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Biomedical subjects

S L Brown

Publications and source records attributed to S L Brown.

At least 91 records · Page 5Linked to original sources
PubMed1996

Preferential radiosensitization of human prostatic carcinoma cells by mild hyperthermia.

PURPOSE: Recent cell culture studies by us and others suggest that some human carcinoma cells are more sensitive to heat than are rodent cells following mild hyperthermia. In studying the cellular mechanism of enhanced thermosensitivity of human tumor cells to hyperthermia, prostatic carcinoma cells of human origin were found to be more sensitive to mild hyperthermia than other human cancer cells. The present study was designed to determine the magnitude of radiosensitization of human prostatic carcinoma cells by mild hyperthermia and to examine whether the thermal radiosensitization is related to the intrinsic thermosensitivity of cancer cells. METHODS AND MATERIALS: Two human prostatic carcinoma cell lines (DU-145 and PC-3) and other carcinoma cells of human origin, in particular, colon (HT-29), breast (MCF-7), lung (A-549), and brain (U-251) were exposed to temperatures of 40-41 degrees C. Single acute dose rate radiation and fractionated radiation were combined with mild hyperthermia to determine thermal radiosensitization. The end point of the study was the colony-forming ability of single-plated cells. RESULTS: DU-145 and PC-3 cells were found to be exceedingly thermosensitive to 41 degrees C for 24 h, relative to other cancer cell lines. Ninety percent of the prostatic cancer cells were killed by a 24 h heat exposure. Prostatic carcinoma cells exposed to a short duration of heating at 41 degrees C for 2 h resulted in a substantial enhancement of radiation-induced cytotoxicity. The thermal enhancement ratios (TERs) of single acute dose radiation following heat treatment 41 C for 2 h were 2.0 in DU-145 cells and 1.4 in PC-3 cells. The TERs of fractionated irradiation combined with continuous heating at 40 degrees C were similarly in the range of 2.1 to 1.4 in prostate carcinoma cells. No significant radiosensitization was observed in MCF-7 and HT-29 cells under the same conditions. CONCLUSION: The present data suggest that a significant radiosensitization of prostatic cancer cells could be obtained by the combined treatment of radiation and mild hyperthermia. Future clinical trials should be aimed at achieving mild heating and fractionated radiation therapy.

Combined Modality Therapy↗
PubMed1996

Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease.

BACKGROUND: Obesity is known to predispose to attenuated fibrinolysis attributable to increased concentrations in plasma of type-1 plasminogen activator inhibitor (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis. PAI-1 is present in neointimal vascular smooth muscle cells and lipid-laden macrophages. METHODS AND RESULTS: The present study was designed to determine whether PAI-1 expression occurs in adipose tissue as well, thereby potentially contributing to increased cardiovascular risk associated with obesity. 3T3-L1 preadipocytes were differentiated into adipocytes by exposing them to isobutylxanthine (0.5 mmol/L) and dexamethasone (0.25 mumol/L) over 7 days and incubated for 24 hours with transforming growth factor-beta (TGF-beta), known to augment PAI-1 synthesis in several cell types and to be released from platelets when they are activated. TGF-beta increased PAI-1 activity in the conditioned media of the 3T3-L1-derived cells in a concentration-dependent fashion without significantly affecting cell proliferation. Western blotting and immunoprecipitation of 35S-labeled PAI-1 showed that the increased PAI-1 activity paralleled increased PAI-1 protein. Northern blotting showed that increased PAI-1 mRNA preceded increased accumulation of PAI-1 activity and protein in the conditioned media. Furthermore, TGF-beta (10 ng/g body wt) administered in vivo increased PAI-1 activity in mouse plasma and PAI-1 mRNA expression in mouse adipose tissue. CONCLUSIONS: Increased plasma PAI-1 activity in obese human subjects may result from PAI-1 release from an increased mass of adipose tissue, particularly in association with thrombosis and elaboration of TGF-beta from platelet alpha-granules into the circulation. The increased PAI-1 may exacerbate vascular disease by shifting the balance between thrombosis and thrombolysis toward thrombosis and consequently exposing luminal surfaces of vessels to mitogens associated with microthrombi over protracted intervals.

Adipocytes↗
PubMed1996

Phenotypic evolution of classic 21-hydroxylase deficiency.

