Biomedical subjects

R W Brown

Publications and source records attributed to R W Brown.

At least 55 records · Page 3Linked to original sources

PubMed1997

Absence of prognostic significance of bcl-2 immunopositivity in non-small cell lung cancer: analysis of 427 cases.

The bcl-2 gene product inhibits apoptosis and is thought to participate in oncogenesis. Association of bcl-2 immunopositivity with improved prognosis of non-small cell lung cancers (NSCLC) is controversial. Although two studies have reported better survival in bcl-2-immunopositive NSCLCs, a third series has contradicted this finding. The authors studied a relatively larger case series involving 427 patients for whom detailed information on long-term follow-up was available to determine the prognostic significance of bcl-2 expression. The study included 252 adenocarcinomas (AC), 111 squamous cell carcinomas (SCC), and 64 large cell carcinomas (LC). After antigen retrieval, sections were immunostained using a monoclonal anti-bcl-2 antibody (1:60, Clone 124, Dako) and the avidin-biotin complex technique. Staining was scored as positive or negative and also on a semiquantitative scale as 0, low (<10%), moderate (10% to 75%), or extensive (>75%). Bcl-2 immunoreactivity was correlated with survival using the actuarial survival method, Kaplan-Meier method, and log-rank test and was not associated with statistically significant differences in survival for NSCLCs (P = .5537). Differences in survival remained insignificant even after NSCLCs were stratified for cell type, stage, or grade, singly or in combination. Therefore, using this method, bcl-2 immunopositivity does not appear to act as an independent prognostic indicator in NSCLCs.

Adenocarcinoma↗

PubMed1997

Impact of d-amphetamine on temporal estimation in pigeons tested with a production procedure.

The influence of d-amphetamine on timing in pigeons was examined with a production procedure. Birds were trained with a fixed time schedule in which food reinforcement was contingent on the first response made after a duration signal had appeared for 30 s. Probe tests involved trials in which the duration signal was extended to 90 s and reinforcement was omitted. In Experiment 1, 2.0 mg/kg d-amphetamine shifted peak responding to a duration shorter than that found with saline. In Experiment 2, the dose-response function for this drug effect was examined. A 0.3-mg/kg dose of d-amphetamine had no impact on performance, but a 1.0-mg/kg dose shifted the peak duration significantly relative to saline; a 2.0-mg/kg dose shifted the function even more. These results complement previous findings with rats tested with the peak procedure and pigeons tested with a discrimination procedure.

Animals↗

PubMed1997

Morris water maze deficits in rats following traumatic brain injury: lateral controlled cortical impact.

This experiment utilized a laterally placed controlled cortical impact model of traumatic brain injury (TBI) to assess changes on spatial learning and memory in the Morris water maze (MWM). Adult rats were subjected to one of two different levels of cortical injury, mild (1 mm) or moderate (2 mm) deformation, and subsequently tested for their ability to learn (acquisition) or remember (retention) a spatial task, 7 or 14 days after injury. Results revealed an injury-dependent deficit for experimental animals compared to sham-operated controls. Not only did the TBI result in longer escape latencies, but also significant deficits in search time and relative target visits. Although the moderately injured animals demonstrated significant histopathology in the cortex and hippocampus, mildly injured subjects demonstrated no obvious tissue destruction, but did manifest significant behavioral change. These results demonstrate that a laterally placed controlled cortical impact is capable of producing significant cognitive deficits on both acquisition and retention paradigms utilizing the MWM.

Analysis of Variance↗

PubMed1997

Immunohistochemical identification of tumor markers in metastatic adenocarcinoma. A diagnostic adjunct in the determination of primary site.

