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Biomedical subjects

B G Brown

Publications and source records attributed to B G Brown.

At least 19 recordsLinked to original sources
PubMed1995

Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).

OBJECTIVE: To determine if lowering elevated low-density lipoprotein cholesterol (LDL-C) levels offsets the adverse effect of raised lipoprotein(a) (Lp[a]) levels on coronary artery disease (CAC) in men. DESIGN: Randomized, double-blind, placebo-controlled trial of lipid lowering for CAD. SETTING: Post hoc analysis of the Familial Atherosclerosis Treatment Study. PARTICIPANTS: A total of 146 men aged 62 years or younger with CAD and apolipoprotein B levels of at least 125 mg/dL. INTERVENTION: Patients received a Step II Diet and lovastatin (40 mg daily) plus colestipol (30 g daily), niacin (4 g daily) plus colestipol, or placebo (plus colestipol if LDL-C > 90th percentile) for 2.5 years. They were grouped by their LDL-C responses: "minimal" if LDL-C decreased by 10% or less from baseline (mean [SD] change, +6% [13%]) and "substantial" if LDL-C decreased more than 10% (mean [SD] change, -40% [16%]). MAIN OUTCOME MEASURE: Impact of lowering elevated LDL-C on the cardiac event rate (death, myocardial infarction, and revascularization for refractory ischemia) and CAD change associated with elevated Lp(a). RESULTS: In multivariate analyses, the best correlate of baseline CAD severity was Lp(a) (r = 0.30; P < .001). For 36 patients with minimal LDL-C reduction, CAD progression correlated only with in-treatment Lp(a) levels (r = 0.45; P < .01), but for 84 patients with substantial LDL-C reduction, disease regressed and its change correlated with in-treatment LDL-C (r = 0.24; P < .05) but not with Lp(a) (r = -0.05). Lipoprotein(a) levels were not significantly altered in either group. For 40 patients with Lp(a) at the 90th percentile or higher, events were frequent (39%) if reduction of LDL-C was minimal, but were few (9%) if reduction was substantial (relative risk, 0.23; 95% confidence interval, 0.06 to 0.99). CONCLUSIONS: In men with CAD and elevated LDL-C, Lp(a) levels were dominant correlates of baseline disease severity, its progression, and event rate over 2.5 years. However, with substantial LDL-C reductions, persistent elevations of Lp(a) were no longer atherogenic or clinically threatening. This provides a possible direction for treatment in such patients with elevated Lp(a) and LDL-C.

Adult↗
PubMed1995

Effect of pH of the T4 polynucleotide kinase reaction on the 32P-postlabeling assay of DNA adducts.

Among the currently available methods for detecting bulky hydrophobic compounds bound to DNA, the 32P-postlabeling is the most sensitive and most widely practiced. One of the key reaction steps of this assay is the polynucleotide kinase (PNK)-catalyzed incorporation of 32Pi into nucleotides. To ensure high sensitivity and reproducibility of the assay, it is imperative that the PNK reaction be conducted under optimal conditions. The PNK reaction is generally conducted at pH 9.6 in the 32P assay. We have investigated pH profiles of the PNK reactions using both normal (2'-deoxyadenosine 3'-monophosphate) and adducted (benzo[ alpha]pyrene- and cigarette smoke condensate-modified) nucleotides. The optimum pH range for the PNK reaction was between 7.4 and 8.4 with both types of nucleotides. Higher pH levels such as 9.4 and 9.6 were detrimental to the PNK reaction, yielding only about one-third or less of the labeling obtained at the optimum pH. Based on these results, the PNK reaction in the 32P-postlabeling assay should be conducted in the pH range between 7.8 and 8.0 to achieve quantitative labeling of adducted nucleotides.

Animals↗
PubMed1995

Molecular toxicology endpoints in rodent inhalation studies.

