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Biomedical subjects

A Wells

Publications and source records attributed to A Wells.

At least 109 records · Page 6Linked to original sources
PubMed1998

Effects of attention training on hypochondriasis: a brief case series.

BACKGROUND: Empirical evidence indicates that manipulations of attention may facilitate changes in cognition and stress symptoms in emotional disorder. METHODS: The present study reports the effects of Attention Training (ATT) in a brief case series of three patients with primary hypochondriasis using an A-B-A design. RESULTS: ATT produced clinically significant improvements in self-reported measures of affect, and illness-related behaviour and cognition. Treatment gains were maintained at 6 months follow-up assessments. Measures of body-focused attention indicated that the ATT procedure acted on attentional processes as intended. CONCLUSIONS: The present case series extends the effects of ATT to problems of hypochondriasis. A number of studies now suggest that ATT is associated with a reduction in anxiety and negative beliefs across disorders of panic, social phobia and hypochondriasis. Controlled clinical trials are now required to establish firmly the effects of ATT as a component of cognitive therapy.

Aged↗
PubMed1998

Regulation of proliferation-survival decisions during tumor cell hypoxia.

Hypoxia may influence tumor biology in paradoxically opposing ways: it is lethal as a direct stress trigger, yet hypoxic zones in solid tumors harbor viable cells which are particularly resistant to treatment and contribute importantly to disease relapse. To examine mechanisms underlying growth-survival decisions during hypoxia, we have compared genetically related transformed and untransformed fibroblast cells in vitro for proliferation, survival, clonogenicity, cell cycle, and p53 expression. Hypoxia induces G0/G1 arrest in primary fibroblasts but triggers apoptosis in oncogene-transformed derivatives. Unexpectedly, the mechanism of apoptosis is seen to require accumulated acidosis and is rescued by enhanced buffering. The direct effect of hypoxia under nonacidotic conditions is unique to transformed cells in that they override the hypoxic G0/G1 arrest of primary cells. Moreover, when uncoupled from acidosis, hypoxia enhances tumor cell viability and clonogenicity relative to normoxia. p53 is correspondingly upregulated in response to hypoxia-induced acidosis but downregulated during hypoxia without acidosis. Hypoxia may thus produce both treatment resistance and a growth advantage. Given strong evidence that hypoxic regions in solid tumors are often nonacidotic (G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3:177-182, 1997), this behavior may influence relapse and implicates such cells as potentially important therapeutic targets.

Animals↗
PubMed1998

Two psychological treatments for hypochondriasis. A randomised controlled trial.

BACKGROUND: Hypochondriasis is generally considered difficult to manage. This study aimed to assess the effectiveness of cognitive therapy and to compare it with an equally credible, alternative treatment. METHOD: Forty-eight patients with hypochondriasis were initially randomly assigned to either cognitive therapy, behavioural stress management or a no treatment waiting list control group. At the end of the waiting period, patients in the control group were randomly assigned to one of the two treatments. Assessments were at pre-, mid- and post-treatment or waiting list and at three-, six- and 12-month post-treatment follow-up. RESULTS: Comparisons with the waiting list group showed both treatments were effective. Comparisons between the treatments showed that cognitive therapy was more effective than behavioural stress management on measures of hypochondriasis, but not general mood disturbance at mid-treatment and at post-treatment. One year after treatment patients who had received either treatment remained significantly better than before treatment, and on almost all measures the two therapies did not differ from each other. CONCLUSIONS: Cognitive therapy is a specific treatment for hypochondriasis. Behavioural stress management is also effective but its specificity remains to be demonstrated.

Adult↗
PubMed1998

Epidermal growth factor alters fibroblast migration speed and directional persistence reciprocally and in a matrix-dependent manner.

