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Biomedical subjects

R Lyons

Publications and source records attributed to R Lyons.

At least 19 recordsLinked to original sources
PubMed2005

Microdialysis sampling and the clinical determination of topical dermal bioequivalence.

Our objective was to determine whether the degree of variability associated with dermal microdialysis allows its practical application to determinations of bioequivalence of topically applied agents with a reasonable number of subjects. A statistical review of literature data was conducted to estimate the variances associated with subject-to-subject variability and the probe-to-probe variability within the subjects. In order to successfully utilise dermal microdialysis to establish bioequivalence of topically applied agents, particular care must be applied to study design. Due to the inherent variability between subjects, to maintain subject numbers at reasonable levels, each subject should act as their own control, thus removing the element of subject-to-subject variability from calculations of sample sizes. It is also recommended that measurements are made in duplicate in each subject to reduce the element of variability further. It is then possible to demonstrate, within 80-125% confidence limits and a subject population of approximately 20, that two formulations are bioequivalent.

Administration, Cutaneous↗
PubMed2003

The DNA sequence quality machine at IFOM: a simple Web-based tool for quantitative assessment of sequencing reactions.

DNA sequence quality is a factor of paramount importance in the world of modern genetic and genomics. Both the sequencing of Human Genome in the "post-draft" era [NHGRI Standard for quality of Human Genomic Sequences, Rev. 7 July (2002) where http://www.nhgri.nih.gov/Grant_info/Funding/ Statements/RFA/quality_standard.html is the HTTP address] and recent "high-throughput" approaches to genetic investigation such as SAGE [Velculescu, V.E., Zhang, L., Vogelstein, B. et al. (1995) "Serial analysis of gene expression", Science 270, 484-487] need a reliable, standardized measure of the quality of a sequencing reaction. The increasing importance of SNP studies also requires a stronger quality control on sequencing reactions by the final user. We propose here a simple, web-based tool for integrated sequence quality evaluation, high quality region quantitative value calculation and chromatogram display. This software is aimed at the small to medium DNA sequence laboratory or to the single researcher, interested in getting a quantitative measure of the sequence quality, browsing the chromatogram and checking the quality values base by base. The program is freely available from the IFOM bioinformatics web Server at http://bio.ifom-firc.it/Phred20/index.html.

Algorithms↗
PubMed2001

A combination vaccine confers full protection against co-infections with influenza, herpes simplex and respiratory syncytial viruses.

Combined/composite vaccines should be useful in reducing the number of vaccinations and provide more flexibility in confronting biological warfare scenarios. We tested the effectiveness of a composite genetic vaccine designed from previously known protective antigens directed against influenza A virus (INF-A), herpes simplex virus type-1 (HSV-1) and respiratory syncytial virus (RSV) in a mouse-based challenge. Immunizing mice with a pool of four plasmids; INF-A haemagglutinin (HA), INF-A nucleoprotein (NP), HSV-1 glycoprotein D (gD) and RSV glycoprotein F, against the three pathogens provided full protection when mice were challenged with each pathogen. Remarkably, mice challenged with all three pathogens at once were also fully protected, even when a bacterial pathogen, Mycoplasma pulmonis, was included in the challenge. If these results are extendable to other combinations of vaccines in other hosts, it would support the development of gene vaccines as multi-component, combination vaccines.

Animals↗
PubMed2000

Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats.

