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Biomedical subjects

A J Harris

Publications and source records attributed to A J Harris.

At least 19 recordsLinked to original sources
PubMed2001

Tissue interactions and antlerogenesis: new findings revealed by a xenograft approach.

Tissue interactions play a pivotal role in organogenesis. Here we describe a xenograft approach to investigate how heterotypic tissue interactions control antler formation in deer. Deciduous antlers grow from the apices of permanent protuberances, called pedicles. Histogenesis of pedicles depends on the antlerogenic periosteum (AP). Pedicles and growing antlers are made up of interior osseocartilage (a mixture of bone and cartilaginous tissue) and exterior skin. In a previous study we hypothesised that pedicle growth may result from mechanical interactions between the interior and exterior components whereas antler generation from a pedicle would involve molecules communicating between the interior and exterior components. To test this hypothesis, we subcutaneously transplanted AP of red deer (Cervus elaphus), either alone or with future pedicle skin, onto nude mice. The results showed that under the nude mouse skin, subcutaneously xenografted AP alone not only could form pedicle-shaped protuberances but also could differentiate into well-organised pedicle-like structures. The overlying mouse skin accommodated the expansion of the grafted AP by initial mechanical stretching and subsequent formation of new skin. Nude mouse skin was not capable of participating in antler tissue formation. However, grafted deer skin together with AP may have successfully rescued this failure after wounding, which highlights the necessity of the specificity of the overlying skin for antler tissue generation. Therefore, we conclude that it is the interaction between the antlerogenic tissue and the overlying skin that results in antlerogenesis: reciprocal mechanical interactions cause pedicle formation, whereas reciprocal instructive interactions induce first antler generation.

Animals↗
PubMed2001

A structured approach to evaluating change among sexual offenders.

Presently, there are no established scales that evaluate change in risk among sexual offenders. The Sex Offender Need Assessment Rating (SONAR) was developed to fill this gap. The SONAR includes five relatively stable factors (intimacy deficits, negative social influences, attitudes tolerant of sex offending, sexual self-regulation, general self-regulation) and four acute factors (substance abuse, negative mood, anger, victim access). The psychometric properties of the scale were examined using data previously collected by Hanson and Harris (1998, 2000). Overall, the scale showed adequate internal consistency and moderate ability to differentiate between recidivists and nonrecidivists (r = .43; ROC area of .74). SONAR continued to distinguish between the groups after controlling for well-established risk indicators, such as age, and scores on the Static-99 (Hanson & Thornton, 2000) and the Violence Risk Appraisal Guide (Quinsey, Harris, Rice, & Cormier, 1998).

Adult↗
PubMed1999

Differential protooncogene expression in Sprague Dawley and Fischer 344 rats during 1,2-dichlorobenzene-induced hepatocellular regeneration.