Growth factors stimulate sustained cell migration as well as inducing select acute motility-related events such as membrane ruffling and disruption of focal adhesions. However, an in-depth understanding of the characteristics of sustained migration that are regulated by growth factor signals is lacking: how the biochemical signals are related to physical processes underlying locomotion, and how these events are coordinately influenced by interplay between growth factor and matrix substratum signals. To address these issues, we studied sustained migration of NR6 fibroblasts on a complex human matrix substratum, Amgel, comparing effects of epidermal growth factor (EGF) treatment across a range of Amgel levels. In the absence of EGF, cell migration speed and directional persistence are relatively independent of Amgel level, whereas in the presence of EGF speed is increased at intermediate Amgel levels but not at low and high Amgel levels while directional persistence is decreased at intermediate but not at low and high Amgel levels. The net effect of EGF is to increase the frequency of changes in the cell direction, and at the same time to slightly increase the path-length and thereby greatly enhance random dispersion of cells. Despite increasing migration speed during long-term sustained migration EGF treatment does not lead to significantly increased absolute rates of membrane extension in contrast to its well-known elicitation of membrane ruffling in the short term. However, EGF treatment does decrease cell spread area, yielding an apparent enhancement of specific membrane extension rate, i.e. normalized to cell spread area. Cell movement speed and directional persistence are thus, respectively, directly related and indirectly related to the increase in specific membrane extension rate (alternatively, the decrease in cell spread area) induced by EGF treatment during sustained migration. These results indicate that growth factor and matrix substrata coordinately regulate sustained cell migration through combined governance of underlying physical processes.

Animals↗
PubMed1998

EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCgamma signaling pathway.

A current model of growth factor-induced cell motility invokes integration of diverse biophysical processes required for cell motility, including dynamic formation and disruption of cell/substratum attachments along with extension of membrane protrusions. To define how these biophysical events are actuated by biochemical signaling pathways, we investigate here whether epidermal growth factor (EGF) induces disruption of focal adhesions in fibroblasts. We find that EGF treatment of NR6 fibroblasts presenting full-length WT EGF receptors (EGFR) reduces the fraction of cells presenting focal adhesions from approximately 60% to approximately 30% within 10 minutes. The dose dependency of focal adhesion disassembly mirrors that for EGF-enhanced cell motility, being noted at 0.1 nM EGF. EGFR kinase activity is required as cells expressing two kinase-defective EGFR constructs retain their focal adhesions in the presence of EGF. The short-term (30 minutes) disassembly of focal adhesions is reflected in decreased adhesiveness of EGF-treated cells to substratum. We further examine here known motility-associated pathways to determine whether these contribute to EGF-induced effects. We have previously demonstrated that phospholipase C(gamma) (PLCgamma) activation and mobilization of gelsolin from a plasma membrane-bound state are required for EGFR-mediated cell motility. In contrast, we find here that short-term focal adhesion disassembly is induced by a signaling-restricted truncated EGFR (c'973) which fails to activate PLCgamma or mobilize gelsolin. The PLC inhibitor U73122 has no effect on this process, nor is the actin severing capacity of gelsolin required as EGF treatment reduces focal adhesions in gelsolin-devoid fibroblasts, further supporting the contention that focal adhesion disassembly is signaled by a pathway distinct from that involving PLCgamma. Because both WT and c'973 EGFR activate the erk MAP kinase pathway, we additionally explore here this signaling pathway, not previously associated with growth factor-induced cell motility. Levels of the MEK inhibitor PD98059 that block EGF-induced mitogenesis and MAP kinase phosphorylation also abrogate EGF-induced focal adhesion disassembly and cell motility. In summary, we characterize for the first time the ability of EGFR kinase activity to directly stimulate focal adhesion disassembly and cell/substratum detachment, in relation to its ability to stimulate migration. Furthermore, we propose a model of EGF-induced motogenic cell responses in which the PLCgamma pathway stimulating cell motility is distinct from the MAP kinase-dependent signaling pathway leading to disassembly and reorganization of cell-substratum adhesion.

Animals↗
PubMed1998

Psychiatric comorbidity in methadone maintained patients.

Diagnosing comorbid psychiatric disorders in methadone maintained patients may help to identify subgroups with different outcomes and needs for treatment. In this study, 75 methadone maintenance clinic patients in treatment longer than 30 days were assessed with the Addiction Severity Index, Global Assessment Scale and Mini-Mental Status Exam, and were interviewed for DSM-III-R psychiatric diagnosis using the computerized Diagnostic Interview Schedule. Psychiatric diagnoses were prevalent in the sample with depression, phobic disorders, antisocial personality and generalized anxiety the most common. Both number of DSM-III-R diagnoses and severity of psychopathology were correlated with outcome measures such as concurrent drug abuse, family-social problems and employment status.

Adolescent↗
PubMed1998

A primer on financial aid.

It is apparent that financial aid is a complicated, ever-changing business. The information provided in this article is only the tip of the financial aid iceberg. As student debt levels continue to increase, I encourage deans to work cooperatively with their financial aid officers. Invite your financial aid officers to participate in orientation and other pre- and post-admission activities, help facilitate effective entrance and exist interviews, and encourage financial aid officers to meet and work with your students on a frequent basis. I also strongly encourage you to support their participation in national meetings such as the Professional Development Conference (PDC) for Health Professionals (which AADS cosponsors with the AAMC) and the National Association of Student Financial Aid Officers (NASFAA). Participation in annual conferences is an important way for financial aid officers to network with other officers and to learn about important new legislation.

