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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 163 records · Page 9Linked to original sources
PubMed1999

Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium.

Steroid receptor coactivator-1 (SRC-1) family members interact with steroid receptors, including estrogen receptor alpha (ERalpha) and progesterone receptor (PR), to enhance ligand-dependent transcription. However, the expression of ERalpha and SRC-1 was found to be segregated in distinct subsets of cells within the epithelium of the estrogen-responsive rat mammary gland. This finding was in contrast to the finding for the stroma, where significant numbers of cells coexpressed ERalpha and SRC-1. Treatment of animals with estrogen induced PR expression in the ERalpha-expressing mammary epithelial cells in the absence of detectable SRC-1 and did not affect the segregated pattern of SRC-1 and ERalpha expression. PR was neither expressed nor induced by estrogen treatment in stroma, despite the coexpression of ERalpha and SRC-1. These results suggest that SRC-1 is not necessary for ERalpha-mediated induction of PR in mammary epithelial cells and is also not sufficient for PR induction in stromal cells expressing both ERalpha and SRC-1. Furthermore, the expression of SRC-1 in a subpopulation of mammary epithelial cells distinct from those expressing ERalpha or PR raises the possibility that SRC-1 has cell type-specific functions other than simply to act as coactivator for ERalpha or PR in the mammary epithelium.

Animals↗
PubMed1999

Provider-reported illness and absence due to illness among children attending child-care homes and centers in San Diego, Calif.

PURPOSE: To compare the incidence of provider-reported illness and absence due to illness among children attending small child-care homes, large child-care homes, and child care centers in a large metropolitan area. METHODS: From July 6, 1992, through January 28, 1994, we collected information from child-care providers on illness and absence due to illness at 64 small and 58 large child-care homes and 41 child-care centers. This included 113 446 child-weeks of information on 5360 children. RESULTS: Providers reported 14 474 illness episodes (6.6 episodes per child-year) and 8593 days of absence due to illness (3.9 days per child-year). The incidence of illness episodes was greatest in children who were younger than 1 year, white, or enrolled in small child-care homes. The incidence of absence due to illness was greatest in children who were 1 year of age, Hispanic, or enrolled in child-care centers. Respiratory symptoms were most commonly associated with illness episodes and absence due to illness. CONCLUSIONS: Children in child-care homes had a greater incidence of provider-reported illness than did those in centers. This risk varied by the type of facility and was greatest in small child-care homes. The increased risk for absence due to illness among children in child-care centers reflects exclusion and attendance patterns. It may be possible to reduce the incidence of absence due to illness and subsequent economic impact of child-care-associated illness by educating providers on exclusion guidelines.

Absenteeism↗
PubMed1999

Treatment of Guillain-Barré syndrome: a cost-effectiveness analysis.

Acute Guillain-Barré syndrome is the most common cause of neuromuscular paralysis. Plasma exchange and intravenous immune globulin (IV IgG) are both effective treatments for this condition and the purpose of this report was to compare the cost-effectiveness of these two modalities. A MEDLINE search was performed to identify randomized studies that compared the use of IV IgG and plasma exchange for treatment of acute Guillain-Barré syndrome to determine if one modality was more effective and/or safer for the management of this condition. A decision analysis was structured around the alternatives facing neurologists who must choose a treatment regimen for patients diagnosed with acute Guillain-Barré syndrome who require active therapy. Cost information was obtained directly from product manufacturers and hospital sources. Two head-to-head trials comparing the effectiveness of plasma exchange and IV IgG for treatment of acute Guillain-Barré syndrome determined that there was insufficient evidence to suggest one therapy was more effective than the other; therefore, a cost minimization analysis was performed. The costs per patient of plasma exchange and IV IgG for the treatment of acute Guillain-Barré syndrome were $6,204 and $10,165, respectively. A sensitivity analysis determined the model was sensitive to the cost of IV IgG. The cost savings per patient treatment for the use of plasma exchange varied from $304 to $6,625 depending on the IV IgG product selected. Plasma exchange and IV IgG are both effective treatments for Guillain-Barré syndrome. However, our analysis determined plasma exchange on average was almost $4,000 less costly per patient than IV IgG. Further research is required to determine the impact of patient and physician preferences on the treatment of this disorder.

Canada↗
PubMed1999

Stiffness and muscle function with age and reduced muscle use.

