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Biomedical subjects

J Fawcett

Publications and source records attributed to J Fawcett.

At least 91 records · Page 5Linked to original sources
PubMed1997

Synaptic innervation density is regulated by neuron-derived BDNF.

In this report, we have examined the role of neuron-derived BDNF at an accessible synapse, that of preganglionic neurons onto their sympathetic neuron targets. Developing and mature sympathetic neurons synthesize BDNF, and preganglionic neurons express the full-length BDNF/TrkB receptor. When sympathetic neuron-derived BDNF is increased 2- to 4-fold in transgenic mice, preganglionic cell bodies and axons hypertrophy, and the synaptic innervation to sympathetic neurons is increased. Conversely, when BDNF synthesis is eliminated in BDNF -/- mice, preganglionic synaptic innervation to sympathetic neurons is decreased. Together these results indicate that variations in neuronal neurotrophin synthesis directly regulate neuronal circuitry by selectively modulating synaptic innervation density.

Animals↗
PubMed1997

Effect of insulin-like growth factor binding proteins on the response of proximal tubular cells to insulin-like growth factor-I.

The insulin-like growth factor binding proteins (IGFBP) are major modulators of insulin-like growth factor-I (IGF-I) action, but relatively little is known about their production by kidney tubular cells or about their modulating effects on the action of IGF-I on these cells. In this study we demonstrated that rabbit proximal tubular cells express the genes for IGFBP-2, -4 and -5 and secrete 24 and 32 kDa size binding proteins. The rate of IGFBP production by these cells was regulated by several growth factors including hydrocortisone, which was potently stimulatory, and EGF, which was inhibitory. The overall effect of these kidney cell-secreted IGFBPs was to inhibit the mitogenic activity of IGF-I. Similarly, recombinant IGFBP-3, the major circulating IGFBP that in kidney is produced close to the proximal tubules, also inhibited IGF-I stimulated DNA synthesis in cultured rabbit proximal tubular cells and in cultured opossum kidney (OK) cells. IGFBP-3 also inhibited basal DNA synthesis in OK cells in the absence of added IGF-I, suggesting that this IGFBP may have an IGF-I independent action. These findings highlight the important effect that IGFBPs have on the action of IGF-I on kidney cells and support the notion that the changes in IGFBPs observed in various renal diseases may contribute to the pathophysiology of these diseases.

Animals↗
PubMed1997

Fluoxetine and norfluoxetine plasma concentrations in major depression: a multicenter study.

OBJECTIVE: Prior studies examining the relationship between fluoxetine plasma concentrations and response in major depression have either found no relationship between plasma concentration and response or suggested a curvilinear relationship with a therapeutic window. To elucidate this relationship, plasma concentrations of fluoxetine, norfluoxetine, fluoxetine plus norfluoxetine, and fluoxetine/norfluoxetine ratio were compared to therapeutic response. METHOD: A total of 839 patients (577 women, 262 men; mean age = 40 [SD = 11] with a DSM-III-R diagnosis of major affective disorder who were in the course of either depression or bipolar disorder not otherwise specified and had a minimum baseline score of 16 on the 17-item Hamilton Depression Rating Scale were initially treated. Response was defined as follows: 1) nonresponders had less that a 50% or more reduction from baseline Hamilton depression score, 2) nonremitting responders had a 50% or more reduction from baseline Hamilton depression score but a final score higher than 7, and 3) remitters had a final Hamilton Depression score of 7 or lower. Plasma fluoxetine and norfluoxetine concentrations were measured after 8 weeks of fixed-dose treatment of 20 mg/day. RESULTS: Plasma concentration data were available from 615 patients. Plasma concentration were similar in responders, both remitting and nonremitting (N = 411), and nonresponders (N = 204) for fluoxetine concentrations, for norfluoxetine concentrations, as well as for the sum of fluoxetine and norfluoxetine and for the ratio of fluoxetine to norfluoxetine. No apparent relationship was observed between plasma drug concentration and clinical response. CONCLUSION: Plasma concentrations of fluoxetine and norfluoxetine do not appear to be related to clinical outcome and should not be used to make treatment decisions.

Adult↗
PubMed1997

Nuclear transport of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in opossum kidney cells.

