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M Brown

Publications and source records attributed to M Brown.

At least 217 records · Page 12Linked to original sources
PubMed1998

The impact of mammography quality improvement legislation in Michigan: implications for the National Mammography Quality Standards Act.

OBJECTIVES: This study examined the impact of state legislation on mammography quality and access in Michigan. METHODS: The impact of state legislation was analyzed with respect to utilization, numbers of machines and facilities, and image quality. RESULTS: The legislation had a positive effect on image quality improvement, had no impact on utilization by women aged 50 years and above, and resulted in few facility closures. CONCLUSIONS: Michigan's legislative intervention appears to have had a positive effect on efforts to improve mammography quality assurance with implications for other federal and state efforts to achieve quality assurance in health care delivery.

Aged↗
PubMed1998

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California↗
PubMed1998

Secretor status and ankylosing spondylitis.

OBJECTIVE: To assess the genetic association between secretor status and ankylosing spondylitis (AS). METHODS: A restriction digest method for determining secretor status was developed; 166 patients with AS and 216 healthy British white controls were typed for secretor status using this method. RESULTS: The frequency of nonsecretors among patients with AS (47/166, 28%) was not significantly different from controls (72/216, 33%). CONCLUSION: Secretor status does not influence susceptibility to AS.

Cohort Studies↗
PubMed1998

The androgen receptor gene GGN microsatellite and prostate cancer risk.

The androgen receptor (AR) gene contains a polymorphic GGN microsatellite in exon 1, which encodes polyglycine in the amino terminus of the AR. Previous work has shown that a polymorphic region of CAG repeats also in exon 1 is inversely related to the ability of the AR to transactivate other genes and to prostate cancer risk. We investigated whether AR gene GGN repeat length is related to prostate cancer in a nested study of 582 cases and 794 controls matched on age and smoking status in the Physicians' Health Study. DNA was prepared from archived blood. Using PCR, the region surrounding the GGN repeat was amplified. Fluorescence-labeled primers were used such that the fragment produced could be sized using polyacrylamide gels and Genescan software. We estimated odds ratios and 95% confidence intervals from logistic models controlling for the matching variables for the relation between GGN repeat length and total prostate cancer and by stage/grade and by age at diagnosis. Among controls, the most frequent GGN repeat lengths were 23 (53.5%) and 24 (34.0%), with a range of 10-29. There was no statistically significant difference in the mean GGN repeat length between cases (23.13) and controls (23.05). However, cases had a narrower spread of repeats lengths (parametric test, P = 0.03; nonparametric test, P = 0.07) than controls, with fewer extreme lengths in either direction. The risk of total prostate cancer was slightly increased for a GGN repeat length of 23 compared to all others (odds ratio, 1.20; 95% confidence interval 0.97-1.49); risk did not vary by tumor stage/grade. For every one repeat deviation in either direction from 23, the risk of prostate cancer decreased by 8% (P = 0.04). Although the AR gene GGN repeat probably plays only a modest role in prostate cancer, the observed relation of this repeat with prostate cancer risk supports the evaluation of the effect of GGN repeat length on AR transactivation.

Adult↗
PubMed1998

Molecular size of recombinant alpha1beta1 and alpha1beta1gamma2 GABAA receptors expressed in Sf9 cells.

The present study examines the physical properties of recombinant human GABAA receptors. The baculovirus/Sf9 cell system was used to express combinations of human GABAA receptor subunits: alpha 1 alone, alpha 1 with beta 1, and alpha 1 with beta 1 and gamma 2. Receptors were solubilized using 1% Triton X-100. In sucrose density gradients containing 150mM NaCl, alpha 1 beta 1 receptor-detergent complexes sedimented more slowly than alpha 1 beta 1 gamma 2 constructs (sedimentation coefficient = 7.00 +/- 0.32 and 8.63 +/- 0.48 S, respectively). Stokes' radii for the two receptor-detergent complexes were determined by gel filtration in Sephacryl S-300. These experiments were performed in the presence of 1 M sodium chloride to prevent aggregation. The Stokes' radii for alpha 1 beta 1 and alpha 1 beta 1 gamma 2 receptor-detergent complexes were 9.06 +/- 0.23 and 7.91 +/- 0.19 nm, respectively. Sedimentation experiments in 1 M NaCl revealed similar sedimentation coefficients for alpha 1 beta 1 and alpha 1 beta 1 gamma 2 receptor-detergent complexes (8.79 +/- 0.59 and 8.46 +/- 0.72 S, respectively). The molecular weight of the alpha 1 beta 1 receptor excluding detergent was estimated to be 281 +/- 19 kDa, that of the alpha 1 beta 1 gamma 2 receptor, 247 +/- 21 kDa. This difference is not statistically significant. Given subunit molecular weights which are close to 50 kDa, this suggested a pentameric structure for the majority of alpha 1 beta 1 gamma 2 receptors, and that alpha 1 beta 1 receptors are not"assembly intermediates" with fewer subunits.

Animals↗
PubMed1998

Debrisoquine hydroxylase (CYP2D6) and prostate cancer.

