Search PubMed⌕ Search

Biomedical subjects

D C Anderson

Publications and source records attributed to D C Anderson.

At least 253 records · Page 14Linked to original sources
PubMed1990

Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14.

The PBj14 isolate of simian immunodeficiency virus from sooty mangabey monkeys (SIVSMM-PBj14) is the most acutely pathogenic primate lentivirus so far described, always causing fatal disease in pig-tailed macaques (Macaca nemestrina) within 8 days of inoculation. As a first step in identifying viral genes and gene products that influence pathogenicity, the SIVSMM-PBj14 genome was amplified by the polymerase chain reaction as 5' and 3' genomic halves of 5.1 and 5.8 kilobases, respectively, and molecularly cloned. DNA sequence analysis revealed a high degree of conservation with other SIVs, except for a 22-base-pair duplication in the enhancer region of the viral long terminal repeat which included a second binding site for the transcription factor NF-kappa B. Of six genomic halves examined, four contributed to the formation of infectious virus that induced acute disease and death in pig-tailed macaques as early as 6 days post-inoculation, with pathology, disease syndromes and kinetics indistinguishable from those induced by the uncloned isolate. To our knowledge this is the first example of acute immunodeficiency disease induced by a molecularly defined lentivirus. Furthermore, the molecularly cloned SIVSMM-PBj14 viruses share with the uncloned virus cytopathicity for mangabey CD4+ cells, a property that may correlate with their observed pathogenicity in vivo.

Animals↗
PubMed1990

Molecular mapping of interactions between a Mycobacterium leprae-specific T cell epitope, the restricting HLA-DR2 molecule, and two specific T cell receptors.

A systematic series of 89 single residue substitution analogs of the Mycobacterium leprae 65-kDa protein-derived peptide LQAAPALDKL were tested for stimulation of two HLA-DR2 restricted 65 kDa-reactive T cell clones from a tuberculoid leprosy patient. Some analogs with substitutions outside a "core" region showed enhanced stimulation of the T cell clones. This core region of seven or eight residues was essential for recognition, whereas substitution of amino acids outside this region did not affect T cell recognition although these residues could not be omitted. Thus these core residues interact directly with the presenting HLA-DR2 molecule and/or the TCR. Except for analogs of position 419 for clone 2B6, the majority of the nonstimulatory substitution analogs did not inhibit the presentation of LQAAPALDKL and thus probably failed to bind to the HLA-DR2 molecule. Unless all of the core residues are physically involved in binding to DR2, substitution at a position not directly involved in binding appears to have an influence on other residues that do bind to the DR2 molecule. Active peptide analogs with two or more internal prolines suggest that not all analogs need be helical for activity with clone 2F10.

Amino Acid Sequence↗
PubMed1990

CD18-deficient cells respond to lipopolysaccharide in vitro.

The CD11/CD18 complex of leukocyte adhesion molecules has been shown to bind LPS on the surface of gram negative bacteria and LPS-coated erythrocytes (J. Exp. Med. 164:1876, 1986). LPS elicits several responses in leukocytes including secretion of TNF-alpha and IL-1 beta, and priming for enhanced release of oxygen radicals such as superoxide anion. To determine if expression of CD18 molecules is necessary for these effects of LPS, we have examined the responses of leukocytes from CD18-deficient patients. Three of the patients in this study are characterized for the first time here, and three were described elsewhere. Monocytes and macrophages from CD18-deficient patients synthesized normal amounts of IL-1 beta and TNF-alpha in response to LPS. Further, PMN and monocytes from CD18-deficient patients showed normal priming for enhanced release of superoxide anion in response to LPS. Although a small contribution of CD18 molecules to some responses cannot be ruled out by our data, we may conclude that CD18 molecules are not essential for cellular responses to LPS.

Actins↗
PubMed1990

Mac-1 (CD11b/CD18) mediates adherence-dependent hydrogen peroxide production by human and canine neutrophils.

