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Biomedical subjects

J A Rogers

Publications and source records attributed to J A Rogers.

At least 19 recordsLinked to original sources
PubMed2002

Investigation into the relationship between body surface area and total body potassium using Monte Carlo and measurement.

The use of body surface area (BSA) as a means of indexing chemotherapy doses is widespread even though the value of this practice is uncertain. In principle, the body cell mass (BCM) more closely represents the body's metabolic size and this is investigated here as an alternative to BSA; since 98% of body potassium is intracellular the derivation of total body potassium (TBK) via the measurement of 40K in a whole body counter (WBC) will provide a useful normalizing index for metabolic size, potentially avoiding toxicity and underdosing. The Queen Elizabeth Hospital WBC has been used in this study, initially involving single geometrical phantoms and then combinations of these to simulate human body habitus. Monte Carlo N-particle (MCNP) codes were constructed to model the phantoms and simulate the measurements made in the WBC. Efficiency corrections were derived by comparing measurement and modelled data for each detector separately. A method of modelling a person in the WBC as a series of ellipsoids was developed. Twenty-four normal males and 24 females were measured for their 40K emissions. Individual MCNP codes were constructed for each volunteer and the results used in conjunction with the measurements to derive TBK, correcting for body habitus effects and detector efficiencies. An estimate of the component of error arising from sources other than counting statistics was included by analysing data from the measurement of phantoms. The total residual errors (expressed as coefficients of variation) for males and females were 10.1% and 8.5% respectively. The measurement components were determined to be 2.4% and 2.5%, implying that the biological components were 9.8% and 8.1% respectively. These results suggest that the use of BSA for indexing chemotherapy doses is likely to give rise to clinically significant under- or overdosing.

Body Surface Area↗
PubMed2001

Paper-like electronic displays: large-area rubber-stamped plastic sheets of electronics and microencapsulated electrophoretic inks.

Electronic systems that use rugged lightweight plastics potentially offer attractive characteristics (low-cost processing, mechanical flexibility, large area coverage, etc.) that are not easily achieved with established silicon technologies. This paper summarizes work that demonstrates many of these characteristics in a realistic system: organic active matrix backplane circuits (256 transistors) for large ( approximately 5 x 5-inch) mechanically flexible sheets of electronic paper, an emerging type of display. The success of this effort relies on new or improved processing techniques and materials for plastic electronics, including methods for (i) rubber stamping (microcontact printing) high-resolution ( approximately 1 microm) circuits with low levels of defects and good registration over large areas, (ii) achieving low leakage with thin dielectrics deposited onto surfaces with relief, (iii) constructing high-performance organic transistors with bottom contact geometries, (iv) encapsulating these transistors, (v) depositing, in a repeatable way, organic semiconductors with uniform electrical characteristics over large areas, and (vi) low-temperature ( approximately 100 degrees C) annealing to increase the on/off ratios of the transistors and to improve the uniformity of their characteristics. The sophistication and flexibility of the patterning procedures, high level of integration on plastic substrates, large area coverage, and good performance of the transistors are all important features of this work. We successfully integrate these circuits with microencapsulated electrophoretic "inks" to form sheets of electronic paper.

Journal Article↗
PubMed2001

A confidence-set approach for finding tightly linked genomic regions.

As more studies adopt the approach of whole-genome screening, geneticists are faced with the challenge of having to interpret results from traditional approaches that were not designed for genome-scan data. Frequently, two-point analysis by the LOD method is performed to search for signals of linkage throughout the genome, for each of hundreds or even thousands of markers. This practice has raised the question of how to adjust the significance level for the fact that multiple tests are being performed. Various recommendations have been made, but no consensus has emerged. In this article, we propose a new method, the confidence-set approach, that circumvents the need to correct for the level of significance according to the number of markers tested. In the search for the gene location of a monogenic disorder, multiplicity adjustment is not needed in order to maintain the desired level of confidence. For complex diseases involving multiple genes, one needs only to adjust the level of significance according to the number of disease genes--a much smaller number than the number of markers in a genome screen-to ensure a predetermined genomewide confidence level. Furthermore, our formulation of the tests enables us to localize disease genes to small genomic regions, an extremely desirable feature that the traditional LOD method lacks. Our simulation study shows that, for sib-pair data, even when the coverage probability of the confidence set is chosen to be as high as 99%, our approach is able to implicate only the markers that are closely linked to the disease genes.