We describe a female patient who was diagnosed and treated at birth for a classic form of salt-losing congenital adrenal hyperplasia. At 17 years of age, against medical advice, she discontinued both mineralocorticoid and glucocorticoid replacement with no resulting clinical symptoms other than the occurrence of amenorrhoea. Steroid metabolites revealed significant abnormalities of the renin-angiotensin-aldosterone axis, as well as of pituitary-adrenal function. Analysis of our patient's DNA showed only one deleterious CYP21 mutation, an intron 2 base pair change activating a cryptic splice site. We speculate that expression of this patient's CYP21 genes may be altered by the effects of ageing or by changes in the steroid milieu.

Adolescent↗
PubMed1995

Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents.

PURPOSE: To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. METHODS AND MATERIALS: Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. RESULTS: The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 micrograms/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 +/- 0.1 and 1.3 +/- 0.1, respectively. Exposure of cells to 10 micrograms/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 +/- 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. CONCLUSION: An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors.

Acyclovir↗
PubMed1995

Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin. A potential link between lipid lowering and fibrinolysis.

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of endogenous plasminogen activators, has been implicated as a potentiating factor in atherogenesis as well as in coronary thrombosis. We and others have observed attenuation of PAI-1 expression by gemfibrozil both in vivo and in vitro. METHODS AND RESULTS: To determine whether other lipid-lowering agents with different mechanisms of action exert similar effects, we exposed Hep G2 cells, a highly differentiated human hepatoma cell line, to selected concentrations of niacin. Accumulation of PAI-1 protein, assayed with an ELISA, decreased in conditioned media by 72% in 48 hours in a specific, concentration-dependent fashion. Metabolic labeling experiments demonstrated a decrease in the rate of PAI-1 synthesis. Northern blot analysis demonstrated a preceding, parallel, and specific decrease in the concentration of PAI-1 mRNA. Niacin attenuated the increased PAI-1 synthesis induced by mediators released from thrombi as well. Thus, with 4.25 ng/mL transforming growth factor-beta 1, PAI-1 accumulation increased 4.5-fold in conditioned media in 48 hours. However, niacin attenuated the increase by 65%. Again, both the rate of PAI-1 synthesis and PAI-1 mRNA were reduced. The increased plasma PAI-1 activity and PAI-1 mRNA in liver induced by dexamethasone (0.8 mg IP) in vivo in rats were attenuated by 3 weeks of pretreatment with niacin. CONCLUSIONS: These results suggest that niacin, by decreasing PAI-1 expression, may potentiate fibrinolysis, thereby decreasing the stimulation of atherogenesis by clot-associated mitogens associated with microthrombi. Furthermore, the results imply that a pathogenetic link may exist between intracellular lipid metabolism and regulation of expression of fibrinolytic system components.

Animals↗
PubMed1995

Nicotinamide pharmacokinetics in patients.

Pharmacokinetic analyses were performed on blood samples of 12 patients undergoing treatment with nicotinamide, hyperthermia and radiation therapy for a variety of recurrent/metastatic cancers. Escalating oral doses of 3, 4, 5, 6 and 10 g of nicotinamide showed a linear relationship between maximum recorded plasma concentrations and the dose in grams (correlation coefficient, r = 0.91). Maximum plasma levels were observed by 30 min in most patients ingesting up to 6 g of nicotinamide. In marked contrast, five out of six patients ingesting 10 g of nicotinamide demonstrated increasing plasma levels at least up to 3 h post-ingestion. Doses up to 6 g were well tolerated and resulted in average maximum recorded plasma levels (mean +/- 1 SEM) of 156.4 +/- 33.6 micrograms/ml. Doses of 10 g were generally not well tolerated, but a high plasma level was maintained on average for at least 4 h. Plasma concentrations of the above order have been previously associated with maximal enhancement of radiation damage in mouse tumor models. This suggests that radiosensitization can be expected to occur in human tumors following oral administration of a safe and well tolerated dose of 6 g. However, at higher doses (i.e., 10 g), the pharmacokinetics, and perhaps radiosensitization, may differ markedly.

Administration, Oral↗
PubMed1995

Earthworms and radionuclides, with experimental investigations on the uptake and exchangeability of radiocaesium.

