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Biomedical subjects

M E Thompson

Publications and source records attributed to M E Thompson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Growth retardation and tumour inhibition by BRCA1.

Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the role of BRCA1 in sporadic breast and ovarian cancer has previously been elusive. Here, we show that retroviral transfer of the wild-type BRCA1 gene inhibits growth in vitro of all breast and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1 has no effect on growth of breast cancer cells; ovarian cancer cell growth is not affected by BRCA1 mutations in the 5' portion of the gene, but is inhibited by 3' BRCA1 mutations. Development of MCF-7 tumours in nude mice is inhibited when MCF-7 cells are transfected with wild-type, but not mutant, BRCA1. Most importantly, among mice with established MCF-7 tumours, peritoneal treatment with a retroviral vector expressing wild-type BRCA1 significantly inhibits tumour growth and increased survival.

Animals↗
PubMed1996

BRCA1 is secreted and exhibits properties of a granin.

Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer. However, the function of the BRCA1 protein has remained elusive. We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family. Interestingly, BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are post-translationally glycosylated and are responsive to hormones. As a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products.

Amino Acid Sequence↗
PubMed1996

Medical compliance and its predictors in the first year after heart transplantation.

BACKGROUND: Although poor medical compliance is a major risk factor for morbidity and mortality after heart transplantation, no prospective data are available on rates of noncompliance with each component of the posttransplantation regimen. Little is known about the impact of health history, sociodemographic, or perioperative psychosocial variables on long-term compliance. METHODS: Compliance in eight domains was examined in a cohort of 101 heart recipients followed through the first year after transplantation. Patients received detailed interviews at 2, 7, and 12 months after transplantation. Additional corroborative information was obtained from family member interviews and nurse evaluations. Potential predictors of noncompliance were obtained from medical record reviews and from initial patient interviews. Predictors pertained to cardiac-related history, psychiatric history, sociodemographic variables, and perioperative psychosocial status (psychologic adaptation, social supports, coping strategies). RESULTS: Although degree of noncompliance varied across timepoints, rates of persistent noncompliance during the year were as follows: 37% (exercise); 34% (monitoring blood pressure); 20% (medications); 19% (smoking); 18% (diet); 15% (having blood work completed); 9% (clinic attendance); and 6% (heavy drinking). Compliance in most areas worsened significantly (p < 0.05) over time. Background health-related and sociodemographic characteristics showed no significant influence on any area of posttransplantation compliance. Perioperative psychosocial characteristics were strong and significant predictors of noncompliance. CONCLUSIONS: Pretransplantation screening for background and demographic variables may have limited utility for compliance outcomes. Strategies to improve compliance should focus on psychosocial risk factors pertaining to early psychologic reactions to transplantation, the quality of family relationships, and patients' styles of coping. These risk factors are each potentially modifiable through appropriate educational and supportive interventions.

Adolescent↗
PubMed1995

Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.

We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression.

Alleles↗
PubMed1994

Purification and characterization of O-acetylserine sulfhydrylase isoenzymes from Datura innoxia.

Three isoenzyme forms (designated A, B, and C) of O-acetylserine sulfhydrylase were purified from Datura innoxia suspension cultures. Isoenzyme A is the most abundant form, comprising 45-60% of the total activity. Isoenzymes C and B comprise 35-40% and 10-20% of the activity, respectively. The specific activities of the purified isoenzymes are similar (870-893 mumol of cysteine/min/mg of protein). Molecular masses for isoenzymes A, B, and C, estimated by analytical size exclusion high performance liquid chromatography, are 63, 86, and 63 kDa, respectively. Isoenzymes A and B are homodimers; isoenzyme C is a heterodimer. Spectral analysis indicates that these isoenzymes possess a pyridoxal 5'-phosphate cofactor that binds the O-acetylserine substrate. Binding is reversible by addition of the sulfide substrate. The O-acetylserine sulfhydrylase isoenzymes are active over a broad temperature range, with maximum activity between 42 and 58 degrees C. They are active only between pH 7 and 8, with optimal activity at pH 7.6. Kinetic analysis indicates these enzymes are allosterically regulated and exhibit positive cooperativity with respect to both substrates. They are inhibited by sulfide concentrations above 200 microM. The kinetic analysis together with the physical and spectrophotometric characteristics indicate that the O-acetylserine sulfhydrylase enzymes have two active sites.