Changes in passive muscle stiffness with age and disuse were assessed in male Fischer-344 and Brown Norway rats. Three groups of rats were studied: young (approximately 7 months old), old (approximately 33 months old), and old that had undergone 2 weeks of hindlimb unweighting, a model of reduced muscle use. Four hindlimb muscles were examined: the soleus (postural), plantaris (locomotor), extensor digitorum longus (nonpostural), and peroneus longus (nonpostural). Supramaximal stimuli elicited peak tetanic tensions throughout the available range of motion (amount of muscle elongation before the maximal attainable contractile or tetanic tension is obtained) for each muscle, permitting the creation of length-tension curves. Passive tension (amount encountered at each millimeter of change in muscle length) was also recorded throughout the available range of motion and was unchanged with aging and unchanged or reduced with hindlimb unweighting; muscle stiffness remained unchanged under both conditions. Passive tension, however, accounted for a greater proportion of total tension with age and particularly with hindlimb unweighting. A significant loss in muscle range of motion, resulting in a leftward shift in the length-tension curve, occurred with aging in only the plantaris. Hindlimb unweighting resulted in a marked loss in muscle range for all four muscles studied, suggesting that the remaining muscle force was constrained to a very small arc. Significant declines in muscle mass and peak contractile tension, associated with age and hindlimb unweighting, were observed for all four muscles.

Aging↗
PubMed1999

The role of ischemic preconditioning in the recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion.

BACKGROUND: We have recently shown that hepatic ischemia/reperfusion (I/R) results in rolling and adherence of leukocytes in terminal hepatic venules (THV) followed by hepatic enzyme elevation and tissue destruction. The objective of this study was to determine the effect of ischemic preconditioning on the recruitment of leukocytes in THV after liver I/R. METHODS: Left hepatic lobe ischemia was induced for 5 min (preconditioning) in anesthetized C57B1/6 mice followed by reperfusion for 10 min and then prolonged ischemia for 30 min. The number of rolling, saltating, and adherent leukocytes in THV was measured at 0.5, 2, 5, 12, and 24 h after reperfusion using intravital video microscopy. Matching sham groups were evaluated after 30 min of ischemia. RESULTS: Hepatic I/R elicited significant increases in the number of rolling, saltating, and adherent leukocytes, with peak values observed at 30 min and 5 h after reperfusion. All of these responses were significantly attenuated in mice undergoing ischemic preconditioning. Rolling leukocytes in THV following I/R without preconditioning reached peak levels of 25.2 +/- 1.4 leuk/2 min (leukocytes/2 min) at 30 min reperfusion and 31.4 +/- 1.5 leuk/2 min at 5 h reperfusion. With ischemic preconditioning these values fell to 12.3 +/- 0.9 leuk/2 min and 14.4 +/- 1.0 leuk/2 min, respectively (P < 0.001). Similarly, adherent leukocytes in nonpreconditioned mice reached peak values of 4.8 +/- 1.3 leuk/2 min at 30 min reperfusion and 8.3 +/- 1.2 leuk/2 min at 5 h reperfusion compared with 2.0 +/- 1.5 leuk/2 min and 1.6 +/- 1.1 leuk/2 min in preconditioned mice, respectively (P < 0.001). CONCLUSION: Ischemic preconditioning attenuates the initial events leading to leukocyte-mediated hepatic destruction following I/R injury. Delineating these mechanisms may play an important role in hepatic transplantation, resection, shock, and sepsis.

Animals↗
PubMed1999

Assessment of technical skills transfer from the bench training model to the human model.

BACKGROUND: This study examines whether technical skills learned on a bench model are transferable to the human cadaver model. METHODS: Twenty-three first-year residents were randomly assigned to three groups receiving teaching on six procedures. For each procedure, one group received training on a cadaver model, one received training on a bench model, and one learned independently from a prepared text. Following training, all residents were assessed on their ability to perform the six procedures. RESULTS: Repeated measures analysis of variance revealed a significant effect of training modality for both checklist scores (F(2,44) = 3.49, P <0.05) and global scores (F(2,44) = 7.48, P <0.01). Post-hoc tests indicated that both bench and cadaver training were superior to text learning and that bench and cadaver training were equivalent. CONCLUSIONS: Training on a bench model transfers well to the human model, suggesting strong potential for transfer to the operating room.

Cadaver↗
PubMed1999

Extent and direction of joint motion limitation after prolonged immobility: an experimental study in the rat.