The potential influence of earthworm activity on the mobility of radionuclides in soils and their subsequent availability for uptake by plants and transfer to higher trophic levels is briefly reviewed. The accumulation of caesium by the earthworm Aporrectodea longa from soil and from plant litter was investigated in laboratory experiments, as was the effect of reworking (through burrowing and ingestion) soil and soil with added organic material, on the extractability of caesium (ammonium acetate extraction). Soil was spiked with (134)Cs, organic matter with (137)Cs. In soil-fed worms, most of the radioactivity measured was eliminated with the gut contents; 5-25% of the ingested radioactivity was retained or assimilated. Loss of caesium from soil-fed worms followed a two component curve, with an initial rapid loss due to gut clearance (half-life of loss (Tb1/2) of about 0.2-0.6 days) and a slower loss of assimilated caesium (Tb1/2 of 15-26 days). Loss rates of assimilated caesium from worms fed on fragmented apple leaves were found to have half-lives of 18-54 days. Assimilation of caesium from apple leaves was higher than from soil, ranging from 55-100% of the activity measured before gut clearance. Dry weight transfer factors (concentration in worm tissue/concentration in substrate) for worms cleared of their gut contents were similar for the two substrates 0.04 and 0.04 for two loss experiments with worms fed on radioactive soil, and 0.03 and 0.05 for worms fed on apple leaves. After three months of reworking soil and soil/organic mixtures, A. longa was found to have no measurable effect on the extractable fraction of caesium. If earthworms have any subtle effects they were masked by changes in availability that occurred when the spiked soil and organic substrates were mixed together. Only about half of the extractable fraction in soil was recovered when soil was mixed with organic material suggesting that some of the labile fraction in soil had become complexed with organic material. This exchange occurred in substrate mixtures with and without worms. The limitation of chemical extraction procedures is discussed and suggestions for further work are presented.

Journal Article↗
PubMed1995

Depressive symptoms in the elderly: association with total white blood cell count.

1. The white blood cell (WBC) count in those with high depressive symptoms and non-depressed participants in the Established Populations for Epidemiologic Studies of the Elderly (EPESE) were compared. 2. Of 3769 participants 10.8% had high depressive symptoms as assessed by the Centers for Epidemiologic Studies Depression (CES-D) Scale. The mean white blood cell count was higher in the high depressive symptoms group compared to the non-depressed group (6.8 +/- 0.12 x 10(9) WBC/1 and 6.5 +/- 0.03 x 10(9) WBC/1, respectively, p < 0.01). 3. Because older adults frequently have disabling chronic conditions which could both influence their leukocyte count and cause depressive symptoms, models were developed which controlled for the potential confounding. Even after adjusting for potential confounders, high depressive symptoms were still associated with higher white blood cell counts.

Adult↗
PubMed1995

Antidepressant use in the elderly: association with demographic characteristics, health-related factors, and health care utilization.

The characteristics of antidepressant use and its correlates were assessed in the four Established Populations for Epidemiologic Study of the Elderly (EPESE) communities (n = 13,074). Women were significantly more likely to be treated with an antidepressant drug than men, and African-Americans were significantly less likely than whites to be using antidepressant medication. Of the health-related measures, poor self-perceived health, polypharmacy, disabilities in activities of daily living, and a history of stroke were associated with the use of antidepressants. Each utilization of health care variable, (number of doctors visits, overnight hospitalization in the past year, and use of a regular doctor), was associated with antidepressant use in at least two of the four communities. After entering variables in a multivariate regression model, higher antidepressant use was significantly associated with female gender, race, poor self-perceived health, and a greater number of contacts with doctors in the past year.

Aged↗
PubMed1995

The neuroendocrine challenge paradigm in headache research.

The neuroendocrine challenge paradigm provides a "window" on central neurotransmitter function in vivo. This strategy is based on the premise that the sensitivity of certain central receptors can be inferred from the magnitude of the hormonal response to specific pharmacologic probes. For example, the serotonin (5HT) receptor agonist m-chlorophenylpiperazine (m-CPP) stimulates the release of cortisol and prolactin and induces migraine-like headaches. We have previously reported that the headache and cortisol responses to m-CPP are highly correlated, which may implicate a disturbance in central serotonergic neurotransmission in the pathogenesis of migraine. As pharmacologic probes with greater specificity for 5HT receptor subtypes become available, we may be able to elucidate these mechanisms with greater precision. The neuroendocrine challenge methodology is also applicable to the study of other neurotransmitter systems and other headache disorders.

Headache↗
PubMed1995

Sleep complaints among elderly persons: an epidemiologic study of three communities.

The frequencies of five common sleep complaints--trouble falling asleep, waking up, awaking too early, needing to nap and not feeling rested--were assessed in over 9,000 participants aged 65 years and older in the National Institute on Aging's multicentered study entitled "Established Populations for Epidemiologic Studies of the Elderly" (EPESE). Less than 20% of the participants in each community rarely or never had any complaints, whereas over half reported at least one of these complaints as occurring most of the time. Between 23% and 34% had symptoms of insomnia, and between 7% and 15% percent rarely or never felt rested after waking up in the morning. In multivariate analyses, sleep complaints were associated with an increasing number of respiratory symptoms, physical disabilities, nonprescription medications, depressive symptoms and poorer self-perceived health. Sleep disturbances, particularly among older persons, oftentimes may be secondary to coexisting diseases. Determining the prevalence of specific sleep disorders, independent of health status, will require the development of more sophisticated and objective measures of sleep disturbances.