Although histopathology will continue to be essential for assessing the results of rodent inhalation studies, molecular toxicology endpoints are of increasing importance, as these techniques often complement and extend histopathological examinations. One of the primary uses of molecular toxicology is determining the delivered dose of the inhaled material to macromolecules in target tissues. During inhalation studies this is most often done by measuring DNA adducts in the respiratory tract. DNA adducts may be measured specifically (e.g. using monoclonal antibodies or mass spectrometry) or non-specifically (e.g. by using the 32P-post-labeling assay). Another major use of molecular toxicology techniques is the assessment of cellular and molecular changes in target tissues which may precede or be more sensitive than histopathologic alterations. For example, rates of cellular DNA synthesis occurring in target tissues may be quantified at any time during the study by administering the animals either radiolabelled thymidine or the non-radiolabelled thymidine analog bromodeoxyuridine (BrdU). Pulmonary changes may be assessed in bronchoalveolar lavage fluid using either cellular (e.g. macrophage number, granulocyte number) or biochemical (e.g. alkaline phosphatase, lactate dehydrogenase) techniques. The potential of the inhaled material to produce genetic alterations may be evaluated by examining the chromosomes of pulmonary alveolar macrophages for cytogenetic changes. To illustrate the use of these endpoints, an experiment was conducted to determine the molecular toxicology of aged and diluted sidestream smoke (a surrogate for environmental tobacco smoke) in rodent inhalation studies. The endpoints measured were DNA adducts in target and non-target tissue, chromosome aberrations in pulmonary alveolar macrophages, and DNA synthesis in the epithelial lining of the nasal turbinates.

Administration, Inhalation↗
PubMed1995

Lipoprotein (a) and coronary heart disease.

The role of lipoprotein (a) in the atherosclerotic process is continually being unraveled, and many of its potential proatherogenic and prothrombotic features have already been elucidated. Whereas most studies have demonstrated a strong association between lipoprotein (a) and the presence and severity of coronary heart disease, other groups have failed to observe such a relationship, which does question the importance of this particle in promoting atherosclerosis. Evidence from a study of human coronary atherosclerosis appears to demonstrate that the pathogenicity of lipoprotein (a) is modulated by concomitant LDL-cholesterol levels. Such a modulation of the pathogenicity of lipoprotein (a) may underlie the conflicting results regarding its association with coronary heart disease. This article will examine this possibility, and will also outline the potential mechanisms through which lipoprotein (a) may interact with LDL to exert its adverse effects. As a consequence of its interaction with LDL, alternative strategies for treating high levels of lipoprotein (a) will be discussed.

Adult↗
PubMed1994

Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol.

OBJECTIVES: Do the benefits of intensive lipid-lowering therapy extend to patients with only borderline or moderately elevated levels of low density lipoprotein (LDL) cholesterol? BACKGROUND: The merits of the present LDL cholesterol treatment goal of < or = 100 mg/dl need to be clarified for patients without high levels of LDL cholesterol, particularly for those patients previously classified as having only borderline high (130 to 159 mg/dl) or desirable (101 to 130 mg/dl) levels. METHODS: Disease change and clinical events were examined in LDL cholesterol subgroups in the Familial Atherosclerosis Treatment Study (FATS) trial, a randomized, blinded, quantitative arteriographic comparison of one conventional and two intensive lipid-lowering strategies in men with coronary artery disease, a positive family history and apolipoprotein B > or = 125 mg/dl. The primary end point, disease change per patient, was measured as the mean change in severity of stenosis (delta %SProx) among nine standard proximal segments. RESULTS: Of the 120 patients completing the 30-month protocol, 60 had a baseline LDL cholesterol < 90th percentile (mean LDL cholesterol 152 mg/dl) and 60 > 90th percentile (mean LDL cholesterol 221 mg/dl). Thirty-one patients had levels < 160 mg/dl (mean LDL cholesterol 134 mg/dl) and 89 > 160 mg/dl (mean LDL cholesterol 205 mg/dl). Patients with LDL cholesterol < 90th percentile benefited angiographically from therapy (delta %SProx = -1.5% diameter stenosis [regression] during intensive therapy vs. +2.3% diameter stenosis [progression] during conventional therapy, p < 0.01), as did patients with LDL cholesterol < 160 mg/dl (delta %SProx = -4.2% vs. +3.3% diameter stenosis, p = 0.0001). By comparison, angiographic benefit was less pronounced among those entering with very high LDL cholesterol (delta %SProx = -0.2% vs. +1.9% diameter stenosis, p = 0.07) or with LDL cholesterol > or = 160 mg/dl (delta %SProx = +0.2% vs. +1.6% diameter stenosis, p = 0.13). Intensive therapy resulted in a statistically significant reduction in clinical events only in the subgroup with baseline LDL cholesterol < 90th percentile (2 of 42 vs. 8 of 29 patients initially enrolled, p = 0.01) and a trend toward fewer events in patients with LDL cholesterol < 160 mg/dl (2 of 20 vs. 6 of 15 patients, p = 0.05). No such difference was seen in the higher LDL cholesterol subgroups. CONCLUSIONS: Treatment benefit in the FATS trial was not confined to patients with very high levels of LDL cholesterol and was in fact particularly evident in those patients with levels < 160 mg/dl. Such patients should be considered more likely, not less, to benefit from intensive lipid-lowering therapy.

