Biomedical subjects

A Wells

Publications and source records attributed to A Wells.

At least 91 records · Page 5Linked to original sources

PubMed1999

Brief cognitive therapy for panic disorder: a randomized controlled trial.

Cognitive therapy (CT) is a specific and highly effective treatment for panic disorder (PD). Treatment normally involves 12-15 1-hr sessions. In an attempt to produce a more cost-effective version, a briefer treatment that made extensive use of between-sessions patient self-study modules was created. Forty-three PD patients were randomly allocated to full CT (FCT), brief CT (BCT), or a 3-month wait list. FCT and BCT were superior to wait list on all measures, and the gains obtained in treatment were maintained at 12-month follow-up. There were no significant differences between FCT and BCT. Both treatments had large (approximately 3.0) and essentially identical effect sizes. BCT required 6.5 hr of therapist time, including booster sessions. Patients' initial expectation of therapy success was negatively correlated with posttreatment panic-anxiety. Cognitive measures at the end of treatment predicted panic-anxiety at 12-month follow-up.

Adolescent↗

PubMed1999

Methadone-maintained former heroin addicts, including those who are anti-HIV-1 seropositive, comply with and respond to hepatitis B vaccination.

AIMS: To study the efficacy of standard hepatitis B (HB) vaccination in methadone-maintained former intravenous drug users. DESIGN: HB vaccine was administered to subjects at 0, 1 and 6 months. SETTING: Two university-affiliated methadone maintenance clinics. PARTICIPANTS: Forty-three HB-unexposed former heroin addicts in methadone maintenance treatment for heroin addiction. MEASUREMENTS: HB surface antibody (anti-HBs) response to the vaccine was assessed at 0, 1, 6 and > or = 12 months; anti-HIV-1 status was also assessed. FINDINGS: Thirty-seven patients (86%) completed the 6-month vaccination series. Of the 30 anti-HIV-1 seronegative patients who then completed the entire 12-month protocol, 21 (70%) seroconverted (anti-HBs ratio > 2.1) and 19 (63%) were protected (anti-HBs ratio > 10). Two other subjects were anti-HIV-1 seropositive: one was HB-protected at 12 months but later lost immunity. Ten anti-hepatitis C antibody-positive patients completed the 12-month study and six were protected; thus, there was no significant relationship between hepatitis C status and HB vaccine response. CONCLUSIONS: Standard HB vaccination is both feasible and effective.

Adult↗

PubMed1999

Inhibition of phospholipase C-gamma1 activation blocks glioma cell motility and invasion of fetal rat brain aggregates.

OBJECTIVE: Phospholipase C (PLC)-gamma is a cytosolic enzyme activated by several growth factor (GF) receptors (epidermal GF receptor [EGFR], platelet-derived GF receptor, and insulin-like GF 1 receptor), and its activation is associated with increased cell motility (but not cell proliferation) in nonglioma cell lines. Because up-regulated activation of EGFR has been consistently linked to poor patient survival in patients with glioblastoma multiforme (GBM) and because inhibition of EGFR activation by tyrosine kinase inhibitors prevents glioma infiltration in vitro, we hypothesized that inhibition of PLC-gamma activation would inhibit glioma cell invasiveness. METHODS: Our experimental model assesses tumor spheroid invasion of fetal rat brain spheroids by confocal microscopy. We treated U87 GBM spheroids, and those derived from a single patient, with the PLC inhibitor U73122. We also transfected rat C6 glioma cells with the PLCz complementary deoxyribonucleic acid coding for a dominant negative PLC-gamma1 src-homology-2/src-homology-3 peptide fragment, which blocks binding and activation of PLC-gamma1 by GF receptors. Two clones (C6F and C6E) were grown into spheroids and were tested for invasiveness in the spheroid model and for responsiveness to GFs in a standard in vitro motility assay. RESULTS: The infiltration rate of the patient GBM cell line overexpressing wild-type EGFR was reduced by 2 micromol/L U73122 from a slope (percent invasion/h) of 0.74+/-0.08 (with the inactive congener U73343) to 0.04+/-0.053 (P = 8 x 10(-7) by two-tailed t test, 92% reduction); the integral rate, another measure of invasion, was reduced from 49.7+/-13 percent-hours per hour to 13.6+/-12 (P = 0.002, 72% reduction). The U87 spheroid invasion rate was reduced by 0.5 micromol/L U73122 from 46.7+/-8.5 percent-hours per hour to 11.2+/-4.6 (P = 3 x 10(-5)); the slope decreased from 1.7+/-0.41 percent per hour to 0.35+/-0.14 (P = 0.0001). The C6F and C6E clones demonstrated attachment to and "surrounding" of the fetal rat brain aggregate but no true invasion by confocal or light microscopy. PLCz blocked the motility response to epidermal GF, platelet-derived GF, and insulin-like GF. There was a significant decrease in PLC-gamma1-associated tyrosine phosphorylation. CONCLUSION: These results support a key role for PLC-gamma activation as a common postreceptor pathway for GF-induced tumor infiltration and further identify PLC-gamma1 as a possible target for anti-invasive therapy for GBMs.

