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Biomedical subjects

J Robinson

Publications and source records attributed to J Robinson.

At least 253 records · Page 14Linked to original sources
PubMed1995

Placental control of fetal growth.

The placenta exerts its effects on the growth of the fetus from the beginning of pregnancy via metabolic and endocrine mechanisms. To achieve this, the placenta exchanges a wide array of nutrients, endocrine signals, cytokines and growth factors with the mother and the fetus. These exchanges modulate or programme fetal growth and development. This review concentrates on the function and structure of the placenta in humans and in animals, and the effects of experimental perturbation of placental size and function on fetal growth. The consequences for fetal growth of varying the abundance of peptides or, by deleting genes, insulin-like growth factors or cytokines, are also described. Maternal nutritional and hormonal state from as early as the first few days after fertilization, can influence the growth rate of the placenta and the fetus and also the length of gestation. Influences on placental development and their consequences will clearly have an impact on the placental control of fetal growth. Variations in the maternal environment and consequent perturbation of the metabolic and endocrine environment of the placenta and fetus are implicated as being responsible for the associations between prenatal growth of the placenta and its fetus and the subsequent risk of adult disease. The next challenge will be to determine the dominant influences at each stage of fetal and placental growth.

Animals↗
PubMed1995

Contribution of hypervariable domains to the conformation of a broadly neutralizing glycoprotein 120 epitope.

Three of the five hypervariable domains (V1-V3) of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 have previously been shown to be dispensable for antigenic epitopes recognized by broadly neutralizing monoclonal antibodies. In this study, the influence of the V4 and V5 domains on an epitope recognized by a broadly neutralizing human monoclonal antibody, 1.5e, was investigated. In contrast with the V1, V2, and V3 domains of gp120, the V4 and V5 domains were found to be critical for binding to both CD4 and 1.5e. Our results suggest that V4 and V5 are in structurally less flexible regions of gp120 than V1, V2, and V3 and raises the question of whether variable domains V4 and V5 are also indispensable for other broadly neutralizing antibodies in the same class as 1.5e.

Antibodies, Monoclonal↗
PubMed1995

A survey of semen donor attitudes.

Semen donors have been required to register with the Human Fertilization and Embryology Authority since its formation in 1990. Since then many clinics have reported a shortage of donor semen for donor insemination treatment. Is this because potential donors are worried about the protection of their anonymity? No published studies are available concerning the attitudes to semen donation in the UK. It was against this background that an investigation of the attitudes of potential semen donors was carried out. Four dimensions were investigated: (i) motives, (ii) personal detachment and involvement, (iii) detachment and involvement with respect to recipients, and (iv) detachment and involvement with respect to offspring. A total of 55 potential semen donors completed the attitude questionnaire from semen donation programmes in three in-vitro fertilization units. The questionnaire format was found to be an effective method of data collection for this sensitive area of research, and the major findings were (i) 89% of potential donors required confidentiality and guaranteed anonymity; (ii) 82% did not mind providing non-identifying information to the recipients and offspring; (iii) 69% of potential donors expected financial reward; and (iv) 69% did not welcome counselling.

Attitude↗
PubMed1995

Synthetic and biological macromolecules: protection of mouse embryos during cryopreservation by vitrification.

The ability of macromolecules to protect 8-cell mouse embryos during a vitrification protocol was assessed by the comparison of a synthetic macromolecule, polyvinylpyrrolidone (in the form of Percoll), and a biological macromolecule, human serum albumin (HSA). Vitrification solutions, which included glycerol (50% v/v), sucrose (0.75 mol/l) and either macromolecule Percoll (50% v/v) or HSA (1.125% w/v), were found to provide similar rates of survival. Both compounds resulted in a significant reduction in the incidence of disruption to the zonae pellucidae of cryopreserved embryos, to 4.8 +/- 1.3% and 10.3 +/- 1.2% respectively, when compared to the outcome when neither was present in the vitrification solution (20.4 +/- 2.5%; P < 0.01). Polyvinylpyrrolidone in the form of Percoll offers advantages over HSA in this work: it provides a lower rate of zona disruption and avoids the need for screening for pathogenic contaminants such as human immunodeficiency virus and hepatitis B and C.

Animals↗
PubMed1995

Remote telemetry: new twists for old technology.

Availability of telemetry beds was increased cost-effectively by providing telemetry on medical/surgical units with remote monitoring at designated critical care areas. Guidelines were developed for patient selection, education, clinical policy and procedure. A two-hour inservice was completed by all medical/surgical nurses and after a pilot study the system was implemented on three medical/surgical units.

Cost-Benefit Analysis↗
PubMed1995

Information management and technology in England's large acute NHS hospitals. National strategy versus local reality.