The p450 hepatic microsomal enzyme system metabolizes exogenous drugs and carcinogens. Debrisoquine hydroxylase (CYP2D6), one member of the p450 hemoproteins, has polymorphic expression leading to poor metabolism of debrisoquine and similar compounds in approximately 7% of Caucasians. The genetic locus for this enzyme has been characterized, and the mutations responsible for the slowed metabolism have been identified. Epidemiological studies of the CYP2D6 phenotype suggest an association between the normal or rapid metabolism phenotype and increased risk of lung and bladder cancer. Preliminary data have also suggested an association with prostate cancer (CaP). We used a PCR-based assay to investigate possible associations between the CYP2D6 B allele, the most common genetic mutation responsible for the poor metabolism phenotype, and CaP. Using genomic DNA isolated from peripheral blood, we genetically typed 571 men with CaP and 767 matched controls, all participants in the Physician's Health Study. Relative to men homozygous for the wild-type allele, heterozygotes for the B allele have an odds ratio of 1.19 (95% confidence interval, 0.94-1.51) for CaP, and men homozygous for the B allele have an odds ratio of 1.37 (95% confidence interval, 0.86-2.20). When analyzed as a trend over zero, one, or two copies of the B allele, there emerges a possible association between the B allele and an increased risk of CaP of borderline statistical significance (P = 0.07).

Adult↗
PubMed1997

Antibodies capable of releasing diphtheria toxin in response to the low pH found in endosomes.

Diphtheria toxin (DT) undergoes a rapid conformational change in response to the acidity encountered within endosomes. That transition is integral to the passage of its catalytic domain into the cytosol and thus its lethal action. The importance of this translocation mechanism led us to develop several monoclonal antibodies that bind DT at neutral pH but spontaneously release the toxin when critical epitopes denature or unfold upon lowering the pH to 4.5-5.5. Hybridomas were selected using a microtiter plate assay that measured the pH-dependent detachment of antibody from immobilized toxin. The acid-sensitive epitopes involved were on the catalytic, transmembrane, and receptor binding domains of DT. This pH-induced disruption of the binding of toxin to these monoclonal antibodies was analyzed by sedimentation velocity ultracentrifugation. Antibody combining sites were fully occupied at pH 5.5, partially bound at pH 5.0, and totally empty at pH 4.5. It was estimated that the Ka for antibody-toxin binding was approximately 1000-fold lower at pH 5.0 than at neutral pH. This novel acid-triggered release mechanism provides a basis for delivery of antibody-bound toxin into cells accompanied by its immediate dissociation as the complex enters acidic vesicles.

Antibodies, Monoclonal↗
PubMed1997

Intracellular targeting with low pH-triggered bispecific antibodies.

Bispecific antibodies were designed to deliver a reversibly bound ligand into target cells and then spontaneously release it upon passage into acidified vesicles. These reagents were assembled by coupling monoclonal antibodies that recognize acid-sensitive epitopes on diphtheria toxin to cell type-specific monoclonal antibodies. The dual binding capacity of the bispecific antibodies was confirmed by delivery of 125I-diphtheria toxin to target molecules present on intact cells. Bispecific antibodies directed against transferrin receptors on human cells were loaded with toxin and tested for cytotoxicity. The mutant diphtheria toxins CRM107 and CRM45 were used since their inability to bind cell receptors renders them ordinarily nontoxic. Their full cytotoxic potential, however, was restored via bispecific antibody-mediated delivery and release within low pH intracellular vesicles. Cytotoxicity was shown to be specific by blocking receptor sites and to be acidification-dependent by protection using NH4Cl to raise endosomal pH. Kinetics for inhibition of cellular protein synthesis was identical for native diphtheria toxin and the bispecific antibody. CRM107 combination. The rate of inhibition (t1/2 = 20 min) indicated that release of CRM107 from the antibody combining site was fast, and its toxic action was unimpeded by this delivery mechanism.

Antibodies, Bispecific↗
PubMed1997

Inhibition of HIV-1 infection by the beta-chemokine MDC.

CD8(+) T lymphocytes from individuals infected with human immunodeficiency virus-type 1 (HIV-1) secrete a soluble activity that suppresses infection by HIV-1. A protein associated with this activity was purified from the culture supernatant of an immortalized CD8(+) T cell clone and identified as the beta-chemokine macrophage-derived chemokine (MDC). MDC suppressed infection of CD8(+) cell-depleted peripheral blood mononuclear cells by primary non-syncytium-inducing and syncytium-inducing isolates of HIV-1 and the T cell line-adapted isolate HIV-1IIIB. MDC was expressed in activated, but not resting, peripheral blood mononuclear cells and binds a receptor on activated primary T cells. These observations indicate that beta-chemokines are responsible for a major proportion of HIV-1-specific suppressor activity produced by primary T cells.

Amino Acid Sequence↗
PubMed1997

CD40 ligand induces an antileukemia immune response in vivo.

