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Biomedical subjects

J Fawcett

Publications and source records attributed to J Fawcett.

At least 73 records · Page 4Linked to original sources
PubMed1998

Expression of antisense CD44 variant 6 inhibits colorectal tumor metastasis and tumor growth in a wound environment.

Up-regulation of CD44 variant isoforms has been linked to the progression of epithelial tumors and the metastatic phenotype. Here we report a functional role for CD44 variant isoforms in colorectal cancer metastasis. An antisense mRNA approach was used to down-regulate CD44 variant isoforms containing CD44 variant 6 (v6) in the metastatic colorectal tumor cell line HT29. Cell lines stably expressing antisense CD44 exon 10 (v6) showed reduced expression of alternatively spliced CD44 variant isoforms but no significant change in expression of CD44 core protein, as judged by immunohistochemical analysis using CD44 domain-specific monoclonal antibodies. Expression of antisense exon 10 (v6) had no effect on HT29 tumor cell proliferation in vitro or the ability of the cells to bind immobilized hyaluronan, but it resulted in a reduced capacity to form liver metastases in nude mice following intrasplenic injection. Metastases were not detected in nude mice inoculated with antisense CD44 exon 10 (v6)-expressing cell lines after 4 months, against a background of a 30% metastasis rate in the control HT29 parental and vector alone transfected lines. Furthermore, whereas 82% of mice intrasplenically injected with control HT29 parental and vector alone cell lines developed tumors in incisional wound sites, none of the mice injected with antisense exon 10 expressing HT29 cells developed similar tumors. This is the first demonstration that antisense RNA can be used to selectively inhibit expression of specific domains of a molecule generated through alternative mRNA splicing while allowing expression of core domains to remain unaffected. Furthermore, these results provide direct evidence for a functional role of CD44 variant isoforms in the metastasis of human colorectal tumor cells and may suggest a critical role for CD44 variants in promoting cell growth specifically in the cytokine/growth factor-enriched environment of a wound site.

Adenocarcinoma↗
PubMed1998

Use of pattern analysis to predict differential relapse of remitted patients with major depression during 1 year of treatment with fluoxetine or placebo.

BACKGROUND: Delayed and persistent ("true drug") improvement characterizes the response to antidepressant medication. Early or nonpersistent ("placebo") benefit is typical of a placebo response. The prediction was that patients with a true drug response would sustain their benefit best if they continued to receive the drug and that patients with a placebo response would have an equivalent prognosis whether they continued to receive the drug or were switched to placebo. METHODS: Patients with major depression who met the study's response criteria (a modified Hamilton Depression Rating Scale score < or =7 and failure to meet major depression criteria after each of the last 3 weeks following 12 to 14 weeks of treatment with fluoxetine hydrochloride, 20 mg/d) were enrolled in a 50-week randomized placebo substitution trial during which the return of depressive symptoms defined relapse. The timing and persistency of response during initial treatment defined true drug or placebo response patterns. RESULTS: Patients with a true drug response pattern relapsed significantly more frequently if they were switched to placebo than if they continued to receive fluoxetine (P<.001 for weeks 12-26, P<.005 for weeks 26-50, and P<.41 for weeks 50-62). Patients with a placebo response pattern had an equivalent outcome whether maintained on fluoxetine therapy or placebo (P< .20 for weeks 12-26, test invalid for weeks 26-50, and P<.67 for weeks 50-62). Patients with a placebo response pattern relapsed more often when they continued to receive fluoxetine than patients with a true drug response pattern (P<.01 for weeks 12-26, P<.10 for weeks 26-50, and P<.36 for weeks 50-62). CONCLUSIONS: These findings confirm that pattern analysis validly differentiates true drug from nonspecific initial responses and extend its use to the continuation and maintenance phases of treatment for depression. Investigations into the mechanisms of antidepressant activity might best be limited to those that can account for delayed efficacy. Fluoxetine's efficacy during the continuation and maintenance phases of treatment may be limited to patients with a true drug pattern of initial response.

Adolescent↗
PubMed1998

Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression.

Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by increasing noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a consequence of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated addition to the antidepressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four metabolites via demethylation and hydroxylation, followed by glucuronide conjugation. The unconjugated desmethyl metabolite is pharmacologically less active than the parent compound. Mirtazapine lacks auto-induction of hepatic isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and 3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of these enzymes. Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose. Mirtazapine is a unique addition to the antidepressant armamentarium as first-line therapy in patients with major depression and symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia and as a useful alternative in depressed patients who do not adequately respond to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake inhibitors.