Adult↗
PubMed1994

Differential replication and pathogenic effects of HIV-1 and HIV-2 in Macaca nemestrina.

OBJECTIVE: HIV-1 and HIV-2 isolates representing various geographic regions and distinct viral subtypes were examined for their ability to establish both in vitro and in vivo productive infections of Macaca nemestrina (pigtail macaque) peripheral blood mononuclear cells. METHODS: Animals were inoculated with either autologous cell-associated or cell-free viral preparations of selected isolates. HIV-specific immune responsiveness, hematologic changes, genetic variation, and virus burden were monitored as delineators of HIV pathogenesis. RESULTS: HIV-2 replication in vitro and in vivo correlated with nascent antigen production and rising viral titers as determined by infectious center assays. Infection was detectable by polymerase chain reaction amplification of proviral sequences in macaque cells as early as 1 week postinoculation. Two distinct patterns of CD4+ cell depletion induced by HIV-2 infection were observed during the first month postinoculation and characterized by a moderate loss sustained through 20 weeks postinoculation or a substantial loss maintained long-term (> 90 weeks). Identity between inoculating viral stocks and subsequent viral isolates from animals was established comparatively by limited sequence analysis of specific domains within the HIV-2 pol and env genes. In contrast, replication of HIV-1 isolates was limited or only semipermissive in vitro. Intravenous inoculation of HIV-1 field isolates, using conditions successful for HIV-2 (for example, identical viral titers), failed to establish a productive viral infection leading to seroconversion of fluctuations in hematologic cell markers. Infection with a high-titer inoculum of a laboratory-adapted HIV-1 strain in vivo, as demonstrated by polymerase chain reaction analysis, produced seroconversion in the absence of overt viral replication or hematologic variations in one out of four animals. CONCLUSIONS: This system provides for multifaceted modeling of HIV pathogenesis, primarily with HIV-2 and potentially with HIV-1/-2 chimerics, in support of immunotherapeutic developments and critical evaluation of intervention practices.

Amino Acid Sequence↗
PubMed1993

Effects of intensive lipid-lowering therapy on the coronary arteries of asymptomatic subjects with elevated apolipoprotein B.

BACKGROUND: Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms? METHODS AND RESULTS: Of 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B > or = 125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P < .001). Among the 91 symptomatic patients, those in the intensive group experienced definite (> or = 10%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P = .009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0% of conventional, regression (P = .04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P < .01); no asymptomatic patient had an event. CONCLUSIONS: Asymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.

Adult↗
PubMed1992

Filovirus clearance in non-human primates.

There has been concern in the USA and Europe about filovirus outbreaks in recently imported monkeys, and possible transmission to human beings. Healthy monkeys have been found to have low-titre immunofluorescence antibody (IFA) to Asian filoviruses (Reston and Pennsylvania viruses) as well as to the African filoviruses that caused fulminating human outbreaks in the 1970s (Ebola [Zaire] and Sudan viruses). We have assessed whether such monkeys are a risk to man. We studied 42 non-human primates; 31 were experimentally infected with African and Asian filoviruses, 6 were infected during a documented Reston filovirus outbreak, and 5 had serological evidence suggestive of recent filovirus infection. During the first 15 days after infection, virus could be routinely recovered from serum or biopsy or necropsy tissue, and Asian filovirus RNA could be detected by polymerase chain reaction. 20 to 600 days after challenge, filovirus could no longer be recovered nor viral RNA detected in 141 serum, liver, spleen, or kidney specimens. Animals surviving filovirus infection develop high-titre, cross-reacting filovirus-specific antibody 14 to 21 days after infection, and this coincides with virus clearance. Healthy monkeys with low-titre filovirus antibody may be regarded as uninfected.

Animals↗
PubMed1992

Detection of simian T-lymphotropic virus type I using the polymerase chain reaction.

