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Biomedical subjects

C R Roberts

Publications and source records attributed to C R Roberts.

At least 37 records · Page 2Linked to original sources
PubMed1997

The functional consequences of airway remodeling in asthma.

Structural changes in the airway walls involving extracellular matrix remodelling are prominent features of asthma. These changes are probably driven by mediators released as a consequence of chronic allergic inflammation. It is clear that changes in the extracellular matrix have the capacity to influence airway function in asthma. However, it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma. Collagen deposition in the subepithelial matrix, and hyaluronan and versican deposition around and internal to the smooth muscle would be expected to oppose the effect of smooth muscle contraction. Conversely, geometric considerations would result in exaggerated airway narrowing for a given degree of smooth muscle shortening, as the airway wall is thickened by the deposition of these molecules internal to the smooth muscle. Elastin and cartilage reorganization and degradation in the airway walls would be expected to result in decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle. Degradation of matrix associated with the smooth muscle may both decrease the stiffness of the parallel elastic component and uncouple smooth muscle from the load provided by lung recoil, allowing exaggerated smooth muscle shortening. Increase in muscle mass may be associated with an increase, a decrease or no change in smooth muscle contractility. If an increase in muscle mass was associated with preservation of its contractile capacity modelling studies suggest that it could be the most important contributor to exaggerated airway narrowing. Modelling studies also suggest that the pattern of mucosal folding during smooth muscle contraction may be an important determinant of airway narrowing. The greater the number of folds, and the stiffer the subepithelial collagenous layer the more resistant the airway will be to narrowing.

Asthma↗
PubMed1996

Plasmodium falciparum circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya.

It has been hypothesized that antibody induced by Plasmodium falciparum circumsporozoite protein vaccine would be effective against endemic human malaria. In a malaria endemic region of Kenya, 76 volunteers, in 38 pairs sleeping adjacently, were immunized with subunit circumsporozoite protein Asn-Ala-Asn-Pro tetrapeptide repeat-pseudomonas toxin A, or hepatitis B vaccine. After quinine and doxcycycline, volunteers were followed for illness daily, parasitemia weekly, antibody, T-lymphocyte responses, and treated if indicated. Anopheles mosquitoes resting in houses were collected, and tested for P. falciparum antigen, or dissected for sporozoites and tested for blood meal ABO type and P. falciparum antigen. Vaccine was safe, with side-effects similar in both groups, and immunogenic, engendering IgG antibody as high as 600 micrograms ml-1, but did not increase the proportion of volunteers with T-lymphocyte responses. Estimation of P. falciparum challenge averaged 0.194 potentially infective Anopheles bites/volunteer/ day. Mosquito blood meals showed no difference in biting intensity between vaccine and control groups. Both groups had similar malaria-free survival curves, cumulative positive blood slides, cumulative parasites mm-3, and numbers of parasites mm-3 on first positive blood slide, during three post-vaccination observation periods. Every volunteer had P. falciparum parastemia at least once. Vaccinees had 82% and controls 89% incidences of symptomatic parasitemia (P = 0.514, efficacy 9%, statistical power 95% probability of efficacy < 50%). Vaccine-induced anti-sporozoite antibody was not protective in this study. Within designed statistical precisions the present study is in agreement with efficacy studies in Colombia, Venezuela and Tanzania.

Animals↗
PubMed1996

Proteoglycan deposition in pulmonary fibrosis.

This study compares the deposition of proteoglycans in the extracellular matrix of the lung lesions of the adult respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) to those present in idiopathic pulmonary fibrosis (IPF). Tissue from individuals with ARDS (n = 7), BOOP (n = 5), IPF (n = 5), and control subjects (n = 5) was examined for glycosaminoglycans and collagen by histochemistry, and for hyaluronan, versican, decorin, biglycan, Types I and III collagen, type I procollagen and alpha-smooth muscle actin (alpha-SMA) using immunohistochemistry. The results showed that glycosaminoglycan deposition in the lesions of ARDS, BOOP, and IPF corresponded to the deposition of versican. Versican localized to the thickened interstitium in the fibroproliferative phase of ARDS, to the intraluminal buds in BOOP, and to early fibroblast foci in IPF. The versican-rich areas contained little mature collagen, but the myofibroblasts in these areas stained for type I procollagen, suggesting early collagen synthesis, and stained intracellularly for decorin. The localization of versican in ARDS, BOOP, and IPF suggests that this proteoglycan may influence early repair processes in the lung.