When added to cultured opossum kidney cells, IGF-I is internalized and transported to distinct intracellular compartments that depend on the cell location within the monolayer. In resting cells away from the periphery of the monolayer, IGF-I is internalized by a clathrin coated pit pathway and delivered to the endosomal compartment. In contrast, cells growing at the edges of a monolayer or an experimental wound internalize IGF-I by an alternative route which rapidly delivers IGF-I to the nucleus. Similarly to IGF-I, IGFBP-3 is also internalized and accumulates in the endosomal compartment in resting cells whereas it is targeted to the nucleus in proliferating cells. IGFBP-3, which contains a putative nuclear targeting signal, may act as a carrier for IGF-I nuclear transport. The transport of IGF-I and IGFBP-3 to two different compartments may influence their biological activity.

Animals↗
PubMed1997

Efficacy issues with antidepressants.

Clinical trials of antidepressant medications have shown that, overall, these drugs are effective, as measured by a > or = 50% decrease in Hamilton Rating Scale for Depression (HAM-D) total scores in about two thirds of patients. However, the results of long-term trials under rigorously controlled conditions show that, even with close follow-up and provision of interpersonal psychotherapy, a third or more of the patients will not achieve or maintain a response to medication for depression. Nevertheless, the improved efficacy of some antidepressants for certain features or types of depression has been shown. Factors associated with a better response to a specific agent or class of drugs include severity of symptoms, patient age, and the symptom profile of the depressive episode, as revealed by assessment scales or subscale scores for selected symptoms. Moreover, a number of studies indicate that a patient's early response to a given medication may assist in predicting long-term outcome. However, outcome measures in traditional trials of antidepressant drug efficacy, such as a 50% reduction in scores on one or more depression rating scales, do not necessarily reflect an improvement in the patient's ability to function in the workplace; they only show that a particular patient at a particular time has responded to treatment in a significant manner by measurement of a depression scale.

Absenteeism↗
PubMed1997

The detection and consequences of anxiety in clinical depression.

Anxiety symptoms and comorbid anxiety are common in depressive syndromes, and there is evidence they are associated with increased severity of depression and a poorer outcome. Anxiety and agitation symptoms also appear to be an acute risk factor for suicide in patients who have major affective disorder, an observation that has been supported by a number of biological correlates. Rapid and aggressive treatment of these anxiety/agitation symptoms with suitable antidepressants or benzodiazepines should be considered in order to avoid the immediate risk of suicide and to permit successful treatment of the affective disorder.

Adult↗
PubMed1997

Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory.

Rates of antidepressant-associated treatment emergent changes in sexual function and satisfaction vary with method of ascertainment. We used the Rush Sexual Inventory (RSI) to assess the effect of SSRIs on sexual function and satisfaction. The RSI is a comprehensive, succinct, patient-rated scale designed to provide an accurate depiction of premorbid, current, and followup changes in sexual function and satisfaction. We assessed 42 outpatients, diagnosed with major depressive disorder with or without comorbid obsessive-compulsive disorder, over their first 8 weeks of treatment with paroxetine 20 mg/day, sertraline 50-200 mg/day, or fluoxetine 20-60 mg/day. Males and females were found to experience similar rates of treatment emergent sexual dysfunction at 60 percent and 57 percent, respectively. Despite the same mechanism of action, medication treatment groups experienced varying levels of changes in sexual function and satisfaction over time. No variation existed between responders and nonresponders over time.

1-Naphthylamine↗
PubMed1996

Two-dimensional separation and cloning of chromosome 1 NotI-EcoRV-derived genomic fragments.

The two-dimensional (2-D) separation of genomic digests has provided the means to analyze over 2000 unique restriction fragments simultaneously in a single gel, for genetic variation as well as for genomic alterations in cancer. By utilizing different combinations of restriction enzymes or different electrophoretic conditions, the number of analyzable fragments in multiple 2-D patterns can be augmented. We have previously shown the feasibility of distinguishing between spot intensities representing fragments from one allele and from two alleles and have implemented approaches for the cloning of fragments of interest in 2-D gels. In this study, the 2-D separation and cloning of chromosome 1 NotI-EcoRV-derived genomic fragments was performed. Three hundred forty-six NotI fragments in whole genomic preparations were assigned to chromosome 1. To verify the reliability of the assignment, two of the NotI fragments attributed to chromosome 1 were cloned and sequenced. The fragments that contained CpG islands were mapped by FISH to 1p35-p36.1 and to 1p13.3-p21, respectively. Our study indicates the feasibility of analyzing 2-D separations of whole genomic digests for the detection of alterations in specific chromosomes. The large number of restriction fragments attributed to chromosome 1 provides the means to screen 2-D patterns for chromosome 1 deletions and amplifications with a high marker density.