Discusses the NHS Executive's information management and technology (IM&T) strategy and its relationship to the 1991 reforms. Examines the recommendation for large acute hospitals to adopt integrated hospital information support systems (HISS). Reports that a recent census of these hospitals, undertaken by the authors, suggests that the implementation of the strategy's recommendations has been slow at the local level. Attempts to diagnose the factors that are impeding implementation, using the evidence provided by the census. Identifies four main problem areas: the lack of success of past IM&T initiatives undermines confidence in the current strategy; the strategy is poorly aligned with other policy initiatives; the legacy of discrete, proprietary information systems within hospitals makes the creation of an integrative information environment difficult to accomplish without massive investment in new systems; and there are implicit contradictions between the following: the absence of a comprehensive post-implementation evaluation of the economic, technological and cultural feasibility of HISS at any of the three HISS pilot sites; the strategy's advocacy of HISS as the way forward for large acute hospitals; the requirement for a comprehensive business case to support any substantial investment in IM&T. Concludes that a massive rethink of policy is required, with a much greater emphasis on research, development and independent evaluation.

Confidentiality↗
PubMed1995

Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120.

A panel of anti-gp120 human monoclonal antibodies (HuMAbs), CD4-IgG, and sera from people infected with human immunodeficiency virus type 1 (HIV-1) was tested for neutralization of nine primary HIV-1 isolates, one molecularly cloned primary strain (JR-CSF), and two strains (IIIB and MN) adapted for growth in transformed T-cell lines. All the viruses were grown in mitogen-stimulated peripheral blood mononuclear cells and were tested for their ability to infect these cells in the presence and absence of the reagents mentioned above. In general, the primary isolates were relatively resistant to neutralization by the MAbs tested, compared with the T-cell line-adapted strains. However, one HuMAb, IgG1b12, was able to neutralize most of the primary isolates at concentrations of < or = 1 microgram/ml. Usually, the inability of a HuMAb to neutralize a primary isolate was not due merely to the absence of the antibody epitope from the virus; the majority of the HuMAbs bound with high affinity to monomeric gp120 molecules derived from various strains but neutralized the viruses inefficiently. We infer therefore that the mechanism of resistance of primary isolates to most neutralizing antibodies is complex, and we suggest that it involves an inaccessibility of antibody binding sites in the context of the native glycoprotein complex on the virion. Such a mechanism would parallel that which was previously postulated for soluble CD4 resistance. We conclude that studies of HIV-1 neutralization that rely on strains adapted to growth in transformed T-cell lines yield the misleading impression that HIV-1 is readily neutralized. The more relevant primary HIV-1 isolates are relatively resistant to neutralization, although these isolates can be potently neutralized by a subset of human polyclonal or monoclonal antibodies.

Amino Acid Sequence↗
PubMed1995

A human monoclonal antibody to a complex epitope in the V3 region of gp120 of human immunodeficiency virus type 1 has broad reactivity within and outside clade B.

We have used virus neutralization and antibody-binding techniques to define the epitope for a human monoclonal antibody, designated 19b, within the V3 region of the gp120 surface glycoprotein of human immunodeficiency virus type 1. Unusually, the 19b epitope encompasses residues on both flanks of the V3 loop. However, 19b binding to gp120 is independent of sequences at the crown of the V3 loop, provided that they are compatible with the formation of a type II beta turn that is presumably necessary to juxtapose the antigenic residues on the V3 flanks. By comparing the V3 sequences of virus gp120s able and unable to bind 19b, we were able to define the canonical 19b epitope as -I----G--FY-T, where residues at the positions indicated by the gaps do not contribute directly to the 19b-binding site. A few conservative substitutions at the more critical residues are also compatible with 19b binding. Inspection of V3 sequences in the human immunodeficiency virus database indicated that the canonical 19b epitope is well conserved among isolates from the North American-European clade B and also among clade E isolates from Thailand and clade F isolates from Brazil. A minority of gp120s from clades A and C also possess the 19b epitope. Consistent with the theoretical predictions of its cross-clade reactivity, 19b was found to bind to gp120s from clades A, B, C, E, and F in immunoassays. However, 19b was not able to reduce the infectivity of primary viruses from clades A, E, and F that were predicted to possess the 19b epitope and only modestly reduced the infectivity of a clade C virus at low input virus concentrations. Cross-clade neutralization via V3-directed antibodies may, therefore, be difficult, even if the antibodies show broad reactivities in binding assays and the viruses theoretically possess the relevant binding site.

Amino Acid Sequence↗
PubMed1995

Phorbol ester-induced down modulation of tailless CD4 receptors requires prior binding of gp120 and suggests a role for accessory molecules.