Actins↗
PubMed1996

Prominence of apolipoproteins B, (a), and E in the intimae of coronary arteries in transplanted human hearts: geographic relationship to vessel wall proteoglycans.

BACKGROUND: Transplant arteriopathy (TA) is characterized by vessel wall thickening with prominent glycosaminoglycan and lipid deposits. In this light, we have recently demonstrated the distribution of proteoglycans in allograft coronary arteries. The aim of this study is to examine the distribution of apolipoproteins within allograft coronary arteries and to investigate their localization in relation to proteoglycans. METHOD: Particular transverse sections of left and right epicardial coronary arteries from 46 human cardiac allografts, 11 normal hearts, and 11 hearts with native atherosclerosis were stained immunohistochemically for apolipoprotein B, apolipoprotein (a) (apo[a]), apolipoprotein E (apoE), biglycan, decorin, and versican by use of an automated immunostainer. RESULTS: Apo(a) and apoE immunopositivity in TA was much more intense than that in native atherosclerosis, whereas the reverse was true for apoB. Prominent apoE deposits were evident circumferentially in endothelia and extracellularly in superficial intima of mildly diseased TA, as well as in deeper intima of severely diseased TA. Apo(a) had a staining pattern very similar to apoE except for a patchy deposition also seen in TA media. The intimal areas staining prominently with apoE or apo(a) in TA arteries corresponded very closely to the areas with proteoglycan deposits, especially versican. CONCLUSION: The distinctive patterns of apolipoprotein accumulation in TA and native atherosclefosis appear to reflect different pathogenetic processes in the two conditions. The colocalization of proteoglycans and apolipoproteins in TA intima supports the hypothesis that interactions between proteoglycans and apolipoproteins influence lipid retention and overload in allograft coronary arteries.

Apolipoproteins↗
PubMed1996

Biglycan, decorin, and versican protein expression patterns in coronary arteriopathy of human cardiac allograft: distinctness as compared to native atherosclerosis.

BACKGROUND: Histochemical staining has demonstrated previously dramatic deposits of glycosaminoglycans associated with prominent lipid accumulations in thickened vessel walls of allograft coronary arteries. In this study, we characterized the amount, distribution, and types of proteoglycan in the walls of coronary arteries from human cardiac allografts and from native atherosclerotic (NA) controls as part of a strategy to understand the pathogenesis of transplant arteriopathy (TA). METHOD: We used polyclonal rabbit antibodies against human biglycan, decorin, and versican localize the proteoglycan molecules in standardized transverse sections of the proximal left anterior descending and right coronary arteries. Slides were scored in a blinded fashion for intensity of proteoglycan staining (0 to 6+) and for localization in the vessel walls. RESULTS: Unique patterns of proteoglycan distribution were present in TA and NA. Biglycan was particularly prominent in intima and evolving atheromata in severely diseased TA coronary arteries, but not in NA. Decorin was present mainly in adventitia of all vessels and in the intima of NA. Prominent versican accumulation occurred in intima and media of TA coronaries, associated with smooth muscle cells and foam cells. There was a reciprocal pattern of biglycan and decorin staining. Versican colocalized with biglycan. Intimal biglycan and versican deposits were positively correlated to the extent of luminal narrowing in TA. CONCLUSION: The distinctive staining patterns for biglycan, decorin and versican in both native and allograft disease indicate that the synthesis and distribution of these proteoglycans are regulated by different local mechanisms in different atheromatous diseases.

Biglycan↗
PubMed1995

Japan-U.S. comparison of responses to depression scale items among adult workers.