Animals↗

PubMed1999

Effect of digoxin fab antibody on the measurement of total and free digitoxin by fluorescence polarization and a new chemiluminescent immunoassay.

Digoxin fab antibody (Digibind; Burroughs Wellcome, Research Triangle Park, NC, USA) is used in the treatment of digoxin overdose. The effect of digibind on the measurement of total and free digoxin has been extensively studied. However, the effect of digibind on digitoxin measurements has not been studied thoroughly. The authors studied the effect of digibind on the measurement of total and free digitoxin in vitro using the fluorescence polarization immunoassay and a new chemiluminescent immunoassay. We also studied the capability of digibind to bind digitoxigenin, the major aglycon metabolite of digitoxin. Digibind neutralized both digitoxin and digitoxigenin in vitro, as evidenced by significant reductions in free digitoxin and digitoxigenin (measured as digitoxin equivalent) concentrations. Digibind caused negative interference in the measurement of total digitoxin concentrations by both fluorescence polarization and chemiluminescent assays. However, the magnitude of negative interference was significantly higher with the chemiluminescent assay. For example, in a serum pool supplemented with 80 ng/mL of digitoxin, the concentrations of total and free digitoxin measured by the fluorescence polarization immunoassay were 82.1 ng/mL and 3.3 ng/mL respectively. In the presence of 5 microg/mL of Digibind, the corresponding total and free digitoxin concentrations were 73.9 ng/mL and none detected, respectively. In another serum pool supplemented with 70 ng/mL of digitoxin, the concentrations of total and free digitoxin as measured by the chemiluminescent assay were 69.1 ng/mL and 3.8 ng/mL, respectively. In the presence of 5 microg/mL of Digibind, the corresponding total and free digitoxin concentrations were 29.0 ng/mL and none detected, respectively. Because this effect may also occur in vivo, the progress of Digibind therapy in treating a patient with digitoxin overdose may be monitored by measuring the free digitoxin concentrations.

Cardiotonic Agents↗

PubMed1999

Effect of heating human sera at a temperature necessary to deactivate human immunodeficiency virus on measurement of free phenytoin, free valproic acid, and free carbamazepine concentrations.

Minimizing the risk for infection to laboratory staff from a contaminated blood sample is a major safety goal in the clinical laboratory. One dangerous pathogen, the human immunodeficiency virus (HIV), can be deactivated by heating sera at 56 degrees C for 30 minutes. The authors previously reported that if serum was subjected to those conditions, the concentrations of the nine most commonly monitored drugs were not altered, whereas phenytoin and carbamazepine concentrations were reduced slightly. Monitoring free phenytoin, free valproic acid, and free carbamazepine concentrations is strongly recommended for patients with uremia, liver disease, and hypoalbuminemia. Because drug protein binding can be affected by temperature, the authors investigated the effect on free drug concentrations of sera heated to levels necessary for deactivation of the HIV virus. They measured total and free drug concentrations in serum pools prepared from patients receiving phenytoin, valproic acid, and carbamazepine. Serum pools were heated at 56 degrees C for 30 minutes and then brought to room temperature. The total and free drug concentrations were measured immediately after heating and then at 20- and 45-minute intervals. The concentrations of free phenytoin and free valproic acid were significantly higher after heat treatment. However, after equilibration of sera at room temperature for 20 minutes, the free concentrations of phenytoin were comparable to preheating values, although total phenytoin concentrations (Serum Separator Tubes) were reduced slightly. In contrast, free valproic acid concentrations did not return to the original levels even after 45 minutes. Free carbamazepine concentrations did not change even immediately after heating. However, total carbamazepine concentrations were reduced slightly when sera were heated in serum separator tubes (SST Tubes).