Cells, Cultured↗
PubMed1994

Psychosocial predictors of vulnerability to distress in the year following heart transplantation.

This study examines psychological symptomatology in a cohort of 72 heart transplant recipients followed longitudinally during their first year post-transplant. In keeping with research on other domains of life stressors and illnesses, a central study goal was to identify pre-transplant and perioperative psychosocial factors associated with increased vulnerability to, and maintenance of, elevated psychological distress levels post-transplant. Average anxiety and depression levels, but not anger-hostility symptoms, were substantially elevated in the early post-transplant period, relative to normative data. Average symptom levels improved significantly over time, although one-third of the sample continued to have high distress levels at all follow-up assessments. Recipients with any of seven psychosocial characteristics at initial interview were particularly susceptible to continued high average distress levels over time: a personal history of psychiatric disorder prior to transplant; younger age; lower social support from their primary family caregiver; exposure to recent major life events involving loss; poor self-esteem; a poor sense of mastery; and use of avoidance coping strategies to manage health problems. Recipients without such factors showed improvement in average distress levels across the assessment period. These effects were stronger for anxiety than depressive symptoms, with the exception of a sizeable relationship between loss events and subsequent depression. The findings suggest that clinical interventions designed to minimize prolonged emotional distress post-transplant need to be closely tailored to heart recipients' initial psychosocial assets and liabilities.

Adaptation, Psychological↗
PubMed1994

Transcriptional regulation of secretogranin II and chromogranin B by cyclic AMP in a rat pheochromocytoma cell line.

When PC-12 cells were treated with 10 microM forskolin, the expression of two members of the granin family, secretogranin II (SgII) and chromogranin B (CgB), were differentially regulated. SgII mRNA levels declined progressively after forskolin treatment to reach a level of 22 +/- 1% of control after 48 hr, whereas CgB mRNA levels increased more rapidly, reaching a maximum of 3-fold above control after 24 hr. The dependence of these changes on an increase in cellular cAMP levels, activation of cAMP-dependent protein kinase (PKA), protein synthesis, and changes in the rate of transcription was investigated. The effects of forskolin on SgII and CgB mRNAs were reproduced by 1 mM 8-bromo-cAMP but not by 10 microM 1,9-dideoxyforskolin, an inactive analog of forskolin. The actions of forskolin on SgII and CgB mRNAs were blocked by treatment with 60 microM H-89, a selective PKA inhibitor, and were blunted in PKA-deficient PC-12 cell clones. To examine whether forskolin action was dependent on ongoing protein synthesis, PC-12 cells were treated with 1 microgram/ml cycloheximide before the addition of forskolin. The reduction in SgII mRNA levels by forskolin was not evident in PC-12 cells treated with cycloheximide. Rather, in the presence of cycloheximide, forskolin stimulated SgII mRNA levels 3.6 +/- 0.7-fold above control. The induction of CgB mRNA by forskolin was not affected by cycloheximide treatment. The superinduction of SgII mRNA by cycloheximide and forskolin was related to the extent of protein synthesis inhibition, was observed in cells treated with forskolin and other protein synthesis inhibitors, and was blunted in PKA-deficient PC-12 cells, suggesting that this effect was dependent on inhibition of protein synthesis and activation of PKA. To determine whether changes in SgII and CgB mRNA levels resulted from changes in the rate of transcription, nuclear run-on assays were performed in nuclei isolated from PC-12 cells that had been treated for 2 hr with cycloheximide, forskolin, or the two combined. Transcription of the SgII gene was not significantly affected by treatment with either forskolin or cycloheximide alone but was increased 12.9 +/- 1.0-fold above control in nuclei from cells treated with cycloheximide and forskolin together. Forskolin caused a 3.8 +/- 0.8-fold induction of CgB transcription.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1993

A log-linear relationship between reported impairments and age: implications for the multistage hypothesis.