The operating characteristics of the Center for Epidemiologic Studies Depression Scale were compared between Japanese and U.S. adult workers. Data were analyzed from age- and education-matched male white collar workers (n = 368 for each) selected from 2016 workers in Japan and 3059 in the United States. The U.S. data were obtained from the 1974-75 Augmentation Survey of the National Health and Examination Survey I. The Japanese responses to positively worded items markedly differed from those of U.S. workers, whereas responses to negatively worded items were generally comparable in the two groups. Thus, spuriously higher positive subscale and whole scale scores were found among the Japanese workers compared with U.S. workers (mean scores: 6.03 vs. 1.83 for the positive subscale and 9.94 vs. 5.35 for the whole scale, respectively; both differences were statistically significant). Negative subscale scores did not differ significantly in the two samples (3.91 vs. 3.52). The present study confirmed the hypothesis of Iwata et al. that Japanese respondents have a tendency to suppress the expression of positive affect.

Adult↗
PubMed1995

The risk of human T cell leukemia virus and viral hepatitis infection among US Marines stationed in Okinawa, Japan.

The prevalence and incidence of human T cell leukemia virus type I/II (HTLV-I/II) and hepatitis A, B, and C virus infection were determined among US Marines stationed in Okinawa, Japan. Of 2875 personnel, 2 (0.07%) had antibody to HTLV-I/II. After 1-3 years, no HTLV seroconversions were observed, although 23% reported sexual contact with Okinawans. Of 1010 hepatitis-tested marines, 121 (12%) had antibody to hepatitis A virus (anti-HAV), 26 (2.6%) had antibody to hepatitis B core antigen (anti-HBc), and 2 (0.2%) had antibody to hepatitis C virus (anti-HCV). On follow-up, 1 subject seroconverted to anti-HAV, 8 to anti-HBc, and none to anti-HCV. Most marines with recent hepatitis B infection were young, single, and enlisted and had been on short deployments to other countries in Southeast Asia. Marines stationed in Okinawa are not at high risk for HTLV infection but are at increased risk for hepatitis B infection and should be considered for vaccination.

Adolescent↗
PubMed1995

Collagenase increases shortening of human bronchial smooth muscle in vitro.

The recent demonstration of increased shortening of asthmatic airway smooth muscle could result from increased contractility of the muscle itself or from a decreased load that must be overcome by the smooth muscle to shorten. To evaluate the role of smooth muscle-associated extracellular matrix in limiting smooth muscle responses, we investigated the effect of collagenase on the mechanical responses of human bronchial smooth muscle strips. Contractile responses of second- to fourth-generation bronchi were evoked by electrical field stimulation, and measurements of length and tension were made at preloads between 0 and 2.5 g. The passive tension, active isometric, and isotonic responses were obtained at each preload before and after 90 min of incubation with 20 U/ml collagenase. Shortening to 10(-4) M histamine was also measured. Collagenase treatment caused a significant decrease in passive tension, with the most pronounced change occurring below Lmax (optimal length for force generation). At optimal lengths for shortening, the degree of shortening, expressed as a percentage of starting length, increased significantly from 8.9 +/- 1.4% before to 13.8 +/- 2.9% after collagenase treatment (n = 7) (p < 0.02). Shortening to histamine also increased from 14.3 +/- 2.5% before to 23.5 +/- 5.3% after collagenase treatment (n = 7) (p < 0.02). These results suggest that degradation of the collagenous matrix surrounding muscle in the airway wall reduces the load on the muscle, allowing increased smooth muscle shortening.

Acetylcholine↗
PubMed1995

Effect of chronic antigen and beta 2 agonist exposure on airway remodeling in guinea pigs.