Adenocarcinoma that metastasizes from an unknown primary site is a significant oncologic problem. With the exception of prostate-specific antigen and thyroglobulin, no single immunohistochemical marker is entirely site-specific. A retrospective study was undertaken to determine whether a panel of markers could accurately predict the site of origin of common metastatic adenocarcinomas. On the basis of reports of their relatively restricted specificity for carcinomas of colon, breast, lung, ovary, and upper gastrointestinal tract (stomach, pancreas, and bile duct), eight markers were selected for simultaneous evaluation: gross cystic disease fluid protein-15, breast cancer antigen 225 (BCA225), B72.3, DF3 (CA15-3), carcinoembryonic antigen (CEA), CA19-9, CA125, and estrogen receptor. The study population consisted of 128 metastatic nonmucinous adenocarcinomas for which the primary site was known. Staining was performed on formalin-fixed, paraffin-embedded tissue using an enhanced-sensitivity avidin-biotin peroxidase complex detection system. The most informative markers were CEA, CA19-9, CA125, and BCA225. With this four-marker panel, the most predictive multiple-marker phenotypes, as determined by a combination of area under the receiver operating characteristic curve, specificity, and percent correct predictions, were CEA+, BCA225-, and CA125- for colon tumors; BCA225+, CEA-, and CA125- for breast tumors; BCA225+, CEA+, and CA19-9- for lung tumors; CA125+ and CEA- for ovarian tumors; and CEA+, CA19-9+, and CA125+ for upper gastrointestinal tract tumors. Overall, these phenotypes correctly predicted the known primary site in 66% of cases. Until single highly sensitive and specific markers are developed for adenocarcinomas other than prostate and thyroid tumors, the origin of a metastatic adenocarcinoma can best be suggested or excluded with clinicopathologic data combined with a panel of selected immunohistochemical markers.

Adenocarcinoma↗

PubMed1997

An evaluation of initiatives to improve family planning use by African-American adolescents.

Teen pregnancies in the United States have reached epidemic proportions, and consequently, efforts to promote family planning among adolescents have increased. At the Orleans Parish Family Planning Clinic in New Orleans, Louisiana, adolescent-specific initiatives were implemented to improve understanding of family planning services and promote contraceptive use. Since 92% of the patients are African American, the study population was limited to this group. This study examines the efficacy of two initiatives (i.e., orientation sessions and 3-month booster visits conducted in adolescent-specific clinics) for improving initiation and continuation of family planning services among African-American adolescent women. Initiation of services was compared among those who attended the orientation session and those who did not attend. Continuation of services was determined by attendance of the annual visit for those who attended the 3-month follow-up visit and those who did not attend. Of 737 teens entering into the clinic, the mean age was 16 years, 95% were enrolled in school, 23% attended the orientation session, and 71% initiated services. Of the 507 who initiated services and who underwent follow-up for at least 12 months, 29% attended the 3-month follow-up visit and 32% attended an annual visit. Attendance of the orientation session was associated with initiation of services and attendance of the 3-month booster visits was associated with attendance of the annual visit in multivariate logistic regression. Simple and cost-effective techniques such as orientation sessions and follow-up visits conducted in adolescent clinics can improve initiation of family planning and compliance among adolescents.

Adolescent↗

PubMed1997

Errors in medicine.

The medical profession has been reminded of the problem of errors occurring in the practice of medicine by some recent local and overseas studies. These studies provide data on the incidence and demographics of these errors, and they provide a starting point for improving the situation. A body of research is developing on the subject of human error, and it is suggested that the medical profession take advantage of the knowledge derived from this research. In particular, attention should be directed towards developing an atmosphere of reporting errors without fear of blame, developing back-up systems, standardizing processes, monitoring processes extensively, and recertifying operators. Some of these suggestions are already being adopted in this country.

Australia↗

PubMed1997

High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas.