Anticonvulsants↗

PubMed1999

Operator error: a critical determinant of false amikacin and tobramycin concentrations using fluorescence polarization immunoassay kits and TDX analyzer.

Amikacin and tobramycin are aminoglycosides used to treat severe Gram-negative infections. Therapeutic monitoring of both drugs is essential to avoid drug toxicity. Fluorescence polarization immunoassay kits for both amikacin and tobramycin are available from Abbott Laboratories, and assays can be run using the TDx analyzer. The test code for amikacin is 3, whereas the test code for tobramycin is 2. Here the authors report that when the operator mistakenly programmed test code 3 (amikacin code) while using the tobramycin kit, the tobramycin values were falsely elevated. The instrument software does not have any mechanism to detect this error. Similarly, when the amikacin kit was used and the operator mistakenly programmed test code 2 (tobramycin code), the amikacin values were falsely lowered. For example, in a serum sample taken from a patient the true amikacin concentration was 20.9 microg/mL. When the amikacin kit was used correctly but test code 2 was programmed, the observed concentration was falsely lowered to 6.1 microg/mL. Similarly, in another specimen the true tobramycin concentration was 3.1 microg/mL. However, when the tobramycin kit was used correctly but test code 3 was used, the observed concentration was falsely elevated to 14.3 microg/mL. The authors also observed a similar effect with controls and spiked specimens containing either amikacin or tobramycin. They conclude that correct programming of the test code is vital to obtaining useful results in amikacin and tobramycin analysis using the TDx analyzer.

Amikacin↗

PubMed1999

Sensitive methods for determination of free digitoxin concentration using digitoxin immunoassays: demonstration of elevated free digitoxin concentration caused by digitoxin-phenytoin interaction by applying these new techniques.

Digitoxin is very strongly bound to serum albumin. Although free digitoxin is pharmacologically active, it is not monitored because of the lack of a sufficiently sensitive technique. The concentration of free digitoxin in the protein-free ultrafiltrate is usually below the detection limit of digitoxin immunoassays. A modified technique is described by which free digitoxin can be routinely monitored using commercially available immunoassays. The fluorescence polarization immunoassay for determining total digitoxin concentration requires that 100 microL of serum be treated with 300 microL of methanol to precipitate proteins. It is demonstrated that free digitoxin can easily be measured by adding 100 microL of methanol to 300 microL of ultrafiltrate, thus improving the sensitivity of the assay three-fold. The free digitoxin concentration can easily be calculated by dividing the observed value by 3. An attempt to use only ultrafiltrate (no methanol added) caused significant bias in the result, probably as a result of a matrix problem. The chemiluminescent assay for digitoxin does not require any specimen pretreatment and requires only 10 microL of serum. The program was modified and used 50 microL of ultrafiltrate to improve the sensitivity of the free digitoxin assay. If the chemiluminescent assay is used to measure free digitoxin, the true free digitoxin concentration can be calculated by dividing the observed value by 4.3. The free digitoxin concentrations were comparable in eight patients receiving digitoxin as measured by both methods. To show an application of this technique, two serum pools were prepared from patients receiving digitoxin and supplemented with various concentrations of phenytoin. A significant increase in free digitoxin concentration was observed because of the displacement of digitoxin from protein binding sites by phenytoin.

Binding, Competitive↗

PubMed1999

A cognitive model of generalized anxiety disorder.

A cognitive model of generalized anxiety disorder (GAD) is described. The model asserts that generalized anxiety is an abnormal worry state. In this model, GAD results from the usage of worrying as a coping strategy and subsequent negative evaluation of worrying. The use of worry as a strategy is supported by positive metabeliefs concerning worry, whereas the negative appraisal of worrying (worry about worry) is linked to negative metabeliefs developed out of previous experience. These beliefs center on the themes of uncontrollability of worries and the dangerous consequences of worrying. Negative appraisal of worrying is associated with behavioral and cognitive responses that serve to maintain unwanted thoughts, and preserve dysfunctional beliefs. A review of the literature indicates that the model is consistent with existing data. Predictions and treatment implications of the model are discussed.