Human neutrophils exposed to protein-coated polystyrene or cultured endothelial monolayers produce large quantities of H2O2 in response to soluble stimuli that elicit little or no secretion of reactive oxygen species from cells in suspension. To characterize the mechanisms involved in this adherence-dependent respiratory burst, we have investigated the possible role of one integrin known to participate in the adhesion of neutrophils to endothelial cells, CD11b/CD18 (Mac-1). H2O2 production was examined with chemotactic factor-stimulated human and canine neutrophils exposed to protein-coated surfaces and cultured human and canine endothelial cells. The two protein-coated surfaces used were type I collagen-coated glass or plastic, a surface to which neither human nor canine neutrophils adhered, and keyhole limpet hemocyanin (KLH)-coated glass or plastic, a surface to which human and canine neutrophils adhered only after chemotactic stimulation. FMLP-stimulated human neutrophils and platelet activating factor-stimulated canine neutrophils failed to produce detectable H2O2 when in contact with type I collagen, but secreted large amounts of H2O2 when adherent to KLH or endothelial cell monolayers. FMLP-stimulated neutrophils from patients with CD18-deficiency failed to adhere to any of these surfaces and failed to produce H2O2 under these conditions. mAb reactive with CD18 and CD11b were equally effective in markedly inhibiting the adhesion of normal human neutrophils to these surfaces and markedly inhibited the production of H2O2. A mAb reactive with CD18 blocked adhesion of stimulated canine neutrophils, and mAb directed against both CD18 and CD11b blocked H2O2 production by canine neutrophils on KLH and endothelium. A nonbinding mAb and a mAb reactive with CD11a did not inhibit H2O2 production of human cells on KLH or endothelial monolayers, and nonbinding and binding control mAb did not inhibit H2O2 production by canine neutrophils. These results indicate that Mac-1 (CD11b/CD18) can mediate adhesion-dependent H2O2 production by human and canine neutrophils exposed to chemotactic factors.

Antibodies, Monoclonal↗
PubMed1990

Subcellular distribution and mobilization of MAC-1 (CD11b/CD18) in neonatal neutrophils.

The CD11b/CD18 (Mac-1) heterodimeric surface glycoprotein contributes to a broad range of adherence-dependent neutrophil inflammatory functions. Previous investigations have indicated that diminished expression or regulation of Mac-1 may underlie abnormalities of stimulated adhesion and chemotaxis of neonatal neutrophils in vitro and inflammatory deficits in human neonates. To define the pathogenic mechanisms contributing to these findings, we compared the distribution and translocation of Mac-1 in subcellular fractions of neonatal and adult neutrophils before and after chemotactic stimulation. The total cell content of Mac-1 and the proportions of Mac-1 in beta fractions (vitamin B12 binding protein-rich granules), pre-gamma fractions (gelatinase-rich granules), or gamma fractions (plasma membrane) of neonatal neutrophils were comparable with those of adult neutrophils. However, after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10 nmol/L, 37 degrees C, 15 minutes), neonatal neutrophils demonstrated (1) diminished translocation of Mac-1 from pre-gamma fractions (P less than .05), and (2) diminished surface expression of Mac-1 (P less than .05), as compared with healthy adult neutrophils. As shown in enzymatic and immunochemical assays, neonatal cells contained significantly (P less than .01) diminished levels of neutrophil gelatinase. In response to FMLP (0.1 to 10 nmol/L, 37 degrees C, 15 minutes), neonatal suspensions also released significantly (P less than .001) less gelatinase, as compared with adult neutrophil suspensions. These observations demonstrate that diminished mobilization of Mac-1 from gelatinase-rich granular pools in neonatal neutrophils is associated with abnormal surface expression of this glycoprotein after chemotactic stimulation. This abnormality may contribute, in part, to abnormal migratory properties of neonatal neutrophils in response to inflammatory stimuli.

Antigens, Differentiation↗
PubMed1990

Use of flanking sequences to study secondary structure-activity correlations of a Mycobacterium leprae T cell epitope.