c-erbB-3 is a new member of the Type I growth factor receptor family that includes epidermal growth-factor receptor (also called c-erbB-1) and HER-2/neu (also called c-erbB-2). Frequency and significance of c-erbB-3 overexpression in lung cancers have not been reported previously. A series of 549 cases of primary lung carcinomas were immunostained with a monoclonal anti-human c-erbB-3 antibody (Clone RTJ.1) using formalin-fixed, paraffin-embedded archival tissue. Sharp membranous staining or punctate cytoplasmic staining was interpreted as positive and scored 0 (< 5% of tumor cells), 1 (5-9%), 2 (10-49%), or 3 (> or = 50%). Medical records were reviewed for clinical data, including stage and survival. Actuarial cumulative survival analysis with the Mantel-Cox test was performed on 443 cases that had a single primary site in the lung of pure non-small cell carcinoma (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and that also had follow-up data for more than 3 months. In all stages, squamous cell carcinoma showed the greatest rate of high c-erbB-3 positivity (score, 3) (34/119; 28.6%), followed by adenocarcinoma (41/256; 15.9%) and large cell carcinoma (7/66; 10.6%). Patients with high c-erbB-3 expression (score, 3) survived for significantly shorter times than did patients with low c-erbB-3-expression (score, 0-2) in Stages III and IV (P = 0.002), but not in Stage I or II non-small cell lung carcinomas. In conclusion, high c-erbB-3 expression in advanced non-small cell lung carcinomas might be an adverse prognostic factor. This finding suggests that c-erbB-3 might be a potential target for molecular therapy in advanced non-small cell lung carcinomas.

Adenocarcinoma↗

PubMed1996

Purification of 11 beta-hydroxysteroid dehydrogenase type 2 from human placenta utilizing a novel affinity labelling technique.

11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) efficiently inactivates potent glucocorticoid hormones (cortisol and corticosterone), leaving aldosterone unmetabolized. Abundant 11 beta-HSD2 activity in human placenta plays a central role in controlling fetal glucocorticoid exposure, which if excessive is harmful and may predispose to low birth weight and hypertension in adulthood. Similar 11 beta-HSD2 activity in the distal nephron protects mineralocorticoid receptors from glucocorticoids and appears to be important in normal blood pressure control. We have purified human placental 11 beta-HSD2 16000-fold, to homogeneity, and determined over 100 residues of the internal amino acid sequence. Purification was assisted by a novel technique allowing highly specific (single spot on two-dimensional electrophoresis) photoaffinity labelling of active 11 beta-HSD2 in crude tissue extracts by its glucocorticoid substrates. This work reveals that 11 beta-HSD2 is a member of the short-chain alcohol dehydrogenase superfamily (apparent monomer M(r) approximately 40,000). It is a very basic (apparent pI = 9.1) intrinsic membrane protein, requiring as yet undefined membrane constituents for full stability. Affinity chromatography and affinity labelling studies suggest that 11 beta-HSD2 has a compulsory ordered mechanism, with NAD+ binding first, followed by a conformational change allowing glucocorticoid binding with high affinity.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1996

Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2.

By inactivating potent glucocorticoid hormones (cortisol and corticosterone), 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) plays an important role in the placenta by controlling fetal exposure to maternal glucocorticoids, and in aldosterone target tissues by controlling ligand access to co-localized glucocorticoid and mineralocorticoid receptors. Amino acid sequence from homogeneous human placental 11 beta-HSD2 was used to isolate a 1897 bp cDNA encoding this enzyme (predicted M(r) 44126; predicted pI 9.9). Transfection into mammalian (CHO) cells produces 11 beta-HSD2 activity which is NAD(+)-dependent, is without reductase activity, avidly metabolizes glucocorticoids (Km values for corticosterone, cortisol and dexamethasone of 12.4 +/- 1.5, 43.9 +/- 8.5 and 119 +/- 15 nM respectively) and is inhibited by glycyrrhetinic acid and carbenoxolone (IC50 values 10-20 nM). Rabbit antisera recognizing 11 beta-HSD2 have been raised to an 11 beta-HSD2-(370--383)-peptide-carrier conjugate. Recombinant 11 beta-HSD2, like native human placental 11 beta-HSD2, is detectable with affinity labelling and anti-11 beta-HSD2 antisera, and appears to require little post-translational processing for activity. 11 beta-HSD2 mRNA (approximately 1.9 kb transcript) is expressed in placenta, aldosterone target tissues (kidney, parotid, colon and skin) and pancreas. In situ hybridization and immunohistochemistry localize abundant 11 beta-HSD2 expression to the distal nephron in human adult kidney and to the trophoblast in the placenta. 11 beta-HSD2 transcripts are expressed in fetal kidney (but not lung, liver or brain) at 21-26 weeks, suggesting that an 11 beta-HSD2 distribution resembling that in the adult is established by this stage in human development.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1996

Selenium bioaccumulation and hazards in a fish community affected by coal fly ash effluent.

