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Biomedical subjects

S McGuire

Publications and source records attributed to S McGuire.

At least 19 recordsLinked to original sources
PubMed2002

CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours.

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.

Adult↗
PubMed2001

Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson's disease.

High levels of both endocannabinoids and endocannabinoid receptors are present in the basal ganglia. Attention has recently focused on the role of endocannabinoids in the control of movement and in movement disorders of basal ganglia origin such as Parkinson's disease. We investigated CB1 cannabinoid receptor mRNA expression in the reserpine-treated rat model of Parkinson's disease using in situ hybridization. Reserpine treatment caused a topographically organized reduction in CB1 receptor mRNA expression in the striatum (ranging from 11.6% medially to 53.6% laterally and dorsally). No change in CB1 receptor mRNA expression was observed in the cerebral cortex or septum. This reduction in CB1 receptor mRNA expression may be secondary to increased endocannabinoid stimulation of the receptor as increased basal ganglia endocannabinoid levels have been shown to occur in this model of Parkinson's disease. The data support the idea that cannabinoid receptor antagonists may provide a useful treatment for the symptoms of Parkinson's disease.

Animals↗
PubMed2001

Germline mutations in TGM2 do not contribute to coeliac disease susceptibility in the Swedish population.

OBJECTIVE: Coeliac disease (CD) shows a strong genetic predisposition involving HLA-DQ2 and non-HLA components. Tissue transglutaminase, encoded by TGM2, occupies a central role in the CD pathogenesis, necessary for the deamidation of specific glutamine residues of alpha-gliadin creating a T-cell epitope that binds with increased affinity to DQ2. To investigate whether germline mutations in TGM2 contribute to disease susceptibility we have carried out a comprehensive analysis of the gene in 52 patients with CD. DESIGN: Blood samples were collected from 52 children with biopsy proven CD attending one Swedish centre. DNA was extracted from lymphocytes and all exons and intron-exon boundaries of the TGM2 gene and the alternatively spliced form of the gene were screened for mutations. METHODS: Mutational analysis was undertaken by a combination of conformational specific gel electrophoresis and direct sequencing. RESULTS: Three novel polymorphisms were identified but no pathogenic mutations were detected. CONCLUSIONS: There is no evidence from this study that mutations in TGM2, which lead to an altered protein, contribute to CD susceptibility.

Adolescent↗
PubMed2001

Quantitative analysis of intratumoral infusion of color molecules.

Intratumoral infusion has a potential for improving distribution of drugs. To optimize the infusion, we developed a novel technique to quantify the distribution volume of color molecules (Vd) in solid tumors. Evans blue-labeled albumin was infused locally with the use of a needle into a rat fibrosarcoma ex vivo under different pressures. After the infusion, tumor tissues were sectioned serially into thin slices. The blue area in each slice was quantified with the use of the newly developed technique. The Vd was calculated based on the blue area and the slice thickness. Our data showed that infusion pressure and volume (V(i)) had significant effects on Vd. The median of Vd/V(i) decreased from 2.99 to 1.79 when infusion pressure was increased from 50 to 163 cmH2O, presumably due to retardation of convective transport. In addition, the coefficient of variation in Vd/V(i) was increased from 0.13 at 50 cmH2O to 0.64 at 163 cmH2O. The dependence of Vd/V(i) and its variation on infusion pressure suggests that 1) infusion-induced tissue deformation is unpredictable and 2) both the unpredictability and the interstitial retardation of convective transport increase with infusion pressure.

Animals↗
PubMed2000

Molecular and cytogenetic analysis of lymphoblastoid and colon cancer cell lines from cotton-top tamarin (Sagiunus oedipus).