Anxiety↗

PubMed1999

The prediction of parasuicide repetition in a high-risk group.

OBJECTIVES: This study explores whether the specificity of risk assessment for parasuicide repetition can be improved by measurement of two psychological variables (over-generality of autobiographical memory and future fluency for positive events) in the immediate aftermath of the index parasuicide. DESIGN: In a longitudinal study, parasuicide patients deemed to be at high risk of repetition on the basis of sociodemographic factors (Kreitman & Foster, 1991) were followed-up over a 12-month period. METHOD: As soon as practicable after taking a deliberate drug overdose, patients completed the Autobiographical Memory Test, the Personal Future Test and the Beck Hopelessness Scale. The relative power of each of these measures, together with the number of sociodemographic risk factors, in predicting parasuicide repetition was investigated using a forward step-wise logistic regression analysis. RESULTS: The most potent short-term predictor of parasuicide repetition was found to be scores on the Beck Hopelessness Scale, whereas in the longer term the number of previous para-suicides was the major predictor. CONCLUSION: For the heterogeneous parasuicide population as a whole, psychological variables are unlikely to improve upon the Beck Hopelessness Scale, sociodemographic risk factors and clinical interview in the prediction of parasuicide repetition.

Adult↗

PubMed1999

EGF receptor signaling in prostate morphogenesis and tumorigenesis.

The growth and differentiation of the prostate gland are largely dependent on extracellular signaling factors. In addition to androgens, many polypeptide growth factors function through autocrine or paracrine networks. The paracrine interaction between stromal and epithelial cells is critical for androgen regulation, morphogenesis, epithelial cell proliferation, and secretory differentiation. Efforts to identify the essential growth factors and studies on their effects have been prompted by the fact that prostate cells in culture need substances other than androgens for proliferation. In this context, transforming growth factor-alpha and epidermal growth factor, among others, have been studied extensively. Recent advances have suggested that these EGF receptor (EGFR) ligands play roles not only during glandular development but also during neoplastic transformation and tumor progression. The cell responses most relevant to the role of this receptor signaling are both mitogenesis and cell motility. The aim of the review is to provide an overview of current knowledge about EGFR and its ligands in the organogenesis and tumorigenesis of the prostate gland.

Animals↗

PubMed1999

A role for phospholipase C-gamma-mediated signaling in tumor cell invasion.

The invasive and metastatic transformation of cancers often results in death. However, the mechanisms that promote this transformation remain unclear. Two closely related receptors, the epidermal growth factor receptor (EGFR) and ErbB2, are overexpressed in a significant percentage of breast and prostate carcinomas, among others, with this up-regulated signaling correlating with tumor progression. Previous studies in our laboratory have demonstrated that an EGFR-phospholipase C (PLC)gamma-mediated motility-associated signaling pathway is rate-limiting for tumor cell invasion in vitro and in vivo in one model of prostate carcinoma. Therefore, we investigated whether this PLCgamma signaling pathway also was rate-limiting for invasion in other tumor cell lines and types and whether this EGFR activity is subsumed by the closely related ErbB2. We determined the effects of PLCgamma signal abrogation by pharmacological (U73122) and molecular (expression of the dominant-negative PLCz) means on the in vitro invasiveness of tumor cells. Inhibition of PLCgamma signaling concomitantly decreased invasiveness of de novo-occurring transgenic adenocarcinoma mouse prostate (TRAMP) lines and the human breast cancer cell lines MDA-468 and MDA-231; these lines present up-regulated EGFR signaling. Because the prostate and breast cancer lines usually present autocrine stimulatory loops involving EGFR, we also examined transgenic adenocarcinoma mouse prostate C1 and MDA-468 treated with the EGFR-specific kinase inhibitor PD153035 to determine whether invasiveness is dependent on EGFR signaling. PD153035 reduced invasiveness to levels similar to those seen with U73122, suggesting that the autocrine EGFR stimulatory loop is functioning to promote invasiveness. To determine whether this signaling pathway also promotes invasiveness of ErbB2-overexpressing tumors, we examined the human breast carcinoma line MDA-361; again, U73122 inhibition of PLCgamma decreased invasiveness. In all situations, the inhibition of PLCgamma signaling did not decrease mitogenic signaling. Thus, the motility-associated PLCgamma signaling pathway is a generalizable rate-limiting step for tumor cell progression.

