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Biomedical subjects

J Robinson

Publications and source records attributed to J Robinson.

At least 289 records · Page 16Linked to original sources
PubMed1994

Immunological evidence for interactions between the first, second, and fifth conserved domains of the gp120 surface glycoprotein of human immunodeficiency virus type 1.

We have used a combination of genetic and immunological techniques to explore how amino acid substitutions in the second conserved (C2) domain of gp120 from human immunodeficiency virus type 1 (HIV-1) affect the conformation of the protein. It was reported previously (R. L. Willey, E. K. Ross, A. J. Buckler-White, T. S. Theodore, and M. A. Martin. J. Viol. 63:3595-3600, 1989) that an asparagine-glutamine (N/Q) substitution at C2 residue 267 of HIV-1 NL4/3 reduced virus infectivity, but that infectivity was restored by a compensatory amino acid change (serine-glutamine; S/N) at residue 128 in the C1 domain. Here we show that the 267 N/Q substitution causes the abnormal exposure of a segment of C1 spanning residues 80 to 120, which compromises the integrity of the CD4-binding site. The reversion substitution at residue 128 restores the normal conformation of the C1 domain and recreates a high-affinity CD4-binding site. The gp120 structural perturbation caused by changes in C2 extends also to the C5 domain, and we show by immunological analysis that there is a close association between areas of the C1 and C5 domains. This association might be important for forming a complex binding site for gp41 (E. Helseth, U. Olshevsky, C. Furman, and J. Sodroski. J. Virol. 65:2119-2123, 1991). Segments of the C1 and C2 domains are predicted to form amphipathic alpha helices. We suggest that these helices might be packed together in the core of the folded gp120 molecule, that the 267 N/Q substitution disrupts this interdomain association, and that the 128 S/N reversion substitution restores it.

Amino Acid Sequence↗
PubMed1994

Resistance to neutralization by broadly reactive antibodies to the human immunodeficiency virus type 1 gp120 glycoprotein conferred by a gp41 amino acid change.

A neutralization-resistant variant of human immunodeficiency virus type 1 (HIV-1) that emerged during in vitro propagation of the virus in the presence of neutralizing serum from an infected individual has been described. A threonine-for-alanine substitution at position 582 in the gp41 transmembrane envelope glycoprotein of the variant virus was responsible for the neutralization-resistant phenotype (M.S. Reitz, Jr., C. Wilson, C. Naugle, R. C. Gallo, and M. Robert-Guroff, Cell 54:57-63, 1988). The mutant virus also exhibited reduced sensitivity to neutralization by 30% of HIV-1-positive sera that neutralized the parental virus, suggesting that a significant fraction of the neutralizing activity within these sera can be affected by the amino acid change in gp41 (C. Wilson, M. S. Reitz, Jr., K. Aldrich, P. J. Klasse, J. Blomberg, R. C. Gallo, and M. Robert-Guroff, J. Virol. 64:3240-3248, 1990). It is shown here that the change of alanine 582 to threonine specifically confers resistance to neutralizing by antibodies directed against both groups of discontinuous, conserved epitopes related to the CD4 binding site on the gp120 exterior envelope glycoprotein. Only minor differences in binding of these antibodies to wild-type and mutant envelope glycoproteins were observed. Thus, the antigenic structure of gp120 can be subtly affected by an amino acid change in gp41, with important consequences for sensitivity to neutralization.

Animals↗
PubMed1994

Arterial reactivity is significantly impaired in normotensive young adults after successful repair of aortic coarctation in childhood.

