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Biomedical subjects

M A Robinson

Publications and source records attributed to M A Robinson.

At least 19 recordsLinked to original sources
PubMed2003

Issues and strategies for faculty development in technology and biomedical informatics.

Biomedical informatics and technology are becoming important components of dental education. The tools and techniques now available have the potential for significant impact on teaching and research by improving the way information is acquired, stored, retrieved, and managed. However, a gap exists between those who create, introduce, or implement the technology applications and the faculty in dental schools faced with the challenge of using it. For technology and informatics to thrive in the areas of didactic teaching, clinical teaching, and clinical practice, more than a select few must understand the potential applications. This paper provides an overview of the issues and strategies involved with faculty development for the use of technology in the educational setting. The discussion covers important reasons for developing faculty competence in technology applications, significant barriers to faculty development in this area, and several strategies designed to overcome these barriers.

Adaptation, Psychological↗
PubMed2001

Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression.

TEL is a transcriptional repressor that is a frequent target of chromosomal translocations in a large number of hematalogical malignancies. These rearrangements fuse a potent oligomerization module, the SAM domain of TEL, to a variety of tyrosine kinases or transcriptional regulatory proteins. The self-associating property of TEL-SAM is essential for cell transformation in many, if not all of these diseases. Here we show that the TEL-SAM domain forms a helical, head-to-tail polymeric structure held together by strong intermolecular contacts, providing the first clear demonstration that SAM domains can polymerize. Our results also suggest a mechanism by which SAM domains could mediate the spreading of transcriptional repression complexes along the chromosome.

Amino Acid Sequence↗
PubMed2000

The human T-cell leukemia virus type I (HTLV-I) X region encoded protein p13(II) interacts with cellular proteins.

Interactions between the Human T-cell leukemia virus type I (HTLV-I) gene product p13(II) and cellular proteins were investigated using the yeast two-hybrid system. Variant forms of p13(II) were derived from two HTLV-I molecular clones, K30p and K34p, that differ in both virus production and in vivo and in vitro infectivity. Two nucleotide differences between the p13 from K30p (p13K30) and K34p (p13K34) result in a Trp-Arg substitution at amino acid 17 and the truncation of the 25 carboxyl-terminal residues of p13K34. A cDNA library from an HTLV-I-infected rabbit T-cell line was screened with p13K30 and p13K34 as bait. Products of two cDNA clones, C44 and C254, interacted with p13K34 but not with p13K30. Interactions were further confirmed using the GST-fusion protein coprecipitation assay. Sequence analysis of C44 and C254 cDNA clones revealed similarities to members of the nucleoside monophosphate kinase superfamily and actin-binding protein 280, respectively. Further analysis of the function of these two proteins and the consequence of their interaction with p13 may help elucidate a role for p13 in virus production, infectivity, or the pathogenesis of HTLV-I.

Amino Acid Sequence↗
PubMed1999

Invariant or highly conserved TCR alpha are expressed on double-negative (CD3+CD4-CD8-) and CD8+ T cells.

TCR alpha (TCRA) expression was examined in RNA samples from PBMC and isolated populations of CD4+, CD8+, and DN T cells from 15 healthy individuals. The expressed TCR repertoire was surveyed using spectratype analysis, a technique that displays the distribution of complementarity determining region 3 (CDR3) lengths for each TCRAV gene family. The results revealed the presence of unusual populations of double-negative (DN; CD4-CD8-CD3+) T cells that express invariant or conserved TCRAV4A, AV7, AV19, and AV24 chains. Each of the conserved TCRA families was over-represented in >70% of the individuals studied, and all individuals expressed at least one of the over-represented TCRAV families. Over-represented conserved AV4A or AV7 sequences were also present in CD8+ T cells from most donors. The extent of TCRA sequence conservation is unparalleled. TCRAV4A, AV19, and AV24 sequences were invariant, although AV4A and AV19 transcripts contained N region additions. TCRAV24 transcripts derived from the direct juxtaposition of V and J gene segments. TCRAV7 sequences showed some diversity in two amino acids encoded at junctions of V and J gene segments. Although derivation of DN T cells with conserved TCRA chains is puzzling, the wide-spread expression of these unusual cells suggests an important function.