Adenocarcinoma↗

PubMed1999

Influence of practice and personal characteristics on dental job satisfaction.

Job satisfaction has been called a barometer of the dental profession. The Dentist Satisfaction Survey (DSS), an instrument that measures both specific facets related and overall job satisfaction of dentists, was administered to general dentists in Kentucky (N = 987). Independent variables included eleven job facets, plus practice characteristics and personal characteristics including student loan debt. Results of the stepwise multiple regression showed that 60 percent of the variance of the dependent variable, overall job satisfaction, was attributable to six job facets: respect, perception of income, delivery of care, stress, patient relations, and professional time. The most significant predictors of dental job satisfaction involved the intrinsic rewards of being a dentist and the delivery of dental health services. Less satisfying aspects of dentistry included business operations, including practice management and financial planning. Despite concern among educators about the potential influence of student loan debt, there was no significant correlation between student loan debt and overall job satisfaction. Findings from this study have implications for student recruitment, dental school curriculum design, and dental workforce planning.

Adult↗

PubMed1998

Transcriptional suppression of matrix metalloproteinase-2 gene expression in human astroglioma cells by TNF-alpha and IFN-gamma.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that function in the turnover of extracellular matrix components during development. In addition, MMPs also contribute to pathological conditions associated with inflammation, angiogenesis, and tumor invasion. A 72-kDa type IV collagenase, also referred to as gelatinase A or MMP-2, has been proposed to potentiate the invasion and metastasis of malignant tumors. In particular, MMP-2 activity has been shown to constitute an important component of human astroglioma invasion. We investigated the influence of various cytokines, both proinflammatory and immunosuppressive, on MMP-2 gene expression in two human astroglioma cell lines (U251-MG and CRT). Our results indicate that the cell lines constitutively express high levels of MMP-2 mRNA, protein, and bioactivity as assessed by ribonuclease protection assay, immunoblotting, and zymography assays, respectively. The proinflammatory cytokines TNF-alpha and IFN-gamma individually can inhibit constitutive MMP-2 expression, and function in an additive manner for near-complete inhibition of MMP-2 expression. Inhibition of MMP-2 mRNA levels by TNF-alpha and IFN-gamma is not due to destabilization of the MMP-2 message; rather, inhibition is mediated at the transcriptional level. Furthermore, TNF-alpha/IFN-gamma inhibition of MMP-2 expression results in decreased invasiveness of the human astroglioma cells through an extracellular matrix. These results raise the possibility that TNF-alpha and IFN-gamma may have beneficial effects in attenuating astroglioma invasive properties.

Astrocytes↗

PubMed1998

Epidermal growth factor receptor-mediated motility in fibroblasts.

Cell motility is induced by many growth factors acting through cognate receptors with intrinsic tyrosine kinase activity (RPTK). However, most of the links between receptor activation and the biophysical processes of cell motility remain undeciphered. We have focused on the mechanisms by which the EGF receptor (EGFR) actuates fibroblast cell motility in an attempt to define this integrated process in one system. Our working model is that divergent, but interconnected pathways lead to the biophysical processes necessary for cell motility: cytoskeleton reorganization, membrane extension, formation of new adhesions to substratum, cell contraction, and release of adhesions at the rear. We postulate that for any given growth factor some of the pathways/processes will be actively signaled and rate-limiting, while others will be permissive due to background low-level activation. Certain couplings have been defined, such as PLCgamma and actin modifying proteins being involved in cytoskeletal reorganization and lamellipod extension and MEK being implicated in detachment from substratum. Others are suggested by complementary investigations in integrin-mediated motility, including rac in membrane protrusion, rho in new adhesions, myosin II motors in contraction, and calpain in detachment, but have yet to be placed in growth factor-induced motility. Our model postulates that many biochemical pathways will be shared between chemokinetic and haptokinetic motility but that select pathways will be activated only during RPTK-enhanced motility.