BACKGROUND: Despite successful repair of coarctation of the aorta in childhood, adult survivors often have hypertension at rest or on exercise, and their life expectancy is shorter than normal because of premature coronary and cerebrovascular disease. This may be related to persistent structural and functional arterial abnormalities after surgery. METHODS AND RESULTS: Using high-resolution ultrasound, we studied the right brachial arteries of 25 normotensive young adults who had undergone successful repair of coarctation in childhood (mean age at repair, 62 months; range, 0 to 167 months, including 8 patients operated on in infancy; mean age at study, 19 years; range, 14 to 27 years) and 50 age- and sex-matched control subjects. We assessed the degree of reactive hyperemia (RH) produced after distal cuff occlusion and release and the changes in arterial diameter in response to RH (with increased flow causing endothelium-dependent dilation) and to glyceryltrinitrate (GTN, an endothelium-independent dilator). The response of the right femoral artery to GTN was also measured in 12 coarctation subjects and 12 control subjects. Studies were performed 13.7 years (range, 7 to 21 years) after surgery. RH was significantly lower in coarctation subjects (343 +/- 130% versus 482 +/- 147%), as were endothelium-dependent dilation (3.8 +/- 3.3% versus 8.8 +/- 3.6%) and GTN response (13.3 +/- 6.0% versus 20.5 +/- 6.1%) (P < .001 for each), reflecting abnormal dilatory capacity in both the resistance and conduit arteries. In contrast, GTN-induced dilation in the femoral arteries was similar to that in control subjects (9.5 +/- 2.6% versus 10.1 +/- 4.1%, P = .70). On multivariate analysis, GTN response and systolic blood pressure at peak exercise were inversely correlated (r = -.52, P = .04). Vascular responses were not related to the age at repair. CONCLUSIONS: Despite successful repair of coarctation in childhood, arterial dilation is significantly impaired in the precoarctation vascular bed of healthy young adults. This may be an important contributor to exercise-related hypertension and late morbidity or mortality.

Adult↗
PubMed1994

Carriers of healthcare's load of information.

As the market for telemedicine products and services expands, many long distance telecommunications carriers and regional Bell operating companies developed strategies for meeting healthcare's needs. Some initiated projects to display their capabilities or to receive returns on investments in telecommunications infrastructures. Their capabilities and use of advanced technologies vary. The level of their healthcare commitment and involvement also varies. Regional Bell companies compete fiercely with each other and with national carriers for consulting and implementation contracts, unrestricted by service area boundaries. On the following pages, representatives from most of the major telecommunications carriers express their firms' healthcare strategies and offer synopses of their notable healthcare projects. For many, their resources are vast, their expertise undisputed. Access to high-quality healthcare services stands to benefit from their involvement.

Health Services Needs and Demand↗
PubMed1994

Studies with monoclonal antibodies to the V3 region of HIV-1 gp120 reveal limitations to the utility of solid-phase peptide binding assays.

Using human monoclonal antibodies (HuMAbs) r(1)-447 (L-736,523) and 19b to the V3 region of HIV-1 gp120, we have explored epitope presentation on V3-peptides and on the corresponding gp120 proteins. HuMAb r(1)-447 binds strongly to the MN and SF-2 peptides and gp120 proteins. In contrast, while this HuMAb binds equally avidly to both the HxB2 and the BRU/BH10 peptides, it binds but weakly to the HxB2 V3 loop on gp120 and fails to bind at all to BH10 gp120. Thus, the solid-phase peptide binding assay can falsely predict reactivity of an MAb with a gp120 protein. Conversely, HuMAb 19b fails to bind to a peptide from the V3 loop of HIV-1 AD-6 in solid-phase assays, but binds to the same peptide in solution and also to AD-6 gp120. Thus, the solid-phase peptide binding assay can fail to predict reactivity of an MAb with a gp120 protein. Furthermore, serum antibodies from individual AD-6 do not react well with the AD-6 V3-peptide in a solid-phase assay, but react strongly with the corresponding MN V3-peptide. On the basis of peptide binding assays, we had assumed that the AD-6 virus was "MN-like" with a prototypic North American/European subtype B GPGR motif at the crown of the V3 loop. However, direct sequencing demonstrates that the AD-6 V3 loop contains a variant GPGK motif. This highlights a limitation of V3-peptide-based assays for serotyping viruses.