Bioaccumulation of selenium (Se) in the fish community of Pigeon River/Pigeon Lake, which receives inputs of Se from a coal fly ash disposal facility, was studied to assess potential hazards of Se to fish, wildlife, and humans. Se concentrations in fish from sites receiving seepage and effluents from fly ash disposal ponds were significantly greater than those in fish from upstream, where Se concentrations were near background concentrations. Se concentrations differed among fish species, and interspecific variation was greatest at the most contaminated locations. Differences in Se bioaccumulation among fish species were not consistently associated with differences in trophic status. Although Se concentrations in northern pike were consistently less than those in likely prey species, large yellow perch contained Se concentrations as great as those in spottail shiners, their likely prey. Se bioaccumulation may have been influenced by differences in habitat preferences, as limnetic species generally contained greater Se concentrations than benthic species. Se concentrations in fish from the lower Pigeon River and Pigeon Lake did not exceed lowest observable adverse effect concentrations (LOAECs) for Se in tissues of fish species, but exceeded LOAECs for dietary Se exposure of sensitive species of birds and mammals. Human consumption of moderate quantities of fish from the areas studied should not result in excessive Se intake.

Analysis of Variance↗

PubMed1996

Bacterial alkaloids mitigate seizure-induced hippocampal damage and spatial memory deficits.

Studies of human patients with temporal lobe epilepsy and animal models of epilepsy have established relationships between seizures, excitotoxic hippocampal damage, and memory impairment. We report that bacterial alkaloids, recently shown to mimic actions of neurotrophic factors in cell culture, attenuate seizure-induced damage to hippocampal neurons and memory impairment in adult rats when administered subcutaneously. Intrahippocampal administration of convulsant doses of kainic acid (KA) to adult rats resulted in degeneration of neurons in CA3, CA1, and hilus. Rats administered KA exhibited (24 h later) deficits in performance on both goal latency and probe trial tasks in Morris water maze (MWM) tests of visuospatial memory. Seizure-induced damage to hippocampal neurons was significantly reduced, to varying extents, in rats administered the bacterial alkaloids K252a, K252b, or staurosporine (daily injections of 4 micrograms/kg body weight) prior to KA administration. The KA-induced deficits in MWM goal latency performance were abrogated in rats administered K252a or K252b, and K252a and staurosporine completely prevented seizure-induced impairment on the MWM probe trial. The alkaloids did not suppress electroencephalographic seizure activity, suggesting a dissociation between synchronization of activity and synaptically mediated excitotoxic injury to hippocampal neurons. Each alkaloid caused an increase in levels of protein tyrosine phosphorylation as determined by Western blot analysis of hippocampal tissue. Our data indicate that these bacterial alkaloids have potent antiexcitotoxic activities which may have clinical utility in epilepsy and other disorders that involve excitotoxic damage.

Alkaloids↗

PubMed1996

Combined ovarian serous papillary and hepatoid carcinoma.

Hepatoid carcinoma is a rare type of malignant tumor resembling hepatocellular carcinoma that arises in extrahepatic sites. A case of a combined hepatoid and serous papillary carcinoma of the ovary in a 72-year-old woman is reported. The hepatoid component showed alpha-fetoprotein production. Imperceptible merging of the hepatoid and serous papillary components was seen, supporting the theory of a surface epithelial origin of ovarian hepatoid carcinoma.

Aged↗

PubMed1996

Validation of a single-day Morris Water Maze procedure used to assess cognitive deficits associated with brain damage.