Administration, Oral↗
PubMed1998

Women's perceptions of group support and adaptation to breast cancer.

Formal cancer support groups are thought to assist women to adapt to the physiological and psychosocial sequelae of breast cancer. To shed some light on this untested clinical assumption, this Roy Adaptation Model of Nursing-based study was designed to explore women's own reports about their adaptation to breast cancer and their participation in support groups. This article reports the results of the quantitative content analysis of structured telephone interviews with 70 women who participated in group social support and education for breast cancer. Almost three-quarters of the women expressed a positive change in attitude towards breast cancer, and all regarded participation in the groups as positive. A majority reported adaptive physiological, self-concept, role function, and interdependence mode effects of breast cancer and group participation. Additional research is needed to show how different types of cancer support groups, including social support and education groups and psychotherapy groups, contribute to women's responses. Research is also needed to separate the effects of group social support and education from other sources of social support that may have contributed to the women's responses, and to further explore feelings of normalization expressed by some women.

Activities of Daily Living↗
PubMed1998

Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study.

Selective serotonin reuptake inhibitors may be associated with new adverse events after abrupt discontinuation. Hypothesizing that the long half-life of fluoxetine would be protective, this study analyzed the effects of abrupt fluoxetine discontinuation during a randomized, double-blind, placebo-controlled study of depression maintenance treatment. After 12 weeks of fluoxetine treatment (20 mg/day), 395 responders were abruptly randomized to placebo (N = 96) or to continued fluoxetine (N = 299). Patients were seen at weeks 1, 2, 4, and 6 after randomization. Reports of new or worsened adverse events were similar for both groups at each visit after randomization. Patient discontinuations related to adverse events were also similar in both groups. Mild, self-limited lightheadedness or dizziness occurred in a small percentage of patients who discontinued fluoxetine treatment but was of little clinical significance. No cluster of symptoms suggestive of a discontinuation syndrome was observed. Abrupt discontinuation of fluoxetine treatment was well tolerated and did not seem to be associated with significant clinical risk. Fluoxetine may offer a potential safety advantage over shorter-acting agents with respect to treatment interruption and/or discontinuation and may be a better choice for those patients who are likely to miss doses because of travel or forgetfulness.

Adult↗
PubMed1998

Efficacy and safety of fluoxetine in treating bipolar II major depressive episode.

As many as 45% of patients with major depressive episode also meet DSM-IV criteria for bipolar II (BP II) disorder. Although some clinicians advocate using a mood stabilizer in treating BP II depression, antidepressant monotherapy has been less well studied in this disorder. As part of a prospective, placebo-controlled, relapse-prevention study in 839 patients, the efficacy and safety of short- and long-term fluoxetine treatment in patients with BP II major depression compared with patients with unipolar (UP) major depression was retrospectively examined. Eighty-nine BP II patients (mean age, 41+/-11 years) were compared with 89 age- and gender-matched UP patients and with 661 unmatched UP patients (mean age, 39+/-11 years). All received short-term fluoxetine therapy at 20 mg daily for up to 12 weeks. Complete remission was defined as a final Hamilton Rating Scale for Depression score < or = 7 by week 9 that was then maintained for 3 additional weeks. Remitted patients were then randomly assigned to receive double-blind treatment with one of the following: (1) fluoxetine 20 mg daily for 52 weeks; (2) fluoxetine for 38 weeks, then placebo for 14 weeks; (3) fluoxetine for 14 weeks, then placebo for 38 weeks; or (4) placebo for 52 weeks. Antidepressant efficacy was similar in BP and UP patients during short-term therapy. Discontinuation for lack of efficacy was lower in BP II (5%) than in UP (12%) patients (p = not significant [NS]), whereas dropouts for adverse events were similar in BP II (11%) and UP (9%) patients. During long-term relapse-prevention therapy, relapse rates were similar in BP II and UP patients (p = NS). During short-term fluoxetine therapy, three BP II (3.8%) versus no matched UP (p = NS) and 0.3% unmatched UP (p = 0.01) patients had a "manic switch." During long-term fluoxetine therapy, one (2%) BP II and three (1%) unmatched UP patients (one taking placebo) had a manic switch (p = NS). In conclusion, fluoxetine may be a safe and effective antidepressant monotherapy for the short-term treatment of BP II depression with a relatively low manic switch rate. Fluoxetine may also be effective in relapse-prevention therapy in patients with BP II disorder.