The relationship of mortality rates with age can be represented by a log-linear (Gompertz-type) plot and also, slightly less satisfactorily, by a log-log plot. Similar relationships are observed for incidence rates for a number of specific diseases. For a case where the log-log plot seems preferable, a multistage model is often invoked to explain this relationship. This study investigated the relationship between rates of various impairments and age. Both log-linear and log-log plots of data from the HALS study are compared. Because impairment rates are essentially prevalence rates, models explaining linearity in these plots are different from those used for incidence rates; however, a multistage model with independent events occurring simultaneously may apply.

Activities of Daily Living↗
PubMed1992

Hyperuricemia and gout among heart transplant recipients receiving cyclosporine.

PURPOSE: To determine the frequency and characteristics of hyperuricemia and gouty arthritis among cyclosporine-treated heart transplant recipients. PATIENTS AND METHODS: One hundred ninety-six surviving adult heart or heart/lung transplant recipients were evaluated. Medical records were reviewed to determine peak serum uric acid levels after transplantation, and to evaluate potential risk factors for hyperuricemia. Patients were surveyed by postal questionnaire for a history of gouty arthritis, with positive responses evaluated by telephone interview and/or examination of the patient. RESULTS: Hyperuricemia occurred in 72% of male and 81% of female patients and was not correlated with cyclosporine level, presence of hypertension, or degree of renal insufficiency. Eleven (6%) patients had gout prior to transplantation; 14 (8%) had onset of definite gout and seven (4%) had probable gout a mean of 17 months after transplantation. Polyarticular arthritis and/or tophi developed in six (43%) of the posttransplant-onset definite gout group within a mean of 31 months. CONCLUSION: Both hyperuricemia and gouty arthritis occur with increased frequency among cyclosporine-treated heart or heart/lung transplant recipients. The clinical course of gout in these patients is often accelerated, with management complicated by the patients' renal insufficiency and interaction with transplant-related medications.

Arthritis, Gouty↗
PubMed1992

Differential regulation of chromogranin B/secretogranin I and secretogranin II by forskolin in PC12 cells.

The factors which regulate the expression of the granin family of secretory proteins have yet to be completely described. The present study investigated the effects of forskolin (FSK), an activator of adenylate cyclase, on the regulation of chromogranin B/secretogranin I (CgB) and secretogranin II (SgII) mRNA levels in rat PC12 cells. PC12 cells were treated with 10 microM FSK for time points up to 48 h and were harvested for cAMP determination, RNA isolation and Northern blot analysis, or fixed in 4% paraformaldehyde for immunocytochemistry. Cellular cAMP levels peaked after two h of FSK treatment and remained elevated for 48 h. Chromogranin B mRNA increased with FSK treatment, reaching a maximum of 7-fold above control after 24 h, while the level of SgII mRNA decreased to a level of 65 +/- 10% of control after 48 h. The effects of FSK on CgB mRNA appear to be mediated by cAMP, as 8-bromo-cAMP (500 microM) resulted in a 2.8-fold increase in CgB mRNA, and H-89 (30 microM), a selective inhibitor of cAMP-dependent protein kinase, reduced the FSK-mediated response. The level of CgB was also increased in FSK-treated cells, as evidenced by immunofluorescent analysis which showed a more intense staining in PC12 cells treated with FSK for 48 h than in untreated cells. The intensity of SgII staining was diminished by FSK treatment, most likely a result of a decreased rate of synthesis as well as an increase in the release of SgII. This study demonstrated that the mRNA and protein levels of CgB and SgII are differentially regulated by cAMP in PC12 cells.

Amino Acid Isomerases↗
PubMed1992

Prolactin granulogenesis is associated with increased secretogranin expression and aggregation in the Golgi apparatus of GH4C1 cells.