OBJECTIVES: To test the hypotheses that contractures progress at different rates in relation to the time after immobilization, that immobilization in flexion leads to loss of extension range of motion, and that joints of sham-operated animals are better controls than the contralateral joint of experimental animals. STUDY DESIGN: Experimental, controlled study in which 40 adult rats had one knee joint immobilized at 135 degrees of flexion for up to 32 weeks and 20 animals underwent a sham procedure. At intervals of 2, 4, 8, 16, and 32 weeks, 8 experimental and 4 sham-operated animals were killed and their knee motion measured in flexion and extension. RESULTS: In the experimental group, the range of motion decreased in the first 16 weeks of immobility at an average rate of 3.8 degrees per week (p<.0001) to reach 61.1 degrees of restriction. A plateau was then observed from which the contracture did not progress further. The loss in range of motion occurred in extension, not in flexion. CONCLUSION: This study defined an acute stage of contractures starting at the onset of immobility and lasting 16 weeks, during which the range of motion was progressively restricted, and a chronic stage during which no additional limitation was detected. The loss in motion was attributed to posterior knee structures not under tension during immobilization in flexion. Contrary to the hypothesis, the contralateral joint was validated as a control choice for range-of-motion experiments.

Acute Disease↗
PubMed1999

Replacements in the exposed loop of the T15 antibody VH CDR2 affect carrier recognition of PC-containing pathogens.

A panel of mutant antibodies of the phosphocholine (PC)-binding antibody, T15, was tested for binding to PC-protein, Streptococcus pneumoniae, Trichinella spiralis and Ascaris suum. Relative to wildtype T15, all the mutant antibodies showed differential recognition of the panel of PC-associated antigens. These mutant antibodies contain amino acid replacements in the CDR2 region of the heavy chain variable region, indicating the importance of CDR2 in recognition of carrier determinants. A model of T15 is shown that illustrates the strategic placement of mutations that could allow interaction with determinants associated with PC. A direct implication of this finding is that the T15 antibody combining site accommodates structures larger than phosphocholine and that recognition of associated carrier determinants could be a significant force in shaping the immune response to PC-containing pathogens.

Amino Acid Sequence↗
PubMed1999

Partners in life and in death: the suicide pact in England and Wales 1988-1992.

BACKGROUND: We describe the epidemiology of suicide pacts in England and Wales and assess the health, circumstances and motivation of those who died in pacts; the first such account for 35 years. METHODS: We have analysed the death certificates, coroners' records and medical notes of all people who died in suicide pacts in England and Wales between 1 January 1988 and 31 December 1992. RESULTS: The 124 suicides in 62 pacts accounted for 0.6% of all suicides giving a rate of 0.6 per million. The average age was 56 years. Poisoning by car exhaust or medicines caused 95% of deaths, both members of each pair using the same method. Forty-eight pacts were between married couples, five between blood relatives. Mental disorder was present in half and medical illness in one-third. Motives were avoiding loss of a partner from ill-health in 26 pacts, euthanasia in nine, thwarted love in four. CONCLUSIONS: The findings are similar to those of 35 years ago except the incidence of pacts is less. Improved management of illness might avoid some pacts especially when partners in an enduring, affectionate relationship, with few social ties, are both ill.

Adolescent↗
PubMed1999

The effect of moxonidine on feeding and body fat in obese Zucker rats: role of hypothalamic NPY neurones.

The antihypertensive agent moxonidine, an imidazoline Ii-receptor agonist, also induces hypophagia and lowers body weight in the obese spontaneously hypertensive rat, but the central mediation of this action and the neuronal pathways that moxonidine may interact with are not known. We studied whether moxonidine has anti-obesity effects in the genetically-obese and insulin-resistant fa/fa Zucker rat, and whether these are mediated through inhibition of the hypothalamic neuropeptide Y (NPY) neurones. Lean and obese Zucker rats were given moxonidine (3 mg kg(-1) day(-1)) or saline by gavage for 21 days. Moxonidine decreased food intake throughout by 20% in obese rats (P<0.001) and by 8% in lean rats (P<0.001), and reduced weight gain that final body weight was 15% lower in obese (P<0.001) and 7% lower in lean (P<0.01) rats than their untreated controls. Plasma insulin and leptin levels were decreased in moxonidine-treated obese rats (P<0.01 and P<0.05), but unchanged in treated lean rats. Uncoupling protein-1 gene expression in brown adipose tissue was stimulated by 40-50% (P< or =0.05) in both obese and lean animals given moxonidine. Obese animals given moxonidine showed a 37% reduction in hypothalamic NPY mRNA levels (P = 0.01), together with significantly increased NPY concentrations in the paraventricular nucleus (P<0.05), but no changes in the arcuate nucleus or other nuclei; this is consistent with reduced NPY synthesis in the arcuate nucleus and blocked release of NPY in the paraventricular nucleus. In lean animals, moxonidine did not affect NPY levels or NPY mRNA. The hypophagic, thermogenic and anti-obesity effects of moxonidine in obese Zucker rats may be partly due to inhibition of the NPY neurones, whose inappropriate overactivity may underlie obesity in this model.

