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Biomedical subjects

A McKnight

Publications and source records attributed to A McKnight.

At least 37 records · Page 2Linked to original sources
PubMed1996

Cost effectiveness of personal health education in primary care for people with angina in the greater Belfast area of Northern Ireland.

STUDY OBJECTIVE: To investigate the cost effectiveness of personal health education for angina patients being treated in general practice. DESIGN: A randomised controlled trial in which people were randomised to intervention and control groups. All were assessed at the start and end of the study, with details recorded of disease status, coronary heart disease risk factors, and self assessed quality of life. A note was taken of their current use of drugs and over the course of the study their use of all health services. Those in the intervention group had three visits per year from a health visitor, whose brief was discuss ways of living more easily with their disease and in which risks of further events might be reduced. PATIENTS: Altogether 688 patents in the Greater Belfast area aged less than 75 years and known to have angina for at least six months. MAIN RESULTS: Significant improvements in survival and self assessed quality of life were found between the study and control groups. The intervention was associated with a reduction in drug usage and there was no significant difference between the intervention and control groups in terms of their use of other health services. CONCLUSION: Given the improvement in survival and self assessed quality of life and no significant differences in costs to the health service between the two groups, the intervention was deemed to be cost effective.

Angina Pectoris↗
PubMed1996

How do general practitioners qualify for their PGEA?

On average, general practitioners (GPs) achieved their five-day annual target for the postgraduate educational allowance (PGEA) mainly by attending short meetings in the disease management category. The pattern of uptake closely resembled that of provision, with relatively few meetings and attendances in the health promotion category. Sponsored meetings attracted more participants than non-sponsored ones, but mean attendances at all types of meetings were low. Implications and recommendations are discussed.

Accreditation↗
PubMed1995

Cell-to-cell fusion, but not virus entry in macrophages by T-cell line tropic HIV-1 strains: a V3 loop-determined restriction.

T-cell lines chronically infected with laboratory adapted, T-cell tropic HIV-1 strains (RF, LAI, CBL-4, and NY5) induced syncytia after cocultivation with primary macrophages. Such fusion-competent strains, however, replicated inefficiently after cell-free infection of macrophage cultures. Evidence based on proviral DNA synthesis, pseudotype penetration, and a V3 loop mutation revealed that cell-free infection was restricted at a prepenetration stage in entry and controlled by envelope sequences. Our results suggest that primary macrophages are sensitive to cell-to-cell but not to virion-to-cell fusion induced by the envelope glycoproteins of several T-cell tropic HIV-1 strains.

Cell Communication↗
PubMed1995

Immune escape and tropism of HIV.

HIV-1 cell tropisms are partly determined by the hypervariable loops V1/V2 and V3 in gp120, which also contain epitopes for neutralizing antibodies. Mutations conferring tropism changes can result in escape from neutralization and vice versa. We examine whether variant viruses that can colonize new cell types and simultaneously escape neutralizing antibodies have an enhanced advantage in vivo.

Amino Acid Sequence↗
PubMed1995

Change in tropism upon immune escape by human immunodeficiency virus.

The V3 loop of human immunodeficiency virus type 1 is both a determinant of viral cell tropism and a target for neutralizing antibodies. This relationship was investigated. Selection of a dual-tropic (T cells and macrophages) virus to replicate in CD4+ brain cells results in loss of macrophage tropism and of neutralization by an anti-V3 loop monoclonal antibody. Moreover, selection of the brain-selected variant to escape from V3 loop-specific neutralizing monoclonal antibodies results in the reduction or loss of brain cell tropism and the reacquisition of macrophage tropism. These data may indicate that the antigenic diversification of human immunodeficiency virus type 1 apparent after seroconversion can be selected either by immune responses or by colonization of new cell types.

Amino Acid Sequence↗
PubMed1995

Measurement of markers of tobacco smoking in patients with coronary heart disease.

591 patients with a history of coronary heart disease had one or more biochemical markers of tobacco smoking measured. 26% were self reported smokers and a further 4% were apparent 'smoking deceivers'. The urinary nicotine metabolite concentration is an excellent marker for tobacco smoking; breath CO would be a suitable alternative for busy clinics. Half the patients were subjected to regular advice on risk factor management but there was no evidence that this contributed effectively to smoking cessation. Overall smoking cessation rate was poor.

