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Biomedical subjects

A Doherty

Publications and source records attributed to A Doherty.

At least 19 recordsLinked to original sources
PubMed2005

Measured versus reported parental height.

BACKGROUND: Parental height data are essential in the assessment of linear growth in children. A number of studies have documented inaccuracy in self-reported adult height. AIMS: To determine whether there is a tendency for men to overestimate and women to underestimate their height. METHODS: Heights of parents of children attending outpatient clinics were measured (MHt) and compared with reported heights (RHt). RESULTS: Two hundred parents (100 males; 100 females), mean (range) age 37.8 (20.8-69.3) years, were measured. Males overestimated height, with mean (SD) RHt-MHt 1.09 (1.96) cm, while females reported height relatively accurately, with RHt-MHt -0.09 (2.37) cm. CONCLUSIONS: The hypothesis that males overestimate height is confirmed. While the hypothesis that women underestimate is not supported, we recommend accurate measurement of both parents, given the considerable degree of individual variation in RHt-MHt for both sexes.

Adult↗
PubMed2002

Characterisation of the expression of a novel constitutive maize promoter in transgenic wheat and maize.

A novel constitutive promoter from the maize histone H2Bgene was recently identified. In this study, we characterised H2B promoter activity in both wheat and maize tissues using the gusA reporter gene and two synthetic versions of the pat (phosphinothricin acetyl transferase) selectable marker gene, namely mopat and popat. Analyses of transgenic plants showed that the H2B promoter is able to drive the expression of gusA to strong, constitutive levels in wheat and maize tissues. Using an H2B:mopat construct and phosphinothricin selection, we recovered transgenic wheat plants at efficiencies ranging from 0.3% to 7.4% (mean 1.6%), and the efficiency of selection ranged from 40% to 100% (mean 77.7%). In another application, H2B was combined with the maize Ubi-1 or the maize Adh-1 intron to drive the expression of mopat and popat. Transformation efficiencies with the Ubi-1 intron were between 1.4- to 16-fold greater than with the Adh-1 intron. However, the use of either of the introns was necessary for the recovery of transgenic plants. Mopat gave higher transformation efficiencies and induced higher levels of PAT protein in maize tissues than popat.

Acetyltransferases↗
PubMed2002

Detection and characterization of mechanisms of action of aneugenic chemicals.

A comprehensive evaluation of the genotoxic potential of chemicals requires the assessment of the ability to induce gene mutations and structural chromosome (clastogenic activity) and numerical chromosome (aneugenic activity) aberrations. Aneuploidy is a major cause of human reproductive failure and an important contributor to cancer and it is therefore important that any increase in its frequency due to chemical exposures should be recognized and controlled. The in vitro binucleate cell micronucleus assay provides a powerful tool to determine the ability of a chemical to induce chromosome damage. The application of an anti-kinetochore antibody to micronuclei allows their classification into kinetochore-positive and kinetochore-negative, indicating their origin by aneugenic or clastogenic mechanisms, respectively. The availability of chromosome-specific centromere probes allows the analysis of the segregation of chromosomes into the daughter nuclei of binucleate cells to evaluate chromosome non-disjunction. Quantitative relationships between the two major causes of aneuploidy, chromosome loss and non-disjunction, can be determined. The mechanisms leading to chromosome loss and non-disjunction can be investigated by the analysis of morphological and structural changes in the cell division apparatus by the application of specific stains and antibodies for various cell division components. We illustrate such analyses by the demonstration of the interaction of the monomer bisphenol-A with the centrosome of the mitotic spindle and the folic acid antagonist pyrimethamine with the centromeres of chromosomes. Both types of modifications lead to the induction of aneuploidy in exposed cells. Our studies also implicate the products of the p53 and XPD genes in the regulation of the fidelity of chromosome segregation at mitosis.

Aneuploidy↗
PubMed2001

Bladder substitution in women.