We recently reported that chronic exposure to fenoterol (FEN) in guinea pigs increases in vivo and in vitro airway responsiveness to a degree similar to that induced by chronic antigen (ovalbumin [OA]) exposure. We hypothesized that these changes were due to airway inflammation and airway remodeling. To trace newly recruited granulocytes as a marker of inflammation and to detect DNA replication in resident airway wall cells, the nucleotide 5'-bromo-2'-deoxyuridine (BrdU) was administered intermittently over the six-wk period of chronic FEN and/or OA exposure. Noncartilaginous airway dimensions were measured and the area fraction of BrdU-immunoreactive and total nuclei in adventitia, smooth muscle, and epithelium was determined by immunohistochemistry and point counting. The proliferation index was defined as the ratio of the two area fractions in each wall area. The adventitial areas of FEN- and OA-treated airways were respectively 62 and 88% greater than those of control airways (p < 0.05). The inner wall areas were not increased. The smooth muscle cell and epithelial cell proliferation index was increased after OA (smooth muscle index: control, 2.7 +/- 1.1% [SEM]; OA, 23.0 +/- 3.7%; p < 0.02) but not after FEN exposure, and there was an increased number of BrdU-immunoreactive granulocytes in the adventitia and epithelium after OA but not after FEN exposure. The increased in vivo airways responsiveness produced by chronic OA or FEN exposure may be attributable to adventitial thickening and increased in vitro muscle contractility, but the cellular mechanisms underlying these and other airway wall responses are different.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1994

Transforming growth factor beta 1 gene expression in human airways.

BACKGROUND: Asthmatic airways have a characteristic deposition of connective tissue under the epithelial basement membrane, but the mediators involved in this alteration are unknown. Several authors have postulated that transforming growth factor beta 1 (TGF-beta 1) could be overexpressed in asthmatic airways. METHODS: Lung samples from 16 asthmatic patients, six patients with chronic obstructive pulmonary disease (COPD), and six non-obstructed smokers were analysed. RNA was extracted from these tissues to measure expression of TGF-beta 1 by Northern blot analysis using a cDNA probe for TGF-beta 1. The level of expression was quantitated by densitometry using glyceraldehyde 3-phosphate dehydrogenase mRNA as a control. TGF-beta 1 was localised to specific cell types in these lungs by immunohistochemical analysis using polyclonal antibodies specific for intracellular and extracellular TGF-beta 1. RESULTS: The 2.5 kb TGF-beta 1 mRNA was seen in all 18 samples analysed by Northern blotting and densitometric analysis showed no difference between the asthmatic group (mean (SD) 108% (43%)), the group with COPD (122% (33%)), and the non-obstructed group (100% (49%)). The TGF-beta 1 precursor was immunolocalised throughout the airway wall including the epithelium and in alveolar macrophages. The mature TGF-beta 1 was localised primarily within the connective tissue of the airway wall. These patterns of expression of both forms of TGF-beta 1 were similar in lungs from asthmatic patients, those with COPD, and controls. CONCLUSIONS: While TGF-beta 1 mRNA and protein are abundantly expressed in human lungs, there is no clear difference in expression between the airways of asthmatic subjects and those of smokers with and without COPD.

Adolescent↗
PubMed1994

Hypothesis: excessive bronchoconstriction in asthma is due to decreased airway elastance.

Based on the strikingly different mechanical properties of airway smooth muscle preparations of different species, we hypothesized that a decrease in the elastance of nonmuscle elements within airway walls of asthmatics reduces the load limiting smooth muscle shortening, thereby allowing excessive smooth muscle shortening and bronchoconstriction. Full thickness, circumferentially cut, lobar bronchial preparations were obtained from one asthmatic and six nonasthmatic lobectomy subjects. Passive tension of the asthmatic preparation was less than that for any nonasthmatic preparation at all lengths below that for optimal force generation (Lmax). Maximal isometric force generation was greater in the asthmatic specimen (2.32 g) than in the nonasthmatic specimens (0.90 +/- 0.15 g), with stress threefold higher for the asthmatic tissue. Isotonic shortening of the asthmatic preparation was strikingly greater at starting lengths less than or equal to Lmax, with maximal fractional shortening being 31% versus 11 +/- 2% for nonasthmatic preparations. Morphometric analysis revealed no differences in cross-sectional areas of smooth muscle for asthmatic versus nonasthmatic preparations. We conclude that the reduced tissue elastance may account for the greater muscle shortening by placing a lesser load upon the smooth muscle. Airway inflammation in asthma may alter connective tissue matrix elements within airway walls leading to this decreased elastance and excessive smooth muscle shortening.