Adult↗
PubMed1995

Bone mineral density in relation to medical and lifestyle risk factors for osteoporosis in premenopausal, menopausal and postmenopausal women in general practice.

BACKGROUND: Interest in the prevention of osteoporosis is increasing and thus there is a need for an acceptable osteoporosis prevention programme in general practice. AIM: A study was undertaken to identify a cohort of middle-aged women attending a general practice who would be eligible for a longitudinal study looking at bone mineral density, osteoporosis and the effectiveness of hormone replacement therapy. This study aimed to describe the relationship between medical and lifestyle risk factors for osteoporosis and the initial bone density measurements in this group of women. METHOD: A health visitor administered a questionnaire to women aged between 48 and 52 years registered with a Belfast general practice. The main outcome measures were menopausal status, presence of medical and lifestyle risk factors and bone mineral density measurements. RESULTS: A total of 358 women our of 472 (76%) took part in the study which was conducted in 1991 and 1992. A highly significant difference was found between the mean bone mineral density of premenopausal, menopausal and postmenopausal women within the narrow study age range, postmenopausal women having the lowest bone mineral density. A significant relationship was found between body mass index and bone mineral density, a greater bone mineral density being found among women with a higher body mass index. Risk factors such as smoking and sedentary lifestyle were common (reported by approximately one third of respondents) but a poor relationship was found between these two and all the other risk factors and bone mineral density in this age group. CONCLUSION: Risk of osteoporosis cannot be identified by the presence of risk factors in women aged between 48 and 52 years. In terms of a current prevention strategy for general practice it would be better to take a population-based approach except for those women known to be at high risk of osteoporosis: women with early menopause or those who have had an oophorectomy.

Bone Density↗
PubMed1994

Randomised controlled trial of health promotion in general practice for patients at high cardiovascular risk.

OBJECTIVE: To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities. DESIGN: Randomised controlled trial of personal health education given every four months. SETTING: 18 general practices in the greater Belfast area. SUBJECTS: 688 patients aged less than 75 years and known to have had angina for at least six months; 342 randomised to receive education and 346 to no education. MAIN OUTCOME MEASURES: Restriction of everyday activities, dietary habit, smoking habit, frequency of physical exercise; blood pressure, body mass index, and serum total cholesterol concentration at entry to trial and after two years. RESULTS: 317 in the intervention group and 300 in the control group completed the trial. At the two year review more of the intervention group (140, 44%) reported taking daily physical exercise than the control group (70, 24%). The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity. No significant differences were found between the groups in smoking habit, systolic or diastolic blood pressure, cholesterol concentration, or body mass index. CONCLUSION: Despite having no significant effect on objective cardiovascular risk factors, personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities.

Activities of Daily Living↗
PubMed1994

HIV-2 and SIV infection of nonprimate cell lines expressing human CD4: restrictions to replication at distinct stages.

Mouse, rat, rabbit, cat, and mink cell lines expressing human CD4 restrict entry of HIV-1 strains at the cell surface. We now report that CD4+ cat and rabbit cell lines are permissive to cell fusion induced by several HIV-2 and SIV strains. CD4+ rat and mouse cells are only sensitive to HIV-2 and SIV fusion in the presence of active amphotericin B. HIV-2 and SIV replicate in CD4+ cat and CD4+ mink cells, but not in the CD4+ rabbit, rat, or mouse cells. These latter cell lines poorly express a transfected DNA molecular clone of HIV-2 DNA. CD4+ rat cells are sensitive to entry by HIV-2 (HTLV-1) pseudotypes and also to HIV-2 if amphotericin B is present. Early reverse transcription then occurs without subsequent viral gene expression, but the fusion-sensitive CD4+ rabbit cells are not permissive for HIV-2 reverse transcription. Our observations demonstrate (i) that the cat and mink cell lines express everything required except human CD4 for entry and replication by several HIV-2 and SIV strains and (ii) that distinct postpenetration blocks to viral replication are evident in rabbit and rodent cell lines.

