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Biomedical subjects

R French

Publications and source records attributed to R French.

At least 37 records · Page 2Linked to original sources
PubMed2000

Multiple interactions among proteins encoded by the mite-transmitted wheat streak mosaic tritimovirus.

The genome organization of the mite-transmitted wheat streak mosaic virus (WSMV) appears to parallel that of members of the Potyviridae with monopartite genomes, but there are substantial amino acid dissimilarities with other potyviral polyproteins. To initiate studies on the functions of WSMV-encoded proteins, a protein interaction map was generated using a yeast two-hybrid system. Because the pathway of proteolytic maturation of the WSMV polyprotein has not been experimentally determined, random libraries of WSMV cDNA were made both in DNA-binding domain and activation domain plasmid vectors and introduced into yeast. Sequence analysis of multiple interacting pairs revealed that interactions largely occurred between domains within two groups of proteins. The first involved interactions among nuclear inclusion protein a, nuclear inclusion protein b, and coat protein (CP), and the second involved helper component-proteinase (HC-Pro) and cylindrical inclusion protein (CI). Further immunoblot and deletion mapping analyses of the interactions suggest that subdomains of CI, HC-Pro, and P1 interact with one another. The two-hybrid assay was then performed using full-length genes of CI, HC-Pro, P1, P3, and CP, but no heterologous interactions were detected. In vitro binding assay using glutathione-S-transferase fusion proteins and in vitro translation products, however, revealed mutual interactions among CI, HC-Pro, P1, and P3. The failure to detect interactions between full-length proteins by the two-hybrid assay might be due to adverse effects of expression of viral proteins in yeast cells. The capacity to participate in multiple homomeric and heteromeric molecular interactions is consistent with the pleiotropic nature of many potyviral gene mutants and suggests mechanisms for regulation of various viral processes via a network of viral protein complexes.

Animals↗
PubMed2000

Modular regulation of cGATA-5 gene expression in the developing heart and gut.

The evolutionarily conserved GATA-5 transcription factor is an early and persistent marker of heart and gut development in diverse vertebrate species. To search for control regions that might regulate the chicken GATA-5 (cGATA-5) gene, we assayed a set of cGATA-5/lacZ constructs in transgenic mice and found evidence for two functionally conserved control regions that regulate different facets of cGATA-5 gene expression. The more distal control region is activated in embryonic endoderm at the head-fold stage, whereas the other control region contains a regulatory module that is activated in a restricted region of endoderm following closure of the gut tube. Remarkably, the latter control region also contains a complex regulatory module that is activated in the cardiac crescent at the head-fold stage and subsequently functions in several mesodermal components of the developing heart, including the outer (epicardial) layer. We discuss these results in terms of possible contributions of epicardial-derived cells to the formation of heart valves, conduction tissue, and compact myocardium. These transgenes thus reveal, and provide a means to further analyze, transcriptional programs for several facets of heart morphogenesis and gut development.

Animals↗
PubMed2000

The open reading frame 5A of foxtail mosaic virus is expressed in vivo and is dispensable for systemic infection.

Infectious transcripts were successfully derived from full-length cDNA clones of foxtail mosaic potexvirus (FoMV). Full-length clones were constructed by RT-PCR whereby 5' and 3' genomic segments of 2.7 and 3.4 kb, respectively, were ligated into Bluescript II KS. The in vitro RNA transcripts were infectious to moncotyledonous (barley) and dicotyledonous (Chenopodium amaranticolor) plant species. Individual mutation studies on clones of each of the five major ORFs confirmed predicted gene function for the polymerase, TGB (triple gene block), and coat protein (CP) genes. Protoplast studies on expression of a unique open reading frame, ORF 5A, which initiates 143 nts upstream of the CP before it "reads through" the CP, revealed that the 5A protein was produced in vivo. Mutation analysis of the 5A ORF indicated, however, that it was not required for either replication or for productive infection of plants. However, the nucleic acid sequences encoding the extended CP segment were shown to be important for CP expression. Additional mutations in 5A had no effect on FoMV replication in protoplasts but rendered the virus noninfectious to plants. A correlation with diminished CP production from both mutant clones implies that synthesis of subgenomic CP mRNA was compromised, and this limited systemic infection.

3' Untranslated Regions↗
PubMed2000

A plant virus vector for systemic expression of foreign genes in cereals.