BACKGROUND: Nitric oxide (NO) is a potent vasodilator with an important role in the regulation of pulmonary vascular tone. The effects of NO synthase (NOS) gene transfer on pulmonary vascular remodeling associated with hypoxic pulmonary hypertension are unknown. METHODS AND RESULTS: We aerosolized 3 x 10(9) pfu of an adenoviral vector containing inducible NOS gene (AdNOS2), constitutive NOS3 gene (AdNOS3), or no transgene (AdRR5) into rat lungs. Exhaled NO levels, monitored with chemiluminescence, were higher in AdNOS2-infected rats than in AdNOS3- and AdRR5-infected rats (at 3 days, 33+/-6 ppb, n=9, versus 17+/-4, n=9, and 6+/-2 ppb, n=3, P:<0.05 for both). Exposure to FIO(2) 0.10 for 7 days increased pulmonary artery pressure from 19+/-4 mm Hg (baseline) to 27+/-1 and 26+/-2 mm Hg in AdNOS3- and AdRR5-infected rats, respectively, but only to 21+/-1 mm Hg in AdNOS2-infected animals (P:<0.05). After 7 days of hypoxia, total pulmonary resistance in AdRR5- and AdNOS3-infected rats was significantly higher than in AdNOS2-infected animals (0.41+/-0.05 and 0.39+/-0.07 versus 0.35+/-0. 03 mm Hg. mL(-)(1). min(-)(1), respectively, P:<0.05). Right ventricular hypertrophy was reduced in AdNOS2-infected rats [right ventricular/(left ventricular+septal) weight, 0.19+/-0.10 versus 0. 28+/-0.10 and 0.32+/-0.10 in AdRR5- and AdNOS3-infected rats, respectively, P:<0.05]. The percentage of muscularized precapillary pulmonary resistance vessels was also significantly decreased (18+/-4% versus 25+/-8% and 30+/-5% in AdRR5- and AdNOS3-infected rats, P:<0.05). CONCLUSIONS: Aerosol NOS2 gene transfer increases pulmonary NO production and significantly reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Aerosol NOS2 gene transfer may be a promising strategy to target pulmonary vascular disorders.

Aerosols↗
PubMed2000

Approximations for modal coupling in scattered fields from orifices

Previous investigations have used Hankel transforms to establish the velocity potentials of the wave fields resulting from arbitrary angle plane wave impingement on a circular orifice in a rigid, thick wall. The scattered field from the orifice is examined, in particular the modal contributions to the amplitude of its velocity potential. For each m,n mode the amplitude is dependent upon the amplitude of the in-orifice waves and a driving term unique to each m,n mode. In establishing the amplitudes of the in-orifice waves, the effects of modal coupling are also considered. In this work these two components of the scattered wave amplitude are investigated on a modal basis and approximations given for coupling effects. These approximations are then used to calculate the scattered field and the results compared with conventional solutions that use full modal coupling.

Journal Article↗
PubMed2000

Growth factor-independent proliferation of erythroid cells infected with Friend spleen focus-forming virus is protein kinase C dependent but does not require Ras-GTP.

Interaction of erythropoietin (Epo) with its cell surface receptor activates signal transduction pathways which result in the proliferation and differentiation of erythroid cells. Infection of erythroid cells with the Friend spleen focus-forming virus (SFFV) leads to the interaction of the viral envelope glycoprotein with the Epo receptor and renders these cells Epo independent. We previously reported that SFFV induces Epo independence by constitutively activating components of several Epo signal transduction pathways, including the Jak-Stat and the Raf-1/mitogen-activated protein kinase (MAPK) pathways. To further evaluate the mechanism by which SFFV activates the Raf-1/MAPK pathway, we investigated the effects of SFFV on upstream components of this pathway, and our results indicate that SFFV activates Shc and Grb2 and that this leads to Ras activation. While studies with a dominant-negative Ras indicated that Ras was required for Epo-induced proliferation of normal erythroid cells, the Epo-independent growth of SFFV-infected cells can still occur in the absence of Ras, although at reduced levels. In contrast, protein kinase C (PKC) was shown to be required for the Epo-independent proliferation of SFFV-infected cells. Further studies indicated that PKC, which is thought to be involved in the activation of both Raf-1 and MAPK, was required only for the activation of MAPK, not Raf-1, in SFFV-infected cells. Our results indicate that Ras and PKC define two distinct signals converging on MAPK in both Epo-stimulated and SFFV-infected erythroid cells and that activation of only PKC is sufficient for the Epo-independent proliferation of SFFV-infected cells.

Adaptor Proteins, Signal Transducing↗
PubMed1999

In vitro analysis of transformation potential associated with retroviral vector insertions.

While replication-defective retroviral vectors provide excellent vehicles for the long-term expression of therapeutic genes, they also harbor the potential to induce undesired genetic changes by random insertions into the host genome. The rate of insertional mutagenesis for retroviral vectors has been determined in several different assay systems; however, the rate at which such events induce cellular transformation has not been directly determined. Such measurements are critical to determining the actual risk of carcinogenesis resulting from retroviral gene therapy. In this study, the ability of a replication-defective retroviral vector, GlnBgSvNa, to induce cellular transformation in the BALB/c-3T3 in vitro transformation assay was assessed. The transformation frequency observed in vector-transduced BALB/c-3T3 cells, which contained one to six copies of integrated provirus, was not significantly different from that of untreated control cells. The finding that GlnBgSvNa was nontransforming in this assay indicates that the rate of transformation induced by retroviral insertions is less than the spontaneous rate of cellular transformation by BALB/c-3T3 cells, or less than 1.1 x 10(-5). These results are the first to define an upper limit for the rate of transformation induced by retroviral vectors.