The GH4C1 pituitary tumor cell line (GH cells) serves as a model system to study the role of the granins in the packaging of PRL into secretory granules. The number of secretory granules containing PRL and two members of the granin family, chromogranin-B (CgB) and secretogranin-II (SgII), can be hormonally manipulated. In the present study we have investigated whether 1) granulogenesis in GH cells is preceded by condensation of the granins and PRL in the Golgi; 2) granulogenesis is preceded by an increase in granin expression in GH cells; and 3) PRL and the granins aggregate in vitro under high calcium, low pH conditions. GH cells were treated for up to 3 days with 17 beta-estradiol (1 nM), insulin (300 nM), and epidermal growth factor (10 nM) and were fixed in 4% paraformaldehyde for immunocytochemistry or harvested for RNA isolation and Northern blot analysis. After 1 day of hormone treatment, there was a significant increase in staining for PRL and the granins in the Golgi apparatus, which was identified using an antibody to MG-160. After 3 days of hormone treatment, PRL and granin staining was also found in a perinuclear region that was not stained with anti-MG-160 antibody, most likely representing secretory granules. An increase in PRL and granin expression contributed to increased Golgi staining, as the steady state levels of CgB, SgII, and PRL mRNA increased 186 +/- 14%, 203 +/- 7%, and 337 +/- 5% above control levels, respectively, within 6 h after hormone treatment. An in vitro aggregation system was used to determine whether PRL and the granins coprecipitate under high calcium, low pH conditions, which are thought to be characteristic of the trans-Golgi and secretory granules. Aggregation of the granins CgB and SgII was negligible during overnight dialysis against a buffer containing 150 mM NaCl and 10 mM 2[N-morpholino]ethanesulfonic acid-NaOH (pH 5.5) in the absence of calcium. There was significant aggregation of PRL under these conditions. When dialysis was performed in the presence of 10 mM CaCl2, PRL, CgB, and SgII coaggregated. This study indicates that increased expression and aggregation of the granins is associated with PRL granulogenesis in hormone-treated GH cells. However, the role of the granins may not be obligatory, as some cells can store PRL in the absence of detectable levels of CgB and SgII, and PRL has the capacity to self-aggregate.

Animals↗
PubMed1992

Indices of hearing in patients with central auditory pathology. II. Choice response time.

The response times of three groups of subjects with pathology of the auditory pathway, localized either to the eighth nerve or to the right or left temporal cortex, were compared on three psychoacoustic tasks. These tasks included detection, frequency discrimination and duration discrimination. Measurements were made at two stimulus frequencies, 500 and 2000 Hz, in combination with two durations, 50 and 300 ms. The results were compared to those obtained for normal hospitalized and non-hospitalized control subjects. All subjects, except those with acoustic neuroma, had age-corrected normal hearing. Statistically significant group differences were apparent in discrimination but not detection, indicating the importance of task demands for response time measures, especially in patients with cortical pathology. The outcomes were not related to neuropsychological measures of speed or accuracy, supporting the conclusion that the time for decision-making rather than motor function had been affected.

Auditory Cortex↗
PubMed1992

Indices of hearing in patients with central auditory pathology. I. Detection and discrimination.

This paper describes the effect of site of lesion on auditory detection, discrimination and speech processing. Three groups of ten patients with confirmed pathology of the eighth nerve and right and left temporal cortex and two normal-hearing control groups, differing with respect to hospitalization, participated. In each of the fifty subjects, measurements were made of detection thresholds, and difference limens for frequency and duration for 50 and 300 ms pure tones of 500 Hz and 2000 Hz. Consonant discrimination was assessed using the Four Alternative Auditory Feature Test (Foster & Haggard, 1979), presented in quiet. Subjects with left temporal pathology had the largest frequency and duration difference limens. Those with either left temporal or eighth nerve pathology had significantly lower speech intelligibility scores that were correlated with the duration difference limen for short stimuli and detection thresholds, respectively. These findings challenge traditional views of cortical processing and highlight differences between peripheral and central mediators of speech processing.