This experiment was designed to validate a single-day Morris Water Maze procedure used to assess cognitive functioning in rats. Separate groups of randomly assigned rats received either bilateral or unilateral fimbria fornix transections, bilateral or unilateral cortical ablations, or a sham surgical control procedure. Subjects were tested 7 days postoperatively with a modified version of the Morris Water Maze procedure that requires only a single day of training. The results indicated that bilateral fimbria fornix transections severely disrupted acquisition. Unilateral fimbria fornix transections and bilateral and unilateral cortical lesions disrupted acquisition less severely but impaired subsequent test performance. In general, unilateral lesions of both types produced less severe deficits than bilateral lesions. The practical and analytical advantages of the single-day procedure are discussed.

Animals↗

PubMed1996

p53 and MDM2 immunostaining in pulmonary blastomas and bronchogenic carcinomas.

Pulmonary blastomas (PBs) are rare primary malignancies that include adult types: biphasic pulmonary blastoma (BPB) and well-differentiated fetal adenocarcinoma (WDFA); and childhood type: pleuropulmonary blastoma (PPB). Their pathogenesis and relationship to bronchogenic carcinoma (BCA) are controversial. To determine whether or not PB share molecular pathological features with BCA, the authors immunostained three BPB, three WDFA, three PPB, and 80 standard BCA for p53 protein and MDM2 protein, gene products believed to be significant in the pathogenesis of BCA. Paraffin-embedded tissue sections were immunostained with monoclonal antibody to p53 and MDM2 proteins. Strong intranuclear staining in greater than 10% of cells was considered positive. Three (50%) BPB and WDFA stained for p53 and five (83%) for MDM2. None of the PPB stained for p53, and one PPB did not stain for either p53 or MDM2. Five of six adult type PB occurred in smokers, whereas none of the PPB was associated with smoking. Seventy-five (94%) of the BCA stained for MDM2 and 46 (61%) for p53. Immunostaining patterns for p53 and MDM2 in adult types of PB, and not PPB, appear similar to those for BCA. This may suggest that adult type PB, but not childhood PB, have a similar pathogenesis to BCA.

Adenocarcinoma↗

PubMed1996

Apoptosis in renal cell carcinoma: detection by in situ end-labeling of fragmented DNA and correlation with other prognostic factors.

Because stage and grade of renal cell carcinoma (RCC) sometimes fail to predict the patient's outcome, additional prognostic predictors are needed. Apoptosis is a process of programmed cell death seen in both normal and neoplastic tissues, which has been shown to have prognostic significance in some tumor types. Forty-seven RCCs were studied for size, grade, stage, apoptosis, and proliferation. Fragmented DNA, a hallmark of apoptosis, was detected in situ by a process in which the fragmented DNA was labeled with a biotinylated nucleotide, which, in turn, was detected by an avidin-biotin-peroxidase labeling system. The proliferating tumor cells were detected by immunostaining with the MIB-1 antibody. The apoptotic index and proliferation index of each RCC were expressed as the number of tumor cells undergoing apoptosis and proliferation per 1,000 tumor cells. For grade I to IV RCCs, the median proliferative index was 13, 41, 119, and 143; the median apoptotic index was 8, 12, 39, and 73. For stage I to IV RCCs, the median proliferative index was 21, 34, 70, and 144; the median apoptotic index was 8, 9, 20, and 69. There was a statistically significant correlation of tumor grade, stage, and size with both proliferative index and apoptotic index. There was a statistically significant correlation between proliferation index and apoptotic index. In conclusion, apoptosis can be easily and reliably recognized by the in situ end labeling of fragmented DNA and may help predict the outcome of RCC.

Antibodies, Monoclonal↗

PubMed1996

Potential utility of p53 immunopositivity in differentiation of adenocarcinomas from reactive epithelial atypias of the lung.

