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Biomedical subjects

R McFarlane

Publications and source records attributed to R McFarlane.

At least 19 recordsLinked to original sources
PubMed1999

Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus.

AIMS: Arterial endothelial dysfunction is a key early event in atherogenesis, and occurs in asymptomatic adults with Type 1 diabetes mellitus (DM). As angiotensin converting enzyme (ACE) inhibitors have been reported to reverse microvascular endothelial dysfunction acutely, we assessed the longer term effect of ACE inhibition on large vessel endothelial physiology in a randomized, crossover double-blind controlled clinical trial. METHODS: Flow-mediated arterial dilatation (FMD), which is largely due to endothelial release of nitric oxide, was assessed by vascular ultrasound in 20 Type 1 DM subjects with known endothelial dysfunction. These subjects, aged 28+/-5 years, were studied before and after 12 weeks oral therapy with either the ACE inhibitor perindopril 4 mg daily or the diuretic hydrene (triamterene 50 mg with hydrochlorothiazide 25 mg) daily. RESULTS: Although perindopril lowered both systolic and diastolic blood pressure by 2.7/3.2 mmHg, respectively (F3,78 = 4.7, P= 0.006; F3,78 = 3.2, P = 0.03), there was no significant effect of either perindopril or hydrene on FMD (baseline FMD before perindopril 4.6+/-2.5%, after 4.1+/-3.4%, baseline FMD before hydrene 5.4+/-3.6%, after 6.0+/-3.3%; F3,78= 1.9, P=0.1). Glycaemic control deteriorated slightly on hydrene whilst lipid levels, heart rate, resting blood flow and the arterial responses to nitroglycerine, a smooth muscle dilator, were unaffected by the treatment given. CONCLUSION: ACE inhibitor therapy for 3 months did not improve arterial endothelial function in Type 1 DM subjects.

Adult↗
PubMed1998

Cloning and characterization of human and mouse telomerase RNA gene promoter sequences.

Variation in telomerase activity is correlated with cellular senescence and tumour progression. However, although the enzymatic activity of telomerase has been well studied, very little is known about how expression of telomerase genes is regulated in mammalian cells. We have therefore cloned the promoter regions of the human (hTR), and mouse, (terc), telomerase RNA genes in order to identify the regulatory elements controlling telomerase RNA gene transcription. 1.76 kb encompassing the hTR gene promoter region was sequenced, as was 4 kb encompassing the terc promoter. No significant sequence similarity could be detected in comparisons between human and mouse 5'-regions, flanking the transcribed sequences. However, both the human and mouse telomerase RNA genes are within CpG islands and may therefore be under the regulation of DNA methylation. Transient expression of hTR-reporter gene constructs in HeLa and GM847 cells identified the elements responsible for promoter activity are contained in a 231 bp region upstream of the transcriptional start site. Transient expression of terc-reporter gene constructs in Swiss3T3 and A9 cells identified the elements responsible for promoter activity are contained in a 73 bp region upstream of the transcriptional start site. These studies have implications for novel transcription targeted cancer therapies.

Animals↗
PubMed1997

Serodiagnosis of toxoplasmosis in a common wombat.

An 8-yr-old captive, female common wombat (Vombatus ursinus) from Victoria, Australia was euthanased after an illness of 36 days manifested by lethargy, inappetance and terminal coma with respiratory failure. Toxoplasmosis was diagnosed during life by the Toxoplasma direct agglutination test (DAT) which showed a positive initial titre of 1:1,024 at 22 days after onset of illness and a four fold rise in titre to 1:4,098 2 wk later, just prior to death. The Toxoplasma modified agglutination test (MAT) remained negative over this time period. The serological diagnosis was confirmed by histological diagnosis of granulomatous encephalitis, focal myocarditis, interstitial pneumonia and severe adrenal cortical necrosis and the presence of tachyzoites of Toxoplasma gondii in large numbers within the focal necrotic lesions in the brain, myocardium and adrenal cortices. The serological response in the wombat differed from that of the typical eutherian which exhibits a reaction in both the DAT and MAT within 2 wk of infection with T. gondii. An incidental finding was calcification in the media of the ascending aorta and proximal parts of the major arteries.

Adrenal Glands↗
PubMed1996

Markers for cardiovascular and renal morbidity: expectations for an intervention programme in an Australian aboriginal community.

1. Australian Aborigines have high rates of both cardiovascular mortality and renal failure and the usual male dominance in these conditions is respectively reduced and effaced. 2. In one Aboriginal community, we have demonstrated a strong association between albuminuria and cardiovascular risk factors and a relationship of both with insulin resistance, which is more pronounced in females than males. 3. We propose that albuminuria is a component of Syndrome X and that reduction in levels of albuminuria should prove to be a useful marker of effectiveness in treatment programmes targeting cardiovascular risk as well as renal disease.

Albuminuria↗
PubMed1995

Physical mapping, cloning, and identification of genes within a 500-kb region containing BRCA1.