Bladder substitution in women with transitional cell carcinoma (TCC) is not a universally accepted procedure. There are many concerns, one of which is the potential risk of metachronous and synchronous urethral transitional cell carcinoma involvement. Another concern is that voiding dysfunction may be more frequent than in male patients. The numbers of female patients who have had this procedure are still small, and follow-up data are relatively brief. Thus, the true role for orthotopic bladder substitution in the female is still being evaluated. This paper reviews the data on this type of surgery in women, with emphasis on urethral TCC risk and on voiding dysfunction. Early results from a number of institutions are encouraging, particularly in correctly selected patients. Based on more than 15 years experience in an albeit small number of patients, we believe that if there is a functional external sphincter and tumor margins can be safely cleared, this form of surgery offers patients the best opportunity to preserve quality of life following cystectomy.

Carcinoma, Transitional Cell↗
PubMed2001

Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects.

In the present study, for the first time, PDE4 subtypes were identified and semi-quantified in both CD4 and CD8 lymphocytes from healthy and asthmatic individuals. CD4 and CD8 lymphocytes from healthy and mild asymptomatic asthmatic subjects (receiving beta-agonist therapy only) were isolated from peripheral venous blood using appropriate antibody coated paramagnetic beads. PDE4 subtypes and beta-actin were identified by digoxigenin (DIG)-labelling reverse transcriptase-polymerase chain reaction and semi-quantified by DIG-detection enzyme-linked immunosorbance assay. In CD4 and CD8 lymphocytes PDE4A, PDE4B and PDE4D were detected, with no significant differences observed between healthy and asthmatic groups. In CD8 lymphocytes, enzyme subtype expression was lower and showed more intersubject variability. In functional studies investigating the effects of various PDE inhibitors on PHA-induced proliferation of mononuclear cells from healthy and asthmatic subjects, CDP840 (0.03 - 10 microM), rolipram (0.1 - 10 microM) and theophylline (10 microM - 1 mM) inhibited PHA-induced proliferation of mononuclear cells from healthy and asthmatic subjects in a concentration-dependent manner, although no significant difference was observed between the groups investigated. In additional studies, total monocyte cyclic AMP PDE activity was investigated in cells isolated from asthmatic subjects both prior to and 24 h after allergen challenge. Total monocyte cyclic AMP PDE activity remained unaffected following challenge of asthmatic subjects with either house dust mite or cat dander and was inhibited in a concentration-dependent manner by rolipram (0.01 - 100 microM) both before and after allergen challenge.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

A community needs assessment for rural mental health promotion.

This paper describes the needs assessment phase of a mental health promotion programme for rural communities in Ireland. As part of a larger study encompassing four rural communities, a cross-sectional study of the mental health beliefs and perceptions of 1014 people was carried out. Employing a combination of interviewer-administered questionnaire and the vignette method, the needs assessment explores the levels of awareness, current practices, attitudes and stigma concerning depression and suicide among a randomly selected quota sample of community members. Lower levels of awareness, less confidence in dealing with mental health issues, negative attitudes to help-seeking and social stigma emerge as particular issues for men and the under 40 age group. Women were found to have more positive attitudes generally, were more likely to use informal social support networks and were more open about discussing mental health matters. The predominant interpretation of the depression vignette was to view it as a mental health problem with good prospects for recovery given appropriate help. Social relationships, negative thinking patterns and social stresses were perceived as being particularly important in explaining the origins of depression. The implications of the findings for planning the intervention phase of the project are considered.

Adult↗
PubMed2000

Rapid lupus autoantigen relocalization and reactive oxygen species accumulation following ultraviolet irradiation of human keratinocytes.

OBJECTIVE: In vitro treatment with ultraviolet B (UVB) induces relocalization of lupus autoantigens to the cell surface. We have addressed the relationship between autoantigen relocalization, accumulation of intracellular reactive oxygen species (ROS) and the induction of apoptosis following UVA and UVB exposure. METHODS: Human primary keratinocytes were exposed in vitro to doses of UVA and UVB equivalent to 0.01-4 times the minimal erythemal dose. The cellular locations of Ro60, Ro52, Sm, U2-B" and La were determined using monoclonal antibodies. ROS accumulation and apoptosis induction were assessed using the intracellular ROS probe 2'7'-dichlorodihydrofluorescein diacetate, and the viability stains Hoechst 33342 and propidium iodide. RESULTS: UV treatment induced the relocalization of all five autoantigens investigated and an accumulation of ROS. UVA and UVB induced necrosis and apoptosis, respectively. CONCLUSION: These data suggest that both UVA and UVB induce ROS within keratinocytes but have significantly different effects upon autoantigen relocalization and cell viability.