The cotton-top tamarin (CTT) (Sagiunus oedipus) has been used as an animal model to investigate the etiology and pathophysiology of several human diseases, including ulcerative colitis and its associated colorectal carcinoma (CRC). Little is known, however, about genetic synteny between CTT and humans, and about chromosome aberrations in CTT CRC. To address these issues, we have analyzed CTT lymphoblastoid and CRC cell lines using cytogenetics, fluorescence in situ hybridization (Zoo-FISH), and direct sequencing. The CTT lymphocytes had pseudodiploid chromosomes of 46. The CTT CRC cells showed near-diploid chromosomes of 45. Several clonal structural aberrations were observed, including der(1), a marker chromosome, and double minutes. Zoo-FISH using human chromosome 2, 3, 5, 6, 9, 11, 13, 15, 16, 17, 19, 22, and X paints identified homologous chromosomes and subchromosomal regions in the CTT genome. Fluorescence in situ hybridization with human telomeric probe also detected a homologous sequence in CTT genome. Direct sequencing of CTT genomic DNA using primers amplifying exons 4 and 15 of the human APC gene identified DNA sequences in CTT genome with 99% and 95% homology, respectively. These results provide a basis for further comparative studies of CTT and human genome.

Animals↗
PubMed2000

Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset model of Parkinson's disease.

Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Increased immunoreactivity of glutathione-S-transferase in the retina of Swiss Webster mice following inhalation of JP8 + 100 aerosol.

The current study was designed to determine whether exposure of mice to aerosolized jet fuel (JP8 + 100) resulted in changes in the cellular distribution or immunoreactivity of the enzyme glutathione S-transferase (GST), a biomarker of toxicant exposure. Male mice were exposed to JP8 + 100 at 1000 mg/m3 or 2500 mg/m3 in aerosol for 1 h per day for 7 days and then sacrificed. The retinas were studied by immunohistochemical methods. The JP8 + 100 exposure caused a marked increase in the immunoreactivity of anti-GSTM antibodies with the radial glial cells of the retina, the Müller cells. These results are consistent with the hypothesis that JP8 + 100 acts as a toxicant to mouse retina by permitting the flux of materials across the blood-retina barrier. The findings are relevant to humans because recent studies indicate that Air Force personnel assigned to clean and maintain fuel pods may be exposed to concentrations of JP8 + 100 exceeding 1000 mg/m3.

Aerosols↗
PubMed2000

Neuronal platelet-activating factor receptor signal transduction involves a pertussis toxin-sensitive G-protein.

In most nonneural systems, platelet-activating factor (PAF) receptor effects are mediated by G-proteins that are often pertussis toxin-sensitive. The activation of pertussis toxin-sensitive G-proteins linked to PAF receptors results in the mobilization of intracellular calcium, at least in part, through the second messenger inositol triphosphate. We have sought to determine if a pertussis toxin-sensitive G-protein is involved in the PAF receptor-mediated phenomena of growth cone collapse and of synaptic enhancement in primary neuronal culture. Using infrared differential interference contrast microscopy and patch-clamp recording techniques, pertussis toxin, but not the inactive B oligomer of the toxin, was found to block both the growth cone collapse and the enhanced synaptic release of excitatory transmitter induced by a nonhydrolyzable PAF receptor agonist, making it likely that Go, Gq, or Gi is the G-protein transducer of PAF receptors in primary neurons. We believe that PAF acts directly on neuronal receptors, which are linked to pertussis toxin-sensitive G-proteins, on the tips of developing neurites, and on presynaptic nerve terminals, leading to growth cone collapse and enhanced synaptic release of transmitter.

Animals↗
PubMed2000

Genetic and environmental contributions to loneliness in children.

This report presents the results of the first behavioral genetic studies of children's loneliness. Data were collected using both an adoption design and a twin-sibling design. As part of the Colorado Adoption Project, 133 sibling pairs (69 biologically related pairs and 64 unrelated pairs in adoptive families) completed a general loneliness scale when they were 9, 10, 11, and 12 years old. As part of the San Diego Sibling Study, 142 sibling pairs (22 monozygotic twin, 40 dizygotic twin, and 80 full-sibling pairs) between the ages of 8 and 14 years old completed a scale assessing loneliness at school. Both studies showed significant heritability and nonshared environmental influences for children's loneliness.

Adolescent↗
PubMed1998

Co-occurrence of depressive symptoms and antisocial behavior in adolescence: a common genetic liability.