BRCA1 is a breast/ovarian cancer susceptibility gene on human chromosome 17q21. We describe a complete and detailed physical map of a 500-kb region of genomic DNA containing the BRCA1 gene and the partial cloning in phage P1 artificial chromosomes. Approximately 70 exons were isolated from this region, 11 of which were components of the BRCA1 gene. Analysis of the other exons revealed a rho-related G protein and the interferon-induced leucine-zipper protein IFP-35.

Amino Acid Sequence↗
PubMed1994

Maintenance of identical p53 mutations throughout progression of squamous cell carcinomas of the tongue.

The occurrence of mutations within the coding sequence of the p53 tumour suppressor gene is now well documented for squamous cell carcinomas of the head and neck region. However, evidence that these mutations are required for the maintenance and progression of squamous tumours is still formally lacking. To test this we have examined whether p53 mutations detected in primary squamous cell carcinomas of the tongue are also detected in the corresponding lymph node metastases. Three different p53 mutations were detected in each of three primary tongue squamous cell carcinomas (SCC), and in each case the same mutation was detected in a lymph node metastasis excised from the same patient. Although the sample number is small, the chance of obtaining the same p53 mutation independently in both the primary and metastatic tumour of each patient is at least 10(-4), therefore the results indicate that keratinocytes harbouring these p53 mutations possess a selective advantage throughout SCC progression.

Carcinoma, Squamous Cell↗
PubMed1994

The detailed characterisation of a 400 kb cosmid walk in the BRCA1 region: identification and localisation of 10 genes including a dual-specificity phosphatase.

We have produced a detailed physical and transcriptional map of a 400 kb region within the narrowest flanking markers known to contain the hereditary breast and ovarian susceptibility gene, BRCA1. The approach described here has avoided the problems of chimaerism, instability and rearrangements commonly observed in yeast artificial chromosomes by converting the YAC clones into ordered chromosome 17-specific cosmid contigs and joining these contigs by cosmid end-walking. A detailed long-range restriction map provided a framework for the cosmid contig assembly and further refines existing physical mapping data. We have used a combined approach towards the isolation of the genes housed within these cosmids. This has resulted in the isolation and precise localisation of eight novel genes, including a novel G protein and an endogenous retrovirus related to the HERV-K family, and the previously described dual-specificity VHR phosphatase and MOX1 homeobox genes.

Animals↗
PubMed1993

HTLV-I among Northern Territory blood donors.

OBJECTIVE: Human T-lymphotropic virus type I (HTLV-I) is known to be endemic among Northern Territory (NT) Aborigines, therefore evidence was sought of HTLV-I infection in NT blood donors. DESIGN: Samples were screened for HTLV-I antibodies using the Serodia HTLV-I particle-agglutination assay. Repeatedly reactive sera were tested by western blot. Viro- logical and molecular investigations were also performed. SERA: Aliquots from all 11,121 blood donations collected between June 1991 and August 1992. RESULTS: Four (0.036% of total) blood donations, each from different donors, were repeatedly reactive by particle-agglutination assay. One (0.009%) sample, from a 52-year-old non-Aboriginal man with no verified risk factors, was confirmed as HTLV-I seropositive by western blot. A viral isolate and a 431 base pair polymerase chain reaction product from the env gene were obtained from a culture of his peripheral blood mononuclear cells. Sequencing of the polymerase chain reaction product demonstrates that this isolate is a prototype strain and not the variant identified among Aborigines. The remaining three repeatedly reactive donors, including the positive donor's wife, were western blot indeterminate. CONCLUSIONS: There is a low prevalence of HTLV-I carriage among blood donors in the NT, and presumably in other States. However, most repeatedly reactive donations prove to be western blot indeterminate, therefore additional tests are required to detect or exclude HTLV-I infection. Although universal screening of donations would virtually eliminate HTLV-I transmission by transfusion, it has disadvantages, including financial cost.

Adult↗
PubMed1993

Conditional expression and oncogenicity of c-myc linked to a CD2 gene dominant control region.

Over-expression of the c-myc gene is widely implicated in the genesis of lymphoid neoplasia, including tumours of the T-cell lineage. To study the effects of deregulated c-myc expression on T-cell development and oncogenesis, we sought to generate a transgenic mouse model in which c-myc expression was targeted specifically to the T-cell lineage. A plasmid construct containing a dominant control region (DCR) from the human CD2 locus linked 5' to the human c-myc gene was used to generate 2 lines of transgenic mice. Both strains developed thymic lymphoma at low frequency, but thymic development and peripheral T-cell numbers were otherwise apparently normal. Low tumour penetrance was consistent with the observed lack of stable CD2-myc transgene mRNA in tissues of healthy transgenic mice. In contrast, transgene RNA was detected in all malignant tumours as well as in early lymphomatous lesions. RNase protection analyses confirmed these findings and showed that the PI human c-myc promoter was active in all neoplastic tissues but not in the thymus or other tissues of healthy transgenic mice. Despite the low spontaneous tumour incidence, the presence of the transgene markedly and uniformly accelerated the onset of tumours after neonatal infection with Moloney murine leukaemia virus. All tumours were rearranged for T-cell receptor beta-chain genes and were of T-cell origin from their surface phenotype (Thy-1+, CD3+, CD4+/-, CD8+, sIg-). Virus-accelerated tumours contained clonal integrations of Moloney murine leukaemia virus, suggesting that proviral insertional mutagenesis may have played a role in tumour development. Analysis of several candidate myc-cooperating genes failed to reveal any rearrangements apart from a low frequency involving proviral insertion at the pim-1 locus. The CD2-myc mouse should therefore be a valuable system in screening for novel myc-collaborating genes involved in T-cell lymphoma.