Age Factors↗
PubMed1995

Occult caffeine as a source of sleep problems in an older population.

OBJECTIVE: To evaluate the impact of caffeine in medication on sleep complaints in a community population of persons aged 67 or older. DESIGN: Cross-sectional analysis. SETTING: Iowa 65+ Rural Health Study. PARTICIPANTS: Those who completed their own interview, including a section on the use of medications, during the third annual in-person follow-up in 1984-1985. MEASUREMENTS MAIN OUTCOMES: trouble falling asleep or other sleep complaints. Covariates: use of caffeine-containing medication, spasmolytic, or sympathomimetic drug; number of drugs used; depressive symptoms; self-perceived health; comorbidity, hip fracture, arthritis, ulcer of stomach or intestines; and consumption of caffeinated beverages. RESULTS: The prevalence of caffeinated medication use by participants was 5.4%. Those reporting the use of any caffeine-containing medication were at an increased risk of having trouble falling asleep (Odds Ratio [OR] = 1.79, 95% confidence interval [CI] = 1.19-2.68). There was no significant risk of other reported nighttime or daytime sleep problems associated with use of caffeine-containing drugs. Even after adjusting for other factors that could interfere with initiation of sleep, such as painful disease, depressive symptoms, polypharmacy, use of specific medications known to interfere with sleep, and coffee consumption, the use of caffeine-containing medication still presented a significantly increased risk of having trouble falling asleep (OR = 1.60, CI = 1.04-2.46). Although those participants using over-the-counter analgesic medication containing caffeine had an increased risk of trouble falling asleep (OR = 1.88, CI = 1.22-2.90), there was no significant risk of trouble falling asleep for those who took similar noncaffeinated OTC analgesic drugs (OR = 1.26, CI = 0.87-1.83). CONCLUSIONS: The use of caffeine-containing medication is associated with sleep problems. Healthcare providers should be aware of potential problems associated with over-the-counter medications containing caffeine and should counsel patients about the potential of sleep problems. Older patients should be encouraged to read the label on medications and to select drugs that are caffeine-free when that is possible.

Aged↗
PubMed1994

Selective enhancement by an antiviral agent of the radiation-induced cell killing of human glioma cells transduced with HSV-tk gene.

The activation of antiviral drugs as a consequence of thymidine kinase expression has been shown in recent years to have potential as a treatment for malignant tumors. It was hypothesized that the property of the drugs that make them effective against viruses and proliferating cells, namely their ability to interfere with the integrity of the DNA, may be exploited to sensitize cells to radiation damage. The antiviral drug, BVdUrd, structurally a pyrimidine analogue, was found to enhance selectively the radiation cytotoxicity of human tumor cells transduced with the HSV-tk thymidine kinase gene. Human glioma cells from the U-251 lineage transduced with HSV-tk and exposed to 40 micrograms/ml of BVdUrd for 24 h prior to irradiation were more sensitive to radiation compared with control cells under the same conditions; the sensitization enhancement ratio was 1.9. The results suggest that the addition of radiation will improve the effectiveness of HSV-tk gene therapy for the treatment of brain tumors.

Antiviral Agents↗
PubMed1994

Low cholesterol concentrations and severe depressive symptoms in elderly people.

OBJECTIVE: To investigate the reported association between low serum cholesterol concentration and severe depressive symptoms in an elderly population. DESIGN: Cross sectional analysis of pooled data from three communities of the established populations for epidemiologic studies of the elderly. Participants who completed their interview, including the Centers for Epidemiologic Studies' depression scale and consented to measurement of their cholesterol concentration were included in the study. SUBJECTS: 3939 men and women aged > or = 71. METHODS: chi 2 analysis, t tests, and multivariate regression analysis of the association between low cholesterol concentration and severe depressive symptoms. All analyses were stratified by sex, and multivariate analyses were adjusted for age, self reported health, physical function, number of drugs used, and weight loss. MAIN OUTCOME MEASURE: Score of depressive symptoms on the Centers for Epidemiologic Studies' depression scale. RESULTS: Depressive symptoms, cholesterol concentration, weight, and use of drugs were all associated with age in men and women. The relative odds of severe depressive symptoms (score > or = 16) for those with low cholesterol concentrations (< 4.14 mmol/l) were 1.9 (95% confidence interval, 1.1 to 3.3) for the older group of men and 1.8 (1.1 to 2.9) for the older group of women. This association was also observed when depressive symptoms were analysed as a continuous rather than a categorical variable. In multivariate models that adjusted for age, self reported health, physical function, number of drugs used, and weight loss, the association was substantially weakened. CONCLUSIONS: After several factors relating to health had been controlled for, no significant association between low cholesterol concentration and severe depressive symptoms was found.