Amphotericin B↗
PubMed1994

Rational design of high affinity tachykinin NK2 receptor antagonists.

The rational discovery of a high affinity NK2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK2 receptor binding affinity for each amino acid of the hexapeptide 'minimum fragment': Leu-Met-Gln-Trp-Phe-GlyNH2 (8c), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an 'alanine scan'. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH2 (9a) is a micromolar affinity NK2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK2 receptor antagonist, (2,3di-CH3OPh)CH2OCO(S)Trp(S)alpha-MePheGlyNH2, PD 147714 (19) with an K(i) = 1.4 nM (hamster urinary bladder membranes and using [125I]-iodohistidyl-NKA (0.1 nM) as the radioligand).

Amino Acid Sequence↗
PubMed1993

Is CD4 sufficient for HIV entry? Cell surface molecules involved in HIV infection.

HIV-1, HIV-2 and SIV each bind to CD4 as the first step in virus entry. However, alternative receptors may also be used. HIV-1 binds to glycolipids with terminal galactosylceramide residues on neural cells; opsonized virus binds to Fc receptors; HIV-2 can infect certain CD4-negative cells. Further receptors may also play a role in CD4-mediated infection, including cell adhesion molecules and possibly cell surface proteinases. After binding to CD4, immunodeficiency viruses require secondary molecules to effect fusion between the virus envelope and the cell membrane; these accessory requirements differ between HIV-1, HIV-2 and SIV.

Animals↗
PubMed1993

Further characterization of an antigenic site of HIV-1 gp120 recognized by virus neutralizing human monoclonal antibodies.

OBJECTIVE: The aim of this study is to characterize antigenic sites on HIV-1 gp120 which may be important for the development of active and passive immunization strategies against HIV-1 infection. DESIGN: Two HIV-1-seropositive individuals were selected from the Amsterdam cohort and Epstein-Barr virus (EBV)-transformed B cells were generated from their peripheral blood mononuclear cells, which produce HIV-1-specific human monoclonal antibodies (HuMAb). METHODS: HuMAb were generated and selected based on their reactivities with native gp120. Reactivity with HIV-1 strains from phylogenetically different subfamilies was determined by immunostaining and virus neutralization assays. Specificity for the CD4-binding site was tested by an inhibition enzyme-linked immunosorbent assay and amino acids (aa) involved in the binding of the HuMAb were identified with a set of gp120 molecules with single aa substitutions. RESULTS: Three HuMAb (GP13, GP44, GP68) were generated, all recognizing a conserved conformation dependent epitope within, or topographically near, the CD4-binding site of gp120. HuMAb GP13 and GP68 neutralized a broad range of HIV-1 strains from phylogenetically different subfamilies, whereas HuMAb GP44 exhibited a more restricted pattern of neutralizing activity. The patterns of gp120 aa involved in their binding were unique for each of these HuMAb. CONCLUSIONS: The pattern of reactivities of these three HIV-1-neutralizing HuMAb developed in these studies is similar to, but distinct from other human and rodent MAb that recognize this antigenic site of HIV-1 gp120.

Adult↗
PubMed1992

L-687,306: a functionally selective and potent muscarinic M1 receptor agonist.

The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist at guinea-pig cardiac M2 and ileal M3 muscarinic receptors. This compound gives an opportunity to study receptor reserve involved in muscarinic receptors in vitro and in vivo.

Animals↗
PubMed1992

The control of the antibody isotype response to recombinant human immunodeficiency virus gp120 antigen by adjuvants.