Significant differences in hepatotoxic injury of 1,2-dichlorobenzene (o-DCB) have been reported (Gunawardhana, L., Sipes, I.G., 1991. Dichlorobenzene hepatotoxicity strain differences and structure activity relationships. Adv. Exp. Med. Biol. 283, 731-734; Stine, E.R., Gunawardhana, L., Sipes, I.G., 1991. The acute hepatotoxicity of the isomers of dichlorobenzene in Fischer 344 and Sprague-Dawley rats: isomer specific and strain-specific differential toxicity. Toxicol. Appl. Pharmacol. 109, 472-481; Valentovic, M.A., Ball, J. G., Anestis, D., Madan E., 1993a. Acute hepatic and renal toxicity of dichlorobenzene isomers in Fischer 344 rats. J. Appl. Toxicol. 13, 1-7; Kulkarni, S.G., Duong, H., Gomila, R., Mehendale, H.M., 1996. Strain differences in tissue repair response to 1,2-dichlorobenzene. Arch. Toxicol. 70, 714-723. Kulkarni, S.G., Warbritton, A., Bucci, T., Mehendale, H.M., 1997. Antimitotic intervention with colchicine alters the outcome of o-DCB-induced hepatotoxicity in Fischer 344 rats. Toxicology. 120, 79-88). Although, hepatotoxic injury of o-DCB is greater in Fischer 344 (F344) when compared with Sprague Dawley (S-D) rats, this interstrain difference does not transcend into any difference in lethal effects of o-DCB. Interstrain difference in compensatory tissue repair has been suggested as the underlying mechanism for the lack of strain differences in lethality (Kulkarni et al., 1996; Kulkarni et al., 1997, see these refs. above). However, the mechanism(s) for this interstrain difference in tissue repair is (are) not currently understood. The objectives of the present study were (1) to investigate if the differences in compensatory tissue repair are reflected in differential protooncogene expression in S-D versus F344 rat livers and (2) to investigate if changes in protooncogene expression could explain the decrease and delay in tissue repair response beyond a threshold of 0.6 ml o-DCB/kg. Male S-D and F344 rats (8/9 weeks old) were administered either 0.6 or 1.2 ml o-DCB/kg and changes in expression of protooncogenes c-myc (immediate early) and Ha-ras (delayed early) were examined over a time course. Findings of this study indicate that the timing and extent of c-myc and Ha-ras expression varies in the two strains following administration of o-DCB. Thus, the timing and extent of compensatory liver regeneration that ensues following o-DCB administration in S-D and F344 rats is temporally concordant with the protooncogene expression in the two strains.

Animals↗
PubMed1999

Cortical origin of pathological pain.

Pain without accompanying tissue pathology poses a classic puzzle, presented in extreme form by phantom pain in a non-existent amputated limb. A clue to the origin of such pain is given by the recent discovery of a region of cortex active in response to incongruence between motor intention, awareness of movement, and visual feedback. Phantom-limb sensation, and repetitive strain injuries or focal hand dystonias in writers, musicians, or keyboard operators, are accompanied by plastic changes in sensorimotor cortex and by pathological pain. Disorganised or inappropriate cortical representation of proprioception may falsely signal incongruence between motor intention and movement, which results in pathological pain in the same way that incongruence between vestibular and visual sensation results in motion sickness.

Animals↗
PubMed1999

Measurement of calcium flux through ionotropic glutamate receptors using Cytostar-T scintillating microplates.

Human embryonic kidney cells (HEK293), expressing the human GluR4 receptor sub-unit of 2-amino-3-hydroxy-methylisoxazol-4-ylpropionic acid (AMPA) type non-NMDA receptors were used, in combination with Cytostar-T scintillating microplates, to develop an assay system for the screening of novel compounds with potential AMPA antagonistic characteristics. Agonist dose responses were measured using the agonists: AMPA; quisqualic acid; L-glutamic acid and kainic acid (KA), and EC50 values of 40, 10, 100 and 100 microM were estimated for each of the agonists, respectively. The AMPA receptor antagonists LY293558 and GYK152466 were tested and shown to inhibit agonist induced [45Ca] influx into the cells. An IC50 value of 600 microM was estimated for the competitive antagonist LY293558 and a value of 100 microM estimated for the non-competitive antagonist GYK152466. The developed assay system is homogeneous, allowing increased assay precision and speed. This allows the potential for automation of the assay and it may be used for screening large numbers of novel compounds.

Calcium↗
PubMed1998

Identification of differentially expressed genes in aflatoxin B1-treated cultured primary rat hepatocytes and Fischer 344 rats.

Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR-based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1-responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.

Aflatoxin B1↗
PubMed1997

A novel human papillomavirus identified in epidermodysplasia verruciformis.

