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J Mullins

Publications and source records attributed to J Mullins.

At least 19 recordsLinked to original sources
PubMed1996

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

We have developed a transgenic animal model to investigate the effects of overexpression of rat prorenin on the cardiovascular system. Two transgenic rat lines were generated in which rat prorenin expression was directed to the liver by a human alpha1-antitrypsin promoter. Liver-specific expression was confirmed by RNase protection assay. Plasma prorenin concentrations in transgenic rats were increased 400-fold in the males of both lines but were increased only two- to threefold in the females. Thus, transgene expression exhibited sexual dimorphism. Blood pressures were not significantly higher in transgenic rats than in nontransgenic controls. The ratio of heart weight to body weight was greater in male transgenic rats than in the nontransgenic controls. Histological analysis revealed severe renal lesions and hypertrophic cardiomyocytes in transgenic males only. This transgenic model demonstrates a likely role of prorenin in the development of cardiac and renal pathology independent of hypertension. These animals will facilitate studies of the effects of blockade of the renin-angiotensin system and other pharmacological interventions on the development and treatment of cardiac, vascular, and renal lesions induced by changes in this system in the absence of chronic hypertension.

Angiotensinogen↗
PubMed1996

Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS-M.

Normal mammalian development requires a diploid combination of both haploid parental genomes. Uniparental disomy for certain segments of specific chromosomes results in aberrant development or prenatal lethality, indicating that the parental genomes have undergone modifications during gametogenesis. These modifications result in parent-of-origin specific expression for some genes, a phenomenon called genomic imprinting. Recent work with DNA methyltransferase deficient mice showed that differential methylation is the probable basis of the imprinted character of several genes. Screening for endogenous imprinted loci using restriction landmark genomic scanning with methylation sensitive enzymes (RLGS-M) identified eight imprinted RLGS (Irigs) candidate loci. Molecular analysis of the genomic region of one of the loci (Irigs2) resulted in the discovery of the paternally imprinted U2afbp-rs gene within a previously identified imprinted region on mouse chromosome 11 (refs 5, 7). This paper describes the characterisation of a novel imprinted RLGS-M locus, Irigs3, on mouse chromosome 9 (ref. 6). Within this locus we identified the Grf1 (also called Cdc25Mm) gene, which is homologous to the RAS-specific guanine nucleotide exchange factor gene, CDC25, in Saccharomyces cerevisiae. Grf1 is located about 30 kb downstream of the methylation imprinted site, identified by RLGS-M, and shows paternal allele specific expression in mouse brain, stomach and heart. Our results indicate that imprinting may have a role in regulating mitogenic signal transduction pathways during growth and development.

Animals↗
PubMed1996

The increase in hay fever: pollen, particulate matter and SO2 in ambient air.

To investigate whether the rise in allergic disease is explicable on the basis of an increase in the concentrations of allergen and urban air pollutants to which the population has been exposed, we compared the concentrations of grass pollen, sulphur dioxide and black smoke to which two samples of children with previously measured prevalences of hay fever had been exposed, in Cardiff, South Glamorgan. In these studies there had been a 59% increase in the prevalence of hay fever among 12 year old school children between 1973 and 1988. Exposures to grass pollen of the two populations had been no different, but the earlier sample, with the lower prevalence of hay fever, had been exposed to substantially higher concentrations of ambient particulate matter and sulphur dioxide. The rise in prevalence of hay fever, occurring without a rise in grass pollen concentrations, supports the hypothesis that the population has become more susceptible to airborne allergen. This increased susceptibility is unlikely to be a consequence of concomitant exposure to sulphur dioxide and particulate air pollution.

Air Pollutants↗
PubMed1994

Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island.

In an attempt to find the mechanism by which CpG islands remain free of methylation we have undertaken a detailed examination of the mouse adenine phosphoribosyltransferase (aprt) gene. This housekeeping gene has a CpG island that extends over the gene promoter and includes the first two exons. We show that the island is free of methylation at all CpGs, whereas the flanks are methyated. Detailed patterns of methylation beyond the boundaries of the CpG island vary between cells. In vivo footprinting across the island region shows that three GC boxes clustered at the 5' edge of the CpG island are occupied, most probably by Sp1. No other footprints are detected within the island region. Deletion or mutagenesis of the Sp1 sites causes de novo methylation of the CpG island in a transgenic mouse assay. Thus, the peripherally located Sp1 sites are necessary to keep the aprt island methylation free.

Adenine Phosphoribosyltransferase↗
PubMed1993

Topical levocabastine is more effective than sodium cromoglycate for the prophylaxis and treatment of seasonal allergic conjunctivitis.