Inserts bearing the coding sequences of NPT II and beta-glucuronidase (GUS) were placed between the nuclear inclusion b (NIb) and coat protein (CP) domains of the wheat streak mosaic virus (WSMV) polyprotein ORF. The WSMV NIb-CP junction containing the nuclear inclusion a (NIa) protease cleavage site was duplicated, permitting excision of foreign protein domains from the viral polyprotein. Wheat, barley, oat and maize seedlings supported systemic infection of WSMV bearing NPT II. The NPT II insert was stable for at least 18-30 days post-inoculation and had little effect on WSMV CP accumulation. Histochemical assays indicated the presence of functional GUS protein in systemically infected wheat and barley plants inoculated with WSMV bearing GUS. The GUS constructs had greatly reduced virulence on both oat and maize. RT-PCR indicated that the GUS insert was subject to deletion, particularly when expressed as a GUS-NIb protein fusion. Both reporter genes were expressed in wheat roots at levels comparable to those observed in leaves. These results clearly demonstrate the utility of WSMV as a transient gene expression vector for grass species, including two important grain crops, wheat and maize. The results further indicate that both host species and the nature of inserted sequences affect the stability and expression of foreign genes delivered by engineered virus genomes.

Carrier Proteins↗
PubMed2000

An evaluation of peer-led STD/HIV prevention work in a public sex environment.

This paper describes an independent evaluation of a peer-led STD/HIV prevention intervention conducted by Gay Men Fighting AIDS (GMFA) in a public sex environment (PSE). A variety of quantitative and qualitative research methods were employed to collect data on the intervention process as well as its outcomes. The main aim of the intervention was the distribution of condoms and safer sex literature to PSE users. During a five-month period, over 100,000 condoms and 2,200 safer sex information packs were distributed by GMFA volunteers to the PSE users. Condom provision was identified as the most needed health promotion activity in PSEs in a survey of gay and bisexual men (n = 688) conducted by the evaluators. Data collected showed that condoms provided by GMFA, as well as from other sources, were being used in the PSE. The peer-led focus of the intervention was acceptable to the PSE users. In addition, high levels of commitment and input from the volunteers contributed considerable added value to the intervention. The evaluation found that GMFA was successful in reaching the target population and addressing their needs and demands.

Adolescent↗
PubMed2000

Where the philosopher finishes, the physician begins: medicine and the arts course in thirteenth-century Oxford.

In the thirteenth century the English universities were different from others, particularly those in the south of Europe, in two important ways: they taught more natural philosophy and less medicine. But the survival of students' notes from the second half of the century shows that in the formal course of lectures on natural philosophy attention was paid to medicine inside the arts course. The present discussion examines the nature of this medical material and the institutional and intellectual relationship between medicine and philosophy.

Curriculum↗
PubMed1999

Activity of doxorubicin covalently bound to a novel human serum albumin microcapsule.

UNLABELLED: Doxorubicin is widely used in the treatment of human malignancies, however is associated with significant cardiac, bone marrow and gastro-intestinal toxicity. Delivery systems may ameliorate this toxicity and increase treatment specificity by increasing the proportion of drug delivered to sites of disease. We have developed a novel preparation of doxorubicin (Dox) covalently linked to a heat stabilised human serum albumin microparticle (HSAM) carrier (median particle diameter of 4 microm) and assessed its activity in 4 malignant cell lines. MATERIALS AND METHODS: Doxorubicin microcapsules were compared with free doxorubicin in the rat carcinoma cell line, WRC256, and the human lines, OVCAR3, MCF7 and the Dox resistant MCF7/Dox, using a cell counting technique. IC50 were calculated from regression analysis of the resulting survival curves. Endocytosis of the microcapsules by cells in culture was observed. The rate of microcapsule uptake was assessed using dual wavelength filtered fluorescence microscopy and flow cytometry. RESULTS: The mean IC50 following incubation with the Dox microcapsules was around 5 times greater than Dox for WRC256 (p < 0.001), MCF7 (p < 0.01) and for OVCAR3 (p < 0.01). MCF7/Dox was significantly more sensitive to Dox microcapsules than free Dox (p = 0.034). A negative correlation between the rate of microcapsule uptake and the IC50 values for each cell line in culture exists (r = -0.96, p = 0.04). CONCLUSIONS: We conclude that: 1) Doxorubicin microcapsules retain activity in vitro and appear to overcome p-glycoprotein mediated Dox resistance. 2) The observed activity of Dox microcapsules correlates with the rate of particle uptake. Further studies in animal tumour models are in progress.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Inadequate cervical cytology--the need to audit individual smear takers' inadequate rates.