Reactive atypia of alveolar epithelium occurs in many types of lung injury and may sometimes raise suspicions of adenocarcinoma or bronchioloalveolar carcinoma. To assess whether there is sufficient difference in the frequency of p53 protein immunopositivity in these lesions to provide a practical basis for differentiating malignancy from reactive atypia, we immunostained 110 malignant and inflammatory/fibrotic lung specimens for p53 protein. Paraffin-embedded sections were immunostained with p53 protein antibody (clone BP53-12; BioGenex, San Ramon, CA) and standard capillary gap (Microprobe; Fisher Scientific, Fairlawn, NJ) avidin- biotin complex technique with antigen retrieval solution. Percent of immunopositive cells was semiquantitatively categorized as follows: 0%, less than 1%, 1% to 10%, 10% to 50%, more than 50%. Of reactive atypias, 94% are negative or show p53 immunopositivity in less than 10% of cells. Of p53 positive malignancies, 86% are positive in more than 10% of cells. When p53 immunopositivity occurs in more than 10% of atypical cells, the lesion is usually a malignancy, primarily adenocarcinoma. Most reactive atypias are immunopositive in less than 10% of atypical cells. Important caveats were noted. Rare reactive atypias are p53 immunopositive in greater than 10% of cells. Bronchioloalveolar carcinomas are infrequently p53 immunopositive. Therefore, this approach would be less useful in their differentiation from reactive atypias.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1996

Correlation of very late activation integrin and CD44 expression with extrarenal invasion and metastasis of renal cell carcinomas.

Cell adhesion molecules mediate cell-cell and cell-matrix interactions, and they are thought to play an important role in tumor invasion and metastasis. Altered expression of integrins and CD44 in renal cell carcinoma has been recently demonstrated, but an association with invasive or metastatic behavior has not been reported. We examined very late activation (VLA) integrin and CD44 expression in 37 renal cell carcinomas and correlated adhesion molecule expression with multiple histological and clinical parameters. Most tumors exhibited positive staining for VLA3 (81%). Approximately one third of the tumors stained positively for VLA6 and CD44, and fewer (27%) were positive for VLA2. Only a few tumors were positive for VLA4 (8%) and VLA5 (14%). Most of the tumors exhibiting positive staining showed a combination of membranous and cytoplasmic staining patterns. Low-grade tumors positive for VLA6 showed a tendency for basilar staining of the tumor cells, whereas high-grade tumors exhibited diffuse cytoplasmic staining. All tumors exhibiting weak or strong positive staining for VLA4 or VLA5 showed extrarenal invasion or were known to have developed metastases at the time of nephrectomy. All tumors strongly positive for VLA2 or CD44 showed invasion beyond the renal capsule or metastases. In contrast to a previous study, no association was observed between positive staining and tumor grade. Nor were tumor size, architectural pattern, cell type, or DNA ploidy found to be associated with particular staining patterns. Although many of the invasive tumors showed no difference in VLA integrin or CD44 expression compared with tumors confined to the kidney, increased expression in some of them suggests that these cell adhesion molecules may contribute to the invasive or metastatic phenotype.

Carcinoma, Renal Cell↗

PubMed1996

Passive respiratory mechanics in healthy infants. Effects of growth, gender, and smoking.

This investigation characterizes the normal growth, variability, and effects of gender and smoking on passive respiratory mechanics in healthy infants. Passive respiratory mechanics were assessed at 193 test sessions on 127 infants (55 boys, 72 girls) between 2 wk and 18 mo of age using the single-occlusion passive flow-volume technique. Respiratory compliance (Crs) increased significantly with increasing infant length, whereas respiratory resistance (Rrs) declined. No significant gender differences were apparent for Crs, although there was a tendency for this measure to be both lower at birth and increase at a slower rate in girls than in boys. Rrs was significantly higher at birth in infant boys than in infant girls, but the rate of the normal decline in Rrs during the first 18 mo also occurred at a significantly greater rate in boys. The passive respiratory time constant (Trs) overall showed little change over this age range, but it was both lower near birth and increased at a significantly greater rate versus infant length in girls than in boys. Maternal smoking during pregnancy was associated with lower levels of Rrs at birth, as well as with significantly slower growth of Crs and natural decline of Rrs in the first 18 mo of life. These data suggest that infant girls may have more mature respiratory mechanics at birth, but that postnatal growth/maturation may be faster in boys.

Adult↗