Aged↗
PubMed1994

Drug data coding and analysis in epidemiologic studies.

In epidemiologic studies that collect comprehensive information on medication use, the complexity of dealing with a large number of trade and generic names may limit the utilization of these data bases. This paper shows the specific advantage of using two coding systems, one to maximize efficiency of data entry, and the other to facilitate analysis by organizing the drug ingredients into hierarchical categories. The approach used by two large surveys, one in the USA and one in Italy, is described: the Established Populations for Epidemiologic Studies of the Elderly (EPESE) and the 'Gruppo Italiano di Farmacovigilanza nell' Anziano' (GIFA). To enter the medications into a computerized database, codes matching the drug product names are needed. In the EPESE the prescription and over the counter drug products are coded with the Drug Products Information Coding System (DPICS) and the Iowa Nonprescription Drug Products Information Coding System (INDPICS), respectively. The GIFA study uses the coding system of the Italian Ministry of Health (MINSAN), with a unique numeric code for each drug product available in Italy. To simplify the analytical process the drug entry codes are converted into hierarchical coding systems with unique codes for specific drug ingredients, chemical and therapeutic categories. The EPESE and GIFA drug data are coded with the Iowa Drug Information System (IDIS) ingredient codes, and the Anatomical Therapeutic and chemical (ATC) codes, respectively. Examples are provided that show coding of diuretics in these two studies and demonstrate the analytic advantages of these systems.

Adverse Drug Reaction Reporting Systems↗
PubMed1994

Determination of indwelling ureteral stent patency: comparison of standard contrast and nuclear cystography, and lasix renography.

OBJECTIVE: Because of the difficulty in determining patency of Double-J ureteral catheters, a study was devised at Madigan Army Medical Center to determine the best method to demonstrate stented ureteral patency. METHODS: Forty-two patients requiring Double-J ureteral stenting for various clinical reasons were the study group. Outpatients underwent contrast retrograde cystography, nuclear cystography, and diuretic renography every four to six weeks during the stent duration or just prior to stent removal if the stents were indwelling for less than four weeks. In addition, four weeks after stent removal diuretic renography alone was done to evaluate for possible delayed obstructive effect of the ureteral stenting. RESULTS: A total of 53 stents and 42 patients were evaluated. Seventy-seven sets of studies were obtained. In only four instances did all three imaging methods agree on the obstruction. In the remaining 73 sets of data, at least one imaging technique indicated stented ureteral patency. The contrast retrograde cystogram was positive for reflux 52 times (71%). Nuclear cystography showed patency 54 times (74%) and an unobstructed diuretic renogram was obtained 59 times (81%). In addition, five of the six diuretic renograms accomplished with patients in the supine position only and which showed obstruction were repeated with patients in the upright position, and they showed unobstructed function. The overall sensitivity for diuretic renography was 89 percent when the diuretic renogram was done with patients in the supine and upright positions. CONCLUSIONS: Diuretic renography is the most sensitive test for detecting stented ureteral patency. This test needs to be performed with patients in both the supine and upright positions.

Adult↗
PubMed1994

Effects of alprazolam on increases in hormonal and anxiety levels induced by meta-chlorophenylpiperazine.

The effects of alprazolam, a triazolobenzodiazepine, on hormonal and behavioral responses induced by meta-chlorophenylpiperazine (MCPP), a serotonin receptor agonist, were investigated in 10 healthy men. Alprazolam (0.5 mg) or placebo was given 1 hour before MCPP (0.5 mg/kg) or placebo. Cortisol, prolactin, and growth hormone (GH) release, MCPP and alprazolam plasma levels, anxiety level, and panic symptoms were measured over 210 minutes. MCPP was found to increase cortisol, prolactin, GH, and anxiety levels. Alprazolam decreased cortisol and GH levels but had no effect on prolactin. When used in combination with MCPP, alprazolam blunted MCPP-induced cortisol and GH release, and it blocked the anxiogenic effects of MCPP.

Adult↗