3T3 Cells↗
PubMed1999

Efficacy of antiretroviral agents against murine replication-competent retrovirus infection in human cells.

Retroviral vectors for gene therapy are designed to minimize the occurrence of replication-competent retrovirus (RCR); nonetheless, it is possible that a vector-derived RCR could establish an infection in a patient. Since the efficacy of antiretroviral agents can be impacted by interactions between virus, host cell, and drug, five commonly used antiretroviral drugs were evaluated for their abilities to inhibit the replication of a murine leukemia virus (MLV)-derived RCR in human cells. The results obtained indicate that the combination of nucleoside analogs zidovudine and dideoxyinosine with the protease inhibitor indinavir effectively inhibits MLV-derived RCR replication in three human cell lines. In addition, MLV-derived RCR was found to be inherently resistant to the nucleoside analogs lamivudine and stavudine, suggesting that mutations conferring resistance to nucleoside analogs in human immunodeficiency virus type 1 have the same effect even in an alternative viral backbone.

Cell Line↗
PubMed1997

Expression of human cholesterol 7alpha-hydroxylase in atherosclerosis-susceptible mice via adenovirus infection.

Adenovirus is a vector for the delivery of genes mainly to the liver. Short-term (approximately 3 days) studies using adenovirus transfection have provided valuable insights into how genes can complement normal and pathological phenotypes. When atherosclerosis-susceptible C57BL/6 mice were infected with an adenovirus vector containing the human 7alpha-hydroxylate cDNA (AV17h1) and fed on a chow diet, human 7alpha-hydroxylase mRNA and enzyme activity doubled compared with that in mice infected with an adenovirus vector (AV1Null) alone. In AV17h1-infected mice fed on a high fat cholic acid (HFCA) diet, mRNA expression and activity of both the endogenous and adenovirus (human) 7alpha-hydroxylase were repressed. AV17h1-infected mice fed on a HFCA diet and killed at mid-light had increased 7alpha-hydroxylase activity and mRNA compared with mice killed at mid-dark. Since expression of AV17h1 is driven by a constitutive Rous sarcoma virus promoter, the repression of human 7alpha-hydroxylase by the HFCA diet was unexpected. In spite of this post-transcriptional repression by the HFCA diet, AV17h1-infected mice expressed the human 7alpha-hydroxylase mRNA, causing its enzyme activity to be 3-fold greater than in AV1Null-infected mice. In AV17h1-infected mice, the 7alpha-hydroxylase enzyme activity varied as a linear function of human mRNA abundance. In conclusion, the accumulation of apolipoprotein B-containing lipoproteins in plasma of C57BL/6 mice fed on the HFCA diet was not reduced by longer-term (2 weeks) 7alpha-hydroxylase expression, probably because of its diminished expression caused by the diet and hepatic inflammation from the adenovirus infection. These results may suggest that adenovirus is effective in promoting longer-term (2 weeks) expression of 7alpha-hydroxylase.

Adenoviridae Infections↗
PubMed1997

Ten-year survival of Down syndrome births.

OBJECTIVE: To determine the survival status of children with Down syndrome (DS), and to document factors influencing survival. DESIGN: Follow-up study of cases identified from the Dublin European Register of Congenital Anomalies and Twins (EUROCAT) Register. Follow-up was attempted for each case until death or 1992 or until the date last known to be alive. SETTING: Eastern Health Board, Dublin. SUBJECTS: In all, 389 DS children, born between 1 January 1980 and 31 December 1989 were followed up. RESULTS: Survival rates of 88% at one year and 82% at 10 years were found. There was a non-significant improvement in survival between the cohort born in 1980-1984 and that born in 1985-1989. Congenital heart defects reduced survival to 72% and complete atrio-ventricular canal defects (CAVD) had the poorest prognosis (58% survival at 10 years). Cases with CAVD showed a trend towards improved survival when surgically treated. Maternal age mother's county of residence, sex of infant, season of birth and presence of additional non-cardiac congenital anomalies had no impact on survival. CONCLUSIONS: Four out of five DS children now survive at least 10 years. Adequate educational and health service provision needs to be made for them, especially those with congenital heart defects. The need for studies which compare survival and quality of life in DS children with CAVD who undergo cardiac surgery versus those who do not, taking account of various selection factors, is identified.