Chromosome Mapping↗
PubMed2001

Formulation and evaluation of a folic acid receptor-targeted oral vancomycin liposomal dosage form.

PURPOSE: To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin. via the oral route. METHODS: Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitro in the Caco-2 cell model and in vivo in male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces. RESULTS: Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution. CONCLUSIONS: The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.

Algorithms↗
PubMed2001

Use of optical coherence tomography for assessment of dental caries: quantitative procedure.

A method for quantitative assessment of dental caries using optical coherence tomography (OCT) was demonstrated. Development of caries lesions in 15 bovine teeth, by demineralization in acidic buffer solution, was quantitatively assessed daily for 3 days, using OCT. An OCT system which can collect A-scans (depth versus reflectivity curve), B-scans (longitudinal images) and C-scans (transverse images at constant depth) was used. While the B- and C-scans qualitatively described the lesion detected, the A-scan which showed the depth (mm) resolved reflectivity (dB) of the tooth tissue was used for the quantitative analysis. After a simple normalization procedure to determine the actual depth the light travelled into the tooth tissue, the area (R) under the A-scan was quantified as a measure of the degree of reflectivity of the tissue. The result showed that R (dB mm) decreased with increasing demineralization time. The percentage reflectivity loss (R%) in demineralized tissue, which related to the amount of mineral loss, was also calculated, and it was observed that R% increased with increasing demineralization time. It was concluded that with the above procedure, OCT could quantitatively monitor the mineral changes in a caries lesion on a longitudinal basis.

Animals↗
PubMed2001

Noncontact quantitative spatial mapping of stress and flexural rigidity in thin membranes using a picosecond transient grating photoacoustic technique.

This paper describes a purely optical technique for measuring and spatially mapping out stress and rigidity in thin membranes. Its application to a membrane of aluminum nitride that has significant spatial nonuniformities in its elastic properties demonstrates the method. The attractive features of this technique--fast, noncontacting measurement, good spatial resolution, ability to quantify in-plane anisotropy--make it potentially useful for characterizing elements of microelectromechanical structures, masks for advanced lithography systems, acoustic filters, and other devices in which the mechanical properties of membranes are important.

Journal Article↗
PubMed2000

Survival and differentiation of cultured retinal progenitors transplanted in the subretinal space of the rat.

We have shown that embryonic retina contains progenitors which display stem cell properties in vitro. These cells are proliferative and in addition to expressing the neuroectodermal marker, nestin, are multipotential. These properties and the fact that the putative stem cells can differentiate as photoreceptors when exposed to conducive environment identify them as a viable transplantation reagents to address degenerative retinal diseases. Here we report the survival and differentiation of cultured retinal progenitors upon subretinal transplantation. The retinal progenitor grafts, either as neural spheres or in the form of dissociated cells, survived without disrupting the morphology and laminar organization of the host retina. They did not form rosettes, the morphological barrier to the reconstruction of the normal anatomy of the retina. In addition, transplanted progenitors expressed photoreceptor-specific markers, suggesting that progenitors have the potential to differentiate as photoreceptors. Our observations suggest that cultured retinal progenitors can be a viable reagents for therapeutic transplantation.

Animals↗
PubMed2000

Src homology 2 domain substitution modulates the kinase and transforming activities of the Fes protein-tyrosine kinase.

The c-fes proto-oncogene encodes a Mr 93,000 protein-tyrosine kinase (Fes) that is strongly expressed in myeloid cells and has been implicated in myelomonocytic differentiation. Fes autophosphorylation and transforming activity are highly restrained after ectopic expression in fibroblasts, indicating tight negative regulation of Fes kinase activity in vivo. Here we investigated the regulatory role of the Fes Src homology 2 (SH2) domain by producing a series of chimeric constructs in which the Fes SH2 domain was replaced with those of the transforming oncogenes v-Fps and v-Src or by the NH2-terminal SH2 domain of the Ras GTPase-activating protein. Wild-type and chimeric Fes proteins readily underwent tyrosine autophosphorylation in vitro and produced identical cyanogen bromide phosphopeptide cleavage patterns, indicating that the SH2 substitutions did not influence overall kinase activity or autophosphorylation site selection. However, metabolic labeling of Rat-2 fibroblasts expressing each construct showed that only the Fes/Src SH2 chimera was active in vivo. Consistent with this result, the Fes/Src SH2 domain chimera exhibited potent transforming activity in fibroblasts and enhanced differentiation-inducing activity in K-562 myeloid leukemia cells. In addition, the Fes/Src SH2 chimera exhibited constitutive localization to focal adhesions in Rat-2 fibroblasts and induced the attachment and spreading of TF-1 myeloid cells. These data demonstrate a central role for the SH2 domain in the regulation of Fes kinase activity and biological function in vivo.