Adult↗
PubMed1999

Contributions of CD4+, CD8+, and CD4+CD8+ T cells to skewing within the peripheral T cell receptor beta chain repertoire of healthy macaques.

Diversity in the peripheral T cell receptor repertoire of rhesus (Macaca mulatta) and pig-tailed macaques (Macaca nemestrina) has been studied by examining the profile of CDR3 lengths in TCR beta chains. Expressed CDR3 length distribution profiles for individual TCRBV families were obtained from total peripheral blood mononuclear cells (PBMC) and T cell subsets isolated from PBMC. These studies reveal that the T cell receptor repertoire of PBMC from healthy macaques often exhibits skewing in TCRBV family CDR3 profiles. The skewing of TCRBV family CDR3 profiles was evident as discrete expanded length(s) and was detected in up to 50% of the PBMC profiles. Analyses of separated T cell populations demonstrated that the CD8+ T cell subset was responsible for the majority of observed skewing in CDR3 length profiles. However, CD4+ T cells were also shown to contribute to the skewed peripheral PBMC repertoire in these animals. While certain TCRBV families frequently displayed skewed profiles, there was no concordance in the particular CDR3 lengths expanded among the different animals. Furthermore, an additional feature of the peripheral blood of the animals studied was the presence of an unusual population of extrathymic CD4 and CD8+ (double-positive) T cells (up to 9.6% in the PBMC of rhesus macaques). The double-positive T cells could be differentiated from CD4 single-positive and CD8 single-positive T cells by their increased surface expression of LFA-1 and decreased CD62L expression. The percentage of the double-positive T cells was higher in rhesus than pig-tailed macaques and contributed substantially to the peripheral T cell repertoire.

Animals↗
PubMed1999

Polymorphism of human CD1 genes.

Human CD1 genes have been reported to be invariant or to show limited polymorphism. Recently, certain functions of CD1 antigens have been described to include the presentation lipid and glycolipid antigens. These observations prompted a thorough survey of the genetic polymorphism in the five human CD1 genes (CD1a-CD1e). Using polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) combined with sequence analyses, exons 2 and 3 from CD1a-CD1e were characterized from a total of 110 unrelated healthy donors. Results showed that all five genes (CD1a-CD1e) are polymorphic in exon 2. Substitutions in CD1b and CD1c are silent, whereas, substitutions in CD1a, CD1d and CD1e result in amino acid replacements in the deduced protein products. CD1a and CD1e polymorphisms are prevalent in the population. The substitutions in CD1a have characteristics that may influence interactions with beta2-microglobulin beta2-m) or accessory molecules. The substitution in CD1e is located in the region predicted to interact with ligands and may differentially impact the ability of CD1e alleles to bind antigen.

Amino Acid Sequence↗
PubMed1998

Genes in the pX region of human T cell leukemia virus I influence Vav phosphorylation in T cells.

Human T cell leukemia virus I (HTLV-I) causes acute leukemic disease in a low percentage of infected individuals through obscure mechanisms. Our studies compare two rabbit HTLV-I-infected T cell lines: one, RH/K34, causes lethal experimental leukemia and the other, RH/K30, mediates asymptomatic infection. We show herein that the product of the protooncogene vav is constitutively Tyr-phosphorylated in RH/K34 but not in RH/K30. A role for the retrovirus in phosphorylation of Vav was assigned by transfection experiments with molecular clones of HTLV-I derived from the two lines. The HTLV-I molecular clone from RH/K30, but not that from RH/K34, down-regulates Vav phosphorylation in a Herpesvirus ateles-transformed T cell line. Use of recombinant virus clones revealed that a pX region sequence differing by two nucleotides between the two clones mediates this down-regulation. Because Vav is involved in T cell signaling and Vav phosphorylation occurs upon activation of T cells, control of the activation state of Vav by viral proteins may relate to the leukemogenic potential of certain HTLV-I-infected cells.

Animals↗
PubMed1998

[Nerve growth factor and neurological diseases].