To develop the polymerase chain reaction (PCR) for the detection of simian T-lymphotropic virus type I (STLV-I) infection, cell lines or peripheral-blood mononuclear cells (PBMC) from 2 non-human primate species [African green monkeys (AGM), Cercopithecus aethiops; baboon, Papio cynocephalus] were evaluated for their STLV-I status using oligonucleotide primer pairs and probes specific for the tax and pol gene regions of the closely related human T-lymphotropic virus type I (HTLV-I). These PCR results were compared with serologic (Western blot assay) and viral culture (p24-antigen capture assay) data. PCR products for both gene regions were detected in established baboon, Japanese macaque and rhesus macaque STLV-I-producing cell lines. STLV-I tax and pol products were also detected in PBMC from 4 of 4 infected AGM and 4 of 4 infected baboons, each of which were also Western-blot-positive and p24-antigen-capture-positive. Of the remaining AGM (n = 7) and baboon (n = 1) which were PCR-negative, each was also Western-blot-negative and p24-antigen-capture-negative. Two seronegative and virus-culture-negative AGM were classified as PCR indeterminate with weak reactivity using tax primers. These primer pairs failed to amplify DNA from uninfected human PBMC, an uninfected human lymphoid cell line, a simian immunodeficiency virus macaque (SIVmac251)-infected cell line and a simian-retrovirus-type-D(SRV-D)-infected cell line. HTLV-II-pol-specific primer pairs failed to amplify DNA from STLV-I-infected cell lines and PBMC from STLV-I-infected monkeys. Further, HTLV-I pol and tax primer pairs successfully amplified RNA from HTLV-I- and STLV-I-infected cell lines by reverse transcriptase (RT)-PCR. We have demonstrated excellent specificity in the detection of STLV-I by PCR using these HTLV-I-derived primers and probes. Additionally, our data suggest that the tax and pol gene regions are conserved between HTLV-I and STLV-I strains found among these diverse species of non-human primates.

Animals↗
PubMed1992

DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or heat tobacco.

A prototype cigarette that heats tobacco (test cigarette), developed by R.J. Reynolds Tobacco Company, has yielded consistently negative results in several in vivo and in vitro genetic toxicology tests. The objective of the present study was to evaluate the potential of cigarette smoke condensate (CSC) from the test cigarette to induce DNA adducts in mouse tissues and compare the results with those obtained with CSC from a reference tobacco-burning cigarette (1R4F). CD-1 mice were skin-painted with CSC from reference and test cigarettes three times a week for 4 weeks. The highest mass of CSC applied was 180 mg "tar" per week per animal for both reference and test cigarette. DNA adducts were analyzed in skin and lung tissues using the 32P-postlabeling method with the P1 nuclease modification. Distinct diagonal radioactive zones (DRZ) were observed in the DNA from both skin and lung tissues of animals dosed with reference CSC, whereas no corresponding DRZ were observed from the DNA of animals dosed with either test CSC or acetone (solvent control). The relative adduct labeling (RAL) values of skin and lung DNA from reference CSC-treated animals were significantly greater than those of the test CSC-treated animals. The RAL values of the test CSC-treated animals were no greater than those of solvent controls. The negative results in DNA adduct assays with test CSC are consistent with all previous results of in vivo and in vitro genetic toxicology testing on this cigarette and provide additional evidence that smoke condensate from the test cigarette is not genotoxic.

Animals↗
PubMed1992

Association of apolipoprotein B gene variants with plasma apoB and low density lipoprotein (LDL) cholesterol levels.

The contribution of the variants of the apolipoprotein (apo) B locus to the total variance in plasma apoB and cholesterol levels was examined in four independent populations, two that were composed of normal controls (n = 77 and 85) and two with coronary heart disease (n = 115 and 159). A correlation between genotype at the apoB-XbaI locus and apoB levels was observed. The effects of the (+; presence of restriction site) and (-) alleles were to increase or decrease the apoB and cholesterol levels by approximately 3.5 mg/dl, respectively. None of the 274 individuals in the coronary heart disease (CHD) groups was found to be a carrier of the apoB allele Arg3500----Gln, previously shown to be associated with an apoB protein defective in binding to the low density lipoprotein receptor (LDL-R). No DNA sequence variants were found in the region encoding amino acid residues 3129-3532 within the putative LDL-R binding domain among 35 individuals with apoB levels above the 94th percentile (141 mg/dl).

Adult↗
PubMed1992

Fourteen-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette. II. DNA adducts and alveolar macrophage cytogenetics.