Recent reviews of research on child and adolescent psychopathology have highlighted the consistently high rates of co-occurring dimensions of psychopathology, particularly between internalizing and externalizing disorders, and have suggested that further research examining the causes of co-occurring syndromes is needed. The authors examined this question in a national sample of 720 same-sex adolescent siblings between 10 and 18 years of age consisting of monozygotic and dizygotic twins, full siblings, half siblings, and unrelated siblings. Composite measures of adolescent and parent reports and observational measures of depressive symptoms and antisocial behavior were subjected to behavioral genetic models that examine the genetic and environmental influences on individual differences in each dimension as well as in the co-occurrence between dimensions. Results indicated that approximately half of the variability in depressive symptoms and antisocial behavior is attributed to genetic factors; shared and nonshared environmental influences were also significant. The co-occurrence of depressive and antisocial symptoms was explained by genetic and shared and nonshared environmental influences. Specifically, approximately 45% of the observed covariation between depressive and antisocial symptoms could be explained by a common genetic liability. Results are interpreted in light of contribution of genetic studies to debates on child and adolescent psychopathology.

Adolescent↗
PubMed1998

Global migration and health: ecofeminist perspectives.

Global migration is occurring at an unprecedented rate. The phenomenon of migration is complex and poorly understood by most people in countries who host immigrants. People migrate for numerous reasons related to social, economic, political, cultural, and physical environmental conditions formed by historical antecedents. Migrating people, especially vulnerable women and children, are exposed to numerous health hazards, a situation calling for a response from nursing. To respond effectively nursing needs knowledge development of global migration and health that includes the precursors to migration in addition to the postmigration experience where nurses encounter immigrants. Ecofeminist perspectives allowing for reflection on historical determinants and interlocking socioeconomic, political, and environmental conditions are used as a prism to examine global migration and health.

Ecology↗
PubMed1997

Increased levels of glutathione S transferases and appearance of novel alpha class isoenzymes in kidneys of mice exposed to mercuric chloride. I. Biochemical and immunohistochemical studies.

Glutathione S transferases (GST) are a family of enzymes that detoxify electrophilic xenobiotics. This enzyme family was examined in kidneys of mice exposed to mercuric chloride, a known nephrotoxin, because GST have been shown to protect cells against toxicant-induced damage and may serve as biomarkers for toxicant exposure. The purpose of this study was to determine the effect of mercuric chloride on GST activity, isoenzyme levels, and cellular localization in the kidney of Swiss Webster mice. The cellular localizations of alpha, mu, and pi class GST in the kidneys of control and mercuric chloride treated mice were studied immunohistochemically. The GST isoenzyme levels were measured by high-performance liquid chromatography. The mice treated with mercuric chloride had (1) increased amounts of GSTA1/A2 protein in kidney homogenates as compared with controls when analyzed by chromatography and electrophoresis; (2) two new isoforms of the alpha isoenzyme in kidney as demonstrated by Western blot, polyacrylamide gel electrophoresis, and high-performance liquid chromatography, and (3) increased reactivity between antibodies, against GSTA1/A2 or GSTM1 isoenzymes, and cells in the proximal and distal renal tubules as shown by immunohistochemical techniques. The authors conclude that the GSTA1/A2 may protect those cells in the proximal and distal tubules of the renal cortex from toxicant effects of mercuric chloride. This would be one general mechanism for cell protection against a wide variety of toxicants including heavy metals and halogenated aromatics.

Animals↗
PubMed1996

Cellular localization of glutathione S-transferases in retinas of control and lead-treated rats.