In order to assess the performance of individual smear takers, their rates of inadequate smears, due to insufficient material, were monitored between 1992 and 1996. Although the yearly average clinic inadequate rates were all at acceptable levels, there was great variation of rates between smear takers, ranging from 0% to 19.5%. Identification of individuals with unacceptably high inadequate rates allowed them to undergo further training. Continuous monitoring of these inadequate rates can be used to measure levels of performance amongst all smear takers, but is particularly useful for new smear takers, or those who have required retraining.

Adult↗
PubMed1999

Risk-adjusted measurement of primary cesarean sections: reliable assessment of the quality of obstetrical services.

A two-hospital system reported widely disparate Cesarean section rates in its component institutions. Statistical analysis determined that the apparent discrepancy was due primarily to patient-related factors. When risk-adjusted, both hospitals' rates were indistinguishable from expected rates. Reporting Cesarean section rates without appropriate risk adjustment yields potentially misleading results. Since reliable risk adjustment currently exists only for primary Cesarean sections, primary rates should be reported separately from "raw" rates for other procedures.

Cesarean Section↗
PubMed1999

The importance of capacities in psychoanalysis and the language of human development.

The author explores the human capacity to contain or hold experience--for self and other--by analysing the word capacity itself. Underlying the discussion is the proposition that hidden in the word capacity is a particular perspective on mental mechanisms fundamental to object-relations theory and that specific consideration of the word may, therefore, add to an understanding of these mechanisms. The author suggests that the term may have entered the language of psychoanalysis 'by mistake'. He then looks at its meaning in terms of its etymology, grammatical 'flavour', metaphorical significance and conceptual use, in particular by Bion and Winnicott. It is argued that psychoanalysis is part of, and makes a significant contribution to, a long tradition of learning from experience, in which development is understood as the progressive emergence or evolution of capacities. The underlying meaning of the word suggests that development is expansive rather than linear, step-by-step or cyclical (unlike, for example, stage, level, phase, position or loop). The author suggests that the notion of capacities may provide a framework for applying insights from the theory and practice of psychoanalysis in other organisational and societal contexts.

Humans↗
PubMed1998

An evaluation of partner notification for HIV infection in genitourinary medicine clinics in England.

OBJECTIVE: To evaluate the feasibility and effectiveness of a standardized HIV partner notification programme within genitourinary medicine clinics in England. DESIGN: A prospective survey of HIV partner notification activity over a 12-month period. SETTING: Nineteen genitourinary medicine clinics in England. PATIENTS AND PARTICIPANTS: A total of 501 eligible HIV-positive patients (either newly diagnosed or with whom partner notification had not been undertaken previously) seen during the study period. MAIN OUTCOME MEASURES: The numbers of partners named by patients, and the number of contacts notified, counselled and HIV-tested. RESULTS: Information on overall partner notification activity was obtained by reviewing available medical records of 471 patients; 353 (75%) had discussed partner notification with a health-care worker during the study period and 197 (42%) had undertaken partner notification. Detailed information on outcomes was obtained for only 70 patients who named 158 contacts as being at risk of acquiring HIV. Although 71 (45%) contacts were eventually notified, only 28 were subsequently seen in participating clinics. Almost all contacts (n = 27) requested HIV counselling and testing, and five were diagnosed HIV-positive. Patient referral was the most popular notification method chosen. CONCLUSIONS: This study illustrates some of the practical difficulties that limit HIV partner notification within genitourinary medicine clinics. These include health-care workers' misgivings about undertaking partner notification, insufficient locating information to identify contacts, and migration of newly diagnosed patients, which prevents continuity and completion of notification. Nevertheless, HIV partner notification uncovered previously undiagnosed HIV infections. Further work needs to be undertaken in staff training and policy implementation if higher rates of partner notification and outcome measurements are to be achieved.

Adolescent↗
PubMed1998

Molecular cloning, sequencing, and phylogenetic relationships of a new potyvirus: sugarcane streak mosaic virus, and a reevaluation of the classification of the potyviridae.