Adult↗
PubMed1991

Treatment and career attitudes of prehospital care providers associated with potential exposure to HIV/AIDS.

Career and treatment attitudes related to potential human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) exposure are reported based on a survey of 1,228 Maryland career and volunteer prehospital care providers trained to provide basic (BLS) and advanced (ALS) life support. Sixty-five percent stated potential exposure to HIV/AIDS was a major occupational stressor. Ninety-two percent stated they would treat HIV/AIDS patients if protected. Given a choice, 38% would avoid providing treatment to HIV/AIDS patients. Eighteen percent considered resigning from emergency medical services (EMS) work. An attitudinal scale (AIDSTRESS) was developed to evaluate overall treatment and career reactions. Respondents with significantly higher (more negative reactions) AIDSTRESS scores were: BLS providers, men, paid providers, personnel with more than 3 years of field experience, those working in urban areas, personnel with no formal education beyond high school, and those who stated that their HIV/AIDS training was inadequate. Implications of the findings for quality of care, career decision making, and inservice education are discussed.

Adolescent↗
PubMed1991

Reversible control of oestradiol-stimulated growth of MCF-7 tumours by tamoxifen in the athymic mouse.

We investigated the ability of high concentrations of oestradiol to reverse the growth inhibitory action of tamoxifen on MCF-7 breast cancer cells in vivo. Tamoxifen inhibits the oestradiol stimulated growth of MCF-7 cells in athymic mice. Using a sustained release preparation of tamoxifen we consistently achieved serum concentrations of the drug in the 40 to 50 ng ml-1 range and much higher levels in tissues. These serum levels are sufficient to inhibit the oestrogen stimulated growth of MCF-7 tumours exposed to physiologic (i.e. 300-600 pg ml-1 serum oestradiol concentrations). However, by administering dosages that increase serum oestradiol concentrations to 900-2000 pg ml-1, mimicking the increase often observed clinically in premenopausal women taking tamoxifen, we show that the growth inhibitory action of tamoxifen can be partially reversed. Serum tamoxifen levels were elevated to nearly 400 ng ml-1 by injecting 1 mg day-1 tamoxifen (IP 3 x weekly); this dosage was more effective at inhibiting oestradiol stimulated tumour growth than subcutaneous tamoxifen capsules alone. Our data suggest that at low serum levels tamoxifen may not act optimally. There may be a need to monitor tamoxifen levels in premenopausal patients to ensure that they are high enough not to be overcome by a tamoxifen induced increase in ovarian steroidogenesis.

Animals↗
PubMed1990

Cyclosporine nephrotoxicity in cardiac allograft patients--a seven-year follow-up.

Renal function was observed retrospectively in a population of 228 adults who underwent a cardiac allograft at the University of Pittsburgh from June 1980 through June 1987, survived a minimum of one year, and received cyclosporine. Renal function was determined by serial measurement of serum creatinine concentration. Serum creatinine rose from 1.2 +/- 0.0 mg/dl at time of hospital discharge to 2.0 +/- 0.0 mg/dl at two and four years and 3.3 +/- 0.1 mg/dl at seven years. The fall in renal function was biphasic, with a rapid decline (reciprocal creatinine slope -0.018 dl/mg-mo) through 24 months and a slower decline thereafter -0.0036 dl/mg/month). This occurred despite a progressive decrease in cyclosporine levels from 668 +/- 23 ng/ml (whole blood RIA) to 380 +/- 12 ng/ml at seven years. Three of 222 patients (1.6%) developed end-stage renal disease within 18 months of initiation of cyclosporine therapy. Only one additional patient of 26 followed through 54 months (3.8%) developed end-stage disease thereafter. The decline in renal function seen with cyclosporine is rapid in the first 18 months, with a slower but continuing decline seen with later follow up. At least in heart transplantation, the risk of end-stage renal disease is significant, but not prohibitive.

Adult↗