Aged↗
PubMed1994

Plasmodium falciparum incidence relative to entomologic inoculation rates at a site proposed for testing malaria vaccines in western Kenya.

Relationships between Plasmodium falciparum incidence and entomologic inoculation rates (EIRs) were determined for a 21-month period in Saradidi, western Kenya, in preparation for malaria vaccine field trials. Children, ranging in age from six months to six years and treated to clear malaria parasites, were monitored daily for up to 12 weeks to detect new malaria infections. Overall, new P. falciparum infections were detected in 77% of 809 children. The percentage of children that developed infections per two-week period averaged 34.7%, ranging from 7.3% to 90.9%. Transmission by vector populations was detected in 86.4% (38 of 44) of the two-week periods, with daily EIRs averaging 0.75 infective bites per person. Periods of intense transmission during April to August, and from November to January, coincided with seasonal rains. Relationships between daily malaria attack rates and EIRs indicated that an average of only 7.5% (1 in 13) of the sporozoite inoculations produced new infections in children. Regression analysis demonstrated that EIRs accounted for 74% of the variation in attack rates. One of the components of the EIR, the human-biting rate, alone accounted for 68% of the variation in attack rates. Thus, measurements of either the EIR or the human-biting rate can be used to predict corresponding attack rates in children. These baseline epidemiologic studies indicate that the intense transmission patterns of P. falciparum in Saradidi will provide excellent conditions for evaluating malaria vaccine efficacy.

Animals↗
PubMed1994

Transfusion-associated human immunodeficiency virus type 1 from screened antibody-negative blood donors.

Cases of human immunodeficiency virus type 1 (HIV-1) infection acquired from transfusion of screened antibody-negative blood have been reported since 1986. Recent reports have proposed new combination antibody assays or the addition of HIV-1 p24 antigen testing to enhance the screening of blood donations further. Since antibody testing for HIV-1 began in 1985, 700,000 donor units have been screened at US Army blood donor centers. The US Army blood donor/recipient "lookback" program recently identified two cases of HIV-1 infection that resulted from a screened negative donation. Samples from the implicated unit, as well as from previous donations from the same donor, were available for testing to assess the performance of current screening methods. Sequential donation samples were assayed by five different Food and Drug Administration-approved HIV-1 screening enzyme-linked immunosorbent assays, a Food and Drug Administration-approved Western blot, a recombinant envelope-based enzyme-linked immunosorbent assay, a p24 antigen capture assay, a radioimmunoprecipitation assay, and a polymerase chain reaction. The HIV-1 p24 antigen and genomic RNA material were detected in a donation that was screened as negative by four of the five Food and Drug Administration-licensed screening enzyme-linked immunosorbent assays. Two recipients of transfusion products from this donation became infected with HIV-1. A sample from a prior donation from this donor was negative for HIV-1 by all assays. The status of blood donors who are in the early stages of HIV-1 infection may not be detected by current screening methods. While this is a rare phenomenon, it highlights the need for technologic developments in screening methods to narrow the time between infection and detection. In addition, it emphasizes the need for more effective education and counseling to enhance the utility of self=deferral.

Adult↗
PubMed1993

Use of pharmacological agents to implicate a role for phosphoinositide hydrolysis products in malaria gamete formation.

