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R W Brown

Publications and source records attributed to R W Brown.

At least 37 records · Page 2Linked to original sources
PubMed2000

D-amphetamine facilitation of morris water task performance is blocked by eticlopride and correlated with increased dopamine synthesis in the prefrontal cortex.

The effect of posttraining D-amphetamine on Morris water task (MWT) performance was analyzed in this study by training rats using a single training trial per day procedure. In addition to acquisition latency, learning was assessed by a probe trial given 24 h after the last training trial. Rats given immediate post-trial D-amphetamine demonstrated improved performance over saline rats on both acquisition and the probe trial. An analysis of the mechanisms underlying facilitation revealed that eticlopride (a D2 antagonist) blocked D-amphetamine's facilitatory effects on the probe trial and dopamine synthesis was increased in the medial prefrontal cortex in the D-amphetamine group relative to controls. These results show that chronic administration of posttraining D-amphetamine facilitated MWT performance, and this facilitation may be mediated by the dopaminergic system and dopamine synthesis in the prefrontal cortex.

Animals↗
PubMed2000

The expression of cyclins D1 and E in predicting short-term survival in squamous cell carcinoma of the lung.

Cyclins D1 (cD1) and E (cE) are G1 phase cyclins believed to participate in the pathogenesis of malignancy. Overexpression of cD1 has been reported to influence prognosis in squamous cell carcinomas (SCC) of the larynx, but was not significant in a limited study of non-small cell lung cancers (NSCLC). Altered expression of cE has been proposed as another potential prognostic marker in malignancy but its possible role in NSCLC has not been elucidated. In order to determine the prognostic value of cD1 and cE in NSCLC, paraffin-embedded sections of 467 NSCLC were immunostained with monoclonal antibody to cD1 (1:500, PharMingen, San Diego, CA) and 400 NSCLC with MA to cE (1:2500, PharMingen) using an enhanced sensitivity avidin-biotin complex technique. The number of tumor cells with nuclear and/or cytoplasmic immunopositivity was graded on a scale of: 0 = less than 1%, 1 = 1 to 10%, 2 = 10 to 25%, 3 = 25 to 50%, 4 = 50 to 75%, 5 = more than 75%. Results were correlated with survival by Kaplan-Meier survival plot using Stat-View software (Abacus Concepts, Berkeley, CA). Overall, 426 NSCLC with cD1 and 360 NSCLC with cE had adequate follow-up (median, 76 mo) for survival analysis. Both cyclins independently showed significance in prognosis of SCC but not other cell types. For cD1, absence of immunostaining was associated with worse prognosis than any immunopositivity for all stages of SCC (P = .025). For cE, Stage I and II SCC with less than 50% immunopositivity had a worse prognosis (P = .029). Of 70 Stage I and II SCC immunostained for both monoclonal antibodies, 55% of patients with tumors that demonstrated both absence of cD1 staining and cE immunopositivity in less than 50% of cells were dead at 5 years compared to 35% of patients with tumors that demonstrated positive staining with cD1 and cE immunopositivity in more than 50% of cells. These results strongly suggest cD1 and cE can independently predict prognosis in early stage SCC. Worse prognosis was associated with loss of expression, consistent with mechanisms other than overexpression of these cyclins in the progression of SCC.

Adult↗
PubMed2000

Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney.

Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits (alpha, beta and gamma), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 microg/kg per day), dexamethasone (100 microg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaCalpha mRNA exceeded beta or gamma by approximately 1.75- to 2.8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in beta and gamma, and ENaCalpha decreased sharply ( approximately 50%) across the outer medulla. Expression of ENaCbeta and gamma (but not alpha) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaCbetagamma participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1.9- to 3.5-fold increase in ENaCalpha (particularly marked in outer medullary collecting duct), but changes for beta and gamma were minor and limited to the cortex. The results raise the possibility that medullary ENaCalpha upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role.

Adrenal Cortex Hormones↗
PubMed1999

Treatment of anorexia and weight loss with megestrol acetate in patients with cystic fibrosis.