Cell Line↗
PubMed1996

The deleted in colon cancer (DCC) gene is consistently expressed in colorectal cancers and metastases.

The DCC (deleted in colorectal cancer) gene was originally identified as a candidate tumour suppressor gene in colon carcinogenesis on the basis of allelic losses in chromosome 18q.21 in 70% of colon cancers. Reverse transcriptase polymerase chain reaction (RT-PCR) of DCC mRNA suggests that DCC expression may also be reduced in colon cancers. We have used monoclonal antibodies generated against the DCC immunoglobulin-like domain to investigate DCC isoforms and DCC protein expression during colon cancer progression. Normal mucosa and colonic tumour specimens representative of the range of colonic tumour progression from benign adenomatous polyps to metastases were compared by Western blot analyses. We show that while M(r) 194 000 DCC is present in normal colonic mucosa and adenomatous polyps, it is also similarly expressed in colorectal carcinomas and colonic metastases in the liver. The presence of DCC protein is consistent with the presence of DCC mRNA transcripts in the same tissue specimens. Notably DCC was not completely lost in any colonic tumour specimens examined, even those that had progressed to metastatic cancers. Quantitation of DCC protein expression in tissue specimens by densitometry demonstrated that both normal and malignant specimens exhibit a wide range of DCC protein levels and there was no significant correlation between diminished DCC protein expression and colon cancer progression. These results demonstrate the pattern of expression of the DCC gene product in colonic tumour progression and show that absence of DCC expression is not associated with colonic tumour progression.

Base Sequence↗
PubMed1996

Late reflush in clinical renal transplantation. Protection against delayed graft function not observed.

Mechanical flushing of cadaveric kidneys with organ preservation fluid immediately before transplantation has been reported to be associated with improved early graft function. We report here the results of a prospective randomized controlled study of cadaveric renal transplantation after late reflush with organ preservation fluid in which no benefit with respect to delayed graft function was observed and, indeed, the protocol may have been harmful. The study was terminated after recruitment of only 18 patients (9 to each arm) because postreperfusion biopsies of reflushed kidneys contained unusual features, including abnormal cellular debris within the tubules or eosinophilic proteinaceous material within Bowman's capsule. These features were not present in the control kidneys. Acute tubular necrosis and biopsy-proven acute rejection episodes were more frequently seen in the reflushed kidneys, but at 1 year there was no significant difference in the function of the surviving grafts.

Adult↗
PubMed1996

Processing of 125I-insulin by polarized cultured kidney cells.

Renal clearance of insulin is achieved by glomerular filtration and by passage from the postglomerular peritubular circulation into the renal interstitium. In the proximal tubule, filtered insulin binds to the apical membrane and is internalized and degraded while insulin in the interstitium is taken up by receptor-mediated endocytosis and degraded. To study these processes we have utilized cultured opossum kidney cells. These cells have proximal-like features and process insulin in a manner consistent with that described in vivo. To study apical and basolateral uptake and metabolism of insulin independently, cells were grown on filters suspended in culture wells. insulin was degraded to large insulin-size intermediates and low-molecular-weight products. This occurred whether the protein was internalized from the apical or basolateral pole of the cells. Analysis of the intermediate products by reverse-phase high-performance liquid chromatography revealed that products formed after apical or basolateral internalization were similar. Since products were preferentially released from the side of uptake, it is likely that apically and basolaterally internalized insulin is degraded in comparable organelles located in different regions of the cell. Most of the internalized insulin traversed the degradative pathway but some insulin followed a retroendocytic or minor transcytotic pathway. Degradation was inhibited by chloroquine, which also selectively increased the release of internalized insulin from the apical pole irrespective of the side of uptake. Thus while the polar degradative processes appear to be similar in nature, the polar exocytotic processes appear to be different.

Animals↗
PubMed1996

Development and testing of the symptom experience scale.