The 65-kDa protein of the intracellular pathogen M. leprae is prominent in the immune response to this mycobacterium, and individual T cell epitopes from this protein sequence have been defined. We have tested the stimulatory activity of extended analogs of the minimal peptide representing one such epitope, LQAAPALDKL, with a variety of tetrapeptide extensions added to enhance or destabilize alpha helix formation. The conformational potential of the peptides was measured by circular dichroism using aqueous trifluoroethanol as a secondary structure inducer. Although analogs with high helical potential activated T cells at low concentrations, a less helical variant was similarly potent. Activity also did not correlate with predicted overall alpha helical amphipathicity. One analog was found which stimulated T cell proliferation in the 50 pM range. The effect of tetrapeptide extensions on epitope activity is not consistent with the importance in activity of only a single stable secondary structure such as an alpha helix.

Amino Acid Sequence↗
PubMed1990

Location of osteoclast precursors in fetal rat calvaria cultured on collagen gels.

Although osteoclasts are derived from hematopoietic cells, the exact identity of their precursors and the mechanism for their recruitment onto bone surfaces remain unclear. We wished to study their differentiation in the fetal rat calvaria and to locate its source of osteoclast precursor cells. Osteoclasts were detected by neutral red staining or cytochemical reaction for acid phosphatase of intact bone (cell number and area measured by computerized image analysis) or in cryostat sections of bone (enzyme activity measured by quantitative cytochemistry). Histology of semithin sections of fixed bones was also examined. The 19 day calvariae contained few mature osteoclasts. After 48 h culture on gels of type 1 collagen (1.5 mg/ml) supplemented with 5 mM calcium beta-glycerophosphate, 10 mM proline, and 2 micrograms/ml ascorbic acid, numerous large osteoclasts were seen on their endocranial surfaces. In contrast, cell morphology and enzyme activity deteriorated in bones cultured in liquid medium. The cells that formed in vitro rapidly responded to calcitonin by contraction. Stripping of endocranial membranes from the calvariae prevented osteoclast formation in culture, but these cells were seen when "stripped" bones had been cocultured with their membranes for 48 h or with intact 16 day calvariae (well before the onset of osteogenesis). Few osteoclasts were found when an 0.22 micron filter was inserted between the stripped calvaria and the endocranial membranes. We conclude that the endocranial membranes, which contain the meningeal blood vessels, are a major source of osteoclast precursors and that these cells are present in calvarial tissue even before the onset of osteogenesis.

Acid Phosphatase↗
PubMed1990

The relevance of persistent C-peptide secretion in type 1 (insulin-dependent) diabetes mellitus to glycaemic control and diabetic complications.

The effect of residual C-peptide secretion in longer standing IDDM on glycaemic control and the prevalence and evolution of complications over 2 years was evaluated. Thirty-one subjects with IDDM of 15.4 (1.5) years duration (mean SEM)) and residual C-peptide secretion, were matched for age, duration of diabetes and body mass index with 31 subjects without detectable C-peptide secretion. At trial entry and over 2 years, levels of HbA1, fructosamine and mean blood glucose were essentially similar in both groups. Levels of glycated albumin (GSA) were significantly higher in the C-peptide negative group after 3 and 9 months (P less than 0.05). An increased prevalence of proliferative retinopathy in the C-peptide negative group and of peripheral vascular disease in the C-peptide secretor group was apparent at entry to the study (both P less than 0.05), although no significant differences were observed after 1 or 2 years. There was no difference in the prevalence of peripheral or autonomic neuropathy, hypertension, nephropathy or ischaemic heart disease. Subjects with C-peptide concentrations greater than 0.100 pmol/ml at entry to this study had lower daily insulin requirements after 1 and 2 years, but behaved like the larger group with any detectable C-peptide secretion in all other respects. Residual C-peptide secretion was lost after 1 year in 7 patients, in whom glycaemic control during the year had been particularly poor. Insulin antibody titres were no different in the 2 groups at any time point. This study suggests that residual C-peptide secretion in longer standing IDDM confers the potential for limited improvements in glycaemic control. This effect appears to be insufficient to prevent the evolution of microvascular complications over a 2-year period. Residual C-peptide secretion and relative hyperinsulinaemia may be associated with an excess of peripheral vascular disease.