The entry of human immunodeficiency virus type 1 into cells proceeds via a fusion mechanism that is initiated by binding of the viral glycoprotein gp120-gp41 to its cellular receptor CD4. Species- and tissue-specific restrictions to viral entry suggested the participation of additional membrane components in the postbinding fusion events. In a previous study (H. Golding, J. Manischewitz, L. Vujcic, R. Blumenthal, and D. Dimitrov, J. Virol. 68:1962-1968, 1994), it was found that phorbol myristate acetate (PMA) inhibits human immunodeficiency virus type 1 envelope-mediated cell fusion by inducing down modulation of an accessory component(s) in the CD4-expressing cells. The fusion inhibition was seen in a variety of cells, including T-cell transfectants expressing engineered CD4 receptors (CD4.401 and CD4.CD8) which are not susceptible to down modulation by PMA treatment. In the current study, it was found that preincubation of A2.01.CD4.401 cells with soluble monomeric gp120 for 1 h at 37 degrees C primed them for PMA-induced down modulation (up to 70%) of the tailless CD4 receptors. The gp120-priming effect was temperature dependent, and the down modulation may have occurred via clathrin-coated pits. Importantly, nonhuman cell lines expressing tailless CD4 molecules did not down modulate their CD4 receptors under the same conditions. The gp120-dependent PMA-induced down modulation of tailless CD4 receptors could be efficiently blocked by the human monoclonal antibodies 48D and 17B, which bind with increased avidity to gp120 that was previously bound to CD4 (M. Thali, J. P. Moore, C. Furman, M. Charles, D. D. Ho, J. Robinson, and J. Sodroski, J. Virol. 67:3978-3988, 1993). These findings suggest that gp120 binding to cellular CD4 receptors induces conformational changes leading to association of the gp120-CD4 complexes with accessory transmembrane molecules that are susceptible to PMA-induced down modulation and can target the virions to clathrin-coated pits.

Animals↗
PubMed1995

Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding.

The binding of human immunodeficiency virus type 1 (HIV-1) to the cellular receptor CD4 has been suggested to induce conformational changes in the viral envelope glycoproteins that promote virus entry. Conserved, discontinuous epitopes on the HIV-1 gp120 glycoprotein recognized by the 17b, 48d, and A32 antibodies are preferentially exposed upon the binding of soluble CD4 (sCD4). The binding of the 17b and 48d antibodies to the gp120 glycoprotein can also be enhanced by the binding of the A32 antibody. Here we constructed HIV-1 gp120 mutants in which the variable segments of the V1/V2 and V3 structures were deleted, individually or in combination, while the 17b, 48d, and A32 epitopes were retained. The effects of the variable loop deletions on the function of the HIV-1 envelope glycoproteins and on the exposure of epitopes induced by sCD4 or A32 binding to the monomeric gp120 glycoprotein were examined. The variable-loop-deleted envelope glycoproteins were able to mediate virus entry, albeit at lower efficiencies than those of the wild-type glycoproteins. Thus, the V1/V2 and V3 variable sequences contribute to the efficiency of HIV-1 entry but are not absolutely required for the process. Neither the V1/V2 nor V3 loops were necessary for the increase in exposure of the 17b/48d epitopes induced by binding of the A32 monoclonal antibody. By contrast, induction of the 17b, 48d, and A32 epitopes by sCD4 binding apparently involves a movement of the V1/V2 loops, which in the absence of CD4 partially mask these epitopes on the native gp120 monomer. The results obtained with a mutant glycoprotein containing a deletion of the V1 loop alone indicated that the contribution of the V2 loop to these phenomena was more significant than that of the V1 sequences. These results suggest that the V1/V2 loops, which have been previously implicated in CD4-modulated, postattachment steps in HIV-1 entry, contribute to CD4-induced gp120 conformational changes detected by the 17b, 48d, and A32 antibodies.

Amino Acid Sequence↗
PubMed1995

Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility.