INTRODUCTION: The effects of Nerve Growth Factor (NGF) within and outside the nervous system have been amply discussed in recent decades. Recently clinical studies have shown the effectiveness of this growth factor in the treatment of neurodegenerative disorders. This clinical use makes it necessary to have sensitive, specific methods available to permit measurement of the level of this protein and to determine how it behaves during the course of treatment. OBJECTIVE: To describe the measurement of NGF levels in human serum using an immunoenzymatic method and evaluating the levels of this protein in some neurological disorders. Materials and methods. NGF levels were measured in the serum of healthy persons and in patients with Alzheimer's disease (AD) Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's chorea (HC) using a double site immune-enzymatic assay. Murine 27/21 anti-beta-NGF monoclonal antibody was used as the antibody to cover the plate and as conjugate. RESULTS: Adding a block pass to the method, in which the sample was incubated with an excess of 27/21 antibody effectively reduced the signal observed in the immuno-enzymatic assay. A moderate reduction in beta-NGF levels was seen in the serum of patients with ALS and MS. There was a statistically significant reduction in the patients who were carriers of PD and HC. CONCLUSIONS: The significant reduction in NGF levels in patients with PD and HC may be associated with a disorder in the use of this protein in central and peripheral tissues.

Aged↗
PubMed1997

The human T cell receptor repertoire utilized in response to HBsAg.

The complexity of the T cell receptor beta (TCRB) chain repertoire utilized in the recognition of recombinant hepatitis B surface antigen (HBsAg) was investigated. T cell lines were derived from two individuals vaccinated with Recombivax-HB and the TCRB repertoire was characterized by spectratype analysis, a molecular technology based on the differential size display of the complementarily determining region 3 (CDR3) of the TCRB chain. In contrast to the Gaussian distribution of CDR3 lengths observed for peripheral blood mononuclear cells (PBMCs), highly restricted patterns of CDR3 lengths were observed for most TCRB variable gene families in HBsAg-specific T cell lines (TCL). Although similarities in the repertoire of TCL derived from the two donors were noted, each TCL presented an unique profile of CDR3 length diversity. Among the TCR used by the two donors, no CDR3 sequence identity within or between TCRBV families was observed. Additionally, conservation of specific amino acids at homologous positions of the CDR3s was not evident. The T cell repertoire in response to HBsAg is oligoclonal, involves multiple TCRBV families and is individually specific.

Adult↗
PubMed1997

Perhexiline improves symptomatic status in elderly patients with severe aortic stenosis.

BACKGROUND: The prognosis of severe symptomatic aortic stenosis is poor without aortic valve replacement, with no previous reports of beneficial effects of any medical treatment on either symptoms or outcome. However, this condition is increasingly a disease of the elderly and cardiothoracic surgery is associated with significant mortality and morbidity in this group. AIMS: We postulated that perhexiline, a novel anti-ischaemic agent with an oxygen-sparing metabolic effect in the myocardium (via inhibition of carnitine palmitoyltransferase-1) and no adverse haemodynamic effects, may improve symptomatic status in elderly patients with severe aortic stenosis. We report here our initial experience with perhexiline treatment in such patients. METHODS: Elderly patients with symptomatic severe aortic stenosis, who were deemed unsuitable for aortic valve replacement, were treated with perhexiline, the drug dosage titrated according to steady state plasma perhexiline concentrations. NYHA functional class was determined prior to and three months following commencement of perhexiline, and changes were analysed using McNemar's test. RESULTS: Fifteen patients, age range 73-87, were followed for up to 30 months (median 18 months). Symptomatic status improved in 13 of the 15 patients over the first three months of perhexiline therapy (p < 0.01), five patients becoming asymptomatic. Twelve month actuarial survival was 80% (95% CI = 57, 100). Perhexiline was well tolerated, with no withdrawals due to toxicity or deteriorating clinical status. CONCLUSION: Therapy with perhexiline was associated with a marked improvement in clinical status in this group of elderly patients with severe aortic stenosis.

Aged↗
PubMed1997

[Neuronal toxicity of human recombinant interleukin-2 in rats. Morphological and behavioral validation].

INTRODUCTION AND OBJECTIVE: The memory impairment which accompanies the aging process is a manifestation of diminished cognitive function. This is intimately related to neuropathological and biochemical changes in cholinergic areas of central nervous system (CNS). Cytokines, first described as immunoregulators, are also implied in defense reactions of the brain. Some studies on the action of IL-2 on the CNS suggest an action blocking the release of acetylcholine in the hippocampus. MATERIAL AND METHODS: We have studied the possible central neurotoxic effect of this soluble factor using the chronic intraperitoneal infusion of human recombinant IL-2 (hr-IL 2) to young and old Sprague Dawley rats. RESULTS AND CONCLUSIONS: The results do not show an in vivo action of IL-2 on the cholinergic function but are consistent with the probable role of this cytokine in the senescent cognitive impairment, in particular the age-related loss of spatial memory and/or during the evolution of neurodegenerative related process.