Adolescent↗
PubMed1998

Predictors of response to acute treatment of chronic and double depression with sertraline or imipramine.

BACKGROUND: The literature on predictors of response to treatment of nonchronic major depression has identified shorter duration of illness, acute onset, and less severity of illness as positive predictors. Unfortunately, there are almost no data on predictors of response to treatment for chronic depression. This study examined predictors of response to pharmacotherapy (sertraline or imipramine) in the treatment of outpatients who had DSM-III-R-defined chronic major or double depression. METHOD: The acute phase of the Chronic Major Depression and Double Depression Study is a double-blind, randomized, parallel-group 12-week comparison of sertraline and imipramine. Analyses are based on 623 patients who comprised the intent-to-treat sample, of whom 299 were nonresponders and 324 were responders, defined by a priori criteria as either remission or satisfactory therapeutic response. A stepwise logistic multiple regression analysis was performed on candidate clinical, psychosocial, and demographic variables previously identified as statistically significant in an attempt to develop a predictive model of positive antidepressant response. RESULTS: The sociodemographic variables that were predictive of positive response included living with spouse or partner or being at least a high school graduate. With regard to symptomatology and clinical history, responders had significantly lower baseline depression severity scores. In general, comorbid anxiety, substance abuse, and personality disorders did not influence rates of response. However, the presence of depressive personality traits was associated with a higher nonresponse rate. Among psychosocial variables, longer duration of personal relationships as well as higher baseline quality of life were associated with positive response. A stepwise logistic multiple regression identified 5 variables-living with spouse or partner, higher educational level, passive-aggressive personality, lower introverted-tense personality traits, and higher quality of life--that significantly and independently contributed to the predictive model. This model correctly classified 67% of patients. CONCLUSION: A higher baseline quality of life, living with spouse or partner, and having more education were the strongest predictors of response to acute pharmacotherapy among chronically depressed patients. Clinical variables and comorbidity were not identified as independent predictors, although personality traits did appear to influence treatment response. Overall, the predictive value of these baseline measures was modest, and therefore of limited clinical utility.

Adult↗
PubMed1998

Reporting research results: let's not forget clinical significance.

Writing the report of a research project can seem overwhelming, especially when the researcher begins to interpret the results in light of their clinical or practical significance. This experienced researcher and author presents guidelines for writing the results of a research report in a way that shows the clinical relevance.

Data Interpretation, Statistical↗
PubMed1998

A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety.

BACKGROUND: Patients diagnosed with major depression and prominent symptoms of anxiety often have a poor prognosis for recovery. A meta-analysis was performed to assess the efficacy of mirtazapine in comparison with placebo and amitriptyline for the relief of anxiety/agitation or anxiety/somatization in patients with major depressive illness. METHOD: A meta-analysis of eight randomized, double-blind, placebo-controlled clinical trials was conducted for 161 mirtazapine-treated and 132 placebo-treated patients with a DSM-III diagnosis of major depression, baseline Hamilton Rating Scale for Depression (HAM-D) scores > or = 18, and a baseline score > or = 6 for the sum of HAM-D items 9, 10, and 11 (anxiety/agitation). Four of the clinical trials included an amitriptyline control group (N = 92). RESULTS: Mirtazapine-treated patients demonstrated a statistically significant (p < or = .05) reduction in the sum of HAM-D items 9, 10, and 11 (anxiety/agitation) compared with placebo-treated patients at Weeks 1, 2, 4, and 6 and at the endpoint. There was no statistically significant difference between the mirtazapine- and amitriptyline-treated patients at Weeks 1, 3, 4, 5, and 6 and at the endpoint. Similar results were found for the analysis of the mean of HAM-D items 10, 11, 12, 13, 15, 17 (anxiety/somatization or HAM-D Factor Score I) using all treated patients with a post-baseline evaluation in all 8 studies. Mirtazapine-treated patients demonstrated a statistically significant (p < or = .03) greater reduction at Weeks 1-6 compared with placebo, and improvement in the mirtazapine group was comparable to improvement in the amitriptyline group at Weeks 1-6. CONCLUSION: In this meta-analysis of eight randomized, double-blind, controlled clinical trials, mirtazapine was found to be superior to placebo and comparable to amitriptyline for the treatment of patients with major depression with symptoms of anxiety/agitation or anxiety/somatization.