Epidermodysplasia verruciformis (EV) is a rare inherited condition in which there is widespread infection with human papillomavirus (HPV). Patients have a high risk of developing squamous cell carcinoma and Bowen's disease on sun-exposed sites. We describe a Jamaican man with the typical clinical and histopathological features of EV.HPV 8, 24 and a subtype of HPV 38, along with a novel HPV sequence most closely related to HPV 9 have been detected in his skin lesions. Although skin tumours are rare in black patients with EV and he has lived in a temperate climate most of his life, several of the lesions showed bowenoid atypia and he is at risk of developing invasive cutaneous malignancies.

Epidermodysplasia Verruciformis↗
PubMed1997

Changes in CD44 isoform expression during inflammatory skin disease.

The CD44 family of cell surface glycoproteins is widely expressed in epithelial, mesothelial and haemopoietic tissues and is thought to function primarily as adhesion molecules. The molecule has an intracellular, a transmembrane and an extracellular domain. The membrane proximal region of the extracellular domain is of variable structure depending on which of 10 variable exons are involved in coding for this region. Both in vitro stimulated T cells and cytokine stimulated keratinocytes are known to express certain isoforms. In this study we have investigated whether specific isoforms of the CD44 molecule are expressed on epithelial cells and lymphocytes in the course of two inflammatory skin diseases, namely lupus erythematosus and lichen planus. Monoclonal antibodies, specific to the epitopes of the CD44 molecule encoded by v3, v4/5, v6 and v8/9 variable exons and a pan CD44 marker, were used on 10 lupus and 8 lichen planus frozen skin samples and compared with normal skin from 9 different body sites. Results failed to show detectable levels of variant isoforms of CD44 on lymphocytes in either inflammatory skin disease, despite evidence of T cell activation. All CD44 variant isoforms were reduced on the keratinocytes in some sections of lupus and lichen planus. The results are discussed in the context of the current models for the role of CD44 in the immune response.

Humans↗
PubMed1996

Molecular analysis of lacI mutations in Rat2 cells exposed to 7,12-dimethylbenz[a]anthracene: evidence for DNA sequence and DNA strand biases for mutation.

The Rat2 cell line carries 50-70 stably integrated copies per cell of a lambda/lacI shuttle vector as a target for mutagenicity testing. Rat2 cells were exposed to 1 and 10 micrograms/ml of 7,12-dimethylbenz[a]anthracene (DMBA) for 24 h at 37 degrees C in the presence of primary rat hepatocytes, and grown to confluence. The shuttle vector was rescued from untreated and mutagen-treated cells and mutant frequencies were determined. The low and high doses of DMBA induced mutant frequencies that were 7-fold (25 +/- 4.9 x 10(-5)) and 33-fold (127 +/- 19.9 x 10(-5)) higher, respectively, than the spontaneous mutant frequency (3.8 +/- 0.7 x 10(-5)). DNA sequence analysis of the DMBA-induced lacI- mutants indicated that they contained mainly basepair substitution mutations at A:T and G:C, and that A:T-->T:A and G:C-->T:A transversions were the predominant types. In addition, 23 of 28 (82%) A:T basepair substitution mutations occurred with the mutated dA, the putatively adducted base, on the coding strand. Furthermore, 20 of the 28 (71%) A:T mutations had the mutated dA flanked 5' by a dC, and 17 of these were A:T-->T:A transversions, suggesting a sequence preference for this mutation. Except for a higher proportion of G:C-->A:T transitions in the low dose data, the mutational profiles from low and high doses of DMBA were similar. These results indicate that DMBA mutagenesis in the lacI gene of Rat2 cells displays distinct DNA sequence and DNA strand preferences.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Detection of acoustic schwannoma: use of constructive interference in the steady state three-dimensional MR.