Four patients with severe cystic fibrosis lung disease, anorexia and weight loss, received Megestrol Acetate (MA), as an appetite stimulant. The initial dose was 400-800 mg daily and was continued for 6-15 months. Appetite was improved, with significant weight gain in all patients and an increase in their weight for age percentile from <5% at the start of the study to approximately the 25(th) percentile after 6 months of use and improvement in quality of life. One patient discontinued MA after 6 months, and subsequently appetite and weight were depressed.

Adolescent↗
PubMed1999

A hybrid inverse approach applied to the design of lumped-element RF coils.

A combination of inverse procedures is employed in the design of radio-frequency (RF) coils with specific examples in, but not restricted to, magnetic resonance imaging. The first inverse procedure is the use of functional methods for the optimization of coil characteristics subject to restrictions on the field behavior. Continuous current distributions are derived from analysis of the fields they are required to produce. To make use of these distributions at a desired frequency, the method of moments is applied as a second inverse procedure to a discretized version of the current distribution. The advantage of this hybrid technique is that it provides a computational algorithm for optimization of feeding, tuning, impedance matching and other aspects of RF coil design. A prototype RF coil has been built using the engineering values predicted by the theory. Experimental results including images acquired from the prototype coil are presented.

Algorithms↗
PubMed1999

Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2.

Deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11beta-HSD2 gene. Homozygous mutant mice (11beta-HSD2(-/-)) appear normal at birth, but approximately 50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11beta-HSD2(-/-) mice are markedly hypertensive, with a mean arterial blood pressure of 146 +/- 2 mmHg, compared with 121 +/- 2 mmHg in wild-type controls and 114 +/- 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11beta-HSD2(-/-) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Childhood asthma.

Asthma prevalence in children has increased 58% since 1980. Mortality has increased by 78%. The burden of the disease is most acute in urban areas and racial/ethnic minority populations. Hospitalization and morbidity rates for nonwhites are more than twice those for whites. Asthma is characterized by recurrent wheezing, breathlessness, chest tightness, and coughing. Research in the past decade has revealed the importance of inflammation of the airways in asthma and clinical treatment to reduce chronic inflammation. Asthma is associated with production of IgE to common environmental allergens including house dust mite, animal dander, cockroach, fungal spores, and pollens. Some interventions to reduce symptoms through control of dust mite and animal dander have had positive results. Control of symptoms through interventions to reduce exposures to cockroach antigen has not been reported. Studies illustrating causal effects between outdoor air pollution and asthma prevalence are scant. Increases in asthma prevalence have occurred at the same time as general improvements in air quality. However, air quality appears to exacerbate symptoms in the child who already has the disease. Decreased pulmonary function has been associated with exposure to particulates and bronchial hyperresponsiveness to smoke, SO(2) and NO(2). Symptoms have been correlated with increased levels of respirable particulates, ozone, and SO(2). Interventions that reduce the negative outcomes in asthma associated with outdoor environmental factors have not been reported. Control of asthma in children will entail the collaborative efforts of patients, family, clinical professionals, and school personnel, as well as community-wide environmental control measures and conducive national and local policies based on sound research.

Air Pollution, Indoor↗
PubMed1999

Pheochromocytoma associated with neuroendocrine carcinoma. A new type of composite pheochromocytoma.

The coexistence of pheochromocytoma and other tumor types in a single adrenal gland has been rarely documented. This type of pheochromocytoma is designated "composite" or "mixed," depending on whether the pheochromocytoma and the nonpheochromocytoma components show the same embryologic origin. The nonpheochromocytoma components reported in the composite pheochromocytoma include ganglioneuroma, ganglioneuroblastoma, neuroblastoma, and malignant schwannoma. The components found in the mixed pheochromocytoma include adrenal cortical neoplasms and spindle cell sarcoma. We report a unique case of composite pheochromocytoma in which the nonpheochromocytoma element is a neuroendocrine carcinoma. The histologic and the immunohistochemical profiles of the 2 distinct components of this tumor were typical for those of pheochromocytoma and neuroendocrine carcinoma. This dual differentiation was also supported by ultrastructural findings. This case not only broadens the morphologic spectrum of composite pheochromocytoma but also provides some additional insight into the histogenesis of this rare but fascinating type of tumor.