The nucleic acid of a serologically distinct potyvirus, originally isolated out of sugar cane from Pakistan, was reverse transcribed and the 3' terminal 2000 bp was PCR amplified, cloned, and sequenced. Phylogenetic comparisons of viruses representing each genus of the Potyviridae show that the Pakistani isolate is most closely related to the rymoviruses wheat streak mosaic virus (WSMV) and brome streak mosaic virus. We therefore propose that this new virus species be named sugar cane streak mosaic virus to reflect its similarity to WSMV. The phylogenetic data also show that the genus Rymovirus contains at least two unique evolutionary lineages. Thus the current taxonomy, based on transmission vector, is paraphyletic. We present an analysis of the taxonomic relationships among members of the family and propose a classification that both resolves the paraphyly and more accurately represents the evolutionary history of the Potyviridae.

Amino Acid Sequence↗
PubMed1998

Dose-limiting neurotoxicity in a phase I study of penclomedine (NSC 388720, CRC 88-04), a synthetic alpha-picoline derivative, administered intravenously.

3,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (penclomedine, NSC 338720, CRC 88-04) is an alpha-picoline derivative with anti-tumour activity in preclinical models. Penclomedine administration by 1-h intravenous infusion on 5 consecutive days was repeated 3 weekly in the absence of dose-limiting toxicity (DLT) or disease progression. Five dose levels were investigated (22.5-340 mg m(-2) day[-1]). Eight men and eight women were entered, median age 59 years (range 39-73 years), with good performance status (ECOG 0/1) in 11 patients. A total of 13 out of 16 patients had received previous chemotherapy. Common toxicity criteria grade (CTCg) II vomiting was recorded at all dose levels. Neurotoxicity (cerebellar ataxia and dizziness) was the DLT, CTCg III toxicity occurring in three out of three patients treated at 340 mg m(-2) day(-1). CTCg III dizziness was noted in one out of three patients at 250 mg m(-2) day(-1). Neurotoxicity developed during the 1-h infusion and persisted for a variable period (maximum 5 h) after infusion. Prophylactic antiemetic drugs appeared to reduce associated vomiting but did not prevent ataxia. No antiproliferative toxicities were noted and no anti-tumour responses were documented. Penclomedine pharmacokinetic studies confirmed preclinical evidence of extensive apparent distribution (93 l m[-2]) and rapid clearance (41 l h[-1] m[-2]). Purkinje cell loss has been identified in preclinical models after intraperitoneal administration (O'Reilly et al, 1996a) and further clinical development of penclomedine will focus on oral administration.

Adult↗
PubMed1998

The effect of pregnancy on survival in women infected with HIV: a systematic review of the literature and meta-analysis.

OBJECTIVE: To investigate the effect of pregnancy on disease progression and survival in women infected with HIV by a systematic review of the literature and meta-analysis. METHODS: Appropriate publications were identified using electronic and hand searching of relevant journals from 1983 to 1996. Studies were included in the review if they were cohort studies, either prospective or retrospective, or case-control studies which investigated disease progression of pregnant women infected with HIV and included a control group of non-pregnant women infected with HIV for comparison. Methodological quality was assessed for each study. Data were extracted for predetermined outcome measures. Sensitivity analyses were performed to explore the association between pregnancy and disease progression for the following study characteristics: clinical setting (developed or developing countries), methodological quality (high or poor) and whether studies had controlled for potential confounding. RESULTS: Seven studies, all prospective cohorts, were eligible to be included in the review. The summary odds ratio for the risk of an adverse maternal outcome related to HIV infection and pregnancy were as follows: death 1.8 (85% CI 0.99-3.3); HIV disease progression 1.41 (95% CI 0.85-2.33); progression to an AIDS-defining illness 1.63 (95% CI 1.00-2.67) and fall of CD4 cell count to below 200 x 10(6)/L 0.73 (95% CI 0.17-3.06). Sensitivity analyses showed that HIV progression in pregnancy was significantly more common in a developing country setting (odds ratio 3.71, 95% CI 1.82-7.75) than in developed countries (odds ratio 0.55, 95% 0.27-1.11) and also significantly more common in high quality studies when compared to low quality ones, odds ratios 3.71 (95% CI 1.82-7.57) and 0.55 (95% CI 0.27-1.11), respectively. However, there appears to be less progression of HIV disease and progression to AIDS when studies attempted to control for confounding by matching or restriction techniques, although this was not statistically significant in either case. CONCLUSIONS: The findings of this review have implications for women infected with HIV who are pregnant or are considering a pregnancy. There does appear to be an association between adverse maternal outcomes and pregnancy in women infected with HIV, although this association is not strong. The relation may be due to the result of bias including residual confounding. Further large scale observational studies with long term follow up are required before this issue can be fully resolved.