Leukemia cells may express tumor specific antigens in association with Class I and II major histocompatability complex (MHC) molecules. However, lack of expression of conventional costimulator molecules means that these cells tend to induce specific T-cell anergy rather than activation. CD40 ligand (CD40L) is a costimulator molecule that directly activates T cells and may promote antigen presentation by CD40-expressing cells, which include professional antigen presenting cells and B-acute lymphoblastic leukemia (ALL) cells from many patients. We determined whether transgenic expression of CD40L could enhance an antileukemia immune response using a CD40+ murine lymphoblastic (A20) leukemia and a CD40- myeloblastic (WEHI-3) leukemia in a tumor treatment model. Injection of otherwise nonimmunogenic A20 cells in the presence of CD40L induced an immune response active against preexisting A20 tumor at a distant site. Moreover, concomitant local secretion of transgenic interleukin-2 (IL-2) further amplified the antileukemic response induced and increased protection against preexisting tumor. In ex vivo studies, CD40 activation of A20 cells enhances the antigen presenting potential of A20 cells by upregulating expression of B7.1 (CD80), Class I and II MHC molecules, and increases expression of fas antigens. The importance of CD40 activation to the resulting antitumor response is further emphasized by the failure of transgenic CD40L to protect against the CD40- WEHI myeloblastic leukemia. Depletion studies showed the protective effects against A20 cells to be mediated by a combination of CD4+ and CD8+ T lymphocytes and by natural killer (NK) cells. These results suggest a means by which CD40+ leukemia cells may be rendered immunogenic in vivo.

Animals↗
PubMed1997

Ephedrine abuse causing acute myocardial infarction.

"On the street", the more expensive illegal psychostimulants, such as cocaine or amphetamine, may be mixed with or substituted for cheaper drugs such as ephedrine-with added risk to the user. We report diffuse myocardial injury in a 25-year-old man who presented with pulmonary oedema after intravenously injecting himself with ephedrine, believing it to be amphetamine.

Adult↗
PubMed1997

Epidemiology of suicide pacts in England and Wales, 1988-92.

OBJECTIVE: To describe the epidemiology of suicide pacts in England and Wales DESIGN: Analysis of the death certificates and coroners' records of all people who died in pacts between 1 January 1988 and 31 December 1992. SUBJECTS: 124 people who committed suicide in 62 pacts. RESULTS: Suicide in a pact accounted for 0.6% of all suicides (124/19721), a rate of 0.6 per million people aged 15 and over. Forty eight pacts were between married couples and five were between family members. The mean age was 56 years. 99 of the 124 subjects were of occupational social classes I-III. Poisoning by car exhaust fumes and drugs accounted for 116 deaths, with both members of each pair using the same method. CONCLUSIONS: Suicide pacts are rare and less common than they were 35 years ago, although the epidemiological profile is similar. People who commit suicide in a pact are more likely than those who commit suicide alone to be female, older, married, and of a high social class.

Adolescent↗
PubMed1997

A woman with a post-vacation rash.

A 52-year-old woman was admitted to the hospital with a rash, periorbital edema, dysphagia, and muscle weakness. The rash had appeared on the back of her neck nine months earlier, and because she had recently returned from a wildlife preserve on Assateague Island, Maryland, she assumed that it was due to tick bites. Over the next two months, the rash spread to her forehead, back, chest, and upper extremities, and scaly lesions appeared over metacar-pophalangeal joints. Initial laboratory tests indicated that her creatine kinase level was elevated. She was given prednisone and the level decreased. The rash also improved, but in the next two months the muscle weakness worsened. She became feverish and increasingly fatigued, depressed, and irritable. These later symptoms were attributed to the medication, but when she was weaned from it, her rash, weakness, and dysphagia increased. Over the ensuing months, she was given intramuscular injections of methotrexate (up to 25 mg/wk), followed by oral doses of hydroxychloroquine and azathioprine, but the symptoms persisted.

Antirheumatic Agents↗
PubMed1997

The CAG repeat within the androgen receptor gene and its relationship to prostate cancer.

The length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, is inversely correlated with transcriptional activity by the androgen receptor. Because heightened androgenic stimulation may increase risk of prostate cancer development and progression, we examined whether shorter CAG repeats in the androgen receptor gene are related to higher risk of prostate cancer. We conducted a nested case-control study of 587 newly diagnosed cases of prostate cancer detected between 1982 and 1995, and 588 controls without prostate cancer, within the Physician's Health Study. An association existed between fewer androgen receptor gene CAG repeats and higher risk of total prostate cancer [relative risk (RR) = 1.52; 95% confidence interval (CI) = 0.92-2.49; P trend = 0.04; for men with CAG repeat lengths < or = 18 relative to > or = 26 repeats]. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension or distant metastases (stage C or D) or high histologic grade (RR = 2.14; CI = 1.14-4.01; P trend = 0.001). This association was observed individually both for high stage (RR = 2.23) and high grade prostate cancer (RR = 1.89). Men with shorter repeats were at particularly high risk for distant metastatic and fatal prostate cancer. Variability in the CAG repeat length was not associated with low grade or low stage disease. These results demonstrate that a shorter CAG repeat sequence in the androgen receptor gene predicts higher grade and advanced stage of prostate cancer at diagnosis, and metastasis and mortality from the disease. The clinical implications of these results should be evaluated further.

Adult↗