Amino Acid Substitution↗
PubMed1999

Folic acid-PEO-labeled liposomes to improve gastrointestinal absorption of encapsulated agents.

The design of targeted oral liposomes is anticipated to improve the systemic delivery of poorly absorbed agents, such as proteins and peptides. A poly(ethylene oxide) (PEO)-folic acid (FA) derivative was prepared and evaluated for improving liposome transport across a model gastrointestinal cell line (Caco-2). FA-PEO-cholesterol (Chol) derivatives were synthesized and adsorbed at liposome surfaces encapsulating Texas Red((R))-Dextran 3000 (TR-dex), a poorly-absorbed, neutral, hydrophilic, large molecular weight (M(w)) marker. Apparent permeabilities (P(app)) of Caco-2 cells to FA-PEO conjugates, TR-dex, uncoated TR-dex liposomes, and FA-coated TR-dex liposomes were compared at 2 h post-administration. Intracellular delivery of TR-dex was detected by fluorescence microscopy. An increase in intracellular accumulation of TR-dex associated with FA-PEO-coated liposomes, but not other formulations, was evidence of the potential of FA-targeted liposomes in the oral delivery of poorly absorbed, large M(w) agents.

Absorption↗
PubMed1999

In vitro analysis of a mammalian retinal progenitor that gives rise to neurons and glia.

In vivo lineage studies have shown that retinal cells arise from multipotential progenitors whose fates are regulated by cell-cell interactions. To understand the mechanism underlying their maintenance and differentiation, we have analyzed the differentiation potential of progenitors derived from embryonic rat retina in vitro. These progenitors proliferate and remain undifferentiated in vitro in the presence of epidermal growth factor (EGF) and display properties similar to stem cells. In addition to expressing nestin, the neuroectodermal stem cell marker, retinal progenitors are multipotential. Upon withdrawal of EGF and addition of serum, the progenitors downregulate the expression of nestin and express cell-type specific markers corresponding to neurons and glia. In addition to expressing cell-type specific markers, retinal progenitors and their progeny could be distinguished on the basis of their distinct voltage gated current profile. A proportion of progenitors is lineage restricted and the fate of these cells can be influenced by the microenvironment, suggesting that stage-specific interactions mediated by the local environment influence the progression of progenitors towards acquisition of differentiated phenotypes.

Animals↗
PubMed1999

Preparation and release of ibuprofen from polyacrylamide gels.

The conditions of preparation of polyacrylamide (polyAC) gels, the incorporation of ibuprofen (IB), and the kinetics of IB release under various conditions have been evaluated. Transparent, opaque, or elastic gels were prepared depending on the concentration of acrylamide (AC) and the cross-linking agent, N,N'-methylenebisacrylamide (BIS). Release studies in media below pH 5.0 resulted in opaque gels. The kinetics of IB release was a function of the AC, BIS, and the pH of the medium, but the optimum composition, in terms of gel integrity and release characteristics, was 7% AC cross-linked with BIS at a 50:1 ratio. Modulation of the release rate was possible with the incorporation of 10% of certain polymers. The amount of IB that could be incorporated per gram of transparent gel was a function of the amount of polymer initiator N,N,N',N'-tetramethylene diamine (TEMED) used per gram of gel. More than 200 mg of IB could be incorporated per gram of transparent gel by using 100 microliters of TEMED. The release of IB obeyed matrix/swelling-controlled kinetics and 70-80% of the IB was released from gels containing 10 to 40 mg IB per gram of gel in 5 hr at pH 7.4 and 37 degrees C.

Acrylamides↗
PubMed1999

Regulation of c-Fes tyrosine kinase and biological activities by N-terminal coiled-coil oligomerization domains.