Financing, Personal↗
PubMed1998

High resolution computed tomography in sarcoidosis: a clinical perspective.

In this review, the contribution of high resolution computed tomography (CT) to the diagnosis of pulmonary sarcoidosis, the possible role of CT in defining reversible disease, and the potential use of CT to obtain pathophysiological insights are discussed. The role of CT in the diagnosis of sarcoidosis remains contentious, as the CT manifestations of sarcoidosis are highly variable, and typical appearances are often associated with a classical clinical and chest radiographic profile. The greatest diagnostic utility of CT lies in difficult cases of diffuse lung disease, especially advanced disease; sarcoidosis can often be excluded with confidence when CT appearances are pathognomonic of an alternative disorder (such as extrinsic allergic alveolitis, lymphangitis carcinomatosis, or fibrosing alveolitis). CT patterns indicative of reversible and irreversible disease have been identified, through CT-histological correlations and serial imaging studies; a nodular pattern is almost invariably reversible, reti-cular abnormalities and anatomic distortion denote and irreversible fibrotic histological picture, ground-glass opacification is variably reversible and may be indicative of alveolitis or fine fibrosis. However, CT influences therapeutic decisions in a minority of cases in clinical practice. The potential use of CT to gain pathophysiological insights is discussed briefly.

Biopsy↗
PubMed1997

Epidermal growth factor induces CD44 gene expression through a novel regulatory element in mouse fibroblasts.

Growth factors coordinately regulate a variety of genes associated with pathological states including tumor invasion and metastasis. Overexpressed epidermal growth factor receptor (EGFR) on tumor cell surfaces is associated with enhanced cell attachment and migration into extracellular matrices, which promotes tumor aggressiveness. We have demonstrated that epidermal growth factor (EGF) up-regulates the cell surface adhesion molecule CD44 at both the mRNA and protein levels on mouse fibroblasts expressing full-length wild-type EGFR (NR6-WT) but not on EGFR-deficient cells (NR6-P). This increases cell attachment to hyaluronic acid. In this investigation, transcriptional regulation of CD44 by EGF was confirmed by defining an EGF-regulatory element. By employing human CD44 gene promoter-chloramphenicol acetyltransferase (CAT) constructs transfected into NR6-WT cells, EGF inducibility was observed within a 120-base pair (bp) DNA fragment located 450 bp upstream of the RNA initiation site. Differential EGF inducibility was found among different cell lines chosen, indicating a 3.2- and 1.8-fold enhancement in DU145 cells carrying exogenous wild-type EGFR and in MCF-7 cells, respectively, while minimal EGF induction was found in cervical cancer HeLa cells. Utilizing gel shift assays, a time-dependent increase of DNA-protein complex formation was found upon EGF stimulation in NR6-WT cells but not in NR6-P cells. Based upon these observations, a novel 22-bp EGF regulatory element (ERE) (5'--604CCCTCTCTCCAGCTCCTCTCCC-583-3') was isolated from the CD44 gene promoter. This ERE conferred DNA-protein binding ability in vitro, as well as the full functional recovery of EGF inducibility of CAT activity when linked to a homologous CD44 promoter or a SV40 promoter driving a CAT reporter gene. A two-base mutation of the ERE completely eliminated its binding activity as well as its EGF inducibility of CAT expression. Our studies indicate that EGF induces CD44 gene expression through an interaction between a specific ERE and putative novel transcriptional factor so as to regulate cell attachment to extracellular matrix.

Animals↗
PubMed1997

Expressed sequences from conidial, mycelial, and sexual stages of Neurospora crassa.

In the Neurospora Genome Project at the University of New Mexico, expressed sequence tags (ESTs) corresponding to three stages of the life cycle of the filamentous fungus Neurospora crassa are being analyzed. The results of a pilot project to identify expressed genes and determine their patterns of expression are presented. 1,865 partial complementary DNA (cDNA) sequences for 1,409 clones were determined using single-pass sequencing. Contig analysis allowed the identification of 838 unique ESTs and 156 ESTs present in multiple cDNA clones. For about 34% of the sequences, highly or moderately significant matches to sequences (of known and unknown function) in the NCBI database were detected. Approximately 56% of the ESTs showed no similarity to previously identified genes. Among genes with assigned function, about 43.3% were involved in metabolism, 32.9% in protein synthesis and 8.4% in RNA synthesis. Fewer were involved in defense (6%), cell signalling (3.4%), cell structure (3.4%) and cell division (2.6%).