Adult↗
PubMed1990

Dogs, distemper and osteitis deformans: a further epidemiological study.

There is extensive evidence linking paramyxoviruses, notably measles and respiratory syncytial virus, with Paget's disease of bone. The epidemiology of Paget's disease does not fit with that of known human paramyxovirus infections and it is possible that the disease is a zoonosis with domestic animals acting as host. Canine distemper, a paramyxovirus of the morbillovirus family (closely related to measles) is therefore a potential candidate. We have surveyed previous pet ownership in 150 Paget's patients each of whom was matched with two general practice controls; one from an inner city practice and the other from a suburban practice both in Greater Manchester. Recall of previous dog ownership was higher in Paget's patients with differences being more marked against inner city than suburban controls. 88% of the patients had lived in the same household as a dog at some stage compared with 79% of the inner city controls (P less than 0.05) and 83% of the suburban controls (n.s.). The differences were greater in the years 1930-60 during which the proportion of patients owning dogs was largest. For Paget's patients and controls alike, recalled exposure to dogs with canine distemper appeared to cluster in certain periods between 1930 and 1960. Unexpectedly, significantly more (7 out of 22, P less than 0.01) of the patients with a known first degree relative suffering from Paget's disease had no previous history of dog ownership when compared with the other patients (10 out of 128).

Adult↗
PubMed1990

Bone conditioned medium enhances cell aggregation, cell proliferation and alkaline phosphatase activity in serum-deprived medium.

The effect of medium conditioned by whole bone was examined on the activity of a heterogeneous population of rat calvarial cells grown under serum-deprived conditions. Conditioned medium (CM) had pronounced effects on the appearance of cultures within 24-48 hours of addition. This was characterized by the breakdown of the cell monolayer, rounding of cells and formation of alkaline phosphatase-positive aggregates. Cellular alkaline phosphatase activity was increased compared to controls while acid phosphatase levels were reduced. These aggregates grown in the presence of 10 mM beta-glycerophosphate did not show evidence of mineralization. These results show that soluble factors derived from calvarial bone are responsible for cell aggregation, cell proliferation and increase in alkaline phosphatase activity.

Acid Phosphatase↗
PubMed1990

3'-Azido-2',3'-dideoxyuridine (AzddU): comparative pharmacokinetics with 3'-azido-3'-deoxythymidine (AZT) in monkeys.

The pharmacokinetics of the anti-human immunodeficiency virus type 1 nucleosides, 3'-azido-2',3'-dideoxyuridine (AzddU) and 3'-azido-3'-deoxythymidine (AZT) were characterized in rhesus monkeys. Half-life, total clearance, and steady-state volume of distribution were similar for both compounds. The observed pharmacokinetic parameters for AZT were comparable to those previously reported in humans. Oral absorption of AzddU and AZT was virtually complete after 60 mg/kg. However, bioavailability of both nucleosides was markedly lower (less than 50%) after 200 mg/kg, possibly indicating the involvement of a saturable absorption mechanism. The nucleosides were also well absorbed after subcutaneous administration. AzddU and AZT penetrated the cerebrospinal fluid (CSF) with concentration ratios in CSF:serum ranging from 0.05 to 0.25 one hour after drug administration. The glucuronides of AZT and AzddU were readily detected in urine. Hemogram and blood chemistry values for animals receiving short-term treatment (3 doses) with either AZT or AzddU did not exhibit any significant changes when compared with untreated control monkeys. The similar pharmacokinetic characteristics of AzddU compared with AZT suggest that clinical trials of AzddU are warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Role of complement receptors in opsonophagocytosis of group B streptococci by adult and neonatal neutrophils.