The cytoplasmic protein-tyrosine kinase Fes has been implicated in cytokine signal transduction, hematopoiesis, and embryonic development. Previous work from our laboratory has shown that active Fes exists as a large oligomeric complex in vitro. However, when Fes is expressed in mammalian cells, its kinase activity is tightly repressed. The Fes unique N-terminal sequence has two regions with strong homology to coiled-coil-forming domains often found in oligomeric proteins. Here we show that disruption or deletion of the first coiled-coil domain upregulates Fes tyrosine kinase and transforming activities in Rat-2 fibroblasts and enhances Fes differentiation-inducing activity in myeloid leukemia cells. Conversely, expression of a Fes truncation mutant consisting only of the unique N-terminal domain interfered with Rat-2 fibroblast transformation by an activated Fes mutant, suggesting that oligomerization is essential for Fes activation in vivo. Coexpression with the Fes N-terminal region did not affect the transforming activity of v-Src in Rat-2 cells, arguing against a nonspecific suppressive effect. Taken together, these findings suggest a model in which Fes activation may involve coiled-coil-mediated interconversion of monomeric and oligomeric forms of the kinase. Mutation of the first coiled-coil domain may activate Fes by disturbing intramolecular coiled-coil interaction, allowing for oligomerization via the second coiled-coil domain. Deletion of the second coiled-coil domain blocks fibroblast transformation by an activated form of c-Fes, consistent with this model. These results provide the first evidence for regulation of a nonreceptor protein-tyrosine kinase by coiled-coil domains.

Animals↗
PubMed1998

Activation of STAT3 by the c-Fes protein-tyrosine kinase.

STATs (signal transducers and activators of transcription) are transcription factors that contain SH2 domains and are activated by tyrosine phosphorylation, often in response to cytokine stimulation. Recent evidence indicates that the transforming tyrosine kinases encoded by the v-Src, v-Abl, and v-Fps oncogenes can induce STAT activation, suggesting that their normal cellular homologs may contribute to STAT activation under physiological conditions. In this report, we provide direct evidence that c-Fes, the normal human homolog of v-Fps, potently activates STAT3. Transient transfection of human 293T cells with STAT3 and Fes resulted in strong stimulation of STAT3 DNA binding activity. In contrast, only modest activation of STAT5 by Fes was observed in this system, indicative of possible selectivity. To determine whether Fes-induced STAT3 activation is dependent upon endogenous mammalian kinases, co-expression studies were also performed in Sf-9 insect cells. Fes also induced a dramatic increase in STAT3 DNA binding activity in this system, whereas no activation of STAT5 was observed. As a positive control, both STAT3 and STAT5 were shown to be activated by the Bcr-Abl tyrosine kinase in Sf-9 cells. Fes induced strong tyrosine phosphorylation of STAT3 in both expression systems, consistent with the gel-shift results. Fes and STAT3 have been independently linked to myeloid differentiation. Results presented here suggest that these proteins may cooperate to promote differentiation signaling in response to hematopoietic cytokines.

Animals↗
PubMed1998

The role of NeuroD as a differentiation factor in the mammalian retina.

NeuroD, a vertebrate homolog of Drosophila atonal gene, plays an important role in the differentiation of neuronal precursors (Lee et al., 1995). We have investigated whether NeuroD subserves a similar function in mammalian retinal neurogenesis. Expression of NeuroD is detected in successive stages of retinal neurogenesis and is associated with a differentiating population of retinal cells. The association of NeuroD predominantly with postmitotic precursors in early as well as late neurogenesis suggests that NeuroD expression plays an important role in the terminal differentiation of retinal neurons. The notion is supported by observations that overexpression of NeuroD during late neurogenesis promotes premature differentiation of late-born neurons, rod photoreceptors, and bipolar cells, and that NeuroD can interact specifically with the E-box element in the proximal promoter of the phenotype-specific gene, opsin.

Animals↗
PubMed1998

The c-Fes family of protein-tyrosine kinases.

The human c-fes protooncogene encodes a protein-tyrosine kinase (c-Fes) distinct from c-Src, c-Abl and other nonreceptor tyrosine kinases. Although originally identified as the cellular homolog of several transforming retroviral oncoproteins, Fes was later found to exhibit strong expression in myeloid hematopoietic cells and to play a direct role in their differentiation. Recent work has shown that Fes exhibits a more widespread expression pattern in both developing and adult tissues, suggesting a general physiological function for this kinase and its closely related homolog, Fer. This review highlights the unique aspects of Fes structure, regulation, and function that set it apart from other tyrosine kinase families.

Animals↗