Adolescent↗
PubMed1998

Effects of dialogue and therapeutic touch on preoperative and postoperative experiences of breast cancer surgery: an exploratory study.

PURPOSE/OBJECTIVES: To obtain preliminary data and determine the feasibility of a large-scale experimental study to test the efficacy of the Rogerian Science of Unitary Human Beings-based intervention of dialogue and therapeutic touch (TT) on pre- and postoperative anxiety and mood and postoperative pain from breast cancer surgery. DESIGN: Experimental. SETTING: Mid-Atlantic region; ambulatory. SAMPLE: 29 Caucasian and 2 African American English-speaking women with positive breast cancer biopsy (experimental, n = 14; control, n = 17), ranging in age from 31-84 years old (F = 55.6). METHODS: Treatments administered in subjects' homes within seven days prior to surgery and 24 hours after hospital discharge. Experimental treatment consisted of 10 minutes of TT and 20 minutes of dialogue. Control treatment consisted of 10 minutes of quiet time and 20 minutes of dialogue. Data (Spielberger State-Trait Anxiety Inventory. Affects Balance Scale, and Visual Analog Scale-Pain) were collected at the conclusion of each home visit. MAIN RESEARCH VARIABLES: Anxiety, mood, and pain. FINDINGS: The experimental group had lower preoperative state anxiety than the control groups (p = 0.008). No difference was found for preoperative mood. No differences were found for any postoperative measure. CONCLUSIONS: A large-scale study of dialogue and TT would require changes in design and recruitment strategies. IMPLICATIONS FOR NURSING PRACTICE: Nurses may provide more comprehensive care by incorporating dialogue and TT or quiet time into their pre- and postoperative care. Additional research, however, is recommended to determine the differential effects of dialogue, TT, and quiet time on women's experiences with breast cancer prior to incorporating these noninvasive modalities into clinical practice.

Adult↗
PubMed1998

Nursing assessment and intervention for adult hemodialysis patients: application of Roy's Adaptation Model.

A comprehensive assessment tool and intervention typology for adult hemodialysis patients, based on the Roy Adaptation Model, is presented. The Roy model is reviewed, and examples from the assessment tool and intervention typology are presented. A case study illustrates application of the tool and typology to nephrology nursing. Comparison of the tool and typology with the ANNA Standards of Clinical Practice revealed that the Roy Adaptation Model includes additional important aspects of nephrology nursing practice.

Adaptation, Physiological↗
PubMed1998

The Inventory of Functional Status-Dialysis: development and testing.

OBJECTIVE: Development and psychometric testing of the Inventory of Functional Status-Dialysis (IFS-Dialysis), which was designed to measure functional status in persons who are receiving chronic incenter hemodialysis treatment. DESIGN: Three-phase instrument development design: Phase 1--content validity assessment; Phase 2--examination of internal consistency reliability; Phase 3--examination of construct validity. SAMPLE/SETTING: 175 chronic hemodialysis patients recruited from an urban, free-standing, outpatient dialysis center. METHODS: Content validity was determined using Popham's average congruency proceudre. Internal consistency reliability was determined using Cronbach's alpha reliability coefficient. Construct validity was examined by bivariate correlations between the IFS-Dialysis and the Karnofsky Performance Scale (KPS), and the Medical Outcomes Study Short Form-36 Health Survey (SF-36) in a subsample of 60 patients. RESULTS: Content validity was established at 90%. The alpha reliability coefficient for the IFS-Dialysis was 0.86. Subscale alpha coefficients ranged from 0.71-0.82. Correlation between the IFS-Dialysis and the KPS was 0.55. Correlations between the IFS-Dialysis and SF-36 subscales ranged from 0.14-0.53. CONCLUSIONS: The IFS-Dialysis has acceptable content validity, internal consistency, and initial construct validity. Use of the IFS-Dialysis in clinical practice is appropriate.