PURPOSE: The glutathione S-transferases (GSTs) constitute a family of cytosolic isoenzymes that are involved in the detoxication of electrophilic xenobiotics. The purpose of this investigation was to determine the concentration and cellular distribution of the various classes of cytosolic GSTs in the retina of control and triethyl lead-treated rats and thereby reveal mechanisms by which the cells are protected from damage by lead and other toxicants. METHODS: The regional and cellular distribution of cytosolic GSTs in rat retina of control and lead-treated animals was studied by immunohistochemistry. Enzyme activity was determined by a spectrophotometric assay. The GST subunit distribution of the entire retina of control and lead-treated animals was determined and quantified by reverse-phase high-performance liquid chromatography (HPLC). RESULTS: Polyclonal antibodies against mu-class Yb1 and Yb2 GSTs were primarily and strongly reactive with Müller cells and their processes. Anti-Yb1 also reacted with photoreceptor outer segments. Antibodies against two alpha-class GSTs (Ya and Yk) were strongly reactive with Müller cells and their cell processes. Antibodies against Yp and Yc GSTs were reactive with amacrine cells and their processes, and anti-Yp antibodies were reactive against retinal ganglion cells. Treatment of rats with triethyl lead caused diminished reactions of the antibodies against Yb1 and Yp GSTs and increased reactions of anti-Ya with its retinal targets, whereas the total GST activity did not change significantly. CONCLUSIONS: The positive reaction between the amacrine neuronal cells of retina and the anti-Yp and anti-Yc class antisera broadens the class of neurons that contains GST enzymes protective against toxicant insult. It also has been shown that Müller cells are strongly immuno-positive for Yb1 and Yb2 GST. Because these phagocytic cells are in contact with the vitreous fluid and proximate to pigmented epithelial layer of the eye, these GSTs may protect the cells from toxicants accumulated from this fluid.

Animals↗
PubMed1995

Interactions of a Rel protein with its inhibitor.

Cactus, a Drosophila homologue of I kappa B, binds to and inhibits Dorsal, a homologue of the p50 and p65 components of NF-kappa B. We describe experiments in yeast with various Dorsal and Cactus derivatives showing that Cactus blocks the DNA binding and nuclear localization functions of Dorsal. In contrast, Dorsal's transcriptional activating region is functional in the Dorsal-Cactus complex. We identify two Dorsal mutants, Dorsal C233R and Dorsal S234P, that escape Cactus inhibition in vivo, and we show that these mutants fail to interact with Cactus in vitro. From this and data of others, we identify the likely surface of Dorsal that binds Cactus. We also describe a modified PCR mutagenesis procedure, easier to use than conventional methods, that produces a library of high complexity.

Amino Acid Sequence↗
PubMed1995

Parent ratings of EAS temperaments in twins, full siblings, half siblings, and step siblings.

A twin/family design was used to explore genetic contributions to personality; to evaluate whether twins and nontwins yield different genetic results; and to test for the presence of contrast effects, the tendency of a rater to contrast one sibling with the other, thereby magnifying existing behavioral differences. The sample consisted of 708 adolescent same-sex sibling pairs from 10 to 18 years of age. Pairs included identical (monozygotic; MZ) and fraternal (dizygotic; DZ) twins, and full siblings in nondivorced families; and full, half, and unrelated siblings in stepfamilies. Mothers and fathers rated the temperament of their children on the EAS Temperament Survey (A. H. Buss & R. Plomin, 1984). Model-fitting analyses revealed significant genetic influences on each of the four EAS dimensions; however, for some dimensions, heritability estimates were significantly greater for twins than for nontwins. Overall, the data were best described by a sibling interaction model, which indicated significant contrast effects.

Adolescent↗
PubMed1994

Genetic and environmental influences on perceptions of self-worth and competence in adolescence: a study of twins, full siblings, and step-siblings.

Although it is generally assumed that the origins of adolescents' perceptions of self-competence lie in shared family environmental influences, the contributions of nonshared environmental or genetic influences have not been explored. We investigated sibling resemblance for perceived competence and self-worth in 720 adolescent pairs aged 10 to 18 years, using a twin, full sibling, and step-sibling design. Our goals were to assess the magnitude of shared and nonshared environmental influences and to disentangle resemblance due to shared genetic heritage from that due to shared environmental experiences. Shared environment was not significant for any of the scales. 4 of the subscales showed significant genetic influence: scholastic, social, physical, and athletic competence. We also explored possible sources of genetic influences on perceived competence. Bivariate models revealed common genetic variance between scholastic competence and vocabulary and social competence and sociability. These measures, however, did not account for all of the genetic variance in perceived social and scholastic competence.

Achievement↗