The role of complement receptors in bactericidal activity for types III and Ia group B streptococci (GBS) by adult or neonatal polymorphonuclear leukocytes (PMNL) was explored using polyclonal and monoclonal antibodies to complement receptors one (CR1) and three (CR3). In an opsonophagocytic assay, selective blockade of the CR3 sugar or lectin-like binding site on adult or neonatal PMNL effected a significant reduction in killing of both GBS serotypes that was more pronounced for type III. In contrast, blockade of the iC3b binding site effected greater inhibition of bactericidal activity for type Ia than for type III GBS. When both the CR3 sugar or lectin-like binding site and CR1 were blocked, inhibition was enhanced for type Ia GBS by adult PMNL and for both serotypes by neonatal PMNL. These results demonstrate a role for both CR1 and CR3 in the opsonophagocytosis of GBS. Possibly, differences in CR3 epitope utilization contribute to the differential virulence among GBS serotypes in neonates.

Adult↗
PubMed1990

Serum PP14 levels in a patient with Turner's syndrome pregnant after frozen embryo transfer.

Data are presented on serum levels of the pregnancy-associated placental protein (PP14) in an XO mother, pregnant after frozen embryo transfer. Steroid replacement before and during early pregnancy was provided with transdermal oestradiol and vaginal micronized progesterone. Characterization of a pre-treatment cycle indicated a physiological response by the endometrium. The pregnancy was associated with normal maternal blood levels of all hormones considered responsible for maintenance of early gestation but with consistently subnormal serum levels of PP14. Hitherto, PP14 has been believed to be an endometrial protein arising from the decidua during pregnancy, under the influence of ovarian steroids. The findings in this case suggest that other factors are involved in its production, possibly under the control of, or originating from, the maternal ovary.

Adult↗
PubMed1990

Prevalence of natural infection with simian immunodeficiency virus and simian T-cell leukemia virus type I in a breeding colony of sooty mangabey monkeys.

The seroprevalence of antibodies to simian immunodeficiency virus (SIVsmm) and simian T-cell leukemia virus type I (STLV-I) in a captive breeding colony of sooty mangabey monkeys was determined, and infection by SIVsmm was confirmed in all cases by virus isolation. Among 138 animals tested, 57 and 33% were infected with SIVsmm and STLV-I, respectively. While the proportion of female mangabeys (66%) differed significantly (P less than 0.01) from the proportion of male mangabeys (42%) infected with SIVsmm, the proportions of males and females infected with STLV-I were similar, suggesting independent transmission of the two viruses. Among mangabeys less than 1 year old, none were infected with STLV-I and only five of 27 mangabeys, all of which were at least 6 months old when first tested, were infected with SIVsmm. The data document that natural infection of sooty mangabey monkeys with SIVsmm or in association with STLV-I infection does not result in increased disease or mortality, and that transmission of both SIVsmm and STLV-I appears to occur primarily through sexual activity.

Animals↗
PubMed1990

Experience with a 'physiological' steroid replacement regimen for the establishment of a receptive endometrium in women with premature ovarian failure.

Eighteen women with a premature menopause underwent assessment of serial serum oestradiol (E2) and progesterone levels and endometrial histology and function. Patients received continuous transdermal E2, and progesterone either orally or vaginally for 14 days. Physiological levels of E2 were attained. Significantly higher levels of progesterone were achieved with vaginal progesterone (P less than 0.01). Endometrial biopsies obtained during E2 replacement demonstrated normal proliferative features. Expression of an oestrogen related antigen (ER-Ag) was localized in the cytoplasm of the epithelium. After 3 days of progesterone replacement the endometrium showed normal secretory features and expression of ER-Ag in the stroma as well as in the glands. After 7 days of progesterone supplementation, vaginal administration produced a more consistent physiological appearance than oral administration. Thus transdermal E2 combined with vaginal progesterone is a highly satisfactory combination for establishing a physiological endometrium in women with premature ovarian failure.

Administration, Intravaginal↗