The chemical constituents of cigarette smoke are greatly diluted in environmental tobacco smoke (ETS). In the typical indoor environment where cigarettes are smoked, the mean value of respirable suspended particles is approximately 0.1 mg/m3. In this study, we used aged and diluted sidestream smoke (ADSS) of 1R4F University of Kentucky research cigarettes as a surrogate for ETS and exposed Sprague-Dawley rats nose-only to 0, 0.1, 1.0, and 10 mg wet total particulate matter (WTPM)/m3 for 6 hr per day for 14 consecutive days. DNA from lung, heart, larynx, and liver was tested for adduct formation after 7 and 14 days of exposure and after 14 days of recovery. In addition, alveolar macrophages from animals exposed for 7 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any of the animals at 0.1 or 1.0 mg WTPM/m3, which represent ambient and 10-fold exaggerated ETS concentrations, respectively. Slight diagonal radioactive zones, characteristic of adducts observed in human smokers and in animals exposed to mainstream smoke, were observed, but only in lung and heart DNA of animals exposed to the highest concentration of ADSS (10 mg WTPM/m3), a 100-fold exaggeration of typical field measurements of ETS. The mean relative adduct labeling values (+/- SE) were 8.7 (+/- 0.2) adducts per 10(9) nucleotides for lung DNA and 5.7 (+/- 0.7) adducts per 10(9) nucleotides for heart DNA after 14 days of exposure. No elevation in chromosomal aberrations was observed in alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1992

Effect of lovastatin or niacin combined with colestipol and regression of coronary atherosclerosis.

When aggressive lipid-altering therapy is compared with conventional therapy in patients at very high risk for CHD, i.e. those who have abnormal lipid profiles, established coronary disease, and symptomatic heart disease, aggressive therapy halves the expected frequency of progression, triples the frequency of regression, favours the net regression of disease, and reduces clinical events by nearly 75%. These benefits correlate with reductions in LDL cholesterol, systolic blood pressure and increases in HDL cholesterol, and are highly significant, not only statistically but also clinically. This finding is consistent with the observation that there is a persistent relationship between coronary morbidity and mortality across the spectrum of cholesterol levels, and that this risk can be reduced in men with CHD and abnormal lipid metabolism through aggressive lipid management.

Apolipoprotein A-I↗
PubMed1992

Pathogenic potential of filoviruses: role of geographic origin of primate host and virus strain.

African filoviruses have caused outbreaks of fulminating hemorrhagic fever among humans. In 1989, related filoviruses were isolated from cynomolgus monkeys imported into the United States from the Philippines. The pathogenic potential of these new filoviruses was compared in 16 Asian monkeys (Macaca fascicularis-cynomolgus) and 16 African monkeys (Cercopithecus aethiops-African green) using African filoviruses from Zaire (Ebola virus) and Sudan or Asian filoviruses (Reston and Pennsylvania). African filovirus infections resulted in earlier death (P = .005), had a shorter duration of disease and median incubation period (3-4 vs. 7 days), and had earlier peak viremia (5-7 vs. 7-9 days). African green monkeys showed significantly higher survival than cynomolgus monkeys (P less than .01), and some were asymptomatic as have been humans accidentally infected with Asian filovirus. Rechallenge experiments showed that protection in survivors of filovirus infections against fatal challenge with Ebola (Zaire) virus is unpredictable. The minimal clinical disease observed in humans infected with the Reston strain is consistent with host- and virus-dependent pathogenicity.

Africa↗
PubMed1992

Familial combined hyperlipidemia and abnormal lipoprotein lipase.

A previous study reported that heterozygotes for lipoprotein lipase (LPL) deficiency have reduced LPL, the lipoprotein pattern classified as familial combined hyperlipidemia (FCHL), elevated apolipoprotein (apo) B levels, and reduced high density lipoprotein (HDL) levels. These findings suggest that subjects with reduced LPL may form one subset of the FCHL population. The purpose of the present study is to determine whether a subset of patients with FCHL have reduced LPL. Three patient populations with FCHL were studied: 1) subjects with the diagnosis of FCHL (n = 9) established by previous family studies, 2) clinic patients with a tentative diagnosis of FCHL (n = 14), and 3) subjects undergoing angiography who had coronary artery disease (CAD) and a diagnosis of FCHL by family study (n = 33). Two of nine subjects with the established diagnosis of FCHL, five of the 14 FCHL clinic patients, and 13 of the 33 CAD subjects with FCHL had reduced LPL activity in the same range as do individuals who are obligate heterozygotes for LPL deficiency. Subjects with FCHL and reduced LPL had higher plasma triglyceride (p < 0.01) and lower HDL cholesterol (p < 0.025) levels than did the subjects with FCHL and normal LPL levels (327 +/- 201 versus 210 +/- 122 mg/dl [mean +/- SD] and 36 +/- 7 versus 44 +/- 13 mg/dl, respectively). Thus, in all three groups of patients with apparent FCHL, 20 of 56 subjects (36%) had reduced LPL, suggesting that one subset of the FCHL population may be identified by an abnormality in LPL activity that is associated with lipoprotein abnormalities.

Adult↗