Acetylcholine↗
PubMed1996

Molecular defects in TCRBV genes preclude thymic selection and limit the expressed TCR repertoire.

A prerequisite for the assembly of a functional TCR is the rearrangement of gene segments to result in in-frame transcripts that can vary in length across the CDR3 region. Selection for in-frame 3-bp spaced rearrangements is observed for functional TCRB genes in thymocyte DNA and mRNA transcripts from PBMC. Previous analyses of the expressed human TCRBV gene repertoire have suggested that BV10S1 and BV19S1 gene segments may be expressed at very low levels or not at all in some individuals. CDR3 size analysis for BV10 and BV19 transcripts and thymic DNA rearrangements revealed no such selection of in-frame 3-bp spaced rearrangements. Comparison of the BV19 leader intron sequence with consensus 5'-splice signal sequences suggested that the mature mRNA for this gene would contain the unspliced leader intron. Sequencing of BV19 transcripts from PBMC confirmed that the intron was not spliced, resulting in a predicted translation product that terminates prematurely. Both genomic DNA and mRNA were analyzed for the BV10 gene. The leader sequence contained a single extra base, which would result in a shift in the V region reading frame upon conventional mRNA splicing. This gene is predicted to be nonfunctional due to the presence of a stop codon in the V gene segment just after the splice signal. A splice variant that uses an alternative 3'-splice site further downstream in the V region was also detected. This variant is predicted to be nonfunctional due to the presence of an in-frame stop codon in the V region. These processing defects are sufficient to abrogate positive selection. Therefore, the conclusions drawn from previous studies of the expressed T cell repertoire in normal and disease states based on the presumed functional status of these two genes need to be reassessed.

Base Sequence↗
PubMed1996

Infectivity of chimeric human T-cell leukemia virus type I molecular clones assessed by naked DNA inoculation.

Two human T-cell leukemia virus type I (HTLV-I) molecular clones, K30p and K34p were derived from HTLV-I-infected rabbit cell lines. K30p and K34p differ by 18 bp with changes in the long terminal repeats (LTRs) as well as in the gag, pol, and rex but not tax or env gene products. Cells transfected with clone K30p were infectious in vitro and injection of the K30p transfectants or naked K30p DNA into rabbits leads to chronic infection. In contrast, K34p did not mediate infection in vitro or in vivo, although the cell line from which it was derived is fully infectious and K34p transfectants produce intact virus particles. To localize differences involved in the ability of the clones to cause infection, six chimeric HTLV-I clones were constructed by shuffling corresponding fragments containing the substitutions in the LTRs, the gag/pol region and the rex region between K30p and K34p. Cells transfected with any of the six chimeras produced virus, but higher levels of virus were produced by cells transfected with those constructs containing the K30p rex region. Virus production was transient except in cells transfected with K30p or with a chimera consisting of the entire protein coding region of K30p flanked by K34p LTRs; only the transfectants showing persistent virus production mediated in vitro infection. In vivo infection in rabbits following intramuscular DNA injection was mediated by K30p as well as by a chimera of K30p containing the K34p rex gene. Comparisons revealed that virus production was greater and appeared earlier in rabbits injected with K30p. These data suggest that several defects in the K34p clone preclude infectivity and furthermore, provide systems to explore functions of HTLV-I genes.

Animals↗
PubMed1996

Enantioselective distribution of verapamil and norverapamil into human and rat erythrocytes: the role of plasma protein binding.