PURPOSE: To compare constructive interference in the steady state (CISS) three-dimensional Fourier transform (3DFT) MR imaging with contrast-enhanced T1-weighted spin-echo MR imaging for accuracy in detecting acoustic schwannoma. METHODS: One hundred twenty-five consecutive patients with possible acoustic schwannoma were examined. The accuracy of CISS-3DFT MR imaging in detecting abnormalities of the cerebellopontine angle, the internal auditory canal, and the inner ear was compared with T1-weighted contrast-enhanced spin-echo MR imaging by independent assessment of both image sets by two observers. RESULTS: The postcontrast T1-weighted MR images revealed 18 cases of unilateral disease of the cerebellopontine angle and/or the internal auditory canal and no case of an abnormal bilateral cerebellopontine angle and/or internal auditory canal. Twelve cases were pathologically proved acoustic schwannomas. One meningioma of the cerebellopontine angle and one metastatic ependymoma to the cerebellopontine angle and the internal auditory canal was encountered. The four remaining cases had a provisional diagnosis of acoustic schwannoma and were scheduled for follow-up imaging and clinical review. Analysis of whether contrast material would have been administered to the appropriate patients (ie, those with disease of the cerebellopontine angle and/or internal auditory canal) according to CISS MR imaging findings revealed a sensitivity of 100% and a specificity of 98% for observer 1 and a sensitivity of 94% and a specificity of 94% for observer 2. CONCLUSION: CISS-3DFT MR imaging, in this patient population, provided high sensitivity and specificity in detecting lesions of the cerebellopontine angle and internal auditory canal; however, further experience is required before a definitive statement regarding the suitability of this technique as a screening procedure can be made. When contrast material cannot be administered, CISS MR imaging may be considered an adequate examination for the evaluation of possible acoustic schwannoma.

Adult↗
PubMed1996

Targeting widespread sites of damage in dystrophic muscle: engrafted macrophages as potential shuttles.

Inherited muscle diseases are characterized by widespread muscle damage in the body. This limits the clinical relevance of cell or gene therapy based upon direct injections into muscles. One way to circumvent this obstacle would be to use circulating cells, capable of homing naturally to the sites of lesion, to deliver therapeutic substances. Certain muscular dystrophies present successive cycles of degeneration-regeneration. These sporadic necrotic lesions trigger local inflammations with subsequent infiltration of blood-borne mononuclear cells. We have, therefore, tested the possibility that homing monocytes and macrophages could be appropriate shuttles for delivering a therapeutic agent to disseminated pathogenic sites, their targeting being triggered by the pathogeny itself. First, fluorescently labeled immortalized monocytes were intravenously injected into mice which had previously undergone freeze-damaging of individual muscles. In agreement with our hypothesis, intense labelling was observed in the muscle, specifically in damaged regions. Second, the technique was adapted to meet the needs of chronic diseases with characteristic continuous, widespread degeneration of muscle fibers, by creating a reservoir of genetically engineered monocytes, via bone marrow transplantation. Mdx mice received bone marrow from transgenic mice expressing the lacZ reporter gene, under the control of the vimentin promoter, which is active in monocytes and macrophages. Histological and molecular analyses demonstrated the homing of engineered macrophages at the sites of muscle damage, for periods as long as 2 months. Bone marrow progenitor cells, appropriately engineered to elicit the synthesis, in macrophages, of therapeutically relevant substances, may be of clinical value in various pathologies involving an inflammatory phase.

Animals↗
PubMed1995

Porous graphitic carbon shows promise for the rapid chromatographic analysis of polar drug metabolites.

A rapid and simple HPLC method has been developed and used to separate the polar metabolic conjugates of AZT, chloramphenicol, and beta-estradiol based upon the use of porous graphitic carbon. The HPLC system is sufficiently selective to resolve the polar drug conjugates from their parent compounds and from endogenous material present in urine. The compounds are separated, without the need for sample pretreatment or gradient elution, on a porous graphitic carbon (Hypercarb) column using aqueous trifluoroacetic acid modified with tetrahydrofuran as the mobile phase. Porous graphitic carbon exhibits a novel mechanism of retention towards these very polar substances, which are unretained under reversed-phase conditions on alkyl-bonded silica phases.

Animals↗