Both saponin and muramyl dipeptide (MDP) formulated with a squalane-in-water emulsion of large particle size prepared with a vortex mixer were superior to Al(OH)3 as adjuvants for HIV gp120 in mice. All the adjuvants induced IgG1 antibody, but saponin elicited the highest titers of IgG2a. The secretion of interleukin-5 (IL-5) and interferon gamma (IFN gamma) by lymph node cells cultured in vitro with gp120 was studied. All the cultures secreted IL-5, but only those from saponin-immunized mice produced IFN gamma, suggesting that saponin is capable of activating both the Th1 and TH2 T-cell subsets. The titers of neutralizing antibodies were low with both MDP and saponin, and they occurred in mice which were also positive for antibodies against a V3 loop peptide. Glucosaminylmuramyl dipeptide (GMDP) which is less pyrogenic than MDP and a nonpyrogenic analog GMDPA, displayed equivalent adjuvant activity to MDP. The level and isotype composition of antibodies induced by GMDP in combination with squalane emulsions depended on the dimension of the emulsion particles. With a large (2500 nm) particle size the response was confined to IgG1 in Balb/c mice, but when this was reduced to 150 nm by sonication the antibody response was increased and relatively high levels of IgG2a appeared in some mice.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Development of HIV-1 group-specific neutralizing antibodies after seroconversion.

OBJECTIVE: To study the induction of group-specific (gs) neutralizing antibodies to HIV-1 after seroconversion. DESIGN AND METHODS: Serum samples taken sequentially from seven Dutch homosexual men and four British haemophiliacs (anonymous sample, therefore sex not known) before and after seroconversion were tested for neutralizing antibodies effective against five diverse HIV-1 strains. Strains of HIV-1 tested included isolates from the United States, Europe and Africa. RESULTS: The gs neutralizing antibody response varied between individuals. Only five of the 11 individuals studied produced detectable neutralizing antibodies to laboratory-adapted HIV-1 strains (for example, IIIB) within 32 weeks of seroconversion. Most individuals initially produced antibodies effective against US/European isolates; the response then generally broadened to include the more diverse strains, i.e., African. CONCLUSIONS: These results suggest that the gs neutralizing target for HIV-1 is poorly immunogenic in vivo and is probably not highly conserved among diverse HIV-1 strains.

HIV Antibodies↗
PubMed1992

Mapping of homologous, amino-terminal neutralizing regions of human T-cell lymphotropic virus type I and II gp46 envelope glycoproteins.

Twelve synthetic peptides containing hydrophilic amino acid sequences of human T-cell lymphotropic virus type I (HTLV-I) envelope glycoprotein were coupled to tetanus toxoid and used to raise epitope-specific antisera in goats and rabbits. Low neutralizing antibody titers (1:10 to 1:20) raised in rabbits to peptides SP-2 (envelope amino acids [aa] 86 to 107), SP-3 (aa 176 to 189), and SP-4A (aa 190 to 209) as well as to combined peptide SP-3/4A (aa 176 to 209) were detected in the vesicular stomatitis virus-HTLV-I pseudotype assay. Higher-titered neutralizing antibody responses to HTLV-I (1:10 to 1:640) were detected with pseudotype and syncytium inhibition assays in four goats immunized with a combined inoculum containing peptides SP-2, SP-3, and SP-4A linked to tetanus toxoid. These neutralizing anti-HTLV-I antibodies were type specific in that they did not inhibit HTLV-II syncytium formation. Neutralizing antibodies in sera from three goats could be absorbed with peptide SP-2 (aa 86 to 107) as well as truncated peptides containing envelope aa 90 to 98, but not with equimolar amounts of peptides lacking envelope aa 90 to 98. To map critical amino acids that contributed to HTLV-I neutralization within aa 88 to 98, peptides in which each amino acid was sequentially replaced by alanine were synthesized. The resulting 11 synthetic peptides with single alanine substitutions were then used to absorb three neutralizing goat antipeptide antisera. Both asparagines at positions 93 and 95 were required for adsorption of neutralizing anti-HTLV-I antibodies from all three sera. Peptide DP-90, containing the homologous region of HTLV-II envelope glycoprotein (aa 82 to 97), elicited antipeptide neutralizing antibodies to HTLV-II in goats that were type specific. In further adsorption experiments, it was determined that amino acid differences between homologous HTLV-I and HTLV-II envelope sequences at HTLV-I aa 95 (N to Q) and 97 (G to L) determined the type specificity of these neutralizing sites. Thus, the amino-terminal regions of HTLV-I and -II gp46 contain homologous, linear, neutralizing determinants that are type specific.

Amino Acid Sequence↗