Adipose Tissue↗
PubMed1999

Decreased plasma leptin levels in lean and obese Zucker rats after treatment with the serotonin reuptake inhibitor fluoxetine.

Leptin inhibits feeding, stimulates thermogenesis and decreases body weight. Serotonin reduces food intake when injected into the hypothalamus and may interact with other neurotransmitters in the control of appetite. We therefore investigated the effects of the serotonergic drug fluoxetine, which inhibits serotonin reuptake, on food intake and plasma leptin levels in lean and obese Zucker rats. Fluoxetine significantly reduced food intake in lean and obese rats, both acutely after a single injection (10 mg/kg) and during continuous subcutaneous infusion (10 mg/kg/day for 7 days). Plasma leptin levels were reduced after both 4 hours and 7 days of fluoxetine administration in lean and after 7 days in fatty rats (all p<0.01). We have previously suggested that serotonin may decrease food intake by inhibiting neuropeptide Y neurones, and we further suggest that it also inhibits leptin, possibly by an effect on white adipose tissue.

Animals↗
PubMed1999

Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

Adult↗
PubMed1999

Peak aerobic power is an important component of physical performance in older women.

BACKGROUND: The purpose of this study was to determine the relationship between peak aerobic power (VO2peak) and performance on a modified Physical Performance Test (modified PPT) in older women. METHODS: One hundred one women aged 75 years and older seeking enrollment in randomized, controlled trials of exercise and/or hormone replacement therapy were recruited from the community-at-large and from congregate living sites. Measures obtained included VO2peak, a modified PPT, and self-reports about performance of activities of daily living. RESULTS: Simple regression analysis demonstrated that VO2peak was associated with total PPT score (r =.53, p <.001), gait speed (r =.44, p <.001), time to arise from a chair five times (r =.43, p = <.001), and time to climb one flight of stairs (r =.36, p =.007). Multiple regression analysis revealed that the relationships between VO2peak and total modified PPT score, gait speed, chair rise time, and time to climb one flight of stairs were independent of age. CONCLUSIONS: Peak aerobic power is a significant independent predictor of performance on a standardized test of physical function in older women and is an important component of physical frailty in this population.

Activities of Daily Living↗
PubMed1999

P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion.

We have recently reported that hepatic ischemia/reperfusion (I/R) is associated with a biphasic increase in the expression of P-selectin in the liver microvasculature, with peak expression levels observed at 20 min and 5 h after reperfusion. This I/R-induced upregulation of P-selectin expression is accompanied by leukocyte-endothelial cell adhesion in terminal hepatic venules (THV). The objective of this study was to determine whether the early expression of P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in THV after liver I/R. Left hepatic lobe ischemia was induced for 30 min in anesthetized C57B1/6 and P-selectin knockout (KO) mice. The number of rolling, saltating, and adherent leukocytes in THV was measured at 0, 15, 30, 60, and 120 min after reperfusion using intravital video microscopy. Hepatic I/R elicited significant increases in the number of rolling, saltating, and adherent leukocytes, with peak values observed at 30 min after reperfusion. All of these responses were absent in P-selectin KO mice and in C57B1/6 mice treated with a blocking antibody to P-selectin. Our findings suggest that P-selectin is the primary determinant of leukocyte-endothelial cell adhesion observed in hepatic venules in the initial period after I/R. Hence, this adhesion molecule may represent a target for therapeutic intervention in liver transplantation and other conditions associated with hepatic I/R.

Animals↗
PubMed1999

Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide.