The efficacy, tolerability, and adverse-effect profile of the recently developed, topical antihistamine levocabastine were compared with those of sodium cromoglycate in a 4-week double-blind, placebo-controlled trial in 95 patients with seasonal allergic conjunctivitis. At the end of the trial, global therapeutic efficacy was considered to be excellent or good in 87% of levocabastine-treated patients, as compared with 68% of sodium cromoglycate-treated patients (P = 0.006) and 63% of those who received placebo (P = 0.05). After 4 weeks of treatment, levocabastine patients had experienced significantly greater relief from their most severe ocular symptom than patients in the sodium cromoglycate group (P < 0.05). Furthermore, 37% of levocabastine-treated patients were virtually symptom-free for at least 75% of the treatment period, as compared with only 6% of patients in the sodium cromoglycate group (P < 0.01) and 4% of those who received placebo (P < 0.01). Moreover, this trend was maintained on days when the pollen count was high, when the corresponding figures were 33%, 6% (P = 0.02), and 4% (P = 0.02), respectively. Levocabastine was well tolerated. Indeed, the incidence of adverse reactions was no greater in the levocabastine group than in the placebo group. Topical levocabastine is an effective and well-tolerated drug for the prophylaxis and treatment of seasonal allergic conjunctivitis.

Administration, Topical↗
PubMed1993

Effect of freezing semen and dosage of sperm on number of accessory sperm, fertility, and embryo quality in artificially inseminated cattle.

This experiment was conducted to determine whether use of fresh or frozen semen at either 20 x 10(6) (low) or 100 x 10(6) (high) sperm per dose affects the number of accessory sperm and fertilization status/embryo quality as determined from ova/embryos recovered nonsurgically 6 d after insemination. Ejaculates of four bulls were split and prepared for use as fresh or frozen semen at either the high or low dose. From 129 inseminations to normally cycling cows, 98 ova/embryos were recovered. To reduce male effects, ova/embryos used were randomly balanced across treatments, by ejaculate within bull for evaluation of frozen vs fresh semen (n = 80) and by bull for evaluation of high vs low dosage treatments (n = 76). Distribution of accessory sperm was highly skewed downward; thus, median values were more meaningful than means. Freezing semen had no significant effect on fertility status/embryo quality or number of accessory sperm at either dosage. Increasing dosage improved the number of accessory sperm per ovum or embryo (median value) and fertility status/embryo quality (P < .05). Mean +/- SD and median values for accessory sperm were 37.8 +/- 38.3 and 27.5; 28.9 +/- 62.8 and 3.0 for the high and low dose, respectively. Percentage of unfertilized ova, degenerate embryos, and embryos classified poor to fair and good to excellent were 3, 5, 24, 68, and 21, 16, 18, 45, for the high and low dose, respectively. We conclude that number of accessory sperm and fertility status/embryo quality respond favorably to increased dosage of semen and that freezing semen in this study was not detrimental to these parameters.

Animals↗
PubMed1992

Transgenic rats carrying the mouse renin gene--morphological characterization of a low-renin hypertension model.

Transgenic rats [TGR; strain name TGR(mRen2)27] harboring the mouse Ren-2 renin gene have been recently generated as a model for the study of primary hypertension that offers the advantage of a clearly-defined genetic alteration. Expression of the mouse Ren-2 gene causes severe hypertension (200 to 260 mm Hg) which is responsive to converting enzyme inhibitors. Compared to control transgene-negative littermates, plasma renin and angiotensin II values are lowered in TGR, whereas plasma prorenin values are strongly elevated. The adrenal gland in TGR shows marked overexpression of mouse renin messenger RNA; in situ hybridization using a 35S-labelled mouse-renin RNA probe reveals that enhanced renin expression is mainly localized to cells of the zona glomerulosa and outer zona fasciculata. Immunohistochemically, renin protein in the TGR adrenal gland is stored in larger quantities than in controls. Adrenal transgene expression probably accounts for most of the elevated plasma prorenin level in TGR, since bilateral adrenalectomy (ADX) causes a significant decrease in prorenin level (318 +/- 79 ng angiotensin I/ml/hr before ADX to 70 +/- 43 ng 4 days after ADX, P less than 0.0005). In the kidney, renin synthesis is almost completely suppressed in TGR. In situ hybridization demonstrates that few juxtaglomerular afferent arterioles express renin. Immunohistochemically, the TGR kidney shows significantly reduced renin and angiotensin II immunoreactivity at the afferent arteriole. Ultrastructural analysis of the afferent arteriolar wall frequently shows the complete absence of renin secretory granules since the granular cells are mostly converted into smooth muscle cells. Beginning at an age of approximately four to six months, TGR develop hypertension-related alterations and pathological lesions in various tissues. In the kidney, the wall thickness of arterioles and arteries is strongly increased, and glomerular lesions including different stages of sclerosis are observed. The thoracic aorta displays a considerable increase in tunica media thickness due to both myocyte hypertrophy and interstitial fibrosis. Coronary arteries and arterioles of the heart are thickened and perivascular fibrosis is observed. The data show that TGR(mRen2)27 transgenic rats display all typical characteristics of hypertensive pathology, making them an interesting model for therapeutic interventions. The fact that these changes occur in animals with a single gene difference to normotensive rats makes them a particularly suitable model for studies on gene-related hypertensive processes.

Adrenal Glands↗
PubMed1992

The role of the adrenal gland in hypertensive transgenic rat TGR(mREN2)27.

