessive influx of neutrophils into the airways, cachexia, and hyperglobulinemia, could reflect the effects of cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF-alpha). We hypothesized that these pro-inflammatory cytokines, produced by alveolar macrophages in response to pseudomonas and/or other microorganisms, promote the destructive inflammatory process in the lung. We evaluated bronchoalveolar lavage (BAL) fluid and BAL macrophages from 22 CF patients and 13 healthy control (HC) subjects, measuring soluble TNF-alpha, IL-1 beta, IL-6, and IL-8 and the regulatory molecules TNF soluble receptor (TNF-sR), IL-1 receptor antagonist (IL-1Ra), and IL-10 (cytokine synthesis inhibitory factor). Levels of the proinflammatory cytokines were higher in CF versus HC BAL (p < or = 0.05 for IL-1, TNF, and IL-8; p = 0.06 for IL-6). In contrast, HC BAL contained significantly more IL-10 than CF BAL (p < 0.05), but TNF-sR and IL-1Ra were similar. Immunocytochemistry demonstrated a higher percentage of CF than control BAL macrophages expressing intracellular cytokines (p < 0.05). Thus, enhanced macrophage production of proinflammatory cytokines and decreased production of the regulatory molecule IL-10 may have important roles in the pathogenesis of CF lung disease.

Polyphenols as cancer chemopreventive agents.

Abstract: In recent years, the concept of chemoprevention has matured to be considered as a practical option to reduce the occurrence of cancer (1–5). Chemoprevention—the use of natural and/or synthetic compounds to intervene in the early precancerous stages of carcinogenesis before the onset of invasive disease—offers a viable approach to define substances, either food components or pharmaceuticals, which can prevent, delay, or completely halt the process of carcinogenesis. Often chemoprevention is referred to as “prevention by delay.”

Community level factors and child maltreatment rates

Abstract: Using census and administrative agency data for 177 urban census tracts, variation in rates of officially reported child maltreatment is found to be related to structural determinants of community social organization: economic and family resources, residential instability, household and age structure, and geographic proximity of neighborhoods to concentrated poverty. Furthermore, child maltreatment rates are found to be intercorrelated with other indicators of the breakdown of community social control and organization. These other indicators are similarly affected by the structural dimensions of neighborhood context. Children who live in neighborhoods that are characterized by poverty, excessive numbers of children per adult resident, population turnover, and the concentration of female-headed families are at highest risk of maltreatment. This analysis suggests that child maltreatment is but one manifestation of community social organization and that its occurrence is related to some of the same underlying macro-social conditions that foster other urban problems.

Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15.

Abstract: A subset of patients with Angelman and Prader-Willi syndrome have apparently normal chromosomes of biparental origin, but abnormal DNA methylation at several loci within chromosome 15q11-13, and probably have a defect in imprinting. Using probes from a newly established 160-kb contig including D15S63 (PW71) and SNRPN, we have identified inherited microdeletions in two AS families and three PWS families. The deletions probably affect a single genetic element that we term the 15q11-13 imprinting centre (IC). In our model, the IC regulates the chromatin structure, DNA methylation and gene expression in cis throughout 15q11-13. Mutations of the imprinting centre can be transmitted silently through the germline of one sex, but appear to block the resetting of the imprint in the germline of the opposite sex.