Opening of mitochondrial ATP-sensitive (mitoKATP) channel with diazoxide induces an early phase (EP) of cardioprotection. It is unknown whether diazoxide also induces a delayed phase (DP) of cardioprotection. Because nitric oxide (NO) modulates ATP sensitivity of the KATP channel, we hypothesized that NO may play a role in diazoxide-induced cardioprotection. Diazoxide (1 mg/kg) was administered either 30 min (for EP) or 24 h (DP) before 30 min of lethal ischemia. Blockers of mitoK(ATP) channel [5-hydroxydecanoate (5-HD)] or NO synthase [N(G)-nitro-L-arginine methyl ester (L-NAME)] were given 10 min before ischemia-reperfusion performed by 30 min of left anterior descending coronary artery occlusion and 3 h of reperfusion. A risk area (RA) was demarcated by Evans blue dye, and infarct size (IS) was measured by tetrazolium staining. Diazoxide caused a decrease in IS (%RA) from 27.8 +/- 4.2% in the vehicle group to 12.9 +/- 1.2% during EP and from 30.4 +/- 4. 2% in vehicle-treated rabbits to 19.6 +/- 2.4% during DP (P < 0.05). IS increased to 31.3 +/- 1.1% and 27.9 +/- 1.0% (EP) and 29.9 +/- 2. 3% and 35.1 +/- 1.8% (DP) with 5-HD and L-NAME, respectively (P < 0. 05). 5-HD and L-NAME caused no proischemic effect in controls. Diazoxide induced both early and delayed anti-ischemic effects via opening of mitoK(ATP) channels, which was NO dependent.

Adenosine Triphosphate↗
PubMed1999

Age-related changes in contractile properties of single skeletal fibers from the soleus muscle.

Peak absolute force, specific tension (peak absolute force per cross-sectional area), cross-sectional area, maximal unloaded shortening velocity (Vo; determined by the slack test), and myosin heavy chain (MHC) isoform compositions were determined in 124 single skeletal fibers from the soleus muscle of 12-, 24-, 30-, 36-, and 37-mo-old Fischer 344 Brown Norway F1 Hybrid rats. All fibers expressed the type I MHC isoform. The mean Vo remained unchanged from 12 to 24 mo but did decrease significantly from the 24- to 30-mo time period (from 1.71 +/- 0.13 to 0.85 +/- 0.09 fiber lengths/s). Fiber cross-sectional area remained constant until 36 mo of age, at which time there was a 20% decrease from the values at 12 mo of age (from 5,558 +/- 232 to 4,339 +/- 280 micrometer2). A significant decrease in peak absolute force of single fibers occurred between 12 and 24 mo of age (from 51 +/- 2 x 10(-5) to 35 +/- 2 x 10(-5) N) and then remained constant until 36 mo, when another 43% decrease occurred. Like peak absolute force, the specific tension decreased significantly between 12 and 24 mo by 20%, and another 32% decline was observed at 37 mo. Thus, by 24 mo, there was a dissociation between the loss of fiber cross-sectional area and force. The results suggest time-specific changes of the contractile properties with aging that are independent of each other. Underlying mechanisms responsible for the time-dependent and contractile property-specific changes are unknown. Age-related changes in the molecular dynamics of myosin may be the underlying mechanism for altered force production. The presence of more than one beta/slow MHC isoform may be the mechanism for the altered Vo with age.

Aging↗
PubMed1999

Functional analysis of a novel estrogen receptor-beta isoform.

A new level of complexity has recently been added to estrogen signaling with the identification of a second estrogen receptor, ERbeta. By screening a rat prostate cDNA library, we detected ERbeta as well as a novel isoform that we termed ERbeta2. ERbeta2 contains an in-frame inserted exon of 54 nucleotides that results in the predicted insertion of 18 amino acids within the ERbeta hormone-binding domain. We also have evidence for the expression of both ERbeta1 and ERbeta2 in human cell lines. Competition ligand binding analysis of bacterially expressed fusion proteins revealed an 8-fold lower affinity of ERbeta2 for 17beta-estradiol (E2) [dissociation constant (Kd approximately 8 nM)] as compared with ERbeta1 (Kd approximately 1 nM). In vitro transcribed and translated ERbeta1 and ERbeta2 bind specifically to a consensus estrogen responsive element in a gel mobility shift assay. Furthermore, we show heterodimerization of ERbeta1 and ERbeta2 with each other as well as with ERalpha. In affinity interaction assays for proteins that associate specifically with the hormone-binding domain of these receptors, we demonstrate that the steroid receptor coactivator SRC-1 interacts in an estrogen-dependent manner with ERalpha and ERbeta1, but not with ERbeta2. In cotransfection experiments with expression plasmids for ERalpha, ERbeta1, and ERbeta2 and an estrogen-responsive element-containing luciferase reporter, the dose response of ERbeta1 to E2 was similar to that of ERalpha although the maximal stimulation was approximately 50%. In contrast, ERbeta2 required 100- to 1000-fold greater E2 concentrations for maximal activation. Thus, ERbeta2 adds yet another facet to the possible cellular responses to estrogen.

Alternative Splicing↗