Adrenal Gland Neoplasms↗
PubMed1998

Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions.

Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD type 1 (11beta-HSD1) is a bidirectional enzyme in vitro that acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11beta-HSD type 2 (11beta-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivity in vivo. We have examined the ontogeny of 11beta-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11beta-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11beta-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11beta-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11beta-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11beta-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Adult mesoblastic nephroma: expansion of the morphologic spectrum and review of literature.

Mesoblastic nephroma (MN) is a distinctive tumor that is seen mostly in early infancy and that consists of classic and cellular (atypical) variants. Mesoblastic nephroma rarely occurs in adulthood, but MN in this age group still is poorly characterized because there are only 17 reported cases. We describe five additional cases of adult MN, including one case of the cellular variant, characterize the immunohistochemical profiles in detail, and critically review the previously reported cases. The collective data obtained from these 22 cases of adult MN showed that the patients predominantly were women (20 cases), ranging in age from 19 to 78 years, who were asymptomatic (5 cases) or had nonspecific signs and symptoms referable to a renal mass. Twenty tumors were classified as classic and 2 as cellular. The tumors were 2-24 cm, well circumscribed, and partially encapsulated and displayed a solid/ cystic cut surface, with a predominantly solid component in most tumors. One tumor, however, was almost purely cystic. Most tumors extended to the renal sinus. and some appeared entirely intrapelvic on imaging studies; however, gross and microscopic evaluation did not show destructive invasion of the pelvic wall. Extension of the tumor beyond the renal capsule has not been described. Each tumor was composed of epithelial and stromal components both. The epithelial component, which displayed no difference between the classic and cellular variants, was composed of isolated or clustered tubules and cysts lined by a benign epithelium with a wide range of cytologic differentiation. The stromal cells were composed of fibroblasts, myofibroblasts, and smooth muscle cells in various combinations. Stromal cellularity was low for the classic variant but high for the cellular variant. Hemorrhage, necrosis, and high mitotic index were noted in the stroma of the cellular, but not in the classic variant. Immunohistochemical study applied to the five current cases and seven normal control kidneys confirmed the presence of fibroblasts, myofibroblasts, smooth muscle cells, and prominent vessels in the stroma of each tumor. Most cysts and tubules within the tumors had a distinctive immunohistochemical profile, similar to that of collecting duct but different from those of other portions of the nephron in the normal control kidneys. After total or partial nephrectomy, without adjuvant chemotherapy or radiotherapy, 19 patients, including the 2 with cellular MN, were alive and well at 8-months to 48-years follow-up. Follow-up was not available in two patients. The remaining patient had recurrence at the surgical site 24 years after nephrectomy. Adult MN displays a distinctive morphologic spectrum that parallels that of its pediatric congener. It probably is a benign tumor that can be treated successfully by complete excision. The collecting duct differentiation expressed by most tubules and cysts of adult MN implies ureteric bud, which is the exclusive embryologic origin of collecting duct, as an important element in the histogenesis of this rare but fascinating type of tumor.

Adult↗
PubMed1998

Tissue-specific messenger ribonucleic acid expression of 11beta-hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor within rat placenta suggests exquisite local control of glucocorticoid action.

Placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) regulates transplacental passage of maternal glucocorticoids to the fetus and is thus a key determinant of fetal glucocorticoid levels. It has also been proposed that placental 11beta-HSD expression may influence local glucocorticoid actions by regulating access of corticosterone to the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). Therefore, the present study used a rat model to assess whether the GR or MR are coexpressed with the two forms of 11beta-HSD (types 1 and 2) in the placental labyrinth zone, the major site of maternal-fetal transfer, and in the basal zone, the primary site of placental hormone synthesis. In situ hybridization analysis was used to assess messenger RNA (mRNA) expression for the GR, MR, 11beta-HSD-1, and 11beta-HSD-2 in the two placental zones on days 16, 19 and 22 of pregnancy (term = day 23). Whereas expression of the GR appeared relatively unchanged in both zones at these three stages of pregnancy, that of 11beta-HSD-1 clearly increased in the labyrinth zone but fell in basal zone, whereas the opposite pattern of expression was observed for 11beta-HSD-2. MR expression was not detected at any stage. The pattern of placental 11beta-HSD-2 mRNA expression over days 16, 19, and 22 of pregnancy was paralleled by changes in 11beta-HSD-2-specific bioactivity, but despite clear expression of 11beta-HSD-1 mRNA, no bioactivity attributable to this enzyme was measurable in either placental zone. To assess the role of fetal adrenal maturation on these changes in 11beta-HSD, two experimental models, maternal adrenalectomy and fetectomy, were employed. Maternal adrenalectomy on day 13 advanced maturation of the fetal adrenal cortex but had no effect on 11beta-HSD-2 bioactivity in either of the placental zones at day 19. Placental 11beta-HSD-2 bioactivity on day 22 was also unaffected by fetectomy 3 or 6 days earlier. In conclusion, the consistent expression of the GR in the two placental zones late in pregnancy suggests that concomitant and marked changes in 11beta-HSD-1 and 11beta-HSD-2 expression could have a major influence on glucocorticoid action in the placenta at this time. Moreover, the changes in 11beta-HSD expression appear to be unrelated to development of the fetal adrenal cortex and are likely to reduce the placental glucocorticoid barrier near the end of pregnancy.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Effect of immunization against the amino-terminal peptide (alpha N) of the alpha 43-subunit of inhibin on follicular atresia and expression of tissue inhibitor of matrix metalloproteinase (TIMP-1) in ovarian follicles of sheep.

Ewes actively immunized against alpha N, the N-terminal peptide of inhibin alpha 43 precursor, have lowered fertility associated with ovulation failure, restricted tissue remodelling and reduced matrix metalloproteinase-2 activity in the follicular fluid at the time of expected ovulation. This could be due to altered ratios of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase (TIMP-1), or to the onset of atresia in antral follicles destined to ovulate. The objectives of the present study were to investigate the effects of immunization against alpha N on the localization of TIMP-1 in ovine follicles, and on follicular growth and atresia in the follicular phase. Ewes were either immunized against alpha N or remained as controls and the ovaries were removed before (0, n = 4) and at 12 h (n = 4) and 24 h (n = 4) after hCG administration in a synchronized follicular phase, 48 h after removal of intravaginal pessaries. Observations were made on a single section taken through the largest follicle present in the ovaries of each ewe. There were no healthy antral follicles > 1 mm in immunized ovaries (0/29) compared with controls (16/31) (P < 0.001), whereas the proportion of healthy antral follicles < 1 mm was the same in each group (9/19 versus 5/12). TIMP-1 immunoactivity was localized in large luteal cells, smooth muscle and endothelial cells, and in all antral follicles, including oocytes. At the time of hCG administration, no TIMP-1 immunoreactivity was detected in the apical region of the follicular wall of large follicles (> 6 mm) compared with the rest of the follicle wall, but staining appeared in the apical granulosa layer 24 h later. In newly formed corpora lutea, TIMP-1 expression was found along the invaginating vascular layer. There was no effect of immunization on the patterns of TIMP-1 immunoreactivity, suggesting that changes in TIMP-1 are not involved in the effects of alpha N. These data are consistent with a paracrine role for alpha N in the selection and atresia of antral follicles, and for TIMP-1 in tissue reorganization and steroidogenesis at the time of ovulation.

Analysis of Variance↗
PubMed1998

Artificial neural networks and logistic regression as tools for prediction of survival in patients with Stages I and II non-small cell lung cancer.