Antigens, Surface↗
PubMed2000

Genomic sequence analysis of Fugu rubripes CFTR and flanking genes in a 60 kb region conserving synteny with 800 kb of human chromosome 7.

To define control elements that regulate tissue-specific expression of the cystic fibrosis transmembrane regulator (CFTR), we have sequenced 60 kb of genomic DNA from the puffer fish Fugu rubripes (Fugu) that includes the CFTR gene. This region of the Fugu genome shows conservation of synteny with 800-kb sequence of the human genome encompassing the WNT2, CFTR, Z43555, and CBP90 genes. Additionally, the genomic structure of each gene is conserved. In a multiple sequence alignment of human, mouse, and Fugu, the putative WNT2 promoter sequence is shown to contain highly conserved elements that may be transcription factor or other regulatory binding sites. We have found two putative ankyrin repeat-containing genes that flank the CFTR gene. Overall sequence analysis suggests conservation of intron/exon boundaries between Fugu and human CFTR and revealed extensive homology between functional protein domains. However, the immediate 5' regions of human and Fugu CFTR are highly divergent with few conserved sequences apart from those resembling diminished cAMP response elements (CRE) and CAAT box elements. Interestingly, the polymorphic polyT tract located upstream of exon 9 is present in human and Fugu but absent in mouse. Similarly, an intron 1 and intron 9 element common to human and Fugu is absent in mouse. The euryhaline killifish CFTR coding sequence is highly homologous to the Fugu sequence, suggesting that upregulation of CFTR in that species in response to salinity may be regulated transcriptionally.

Amino Acid Sequence↗
PubMed2000

Global connections in a changing world: Romanian and U.S. nurses unite.

This article describes an international, interdisciplinary, university partnership project to collaborate with health professionals in the city of Cluj-Napoca, Transylvania, Romania, to improve the health status of Romanian workers. Academic and service-based public health nurses from the United States used the model of community competence in outlining the nursing aspect of the project. This model guided the assessment, objectives, collaborative activities, and the outcome evaluation of the project. The dimensions of the model (e.g., commitment, self-other awareness, articulateness, conflict accommodation, management of relations with larger society, and leadership) were used within the context of the political and social environment of the international community.

Community Health Nursing↗
PubMed2000

Antinociceptive effect of pregabalin in septic shock-induced rectal hypersensitivity in rats.

Pregabalin [S-(+)-3-isobutylgaba] is a novel compound under development for its analgesic, anxiolytic, and anticonvulsant properties, and its interaction with the alpha(2)delta-subunit of voltage-dependent Ca(2+) channels. In this study, we investigate the antinociceptive activity of pregabalin in a rat model of delayed visceral hyperalgesia induced by i.p. lipopolysaccharide (LPS) administration. LPS (Escherichia coli, serotype O111:B4) leads to a delayed lowering threshold (9-12 h) of abdominal contractions in response to rectal distension (RD) in awake rats surgically prepared for electromyography of abdominal muscles. This allodynic effect of LPS was blocked by morphine (0.3 mg/kg s.c.), and the action of morphine was antagonized by naloxone (2.5 mg/kg s.c.). A single i.p. (10, 30 mg/kg) and oral (1, 3, 10 and 30 mg/kg) treatment of pregabalin dose dependently suppressed LPS-induced rectal hypersensitivity. When administered 2 h before RD (but preceded 12 h by LPS injection), the oral dose of 10 mg/kg was effective both in the allodynic response induced by LPS and in the intensity of the nociceptive response related to RD. Pretreatment by either naloxone or bicuculline (a GABA(A) antagonist, 0.5 mg/kg i.p.) did not affect the antiallodynic effect of pregabalin. We conclude that pregabalin is a therapeutic candidate in the treatment of gut hypersensitivity not acting through GABA(A) and opiate receptors.