The TGR(mREN2)27 is a new monogenetic rat model in hypertension research. As the mouse Ren-2d renin gene is integrated into their genome, they develop fulminant hypertension between 5 and 15 weeks of age, with blood pressure maxima of 300 mm Hg. Their plasma renin-angiotensin system (RAS) is suppressed, but the transgene is highly expressed in the adrenal gland, so we investigated its possible role in steroid metabolism and the pathogenesis of hypertension. During the phase of hypertension development (between 6-18 weeks), the urinary excretion of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone, and aldosterone is 1.5- to 2.5-fold elevated compared with that in Sprague-Dawley (SD) rats (P less than 0.0005) despite the suppressed plasma RAS. Moreover, the adrenal gland in TGR(mREN2)27 shows an increased maximal response to ACTH stimulation in regard to urinary excretion of DOC (after ACTH, 244 +/- 42 ng/24 h in TGR; 62 +/- 10 ng/24 h in SD; P less than 0.0005) and B (after ACTH, 5144 +/- 346 ng/24 h in TGR; 2607 +/- 324 ng/24 h in SD; P less than 0.0005). Additionally, plasma prorenin in TGR was stimulated more than 10-fold, indicating transgene regulation by ACTH. Since spironolactone treatment did not lower the blood pressure in TGR, hypertension solely due to hypermineralocorticoism is unlikely. Our results indicate that the adrenal steroid metabolism is markedly stimulated in young TGR, and the absolute increase in urinary DOC and B after ACTH injections is enhanced, possibly due to a stimulated local intraadrenal RAS.

18-Hydroxycorticosterone↗
PubMed1991

Mucosal function after ileal mucosal fenestration and colonic autotransplantation.

A method of small bowel mucosal augmentation called ileal mucosal fenestration and colonic autotransplantation (IMFCA) was devised and tested in pigs. In this technique, a vascularized mucosal graft was harvested from a 12-cm ileal loop, fenestrated by serial incision and then expanded to 20 cm. A 20-cm colonic loop was isolated and surgical mucosectomy was carried out. The fenestrated ileal mucosal graft was then autotransplanted into the prepared colon and the resulting composite structure was exteriorized as a Thiry-Vella loop. With this technique, ileal mucosal fenestrations healed by lateral epithelial in-growth, giving a new mucosal continuum within the recipient colon. At 60 days after surgery, the surface area of transplanted mucosa exceeded that within the original ileal loop by approximately 85 per cent. At this time, the transplanted mucosa had morphology and capacity for Na(+)-dependent glucose transport which were indistinguishable from those of control ileal mucosa.

Animals↗
PubMed1991

Transgenic approaches to modification of cell and tissue function.

The past 18 months have seen rapid advances in the use of transgenic techniques for elucidating cellular mechanisms. The modification of gene, cellular and tissue function has been enhanced by developments in the use of antisense and ribozyme constructs, and by improvements in strategies for cell ablation and homologous recombination.

Animals↗
PubMed1990

Autoradiographic localization of mas proto-oncogene mRNA in adult rat brain using in situ hybridization.

The cellular localization and the distribution of the mas proto-oncogene/angiotensin receptor mRNA have been studied in the male rat brain using in situ hybridization with radiolabelled mas cRNA probes. Neuronal cell populations in the forebrain were selectively labelled. A strong specific labelling was demonstrated in the dentate gyrus, the CA3 and CA4 areas of the hippocampus, the olfactory tubercle (medical part), the piriform cortex and the olfactory bulb, while a weak to moderate labelling was present all over the neocortex and especially in the frontal lobe.

Animals↗
PubMed1989

The tissue renin-angiotensin system: a target for angiotensin-converting enzyme inhibitors.

The actions of ACE inhibitors at the tissue level (brain, heart, blood vessels) and their interference with the automatic nervous system through central and peripheral actions may, under certain conditions, be more important than inhibition of the hormonal circulating plasma angiotensin (ANG) II. Recent clinical and experimental studies and new insights into the molecular biology of the renin-angiotensin system support this view, in particular gene expression of renin and angiotensin in tissues of the cardiovascular system. These findings have implications not only for understanding the pharmacokinetics and pharmacodynamics of ACE inhibitors, but also for their therapeutic use.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

City spore concentrations in the European Economic Community (EEC). VII. Oleaceae (Fraxinus, Ligustrum, Olea).

In this paper we present the results of volumetric sampling of the airborne pollen grains of the Oleaceae family (Fraxinus, Ligustrum and Olea) in some European towns, in the period from 1982 to 1986. The sampling and appraisal of pollen content in the air is of particular interest to clinicians and allergic patients in order to assess exposure to the various pollen types in relation to allergy. In the Oleaceae family, the most allergenic pollen is produced by Olea europaea, the olive tree, which in the Mediterranean area has a pollination period lasting from May to the end of June and sometimes causes severe symptoms of pollinosis. In Northern and Central Europe, where there are no olive trees, there are two other commonly occurring genera of the Oleaceae family, namely Fraxinus and Ligustrum, but these have a low frequency of allergic sensitization.

Air Pollution↗