The prognosis of patients with Stage I and II non-small cell lung cancer (NSCLC) can be estimated but cannot be definitively ascertained by use of current clinicopathologic criteria and tumor marker studies. The potential value of probabilistic neural networks (NNs) with genetic algorithms and multivariate logistic regression to predict the survival of NSCLC patients has not been previously evaluated. Multiple prognostic factors (age, sex, cell type, stage, tumor grade, smoking history, and immunoreactivity to c-erbB-3, bcl-2, Glut1, Glut3, retinoblastoma gene and p53 were correlated with 5-year survival in 63 patients with Stage I or II NSCLC, treated solely by surgical excision at Baylor Medical College, Houston, Texas. Several probabilistic NNs with genetic algorithm models were developed using the prognostic features as input neurons and survival at 5 years (free of disease/dead of disease) as output neurons. The probabilistic NN yielded excellent classification rates for dependent variable survival. The best model was trained with 52 cases and classified all 11 "unknown" test cases correctly. Several statistically significant logistic regression models were fitted using 50 cases to build the models and 13 cases as "hold-out" test cases. These multivariate statistical models provide various cutoff values that predict/classify the probability of survival at 5 years. In conclusion, probabilistic NNs and logistic regression models can be useful in estimating the prognosis of patients with Stage I and II NSCLC using multiple clinicopathologic and molecular variables. These multivariate predictive models need to be validated with much larger groups of patients to assess their potential clinical value.

Adult↗
PubMed1997

Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival.

BACKGROUND: Increased expression of Glut1 and Glut3 has been reported in many human cancers, including nonsmall cell lung carcinoma (NSCLC). The aim of this study was to determine the biologic significance of Glut1 and Glut3 overexpression in Stage I NSCLC. METHODS: Using immunohistochemistry and polyclonal anti-Glut1 and anti-Glut3 antibodies, the authors immunostained sections of formalin fixed, paraffin embedded tissues from 289 Stage I NSCLCs. The Kaplan-Meier survival method, the log rank test, and Fisher's exact test were used for statistical analysis. RESULTS: Of the 289 cases, 49 (17%) were negative for both Glut1 and Glut3, 239 (83%) were Glut1 positive, 61 (21%) were Glut3 positive, 179 (62%) were positive for Glut1 but negative for Glut3, 1 (0.3%) was positive for Glut3 but negative for Glut1, and 60 (21%) were positive for both Glut1 and Glut3. Only 1 of 50 Glut1 negative tumors (2%) was positive for Glut3, whereas 60 of 239 Glut1 positive tumors (25%) were positive for Glut3 (P < 0.0001). Glut1 or Glut3 were detected more often in poorly differentiated and undifferentiated tumors (P < 0.0001 and P = 0.0008, respectively). Overexpression of Glut1 and/or Glut3 was associated with poorer survival (P = 0.0133), especially in patients with well-differentiated and moderately differentiated tumors (P = 0.0017). CONCLUSIONS: In Stage I NSCLC, Glut3 overexpression likely occurs after Glut1 overexpression. The appearance of Glut1 positive clones is associated with aggressive biologic behavior, which is worsened by the emergence of Glut3 positive clones. Glut1 and Glut3 are significant of poor prognosis indicators in cases of NSCLC.

Adult↗
PubMed1997

Ontogenetic differences in retention of spatial learning tested with the Morris water maze.

Two experiments examined retention of spatial learning in rats using a Morris water maze. Retention was scored in terms of probe trial performance when the platform was removed. Latency to reach the platform location, percent of time in the quadrant that had contained the platform, and relative frequency of visits to the platform location were analyzed. Results of the first experiment showed that preweanlings and juveniles exhibited substantial forgetting at 3- and 7-day retention intervals. Forgetting in adults was much lower than that found in the younger animals, and no differences in amount of forgetting appeared between the 3- and 7-day retention intervals at any age. The second experiment showed that forgetting in juveniles was alleviated by a single training trial administered just prior to the probe trial. These results are discussed in terms of ontogenetic differences in memory processing and measurement issues pertinent to the Morris water maze test procedure.

Aging↗