Case-Control Studies↗
PubMed1998

The association between maternal HIV infection and perinatal outcome: a systematic review of the literature and meta-analysis.

OBJECTIVE: To investigate the association between maternal HIV infection and perinatal outcome by a systematic review of the literature and meta-analysis. METHODS: Appropriate publications were identified using electronic and hand searching of relevant journals from 1983 to 1996. Studies were included in the review if they were prospective cohorts with pregnant women identified as being HIV-infected with a control group of pregnant women who were not infected with HIV. Methodological quality was assessed for each study. Data were extracted for pre-determined outcome measures. Sensitivity analyses were performed to explore the association between HIV infection and an adverse perinatal outcome for the following study characteristics: clinical setting (developed or developing countries), methodological quality (high or poor) and whether studies controlled for potential confounding. RESULTS: Thirty-one studies were eligible to be included in the review. The summary odds ratio of the risk of pre-defined adverse perinatal outcomes related to maternal HIV infection were as follows: spontaneous abortion 4.05 (95% CI 2.75-5.96); stillbirth 3.91 (95% CI 2.65-5.77); fetal abnormality 1.08 (95% CI 0.7-1.66); perinatal mortality 1.79 (95% CI 1.14-2.81); neonatal mortality 1.10 (95% CI 0.63-1.93); infant mortality 3.69 (95% CI 3.03-4.49); intrauterine growth retardation 1.7 (95% CI 1.43-2.02); low birthweight 2.09 (95% CI 1.86-2.35) and pre-term delivery 1 83 (95% CI 1.63-2.06). Sensitivity analyses showed that the association between infant mortality and maternal HIV infection was stronger in studies conducted in developing countries when compared with developed countries [odds ratios (OR) 3.72 (95% CI 3.05-4.54) and 8.6 (95% CI 0.53-141.05), respectively]; studies of higher methodological quality compared with those of poorer quality [odds ratios 14.57 (95% CI 6.93-30.65) and 3.37 (95% CI 2.74-4.14), respectively] and studies which had used restriction or matching to control for potential confounding factors compared with those that had not [OR 11.60 (95% CI 5.71-23.58) and 3.35 (95% CI 2.73-4.12), respectively]. CONCLUSIONS: The findings of this review have implications for women infected with HIV who are planning a pregnancy or who find themselves pregnant. There appears to be an association, although not strong, between maternal HIV infection and an adverse perinatal outcome. This relationship may be due to bias including uncontrolled or residual confounding. There does, however, appear to be a real and large increase in the risk of infant death in developing countries associated with maternal HIV infection, especially so when there has been an attempt to control for confounding.

Cohort Studies↗
PubMed1998

Interactions between the structural domains of the RNA replication proteins of plant-infecting RNA viruses.

Brome mosaic virus (BMV), a positive-strand RNA virus, encodes two replication proteins: the 2a protein, which contains polymerase-like sequences, and the 1a protein, with N-terminal putative capping and C-terminal helicase-like sequences. These two proteins are part of a multisubunit complex which is necessary for viral RNA replication. We have previously shown that the yeast two-hybrid assay consistently duplicated results obtained from in vivo RNA replication assays and biochemical assays of protein-protein interaction, thus permitting the identification of additional interacting domains. We now map an interaction found to take place between two 1a proteins. Using previously characterized 1a mutants, a perfect correlation was found between the in vivo phenotypes of these mutants and their abilities to interact with wild-type 1a (wt1a) and each other. Western blot analysis revealed that the stabilities of many of the noninteracting mutant proteins were similar to that of wt1a. Deletion analysis of 1a revealed that the N-terminal 515 residues of the 1a protein are required and sufficient for 1a-1a interaction. This intermolecular interaction between the putative capping domain and itself was detected in another tripartite RNA virus, cucumber mosaic virus (CMV), suggesting that the 1a-1a interaction is a feature necessary for the replication of tripartite RNA viruses. The boundaries for various activities are placed in the context of the predicted secondary structures of several 1a-like proteins of members of the alphavirus-like superfamily. Additionally, we found a novel interaction between the putative capping and helicase-like portions of the BMV and CMV 1a proteins. Our cumulative data suggest a working model for the assembly of the BMV RNA replicase.

Animals↗