Amino Acid Sequence↗
PubMed1994

Within-patient correlation between the antihypertensive effects of atenolol, lisinopril and nifedipine.

OBJECTIVE: To investigate whether there are definable subgroups of patients with essential hypertension who respond specifically to particular antihypertensive drugs. DESIGN: Randomized cross-over comparison of the antihypertensive effect of 50 mg atenolol per day, 10 mg lisinopril per day and 20 mg nifedipine retard twice a day. Ambulatory blood pressure monitoring was used to assess the blood pressure level both for recruitment and at the end of each treatment period. The treatment periods lasted 4 weeks and were preceded by 4 weeks of placebo. PATIENTS: Seventy-two untreated hypertensive patients with a mean age of 52 (SD 8.4) years were recruited from six general practices and from the hospital outpatient clinic. Sixty-eight patients completed the trial. MAIN OUTCOME MEASURES: To assess the within-patient correlations among the blood pressure responses to each drug and explore the possible role of simple characteristics, such as the initial blood pressure, plasma renin concentration and age, in identifying the responders to a particular drug. RESULTS: Systolic/diastolic blood pressure fell significantly with each agent (P < 0.001): atenolol reduced it by 16.3 +/- 13.3/9.9 +/- 8.8, lisinopril by 14.8 +/- 15.0/9.4 +/- 9.1 and nifedipine by 11.6 +/- 12.3/6.7 +/- 8.3 mmHg. There was a low degree of correlation between the changes in blood pressure with the three drugs in individual patients. With each drug there was a small percentage (8.9-14.7%) of non-responders. The initial level of systolic blood pressure was weakly correlated with the antihypertensive effect of nifedipine (r = 0.47, P < 0.001) and plasma renin concentration was related to the effect of atenolol (r = 0.32, P < 0.01). Age did not predict the blood pressure response to any agent. CONCLUSIONS: The low level of the correlation between the blood pressure changes with the three drugs suggests that different mechanisms may be involved in the aetiology of essential hypertension. Plasma renin concentration and the initial level of systolic blood pressure contribute only weakly to the identification of responders to the three drugs.

Adolescent↗
PubMed1993

Zebrafish ultraviolet visual pigment: absorption spectrum, sequence, and localization.

In many vertebrates, UV-sensitive photoreceptors have been identified by microspectrophotometry and UV-visual sensitivity has been identified by behavioral studies, but as yet no vertebrate UV-sensitive pigment gene has been isolated. We have sequenced a cDNA clone that hybridizes to short single cone cells in the zebrafish (Brachydanio rerio). These cells, which make up 25% of the cone population in zebrafish retinae, are UV-sensitive (lambda max approximately 360 nm). The visual pigment encoded by this gene is unusual in that its amino acid sequence is more homologous to the rod pigment rhodopsin (up to 89%) than to other cone pigments (35-83%). Like all other vertebrate visual pigments, it contains a lysine residue at position 296, the presumptive retinal binding site, and a glutamate residue at position 113. However, it is unique in possessing a lysine residue at position 126, which may account for the UV-sensitivity of the pigment.

Amino Acid Sequence↗
PubMed1993

Fundholding in northern region: the first year.

OBJECTIVE: To describe the experiences of 10 fundholding practices in the Northern region during 1991-2 and to elicit subjective assessments of the impact of their change in status on practice management and patient care. DESIGN: Semistructured interviews were conducted with clinicians and practice managers; other staff in the practices were asked to fill in questionnaires. Questions were asked about the preparatory year, the impact of fundholding on clinical practice and practice management, perceptions of the costs and benefits of fundholding, and views about the future of the scheme. SETTING: 10 of the 28 first wave fundholding practices in the Northern region, March-July 1992. RESULTS: Two interviews were conducted in nine practices and one interview in the tenth practice. Replies to the questionnaire were received from 35 general practitioners (73%) and 89 (58%) nonmedical staff. Practices sought independence in applying for fundholding status and found the preparatory year challenging and time consuming. General practitioners thought that the greatest change had occurred in relationships with consultants and the least change in relationships with patients. Most respondents thought that fundholding had changed the way they worked. The perceived benefits of fundholding were mentioned more often than the perceived costs. CONCLUSIONS: The results offer some encouragement to the proponents of fundholding, but more longitudinal studies are needed to evaluate the misgivings of critics of the scheme. Fundholders are uncertain about their ability to make savings year after year, particularly in an increasingly cost contained environment.