Actins↗

PubMed1998

Treatment of human prostate cancer cells with dolastatin 10, a peptide isolated from a marine shell-less mollusc.

BACKGROUND: Dolastatin 10 is an anticancer peptide isolated from the sea hare, Dolabela auricularia, which is currently in phase I trials. METHODS: The effects of dolastatin 10 on the DU-145 human prostate cancer cell line were studied both in tissue culture and in athymic nude mice. In tissue culture, after dolastatin 10 treatment, cell cycle kinetics were measured using propidum iodide, apoptosis was estimated using the TUNEL assay, and tubulin architecture studied by direct immunofluorescence. RESULTS: At concentrations of 1 nM (IC50 = 0.5 nM), dolastatin 10 completely inhibited the growth in tissue culture of human prostate cancer DU-145 cells. Growth inhibition was correlated with the arrest of these cells in G2/M and alpha-tubulin depolymerization. In athymic mice at a dose of 5 micrograms every 4 days i.p., dolastatin 10 blocked the diaphragmatic invasion of DU-145 tumor cells. CONCLUSIONS: Dolastatin 10 is a novel marine-derived compound with activity in the treatment of human prostate cancer in animals. The mechanism of action of this agent involves tubulin depolymerization but not the induction of apoptosis.

Animals↗

PubMed1998

Comparative mitogenic potencies of EGF and TGF alpha and their dependence on receptor-limitation versus ligand-limitation.

Transforming growth factor alpha (TGF alpha) has been reported to be a more potent agonist when compared to epidermal growth factor (EGF) in several systems while acting via their common receptor, the epidermal growth factor receptor (EGFR). It has been postulated that this increased potency is mediated by the increased recycling of EGFR upon activation by TGF alpha as against receptor activation by EGF. The authors test this hypothesis by simultaneously measuring mitogenesis and the dynamics of surface receptor number in response to these ligands in NR6 mouse fibroblasts expressing the EGFR. The data demonstrates that increased receptor recycling due to endosomal dissociation of TGF alpha can indeed realise an increased mitogenic potency relative to EGF under appropriate cellular and experimental conditions (i.e. situations in which the increase in the number of occupied receptors due to receptor sparing by TGF alpha represents additional mitogenic signalling capacity). However, this difference in receptor trafficking does not uniquely determine the relative potencies of these ligands since TGF alpha is a less potent mitogen compared to EGF when experimental conditions are dominated by the effects of ligand trafficking on growth factor availability. Thus, the relative potencies of these growth factors are determined in a given context by the relative importance of ligand and receptor trafficking effects which determine the availability of these signalling components. These results are consistent with a suggested model of hormone responsiveness which favours dissociative ligands (such as TGF alpha) in receptor-limited situations and non-dissociative ligands (such as EGF) in the case of ligand limitation.

Animals↗

PubMed1998

How do I look with my minds eye: perspective taking in social phobic imagery.

This study explored perspective taking in social phobics' images of past anxiety-provoking social situations and non-social situations. For images of social situations, social phobics were significantly more likely than non-patient controls to take an observer perspective, viewing themselves as if from an external point of view. In contrast, social phobics and controls did not differ in the perspective taken in images of non-social situations, which were generally viewed from a field perspective (seeing the situation as if looking out through their own eyes). The clinical significance of these findings is briefly discussed.

Adult↗

PubMed1998

Relationships between worry, obsessive-compulsive symptoms and meta-cognitive beliefs.

The present study had two principal aims. First, the overlap between the revised Padua Inventory (PI-WSUR) a measure of obsessive-compulsive symptoms (Burns et al., 1996) and worry was assessed. Second, the relationship between meta-cognitive beliefs, proneness to pathological worry and obsessive-compulsive symptoms was explored when controlling for the interdependency of worry and obsessive-compulsive measures. The results indicate that whilst the PI-WSUR shows reduced overlap with the Penn State Worry Questionnaire, there are still problematic levels of overlap with a more content-based measure of worry. Results of multiple regression analyses demonstrated that specific sets of meta-cognitive beliefs were associated with worry proneness and obsessive-compulsive symptoms. The present data are consistent with recent formulations of generalized anxiety disorder and obsessive-compulsive disorder.

Adult↗