Child↗
PubMed1997

Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Ardeparin Arthroplasty Study Group.

UNLABELLED: We performed a double-blind, randomized clinical trial to compare the efficacy and safety of three different subcutaneous (s.c.) low molecular weight heparin doses (ardeparin sodium 25, 35, or 50 anti-Xa U/kg twice daily [BID]) to adjusted-dose warfarin (international normalized ratio [INR] = 2.0 to 3.0), as venous thromboembolism prophylaxis after total knee replacement surgery. The primary endpoint was total venous thromboembolism prevalence, defined as deep vein thrombosis discovered at postoperative venography of the operated leg, or symptomatic, objectively-documented pulmonary embolism. Of 860 patients randomized, 680 (79%) had an evaluable venogram or pulmonary embolism. The total venous thromboembolism prevalence was significantly greater among patients prophylaxed with warfarin compared to ardeparin 50 BID (38% vs 27%, p = 0.019); the prevalence among ardeparin 25 BID (37%) and 35 BID (28%) patients was similar to warfarin and ardeparin 50 BID patients, respectively. Overt bleeding occurred in 22 (7.9%) ardeparin 50 BID patients compared to 12 (4.4%) warfarin patients (p = 0.08), and in seven ardeparin 25 and 35 BID patients each (5.2% and 5.0%, respectively). Compared to the warfarin group, blood loss was significantly greater in the ardeparin 50 and 25 BID groups, and not different in the ardeparin 35 BID group. CONCLUSIONS: Postoperative, unmonitored, fixed-dose ardeparin 50 anti-Xa U/kg s.c. BID is significantly more effective than adjusted-dose warfarin for this indication. Although overt bleeding among warfarin and ardeparin 50 BID patients did not differ significantly, ardeparin 50 BID patients had significantly greater blood loss. Ardeparin 35 anti-Xa U/kg s.c.BID may provide efficacy similar to ardeparin 50 anti-Xa U/kg s.c. BID but with reduced bleeding.

Adult↗
PubMed1996

The importance of comorbidity in HIV-infected patients over 55: a retrospective case-control study.

PURPOSE: To study the impact of comorbidity on the course of HIV disease in older patients as compared to a matched cohort of younger patients. METHODS: In a retrospective case-control study, we compared 43 HIV-infected patients > 55 years old to a randomly selected cohort of 86 patients < 45 years old, matched by date of HIV diagnosis. We collected data on non-HIV-related morbidity (as assessed by the Charlson comorbidity index), initiator of HIV testing, HIV stage at time of HIV diagnosis (TOHD), AIDS defining diagnoses, AIDS-related illnesses (ARI), observed AIDS-free interval, survival, and frequency of HIV-related and unrelated hospitalizations. RESULTS: The older cohort was more likely to have had HIV testing initiated by a health care provider (36 of 36 versus 50 of 66, P = 0.003), and to have acquired HIV from a transfusion (5 of 43 versus 0 of 86, P = 0.001), had lower CD4 cell counts at TOHD (205 versus 429, P = 0.02), a shorter observed AIDS-free interval (24.0 versus 52.8 months, P = 0.0002) and a shorter survival (28.2 versus 58.9 months, P = 0.0002). The older cohort had more HIV-related (13.4 versus 9.2 per 100 patient-months, P = 0.024) and non-HIV-related hospitalizations (12.9 versus 8.1 per 100 patient-months, P = 0.0001). The comorbidity index was significantly higher in the older cohort (0.907 versus 0.198, P = 0.0001) and was a strong predictor of mortality, independent of age group (risk ratio = 1.38 per comorbidity point, P = 0.0003). CONCLUSIONS: Older HIV-infected patients presented with more advanced disease, which may have been due to lack of HIV awareness in this population. Older patients had a shorter observed AIDS-free interval and shorter survival. In addition, they had more HIV- and non-HIV-related comorbidity. The more rapid course and decreased survival in the elderly may be related to the increase in comorbidity.

AIDS-Related Opportunistic Infections↗