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Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 271 records · Page 15Linked to original sources
PubMed1998

Cisplatin- and paclitaxel-induced apoptosis of ovarian carcinoma cells and the relationship between bax and bak up-regulation and the functional status of p53.

We investigated the roles of p53 and Bcl-2 homologues in the induction of apoptosis by cisplatin and paclitaxel in wild-type p53-expressing human ovarian carcinoma cells and cisplatin-resistant derivatives that have lost p53 function. Cisplatin induced apoptosis in parental A2780 but not in cisplatin-resistant A2780/cp70 cells, whereas paclitaxel induced apoptosis in both cell lines. Immunoprecipitation of p53 using antibodies specific for p53 conformation (pAb 1620 and pAb 240) showed that there were no relative changes in p53 conformation before and after cisplatin treatment in either cell line. A2780/cp70 cells have lost p53 function, yet they have wild-type p53 gene sequence. However, A2780/cp70 cells constitutively express more p53 in a form detected by pAb 240, an antibody that also detects mutant conformations of p53 that are transcriptionally inactive. There were no changes in levels of Bcl-2, Bcl-XL, or 24-kDa Bax over 72 hr after exposure to cisplatin or paclitaxel, but each agent led to up-regulation of Bak and 21-kDa Bax in A2780 cells. Paclitaxel, but not cisplatin, increased Bak and 21-kDa Bax levels in A2780/cp70 cells. These data suggest that apoptosis in A2780 and A2780/cp70 is associated with an increased level of Bak and 21 kDa Bax after drug-induced damage and that functional p53 may be required for this effect after cisplatin but not after paclitaxel.

Antineoplastic Agents↗
PubMed1998

An investigation into lung correction for tangential breast irradiation.

A solid water breast phantom with a lung equivalent material was constructed to investigate interface effects of 6 MV tangential photon fields. The phantom was built so that Thermo-luminescence Dosimeters (TLD) could be used for comparison to a pencil beam and Equivalent Tissue-Air-Ratio (ETAR) algorithms. The investigation highlighted the limitations in both of these algorithms under clinically anatomical conditions. At the lung/tissue interface both algorithms showed errors between 3-12% depending on the position of the TLD. In tissue greater than 1 cm from the interface region the errors on average were within +/- 5%. Dose comparisons in lung tissue showed similar results to the interface region. These results indicate that normalisation of Reference Dose in the interface region for tangential breast treatments cause over or under estimates of dose.

Breast↗
PubMed1998

Detection of sex chromosome abnormalities by nuchal translucency screening at 10-14 weeks.

At 10-14 weeks of gestation more than 80 per cent of fetuses affected by trisomy 21 can be detected by a screening programme based on a combination of maternal age and fetal nuchal translucency thickness (NT). The screen positive group in such a programme also identifies fetuses with sex chromosome abnormalities. In this ongoing multicentre screening study, involving 61,972 singleton pregnancies, 53 cases of sex chromosome abnormalities were identified. The fetal NT was above the 95th centile in 87.9 per cent of the 33 cases with 45,XO, and in 40 per cent of the 20 cases with 47,XXX, 47,XYY or 47,XXX. However, it was estimated that at 12 weeks of gestation our population would contain 42 cases with 45,XO and 104 cases with 47,XXY, 47,XYY or 47,XXX. Since the rate of intra-uterine lethality, between 12 and 40 weeks of gestation, is about 65 per cent for 45,XO and four per cent for 47,XXY, 47,XYY or 47,XXX, the respective number of livebirths with these chromosomal abnormalities would have been 15 and 100, respectively, without prenatal diagnosis. Assuming that all intra-uterine deaths are from those with increased NT, screening for trisomy 21 by maternal age and fetal NT would have identified only 20 per cent of potential livebirths in the 45,XO group and nine per cent of those with 47,XXY, 47,XYY or 47,XXX.

Down Syndrome↗
PubMed1998

Clinically inapparent tuboovarian actinomycosis in a woman with an IUD. A case report.

BACKGROUND: The consequences and management of asymptomatic Actinomyces-like organisms detected on cervical cytologic smears continue to be controversial. CASE: A unilateral tuboovarian actinomycotic abscess was discovered in a woman who had undergone a hysterectomy for uterine leiomyomas. She had had an intrauterine device in place for many years without any symptoms of pelvic inflammatory disease. CONCLUSION: Ascending infection of the upper genital tract by Actinomyces may be clinically inapparent. When Actinomyces-like organisms aer detected on cervical cytologic smears, removal of an intrauterine device should be considered.

Actinomyces↗
PubMed1998

The consequences of paying Medicare managed care plans their costs.