In this in vitro study, the distribution of the enantiomers of verapamil (VER) and its active metabolite, norverapamil (NOR), into the red blood cells (RBCs) of humans and rats was investigated using a chiral liquid chromatographic assay. When plasma was replaced with buffer, the distribution of VER and NOR enantiomers into both human and rat RBCs was substantial (RBC:blood concentration ratios, 1.39-1.79), non-stereoselective, concentration (125-1000 ng mL-1) linear, and species independent. However, in the presence of plasma, the RBC distribution of VER and NOR was stereoselective, with opposite stereoselectivity for human (S > R) and rat (R > S) blood. Additionally, the presence of plasma caused a reduction in the extent of RBC distribution for both VER and NOR enantiomers and in some cases resulted in nonlinearity in the RBC distribution of the enantiomers. Plasma protein binding studies revealed opposite stereoselectivity in the free fractions in human (S > R) and rat (R > S) plasma for both VER and NOR. These data suggest that the stereoselective protein binding is responsible for the apparent stereoselectivity in the RBC distribution of VER and NOR. The data are also in agreement with the opposite stereoselectivity in the plasma concentrations of VER observed in vivo in rats and humans.

Animals↗
PubMed1995

Susceptibility to Reiter's syndrome is associated with alleles of TAP genes.

OBJECTIVE: Although HLA-B27 is strongly associated with susceptibility to Reiter's syndrome (RS), recent data suggest that an additional modifying or susceptibility gene(s) acts in concert with HLA-B27 to contribute to disease pathogenesis. The recently described TAP genes (transporters associated with antigen processing) are potential candidates because they are polymorphic and their function is to transport antigenic peptides to be loaded in HLA class I molecules. METHODS: TAP1 and TAP2 alleles were determined for 34 patients with RS (28 HLA-B27 positive, 6 HLA-B27 negative), and their frequencies were compared with those observed for 52 HLA-B27 positive and 80 random disease-free control subjects. RESULTS: The allele frequency of TAP1C was greater in patients with RS (8 of 62, 13%) than in random controls (5 of 160, 3%) (P = 0.009). The frequency of TAP2A was greater in RS patients (51 of 66, 77%) than in random controls (88 of 160, 55%) (P = 0.002); likewise, the frequency was greater in HLA-B27 positive RS patients (41 of 54, 76%) than in HLA-B27 positive disease-free controls (49 of 94, 52%) (P = 0.004). Furthermore, the TAP2A allele was present in all RS patients (100%), whereas TAP2A was present in 79% (63 of 80) of the random controls (P = 0.003). CONCLUSION: The association observed between TAP alleles and RS is independent of the presence of HLA-B27, and despite the physical proximity of TAP and HLA class II genes, linkage disequilibrium does not account for the observed associations between TAP and RS. Thus, TAP genes are genetically separated but functionally linked to class I genes, and both contribute to susceptibility to RS.

ATP-Binding Cassette Transporters↗
PubMed1995

Dose dependency of the kinetics of dextrans in rats: effects of molecular weight.

The effects of dose on the serum and tissue kinetics of high and low molecular weight (M(r)) dextrans were studied in rats. Single intravenous (iv) doses of 1, 25, or 100 mg of fluorescein-labeled dextrans with average M(r) of approximately 4 kD (FD-4) or 150 kD (FD-150) per kilogram of body weight were administered to rats, and serum, urine, and various tissues were collected over time. The samples were analyzed by a sensitive and specific chromatographic method. For FD-150, the area under the serum concentration-time curves (AUCs) increased disproportionately when the dose was increased from 1 to 100 mg/kg; the dose-corrected AUCs were 50.1 +/- 1.9, 85.9 +/- 2.4, and 122 +/- 3 micrograms.h/mL for the doses of 1, 25, and 100 mg/kg, respectively (p < 0.05). This increase in the dose-corrected AUCs was associated with a high and nonlinear accumulation of FD-150 in the liver; that is, the percent dose recovered in the liver decreased from 68.5 +/- 2.4% to 41.5 +/- 3.4% when the dose was increased from 1 to 100 mg/kg (p < 0.05). On the other hand, the serum kinetics of FD-4 exhibited dose independence [the dose-corrected AUCs were 2.38 +/- 0.04, 2.19 +/- 0.07, and 2.30 +/- 0.07 microgram.h/mL for the doses of 1, 25, and 100 mg/kg, respectively (p > 0.05)]. This dose independence was attributed to a high and linear excretion of FD-4 into urine as indicated by the percent doses of FD-4 excreted into urine [i.e., 82.0 +/- 1.8, 78.7 +/- 4.4, and 82.2 +/- 7.2 for the doses of 1, 25, and 100 mg/kg, respectively (p > 0.05)].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