Analgesics, Non-Narcotic↗
PubMed1999

Correlation of the osteoblastic phenotype with prostate-specific antigen expression in metastatic prostate cancer: implications for paracrine growth.

The characteristic sclerotic appearance of bone metastases from prostate cancer is unexplained but could involve excess peritumoural activity of osteoblast mitogens such as the insulin-like growth factors (IGFs). Since prostatic metastases are distinguished by androgen-dependent secretion of prostate-specific antigen (PSA), a serine protease which cleaves extracellular IGF-binding proteins and thereby enhances the bioavailability of IGFs, the relationship was examined between tumour PSA expression and the osteoblastic phenotype. To this end, a cohort of 27 prostate cancer patients was evaluated to determine the relationship between serum PSA and radiographic bone lesion density at first presentation with metastatic disease. No linear correlation between absolute PSA levels and metastatic osteosclerosis was apparent. However, non-parametric statistical analysis revealed a highly significant link between low-PSA (<20 ng/ml) metastatic prostate cancer and osteolytic bone lesions (p<0.0001, chi(2)=21.5). This finding raises the possibility that the osteoblastic phenotype of prostate cancer derives in part from PSA-dependent proteolysis of IGF-binding proteins within bone matrix.

Bone Neoplasms↗
PubMed1999

Elimination of contaminant Escherichia coli chromosomal DNA from preparations of P1 artificial chromosome recombinants facilitates directed subcloning.

The subcloning of large inserts (>50 kbp) from P1-derived artificial chromosomes (PACs) was found to be hindered by the presence of contaminating Escherichia coli chromosomal fragments which, because of their smaller median size, are recovered preferentially as unwanted subclones. A significant fraction of contaminating DNA was seen to persist after conventional plasmid purification methods. We describe a rigorous protocol for eliminating the bulk of contamination that involves plasmid isolation on commercially available silica-based columns followed by three pulsed field gel electrophoresis steps. Using this, we were able to subclone 55, 85 and 90 kbp PAC inserts but failed to subclone a 195 kbp PAC insert. After surveying a range of DNA purification methods, we devised an optimised protocol that allowed us to subclone the 195 kbp insert. The optimised protocol, which reliably yields DNA with essentially no contaminating material, consists of plasmid isolation on silica-based columns followed by treatment with highly purified DNaseI and retrieval by electroelution of restriction-digested DNA electrophoresed on a single pulsed field gel. By inference it is applicable to the purification of large inserts from other single-copy plasmid vectors such as bacterial artificial chromosomes (BACs).

Chromosomes, Bacterial↗
PubMed1998

Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor.

A class of high-affinity inhibitors is disclosed that selectively target and irreversibly inactivate the epidermal growth factor receptor tyrosine kinase through specific, covalent modification of a cysteine residue present in the ATP binding pocket. A series of experiments employing MS, molecular modeling, site-directed mutagenesis, and 14C-labeling studies in viable cells unequivocally demonstrate that these compounds selectively bind to the catalytic domain of the epidermal growth factor receptor with a 1:1 stoichiometry and alkylate Cys-773. While the compounds are essentially nonreactive in solution, they are subject to rapid nucleophilic attack by this particular amino acid when bound in the ATP pocket. The molecular orientation and positioning of the acrylamide group in these inhibitors in relation to Cys-773 entirely support these results as determined from docking experiments in a homology-built molecular model of the ATP site. Evidence is also presented to indicate that the compounds interact in an analogous fashion with erbB2 but have no activity against the other receptor tyrosine kinases or intracellular tyrosine kinases that were tested in this study. Finally, a direct comparison between 6-acrylamido-4-anilinoquinazoline and an equally potent but reversible analog shows that the irreversible inhibitor has far superior in vivo antitumor activity in a human epidermoid carcinoma xenograft model with no overt toxicity at therapeutically active doses. The activity profile for this compound is prototypical of a generation of tyrosine kinase inhibitors with great promise for therapeutic significance in the treatment of proliferative disease.

Animals↗