This study examines 1993 Medicare expenditures for enrollees in 63 managed care plans that were reimbursed on a cost basis. We find that government spending for enrollees in cost-reimbursed plans in 1993 was substantially greater than it would have been had these enrollees instead received care in traditional fee-for-service Medicare or in a Medicare risk plan. The increase was due entirely to the much higher expenditures for Part B services under cost reimbursement. The findings suggest that Medicare cost reimbursement of health plans should be eliminated or significantly modified.

Centers for Medicare and Medicaid Services, U.S.↗
PubMed1997

11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11beta-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11beta-HSD-1) may function as an 11beta-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11beta-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11beta-HSD-1 -/- mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Efficient transduction of mammalian cells by a recombinant baculovirus having the vesicular stomatitis virus G glycoprotein.

Baculovirus vectors recently have been shown to be capable of efficient transduction of human hepatoma cells and primary hepatocytes in culture. This paper describes the generation of a novel recombinant baculovirus (VGZ3) in which the vesicular stomatitis virus glycoprotein G (VSV G) is present in the viral envelope. The gene encoding VSV G was inserted into the baculovirus genome under the control of the polyhedrin promoter such that it was expressed at very high levels in infected insect cells but not in mammalian cells. Expression of the lacZ reporter gene was driven by a promoter that is functional in mammalian cells (the Rous sarcoma virus long terminal repeat). We show by Western analysis that VSV G protein was present in purified baculovirus preparations. A VSV G monoclonal antibody blocked transduction of mammalian cells by VGZ3. This virus was morphologically distinct from baculovirus lacking VSV G, with virions adopting an oval rather than rod-shaped morphology. VGZ3 transduced human hepatoma cells in vitro at an efficiency roughly 10-fold greater than baculovirus lacking VSV G (the virus Z4). VGZ3 was also capable of transducing cell lines that could not be transduced efficiently by Z4. We provide evidence that VSV G protein may enhance transduction by increasing the efficiency of escape of baculovirus from intracellular vesicles rather than by increasing cell binding or uptake of the virus. The possible use of this and related baculoviruses in gene therapy is discussed.

Animals↗
PubMed1997

Perioperative management of colon cancer under Medicare risk programs.

OBJECTIVE: To determine differences in perioperative care and outcomes for patients with colon cancer enrolled in Medicare health maintenance organizations compared with similar fee-for-service nonenrollees. METHODS: Cross-sectional evaluation of hospital care and posthospital outcomes with data obtained from medical records. Nineteen health maintenance organizations representing all model types were selected from 12 states. The nonenrollee sample was drawn from the same areas. The sample included 412 enrollees and 401 nonenrollees, representing 65 hospitals for health maintenance organizations and 61 hospitals for fee-for-service. RESULTS: Nonenrollees were slightly older and had higher preoperative risk. Enrollees had shorter intervals between admission and surgery (enrollees, 1.55 days vs nonenrollees, 2.85 days). Differences in length of stay (enrollees, 10.9 days vs nonenrollees, 14.2 days) persisted even after controlling for preoperative health status. Differences in admissions to intensive care units (enrollees, 36.4% vs nonenrollees, 44.4%) were highly influenced by preoperative health status. Nonenrollees were more significantly likely to receive preoperative antibiotics, postoperative testing (eg, postoperative chest radiographs and electrocardiograms), and postoperative patient-controlled analgesia. Tumor staging was similar for both groups. Enrollees were more likely to be discharged home, while nonenrollees were more likely to be discharged to a nursing home. There were no significant differences in hospital deaths or postdischarge readmissions. CONCLUSIONS: Health maintenance organization enrollees with colon cancer received less clinical services of several types than similar patients in fee-for-service settings, had shorter hospital stays, and were less likely to be discharged to nursing homes. However, there was no evidence that they experienced different outcomes.

Aged↗
PubMed1997

hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents.

Loss of expression of the hMLH1 and hPMS2 subunits of the MutL alpha-mismatch repair complex is a frequent event (9/10) in independent cisplatin resistant derivatives of a human ovarian carcinoma cell line. However, only hMLH1 mRNA is decreased in these MutL alpha-deficient lines. No alterations in the levels of the hMSH2 and hMSH6 (GTBP) subunits of the MutS alpha-complex are observed. An increase in the proportion of ovarian tumours negative for the hMLH1 subunit is observed in samples taken at second look laparotomy after chemotherapy (36%: 4/11), compared to untreated tumours (10%: 4/39). No significant difference is observed for hMSH2, hMSH6 or hPMS2. Furthermore, cisplatin and doxorubicin-resistant ovarian lines deficient in hMLH1 expression are cross-resistant to 6-thioguanine and the methylating agent N-methyl-N-nitrosourea (MNU). Depletion of O6-alkylguanine-DNA-alkyltransferase (ATase) activity confers only limited increased sensitivity to MNU. Thus the mismatch repair deficient lines retain DNA damage tolerance even after ATase depletion. The hMLH1 deficient lines also lose ability to engage G1 and G2 cell cycle arrest after cisplatin damage. Together these data suggest that loss of hMLH1 expression may be a high frequency event following exposure of ovarian tumour cells to cisplatin and may be critically involved in the development of drug resistance. Thus, the hMLH1 status of these cells appears to be highly correlated with the ability to engage cell death and cell cycle arrest after DNA damage induced by cisplatin.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis.