Animals↗
PubMed1991

Interaction between diabetic patients, their general practitioners and a hospital diabetic clinic.

OBJECTIVE: The aim of this study was to examine the sociodemographic data of diabetic patients referred to our clinic and to correlate these with characteristics of their individual general practitioners. How these factors affect the interaction between patients, general practitioners and a hospital diabetic clinic was evaluated. DESIGN: Prospective recruitment of consecutive referrals. SETTING: The diabetic clinic of a teaching hospital located in the inner city suburbs of Sydney. PATIENTS: Two hundred and forty-six patients with diabetes (10% insulin dependent), aged 20-86 years, participating in our Shared Care Project, a randomised controlled study on various methods of following up diabetic patients. INTERVENTIONS: Data for the study were gathered by interview and questionnaire during first assessment at the clinic. MAIN OUTCOME MEASURES: Clinical and sociodemographic characteristics of patients; the location of general practitioners, their diagnostic equipment and type of practice; and the level of detail recorded in referral letters from general practitioners. RESULTS: Diabetic patients of migrant background who cannot speak English are older and have less formal education. They see their doctors more often and seek out general practitioners who speak their language, even if it means travelling longer distances. Patients referred from 24 hour medical centres are younger, more educated and have less contact with their doctors both in duration and frequency of visits when compared with patients whose general practitioners operate in conventional sole or partnership practices. Many patients have more than one general practitioner, making communication with hospitals difficult. In their referral letters, general practitioners usually concentrate on hypertension, hypercholesterolaemia and metabolic aspects of diabetes, but under-emphasise diabetic complications; they make insufficient use of measurement of the glycosylated haemoglobin level to assess diabetic control while over-using glucose tolerance testing in making the diagnosis. The referral letter often does not contain enough information to help clinical decision making. CONCLUSIONS: Demography of patients and characteristics of general practitioners are important factors which can affect their interaction with public hospitals. Bearing in mind the work load of general practitioners and the diverse nature of patients, hospitals must implement systems which make it easier for general practitioners and patients to interact with them.

Adult↗
PubMed1988

Receptor-mediated leukaemogenesis: hypothesis revisited.

The discovery of the first example of retroviral transduction of an immunological effector molecule has led us to reconsider the possible importance of cell surface receptors of the immune system in leukaemia development. Antigen receptors on lymphoid cells not only bind external ligands but are crucial in the control of cellular proliferation. The concept of autocrine stimulation in oncogenesis is already well established and we see no reason to exclude the possibility of analogous mechanism operating through antigen receptors. At present, we are investigating the oncogenic function of the retrovirus (FeLV-T17) carrying a T-cell receptor gene (v-tcr). In addressing the general concept of oncogenesis by ligand/receptor interactions in the immune system we face the problem of the diversity and, for T-cell antigen receptors, the complex nature of receptor-ligand interaction. Nevertheless, the implications of the model encourage us to continue to search for new experimental tools and approaches to the question.

Animals↗
PubMed1986

Conservation of the c-myc coding sequence in transduced feline v-myc genes.

We have cloned the normal feline c-myc locus and determined the nucleotide sequence of all three exons. The feline c-myc gene shows close homology to other mammalian c-myc genes, particularly human c-myc. The feline and human sequences are colinear within the open reading frame for the putative c-myc product but show insertions and deletions relative to each other outside this domain. We have also analyzed a cloned FeLV provirus, CT4, which contains the host-derived myc gene. In this provirus the v-myc sequences are located at the 3' end of the pol gene, replacing pol and env sequences. Nucleotide sequence analysis of CT4 shows an open reading frame for a v-myc gene product which may be expressed without fusion to any viral protein sequences. This contrasts with another FeLV v-myc (LC), in which myc and gag sequences were found to be fused. Unlike previously identified avian v-myc genes, the feline v-myc genes contain exon 1-derived sequences, but these have been truncated or internally deleted. The FeLV CT4 v-myc sequence shows very few coding changes relative to c-myc and the FeLV LC v-myc coding sequence is unchanged relative to c-myc apart from fusion to gag. These results are discussed in relation to the mechanism of transduction and activation of myc by FeLV.

Amino Acid Sequence↗
PubMedDate not supplied

Dupuytren's disease.

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Dupuytren Contracture↗