Amino Acid Sequence↗
PubMed1997

Fatty acids and breast cancer cell proliferation.

We and others have shown that fatty acids are important regulators of breast cancer cell proliferation. In particular individual fatty acids specifically alter EGF-induced cell proliferation in very different ways. This regulation is mediated by an EGFR/G-protein signaling pathway. Understanding the molecular mechanisms of how this signaling pathway functions and how fatty acids regulate it will provide important information on the cellular and molecular basis for the association of dietary fat and cancer. Furthermore these in vitro studies may explain data previously obtained from in vivo animal studies and identify "good" as well as "bad" fatty acids with respect to the development of cancer.

Animals↗
PubMed1997

The eating disorder belief questionnaire: preliminary development.

This paper describes the development of a self-report questionnaire designed to assess assumptions and beliefs associated with eating disorders. Factor analyses suggested to replicable four-factor structure consisting of the following dimensions: negative self-beliefs; weight and shape as a means to acceptance by others; weight and shape as a means to self-acceptance; and control over eating. The subscales possess good psychometric properties and significant correlations were found between the subscales and other measures of the specific and general psychopathology of eating disorders. The questionnaire also distinguished two groups of patients with eating disorders from normal controls. The usefulness of the measure and implications of the findings for cognitive theories of eating disorders are briefly discussed.

Adult↗
PubMed1997

Fatty acid-induced insulin resistance in adipocytes.

Elevated serum-free fatty acid (FFA) levels induce insulin resistance in whole animals and humans. To understand the direct mechanism by which FFAs impact insulin-responsive tissue, we have used our previously developed in vitro model of long-chain saturated fatty acids (LCSFA)-induced insulin resistance in adipocytes. In addition to explanted rat adipocytes, we now demonstrate that overnight exposure of 3T3-L1 adipocytes to 1 mM individually of the LCSFA palmitate, myristate, and stearate, leads to an approximately 50% inhibition of insulin-induced glucose transport. Insulin resistance can be accomplished at 0.3 mM palmitate, which is within the range ofpalmitate found in diabetic and obese individuals. This inhibition was noted within 4 h of exposure to FFA, which is comparable to in vivo lipid infusion studies. Initial LCSFA-induced resistance is specific to glucose transport and does not affect insulin stimulation of glucose incorporation into glycogen. In 3T3-L1 adipocytes overexpressing the EGF receptor, LCSFA exposure also specifically inhibited EGF-induced GLUT4-mediated glucose transport, but not EGF-induced glycogen synthesis. We find that LCSFA treatment did not impair insulin stimulation of GLUT4 translocation or exofacial presentation on the cell surface as determined by trypsin accessibility. Our results suggest that the initial direct effect of elevated LCSFA is to impair activation of GLUT4 transporter activity and that this effect is specific for glucose transport.

Adipocytes↗
PubMed1997

A role for phospholipase C activity in GLUT4-mediated glucose transport.

Overexpression of surrogate receptors [epidermal growth factor (EGF) receptor (EGFR) and platelet-derived growth factor receptor] in adipocytes has demonstrated that multiple signaling pathways may lead to GLUT4-mediated glucose uptake. These implicated pathways function independently of IRS-1 phosphorylation and PI3-kinase activation. In addition, we previously demonstrated that EGFR tyrosyl autophosphorylation is required to stimulate GLUT4-mediated glucose transport in 3T3-L1 adipocytes. This observation suggests that signaling molecules that are dependent on EGFR autophosphorylation, such as phospholipase C (PLC), may lie in the signaling pathway to glucose transport. As PLC has been implicated in glucose transport by several clinical and basic mechanistic studies, we investigated whether EGFR signaling may promote glucose transport via modulation of PLC activity. Activation of EGFR overexpressing 3T3-L1 adipocytes leads to a 3.4 +/- 1.2-fold stimulation of PLC activity over basal levels vs. only 1.06 +/- 0.01-fold stimulation by insulin. Pharmacological inhibition of PLC by 50 microM U73122 reduced phosphoinositide accumulation by 79.2 +/- 16.9% and resulted in a concomitant 56.0 +/- 12.7% decrease in EGF-induced glucose transport. This inhibition of glucose transport by U73122 was specific, because the inactive congener, U73343, failed to block EGF-induced glucose transport. Despite the low levels of insulin-induced PLC activity, insulin-stimulated glucose transport activity was similarly inhibited by U73122 (55.9 +/- 13.1% inhibition). Inhibition of PLC activation did not impair either EGF- or insulin-induced activation of glycogen synthase or incorporation of glucose into lipid, supporting the hypothesis that both EGF- and insulin-induced glucose disposal can be independent of GLUT4-mediated glucose transport. The diminution of glucose transport secondary to inhibition of PLC activity was reflected by a decrease in GLUT4 translocation to the plasma membrane upon either EGF or insulin stimulation. These results are consistent with either a permissive or an active role for PLC activity in the translocation of GLUT4 to the plasma membrane.