Attitude of Health Personnel↗
PubMed1993

Digoxin pharmacokinetics and perindopril in heart failure patients.

The influence of chronic perindopril treatment on digoxin pharmacokinetics was investigated in 10 patients with mild chronic heart failure under stable diuretic and digitalis treatment and normal renal function. Digoxin was administered at a dose of 0.125 mg/day (n = 2) or 0.250 mg/day (n = 8). The 24-hour steady-state digoxin profile was assessed before and after concomitant administration of perindopril for 1 month at doses of 2 mg once a day for the first 8 days and 4 mg once a day for the remaining 21 days. Chronic treatment with perindopril produced no significant effect on mean (+/- standard deviation) digoxin serum area under the curve for 24 hours (17.9 +/- 7.4 versus 16.3 +/- 4.4 ng/mL.h), peak digoxin concentration (1.3 +/- 0.54 versus 1.2 +/- 0.36 ng/mL), time to peak concentration (3 versus 4 hours), and apparent oral clearance of digoxin (237.7 +/- 109.6 versus 237.4 +/- 79.5 mL/min). Clinical and biologic tolerance of perindopril was good throughout the study. Chronic administration of perindopril did not alter steady-state digoxin kinetics in patients with mild chronic heart failure and normal renal function, indicating that no adaptation of the digoxin dose is required during co-prescription with perindopril in such patients.

Aged↗
PubMed1993

Project 2000: the gap between theory and practice.

This article explores the theory-practice gap in the context of Project 2000. Drawing on the findings of empirical research into the implementation of Project 2000 in one district health authority, we conclude that tensions between education and service staff have far from disappeared with the advent of Project 2000. The article discusses firstly the difference in emphasis between education and service staff over the question of equipping students with practical skills during their Common Foundation Programme. Secondly, we discuss the fact that whilst educationalists are intent on fostering self-directed learning in students, service staff are more concerned with producing safe practitioners. The article concludes on an optimistic note, suggesting that although service and education staff may differ in the relative importance they attach to teaching students particular types of skill; and although they may be operating on different timescales, fundamental disagreements between the two groups are absent.

Clinical Competence↗
PubMed1993

Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents.

OBJECTIVES: Because endothelial dysfunction is an early event in atherogenesis, we aimed to determine whether endothelial function is normal or impaired in the systemic arteries of children with homozygous homocystinuria or in those of heterozygous adults, or both. BACKGROUND: Homocystinuria is strongly associated with premature vascular disease in homozygotes, and even heterozygotes have been shown to be at increased risk from early atherosclerosis associated with hyperhomocystinemia. METHODS: We conducted noninvasive studies on the superficial femoral or brachial arteries of 9 children aged 4 to 17 years (mean 11) with homozygous homocystinuria and on the brachial arteries of 14 obligate heterozygous parents age 33 to 49 years (mean 41). Each subject was matched with two control subjects. Using high resolution ultrasound, we measured vessel diameter at rest, during reactive hyperemia (with flow increase causing endothelium-dependent dilation) and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). RESULTS: Flow-mediated dilation was observed in the control children (9 +/- 0.6%, range 6% to 14%) but was impaired in the children with homocystinuria (2.8 +/- 0.7%, range 0% to 7%, p < 0.0001). In contrast, nitroglycerin-mediated dilation was similar in both groups (15.7 +/- 1.6% vs. 13.1 +/- 1.2%, p = 0.27), indicating that the impaired flow-mediated dilation is secondary to endothelial dysfunction. In the heterozygous parents, both flow-mediated dilation and nitroglycerin responses (6.3 +/- 0.9%, 17 +/- 1.4%, respectively) were similar to control values (6.8 +/- 0.7%, 20.7 +/- 1.7%, p > 0.10). CONCLUSIONS: Children with homozygous homocystinuria had impaired endothelial function in the systemic arteries as early as 4 years of age, representing an early event in their premature vascular disease. However, endothelial function was preserved in the heterozygous adults.