BACKGROUND: Squamous cell carcinoma (SCC) with histologically contiguous actinic keratosis has long been thought of as a tumor with minimal risk for metastasis. The objective of this study was to determine if contiguous actinic keratosis is present in the original tumors of metastatic cutaneous SCC and to describe the histologic features of these tumors. METHODS: The primary lesions of 22 patients with metastatic cutaneous SCC were examined using light microscopy. RESULTS: Contiguous actinic keratosis was present histologically in 44% of the original lesions of cutaneous SCC that metastasized. The average tumor thickness was 6.6 mm. Greater than 66% of the tumors were well or moderately differentiated. The skin adjacent to the tumors showed solar degeneration in almost all instances. CONCLUSIONS: The histologic presence of contiguous actinic keratosis is not a useful predictor of the metastatic behavior of cutaneous SCC. Increased tumor thickness and depth of invasion are the most consistent histopathologic features of cutaneous SCC that metastasize.

Carcinoma, Squamous Cell↗
PubMed1997

Localization of human liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1) within a YAC contig in Xp11.21.

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) catalyzes the synthesis and degradation of fructose-2,6-bisphosphate, a potent regulator of glycolysis. Previous studies assigned the gene for human liver PFK-2/FBPase-2 (HGMW-approved symbol PFKFB1) to the X chromosome; however, precise localization remained ambiguous, with the gene variously placed between Xcen-q13, Xq27-q28, and Xp11.22-p11.21. We have localized the gene within a YAC contig clustered around ALAS2 (human erythroid delta-aminolevulinate synthase) in Xp11.21 and have identified eight YACs positive for the gene. Four of these overlapping YACs were mapped using rare-cutter restriction enzymes to provide in-depth characterization of an 820-kb region encompassing the PFK-2/ FBPase-2 and ALAS2 genes. PFK-2/FBPase-2 was found to lie close (within approx. 250 kb) and telomeric to ALAS2. Three putative CpG islands were also detected in the region.

5-Aminolevulinate Synthetase↗
PubMed1997

Selective recognition of a cisplatin-DNA adduct by human mismatch repair proteins.

The antitumor agent cis-diamminedichloroplatinum(II) (cisplatin) introduces cytotoxic DNA damage predominantly in the form of intrastrand crosslinks between adjacent purines. Binding assays using a series of duplex oligonucleotides containing a single 1,2 diguanyl intrastrand crosslink indicate that human cell extracts contain factors that preferentially recognise this type of damage when the complementary strand contains T opposite the 3', and C opposite the 5'guanine in the crosslink. Under the conditions of the band-shift assay used, little binding is observed if the positions of the T and C are reversed in the complementary strand. Similarly, duplexes containing CC or TT opposite the crosslink are recognised relatively poorly. The binding activity is absent from extracts of the colorectal carcinoma cell lines LoVo and DLD-1 in which the hMutSalpha mismatch recognition complex is inactivated by mutation. Extensively purified human hMutSalpha exhibits the same substrate preference and binds to the mismatched platinated DNA at least as well as to an identical unplatinated duplex containing a single G.T mismatch. It is likely, therefore, that human mismatch repair may be triggered by 1,2 diguanyl intrastrand crosslinks that have undergone replicative bypass.

Adenosine Triphosphatases↗
PubMed1997

Identification of p53 genetic suppressor elements which confer resistance to cisplatin.

Loss of p53 function is associated with the acquisition of cisplatin resistance in the human ovarian adenocarcinoma A2780 cell line. Selection for cisplatin resistance of A2780 cells was used to isolate genetic suppressor elements (GSEs) from a retroviral library expressing random fragments of human or murine TP53 cDNA. Six GSEs were identified, encoding either dominant negative mutant peptides or antisense RNA molecules which corresponded to various regions within the TP53 gene. Both types of GSE induced cisplatin resistance when introduced individually into A2780 cells. Expression of antisense GSEs led to decreased intracellular levels of p53 protein. One sense GSE induced loss of p53-mediated activities such as DNA damage induced cell cycle arrest and apoptosis. A synthetic peptide, representing the predicted amino acid sequence of this GSE, conferred resistance to cisplatin when introduced into A2780 cells and inhibited the sequence specific DNA binding activity of p53 protein in vitro. Overall, these results directly indicate that inactivation of p53 function confers cisplatin resistance in these human ovarian tumour cells. We have identified short structural domains of p53 which are capable of independent functional interactions and highlighted the efficacy of this approach to discriminate biologically active GSEs from a random fragment library.