The Symptom Experience Scale (SES) was designed to measure women's experience of symptoms associated with treatment for breast cancer. The SES, a modification of McCorkle's Symptom Distress Scale, was developed and tested in a sample of 252 women with breast cancer. Exploratory factor analysis yielded six factors, which used all 24 SES items and accounted for 83.2% of the variance. The factors were nausea and appetite, fatigue and sleep, concentration, appearance, bowel pattern, and pain. Cronbach's alpha internal consistency reliability coefficients ranged from 0.92 to 0.96; the alpha for the total SES was 0.94. Subscale to subscale correlations ranged from 0.21 to 0.56. Additional research is recommended with samples large enough to permit confirmatory factor analysis and determine the stability of the factor structure identified in the present study. Additional research also is recommended to determine the applicability of the SES for men and women of diverse ethnic groups with various types of cancer and other chronic illnesses.

Adult↗
PubMed1996

Stable trait components of hopelessness: baseline and sensitivity to depression.

Hopelessness (H) plays an important theoretical and practical role in depression. The authors hypothesized that a patient's H is comprised of (a) a baseline level of H when not depressed and (b) an increment in H related to the severity of depression at the time and the person's rate of increase in H as a function of severity of depression (sensitivity). Baseline and sensitivity are explanatory stable traits; H and depression are observed, time-varying states. The corresponding statistical model described well the longitudinal data of 316 participants. Baseline and sensitivity were uncorrelated and correlated with different clinical and demographic variables. Baseline predicted a future suicide attempt; sensitivity and H when depressed did not. It may be useful to ask "How hopeless is this person when not depressed and how much more hopeless is he or she when depressed?", rather than simply "How hopeless is this depressed person?"

Adolescent↗
PubMed1996

Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer.

Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression.

Alternative Splicing↗
PubMed1996

Sustained antidepressant effect of PEA replacement.

Phenylethylamine (PEA), an endogenous neuroamine, increases attention and activity in animals and has been shown to relieve depression in 60% of depressed patients. It has been proposed that PEA deficit may be the cause of a common form of depressive illness. Fourteen patients with major depressive episodes that responded to PEA treatment (10-60 mg orally per day, with 10 mg/day selegiline to prevent rapid PEA destruction) were reexamined 20 to 50 weeks later. The antidepressant response had been maintained in 12 patients. Effective dosage did not change with time. There were no apparent side effects. PEA produces sustained relief of depression in a significant number of patients, including some unresponsive to the standard treatments. PEA improves mood as rapidly as amphetamine but does not produce tolerance.

Adult↗
PubMed1996

An exploratory study of the relationship between alternative therapies, functional status, and symptom severity among people with multiple sclerosis.

Roy's Adaptation Model guided an exploratory study of the association of alternative therapies with functional status and symptoms in people with multiple sclerosis (MS). Data were collected from 16 volunteers by a telephone-administered interview schedule and a mailed questionnaire. All 16 respondents reported seeking traditional medical treatment and at least 1 alternative therapy (mode = 3, range = 1-9). The correlation between the number of alternative therapies and functional status was -.42; the greater the number of therapies used by the respondents, the lower their functional status. Qualitative data analysis revealed that functional status was enhanced by beneficial effects of specific alternative therapies, pacing oneself, changing the perception of self, and focusing on spiritual aspects of self. Self-reported MS symptoms were less severe following use of alternative therapies (p < .0005). Study of the differential effects of single and combined alternative therapies on functional status and symptom severity for large samples of people with MS is recommended.

Activities of Daily Living↗
PubMed1996

Gender differences in Wechsler performance scores of school-age children who are deaf or hard of hearing.

WISC-III and WISC-R Performance IQs and subtests and WRAT-R scores of 47 deaf or hard-of-hearing school-age children were analyzed to determine whether differences in scores were present as a function of gender. Mean differences were present on the WISC-III and WISC-R Performance IQs, with boys scoring almost a full standard deviation higher than girls, and on the Performance subtests, with boys scoring significantly higher on four of the six WISC-III subtests and four of the five WISC-R subtests. Mean differences between boys and girls were not present on the achievement scores. Discriminant and regression analyses indicated differences between boys and girls in subtests most predictive of the Performance IQ. Hypotheses suggested to account for gender differences were that (a) the factor structure of the IQ measure was different for boys and girls and (b) differential teacher referral patterns were present. Implications of findings for future research are discussed.

Child↗