The kinetics of phosphoinositol 4,5 bisphosphate hydrolysis products in activated Plasmodium falciparum gametocytes suggests a role for inositol trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG) in the signal transduction pathway of malaria gametocytes. To investigate further this role, compounds that have an effect on the metabolism and biologic functions of these second messengers were tested in an in vitro system. Gentamycin, 2,3 diphosphoglycerate (2,3 DPG) and magnesium ion (Mg2+), inhibitors of Ins(1,4,5)P3 5' phosphatase, all stimulated gametocytes to exflagellate in suspended animation buffer, pH 7.4, at room temperature. In addition, methylxanthines, caffeine and theobromine, calcium ionophore (A-23187), and external calcium also stimulated exflagellation. In contrast, neomycin, an aminoglycoside that inhibits phospholipase C activity, and heparin, an antagonist of Ins(1,4,5)P3 binding to its receptor, inhibited microgamete formation. Quinine and chloroquine which can inhibit both phospholipase A and C activity also inhibited gametocyte exflagellation. The consistent manner in which these various compounds affect gametocyte activation further implicates phosphoinositol turnover in the signal transduction pathway of falciparum gametocytes.

2,3-Diphosphoglycerate↗
PubMed1993

Expression of simian type D retroviral (Mason-Pfizer monkey virus) capsids in insect cells using recombinant baculovirus.

Mason-Pfizer monkey virus (M-PMV) is a primate retrovirus that shows type D morphogenesis in mammalian cells. Immature intracytoplasmic A type particles (ICAPs) preassemble in the infected cell cytoplasm migrate to the plasma membrane and are released by budding. This is in contrast to retroviruses that show type C morphogenesis, where assembly and budding occur concurrently at the plasma membrane. We expressed the M-PMV structural genes (gag-pro-pol) in insect cells using a recombinant baculovirus. The polyprotein precursors assembled predominantly intracellularly, although a small proportion also assembled at the membrane. The protease enzyme was active since mature particles were identified in the culture supernatant. We also expressed the M-PMV mutants, D26N and gag-STOP, which carry a nonfunctional protease or fail to express the protease gene, respectively. These baculovirus recombinants generated a homogeneous population of immature M-PMV capsids having exclusively type D morphogenesis. Sufficient quantities of polyprotein precursors were synthesized to be visualized directly on a Coomassie-stained protein gel, and the capsids were subject to purification. These results provide the first expression of type D retrovirus particles using the baculovirus expression system.

Animals↗
PubMed1993

Characterization of human T-lymphotropic virus type I- and II-infected T-cell lines: antigenic, phenotypic, and genotypic analysis.

Eighteen long-term T-cell lines were established from peripheral blood mononuclear cells of individuals infected with human T-lymphotropic virus type I (HTLV-I) or II (HTLV-II). These cell lines (10 HTLV-I and 8 HTLV-II), representing diverse pathologic profiles and geographic regions, have been in culture for over 6 months and have constitutively produced p24gag antigen. Antigenic characterization of the cell lines by Western blot analysis demonstrated that all but one produced gag (p24) and env (gp46 or gp52) structural proteins; one HTLV-I-infected cell line exhibited an aberrant protein profile. Phenotypic analysis of the HTLV-infected cell lines demonstrated phenotypes consistent with activated T-cells (CD5+, CD25+, HLA-DR+). The HTLV-I-infected cell lines were predominantly CD4+ (IR, FS, A212, SP, 1657, 1742, 3669, 1996, and 3614), whereas EG was CD8+. The HTLV-II-infected cell lines were either CD4+ (H2A, Y17, G12.1), CD8+ (H1H, H2E, Y03, Y06), or both (H1B). Restriction map analysis and subtyping of the viral genomes demonstrated heterogeneity among these isolates. Of the HTLV-I-infected cell lines, six were subtype II, one was subtype III and, on the basis of additional restriction sites, another subtype, tentatively classified as subtype IV, could be identified for three of the HTLV-I-infected cell lines. Of the HTLV-II-infected cell lines, six were subtype HTLV-IIa and two were subtype HTLV-IIb. While the majority of the cell lines resemble the prototypic HTLV-I-infected (MT-2) and HTLV-II-infected (MoT) cell lines, the antigenic, phenotypic, and genotypic data collectively demonstrate heterogeneity among viral isolates representing diverse geographic regions.

Adult↗