Animals↗
PubMed1997

Plateletapheresis with a next generation blood cell separator.

Procedure time has been identified as the-most important element in apheresis platelet donor retention. Fenwal has developed a next generation apheresis system, the Amicus, with the intent of efficiently producing high platelet yields with low WBC content in much shorter processing times than currently available. This report describes the Amicus and presents results of a clinical trial of an Amicus prototype and a comparison to Fenwal CS 3000+. Thirty Amicus double-needle plateletapheresis procedures were evaluated. Average processing time was 61 +/- 16 min with 63% of the processing times < or = 60 min. The average preplatelet count was 246 +/- 46 x 10(3)/microliter, platelet yield 4.4 +/- 1.2 x 10(11) plt, collection efficiency 73 +/- 14%, platelet collection rate 0.075 +/- 0.016 plt x 10(11)/min and citrate toxicity incidence 3%. A comparison of double-needle procedures, 20 Amicus and 20 CS 3000+, showed that Amicus had significantly shorter (P < .05) processing times (64 +/- 17 vs. 86 +/- 10 min) and higher (P < .05) platelet collection rates (0.070 +/- 0.017 vs. 0.054 +/- 0.018 plt x 10(11)/min) but comparable (P < .05) platelet yields (4.4 +/- 1.4 vs. 4.7 +/- 1.0 x 10(11) plt). Comparison of 13 single and 13 double-needle Amicus procedures showed comparable (P < .05) processing times (71 +/- 13 vs. 65 +/- 18 min), platelet yields (4.7 +/- 1.0 vs. 4.6 +/- 1.5 x 10(11) plt), collection efficiency (74 +/- 7 vs 74 +/- 17%), and platelet collection rates (0.068 +/- 0.020 vs 0.072 +/- 0.018 plt x 10(11)/min). Using normal probability plots of WBC content at 95% confidence level. Amicus can provide products with < 5.0 x 10(6)WBC or < 1.0 x 10(6) WBC in 99.7% or 92.7% of collections, respectively, compared with 69.0% or 44.0%, respectively, for CS 3000+. We found Amicus was able to provide equivalent quantities of platelets with less WBC content in significantly shorter processing times than CS3000+ as well as shown encouraging results for single-needle procedures.

Humans↗
PubMed1997

Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease.

Six patients with Parkinson's disease were followed for 10 to 72 months after human embryonic mesencephalic tissue from four to seven donors was grafted unilaterally into the putamen (4 patients) or putamen plus caudate (2 patients). After 8 to 12 months, positron emission tomography showed a 68% increase of 6-L-[18F]-fluorodopa uptake in the grafted putamen, no change in the grafted caudate, and minor decreases in nongrafted striatal regions. There was therapeutically valuable improvement in 4 patients, but only modest changes in the other 2, both of whom developed atypical features. Patient 4 was without L-dopa from 32 months and had normal fluorodopa uptake in the grafted putamen at 72 months. Overall, the L-dopa dose was reduced by a mean of 10 and 20%, "off" time was reduced by 34 and 44%, and the "off" phase Unified Parkinson's Disease Rating Scale motor score by 18 and 26%, and the duration of the response to a single L-dopa dose increased by 45 and 58% during the first and second years after surgery, respectively. Rigidity and hypokinesia improved bilaterally, but mainly contralateral to the implant. No consistent changes in dyskinesias were observed. We conclude that transplantation of embryonic mesencephalic tissue leads to highly reproducible survival of dopaminergic neurons, inducing clinically valuable improvements in most recipients.

Adult↗
PubMed1997

The "cold hands sign" in multiple system atrophy.

Patients with multiple system atrophy (MSA) often have cold, dusky, violaceous hands, with poor circulatory return after blanching by pressure. We therefore compared hand skin temperature in nine age-matched subjects with probable MSA, 10 with idiopathic Parkinson's disease (PD), and 10 healthy controls both at rest and following a standard cooling procedure. Baseline skin temperature in the MSA group was significantly lower than in both the PD and control groups, and four of the nine MSA patients were colder at baseline than the coldest control value. After cooling, the MSA group also showed a significantly greater reduction in skin temperature than the PD group. The rate of skin temperature recovery did not differ between the three groups, although the MSA group required more time to return completely to their baseline temperature. Changes in skin colour or temperature are easily detected, and suggest a defect in neurovascular control of distal extremities. The "cold hands sign" is another clinical "red flag" that helps to raise the suspicion of MSA.

Atrophy↗