3T3 Cells↗
PubMed1997

Molecular inhibition of phospholipase cgamma signaling abrogates DU-145 prostate tumor cell invasion.

Up-regulated signaling from the epidermal growth factor receptor (EGFR) has been correlated with tumor invasion and metastasis in numerous human neoplasias. Recently, we have demonstrated that increased levels of EGFR promote the invasiveness of human prostate carcinoma DU-145 cells. However, the intracellular signaling pathway responsible for this enhanced tumor invasiveness has not been identified. We postulated that increased cell motility signaled via phospholipase Cgamma (PLCgamma) activation was critical for tumor invasiveness. Highly invasive DU-145 cells engineered to overexpress the EGFR were stably transfected with a dominant-negative fragment of PLCgamma from the Z-region (PLCz) or with irrelevant peptide minigenes. PLCz was expressed only in the appropriate transfectant lines, with a concomitant decrease in inositol phosphate generation. The transfectant cell lines all formed tumors when inoculated into the peritoneal cavity of athymic mice. Tumors from the cells expressing PLCz fragment were significantly less invasive than the transfectants containing the control minigenes, as assessed by the diaphragm invasion model and invasion into abdominal soft organs. The cells expressing PLCz grew and formed colonies in soft agar at rates comparable to the cells expressing the control minigenes. These data suggest that up-regulated signaling by EGFR promotes prostate tumor invasiveness secondary to increased cell motility. Furthermore, PLCgamma represents a potential therapeutic target to limit tumor progression promoted by up-regulated signaling from the EGFR and related receptors with intrinsic tyrosine kinase activity.

Animals↗
PubMed1996

In vivo expression of full-length human dystrophin from adenoviral vectors deleted of all viral genes.

Adenoviral vectors have been shown to effect efficient somatic gene transfer in skeletal muscle and thus offer potential for the development of therapy for Duchenne muscular dystrophy (DMD). Efficient transfer of recombinant genes has been demonstrated in skeletal muscle using recombinant adenoviruses deleted of E1. Application of this vector system to the treatment of DMD is limited by the vector immunogenicity, as well as by size constraints for insertion of recombinant genes, precluding the incorporation of a full-length dystrophin minigene construct. We describe in this study the use of helper adenovirus to generate a recombinant vector deleted of all viral open reading frames and containing a full-length dystrophin minigene. We show that this deleted vector (delta vector) is capable of efficiently transducing dystrophin in mdx mice, in myotubes in vitro and muscle fibers in vivo. Our modification of adenoviral vector technology may be useful for the development of gene therapies for DMD and other diseases.

Adenoviridae↗
PubMed1996

STAT activation by epidermal growth factor (EGF) and amphiregulin. Requirement for the EGF receptor kinase but not for tyrosine phosphorylation sites or JAK1.

The epidermal growth factor (EGF) receptor activates several signaling cascades in response to the ligands EGF and amphiregulin (AR). One of these signaling events involves the tyrosine phosphorylation of STATs (signal transducers and activators of transcription), a process believed to require the activation of a tyrosine kinase of the JAK family. In this report we demonstrate that EGF- and AR-induced STAT activation requires the intrinsic kinase activity of the receptor but not the presence of Jak1. We show that both wild type (WT) and truncated EGF receptors lacking all autophosphorylation sites activate STAT 1, 3, and 5 in response to either EGF or AR. Furthermore, relative to cells expressing WT receptor, ligand-induced tyrosine phosphorylation of the STATs was enhanced in cells expressing only the truncated receptor. These results provide the first evidence that (i) EGF receptor-mediated STAT activation occurs in a Jak1-independent manner, (ii) the intrinsic tyrosine kinase activity of the receptor is essential for STAT activation, and (iii) tyrosine phosphorylation sites within the EGF receptor are not required for STAT activation.

Amphiregulin↗