Adolescent↗
PubMed1993

Hypercalcaemia due to parathyroid hormone-related protein: long-term circulating levels may not reflect tumour activity.

Parathyroid hormone-related protein is responsible for the hypercalcaemia caused by many tumours. Measurement of parathyroid hormone-related protein is becoming more accessible with the introduction of commercial assays. We report a case of hypercalcaemia of malignancy secondary to parathyroid hormone-related protein in a woman with renal carcinoma. The parathyroid hormone-related protein was assayed using a new immunoradiometric assay. We demonstrated an initial fall in parathyroid hormone-related protein and calcium levels after surgery and a rise in both before clinical relapse. However, the clinical relapse was itself associated with a fall in serum parathyroid hormone-related protein, nephrogenous cAMP and calcium, suggesting that the tumour had stopped producing parathyroid hormone-related protein or perhaps that post-translational processing had occurred as the tumour advanced. The tumour was investigated for parathyroid hormone-related protein mRNA content using reverse transcriptase polymerase chain reaction, both at diagnosis in surgically removed material, and using post-mortem specimens. The level of parathyroid hormone-related protein mRNA, while present, was much reduced in the recurrent tumour suggesting that active parathyroid hormone-related protein production fell substantially as the tumour advanced. This case suggests that, although demonstration of parathyroid hormone-related protein in hypercalcaemia is useful for diagnosis, tumoral secretion of this product may alter.

Adenocarcinoma, Clear Cell↗
PubMed1993

Temporary serine protection in solid phase synthesis of LH-RH analogs.

Methodology for the large-scale, solid-phase synthesis of nafarelin, I, an LH-RH agonist and RS-26306, III, and LH-RH antagonist, is described. N alpha-Boc protected amino acids were used in the synthesis. The only side-chain-protected amino acids required were BocHis(Tos)-OH and BocSer(t-Bu)-OH. The use of temporary protection on serine eliminates the formation of bis-serine derivatives (II and IV), which presents a major limitation to the use of minimal protection schemes for large-scale synthesis. Using this approach, the side-chain protecting groups are cleaved during the synthesis, and HF deprotection in a separate step is not required.

Amino Acid Sequence↗
PubMed1993

Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding.

Interaction with the CD4 receptor enhances the exposure on the human immunodeficiency type 1 gp120 exterior envelope glycoprotein of conserved, conformation-dependent epitopes recognized by the 17b and 48d neutralizing monoclonal antibodies. The 17b and 48d antibodies compete with anti-CD4 binding antibodies such as 15e or 21h, which recognize discontinuous gp120 sequences near the CD4 binding region. To characterize the 17b and 48d epitopes, a panel of human immunodeficiency virus type 1 gp120 mutants was tested for recognition by these antibodies in the absence or presence of soluble CD4. Single amino acid changes in five discontinuous, conserved, and generally hydrophobic regions of the gp120 glycoprotein resulted in decreased recognition and neutralization by the 17b and 48d antibodies. Some of these regions overlap those previously shown to be important for binding of the 15e and 21h antibodies or for CD4 binding. These results suggest that discontinuous, conserved epitopes proximal to the binding sites for both CD4 and anti-CD4 binding antibodies become better exposed upon CD4 binding and can serve as targets for neutralizing antibodies.

Amino Acid Sequence↗