Activities of Daily Living↗
PubMed1997

Suicide: a four-pathway clinical-biochemical model.

This chapter, based on a review of recent research as well as data presented in this report, proposes four hypothetical pathways leading to suicide in clinical depression: (1) an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor (CRF or CRH) levels, (2) trait baseline and reactivity hopelessness, (3) severe anhedonia, and (4) trait impulsiveness associated with low brain serotonin turnover and low total cholesterol as a possible peripheral correlate. Clinical research showing evidence for acute versus chronic high-risk suicide factors and other studies linking severe anxiety/agitation to high CRF levels will be presented as associated with acute suicidal risk, which is potentially reversible with recognition and treatment. Evidence for anhedonia severity as a risk factor and trait, as well as evidence that baseline hopelessness and sensitivity are traits related to chronic suicide risk, will be presented. Finally, evidence relating low serum cholesterol to suicide in depressed inpatients will be presented in the context of literature suggesting a relationship between low serum cholesterol and violent death and suicide in population studies. Data suggesting a relationship between low serum cholesterol and decreased CSF 5-HIAA, suggesting reduced serotonin turnover, will be presented, in light of prior studies relating low CSF 5-HIAA and violent suicide. These data taken together suggest four pathways to suicide that are worth investigating in order to better understand the mechanisms leading to this behavior. Future possibilities and applications of these findings are discussed.

Cholesterol↗
PubMed1997

Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis.

We have asked whether p75(NTR) may play a role in neuronal apoptosis by producing transgenic mice that express the p75(NTR) intracellular domain within peripheral and central neurons. These animals showed profound reductions in numbers of sympathetic and peripheral sensory neurons as well as cell loss in the neocortex, where there is normally little or no p75(NTR) expression. Developmental loss of facial motor neurons was not observed, but induced expression of the p75(NTR) intracellular domain within adult animals led to increased motor neuron death after axotomy. Biochemical analyses suggest that these effects were not attributable to a p75(NTR)-dependent reduction in trk activation but instead indicate that the p75(NTR) intracellular domain may act as a constitutive activator of signaling cascades that regulate apoptosis in both peripheral and central neurons.

Animals↗
PubMed1997

Division of labor of Schwann cell integrins during migration on peripheral nerve extracellular matrix ligands.

Myelination of the peripheral nervous system (PNS) requires the migration of Schwann cells during both development and regeneration. We have characterized the expression pattern of Schwann cell integrins and analyzed their role in migration on different ECM substrates known to be present within the PNS. We found that Schwann cells in cell culture express four beta1 integrins, alpha1 beta1, alpha2 beta1, alpha6 beta1, and another unidentified beta1 integrin, as well as two alpha v integrins, alpha v beta3 and alpha v beta8. Using the Varani migration assay, we found that laminin-1, laminin-2 (merosin), and fibronectin increased Schwann cell migration, while vitronectin and collagen did not increase migration compared to an uncoated plastic substrate. Schwann cell migration on laminin-1 and laminin-2 (merosin) was blocked by antibodies against beta1 integrins, but not affected by RGD peptides or antibodies against beta3 integrins. In contrast, migration on fibronectin was unaffected by antibodies against beta1 and beta3 integrins but was blocked by RGD peptides. This in vitro study shows that there is a division of labor of Schwann cell integrins in the regulation of migration on peripheral nerve ECM components; beta1 integrins mediate migration on laminin-1 and laminin-2 (merosin), while alpha v integrins mediate migration on fibronectin. Taken together, these results suggest that multiple interactions between Schwann cell integrins and ECM within the PNS will contribute to Schwann cell migration during myelination of the PNS.

Animals↗
PubMed1997

Effect of support groups with coaching on adaptation to early stage breast cancer.

The effects of 8-week cancer support groups (CSGs) with and without coaching on adaptation were tested in a sample of 181 women with newly diagnosed early stage breast cancer. CSG participation with coaching resulted in higher quality of relationship with significant other at CSG conclusion; this effect was not sustained 8 weeks later. CSG participation had no effect on symptom distress, emotional distress, or functional status. On average, symptom distress was low, emotional distress was moderate, and functional status was relatively high. Independent of CSGs, symptom distress decreased and functional status increased over time from entry into the study to 16 weeks later. Further research is needed to determine the optimal starting time and length for CSGs.

Adaptation, Psychological↗