OBJECTIVE: To assess a non-invasive test for endothelial dysfunction, an important early event in the atherogenic process. METHODS: Using high resolution ultrasound, the accuracy of detecting small changes in vessel diameter was assessed using phantom "arteries", and the same equipment was then used to measure flow mediated dilatation in the brachial artery of 40 healthy adults aged 22-51 years, studied on four occasions; intervals between scans were 1-2 days, 1-2 weeks, and 2-4 months. RESULTS: Differences between pairs of phantom "arteries" with diameters 0.1-0.2 mm apart were correctly estimated in 162 of 264 cases (61%); no measurement by any of four independent observers was > 0.1 mm in error, and the mean error was 0.04 mm. For in vivo scans, the overall coefficient of variation for flow mediated dilatation was 1.8% (1.6% for women, 1.9% for men, P = 0.18). In 34/40 subjects (85%), all values for flow mediated dilatation were within 2.5% of the overall mean for each subject. A nested analysis of variance showed the expected between patient variability, and also significant day to day variation, but little between weeks or months. Using these data to generate power function analyses, we calculated that for individuals, an improvement in flow mediated dilatation of 4-8% is significantly greater than natural variability. In clinical trials, a mean improvement in flow mediated dilatation of at least 2% would usually be required to detect a treatment benefit, with much larger subject numbers needed for a parallel group compared to a crossover trial design. CONCLUSIONS: Vascular responses to endothelium dependent and independent stimuli in systemic arteries can be studied non-invasively in man. Subjects should be studied on at least two occasions before and after any intervention, to optimise the chance of showing a significant effect from any potentially beneficial therapy.

Adult↗
PubMed1995

Noninvasive pulse wave analysis for the early detection of vascular disease.

A noninvasive technique has been developed and validated for calculating capacitive and oscillatory systemic arterial compliance with the use of pulse wave analysis and a modified Windkessel model. Application of the technique to subjects with hypertension, postmenopausal women with symptomatic coronary artery disease, and appropriate control subjects has confirmed a reduction of oscillatory compliance in the disease states and an increase in capacitive and oscillatory compliances in response to vasodilator drugs. This method should be useful in screening subjects for early evidence of vascular disease and in monitoring the response to therapy.

Blood Pressure↗
PubMed1995

Pharmacologic treatment of abnormal ion transport in the airway epithelium in cystic fibrosis.

Cystic fibrosis (CF) is a recessive genetic disease reflecting mutations in the gene coding for the CF transmembrane regulator (CFTR) protein, which normally functions as a cyclic adenosine monophosphate (cAMP)-regulated chloride (Cl-) channel. Functional abnormalities include thick airway secretions resulting from defective cAMP-mediated Cl- (liquid) secretion and a related defect, excessive sodium (Na+) (liquid) absorption. Novel pharmacologic agents are being tested as therapy for these ion transport defects. Aerosolized amiloride inhibits excessive Na+ absorption, and pilot studies in adult patients with CF show slowing of the disease-associated decline in lung function. Clinical trials of amiloride are currently underway in adults and adolescents, and short-term safety studies have been initiated in children. Aerosolized uridine triphosphate (UTP) induces Cl- (and liquid) secretion in CF airway epithelia via non-CFTR Cl- channels. Short-term aerosolized UTP is well tolerated by normal subjects and patients with CF, and pilot studies in normal subjects show that aerosolized UTP is an effective stimulator of mucociliary clearance. Pharmacotherapy that modifies airway epithelial ion transport may provide new opportunities for treatment of CF lung disease.

Adolescent↗
PubMed1994

Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction.

OBJECTIVES: This study attempted to assess whether coronary risk factors are associated with endothelial dysfunction in the systemic arteries of asymptomatic men and women. BACKGROUND: Endothelial dysfunction is present in adults with established atherosclerosis. It is not known whether risk factors interact to produce endothelial dysfunction in clinically well subjects early in the natural history. METHODS: Using high resolution ultrasound, we measured arterial diameter at rest, after reactive hyperemia (with increased flow causing endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). Arterial responses were studied noninvasively in 500 clinically well, nonhypertensive subjects (252 men, 248 women; mean [+/- SD] age 36 +/- 15 years, range 5 to 73), including 179 current and former smokers. The superficial femoral artery was studied in 46 subjects and the brachial artery in 454. RESULTS: Flow-mediated dilation ranged from -1% to +17%. All arteries dilated in response to administration of nitroglycerin (17 +/- 6%), suggesting an abnormality of endothelial function in subjects with impaired flow-mediated dilation. On univariate analysis, reduced flow-mediated dilation was significantly related to hypercholesterolemia, cigarette smoking, higher blood pressure, male gender, older age, family history of premature vascular disease and larger vessel size (p < 0.01). By multiple stepwise regression analysis, reduced flow-mediated dilation was independently associated with cigarette smoking, older age, male gender and larger vessel size (p < 0.005) but not with total cholesterol level, blood pressure or family history. A composite risk factor score was independently related to flow-mediated dilation (r = -0.30, p < 0.0001), suggesting risk factor interaction. CONCLUSIONS: Loss of endothelium-dependent dilation in the systemic arteries occurs in the preclinical phase of vascular disease and is associated with interaction of the same risk factors known to predispose to atherosclerosis and its complications in later life.

Adolescent↗