Search PubMed⌕ Search

Biomedical subjects

B J Morris

Publications and source records attributed to B J Morris.

At least 109 records · Page 6Linked to original sources
PubMed1994

Haloperidol and fluphenazine induce junB gene expression in rat striatum and nucleus accumbens.

Administration of neuroleptics such as haloperidol to rats is known to induce the expression of the immediate-early genes (IEGs) c-fos and zif/268 in striatal neurones. Another IEG, junB, is of interest because it may be involved in the suppression, rather than the enhancement, of downstream gene transcription. In this study, rat striatal tissue was assayed for IEG expression by in situ hybridisation, after the injection of haloperidol (1 mg/kg) or fluphenazine (3 mg/kg). In addition to c-fos mRNA and zif/268 mRNA, neurones in both the striatum and nucleus accumbens were found to contain high levels of junB mRNA, after treatment with either haloperidol or fluphenazine. The proportion of striatal neurones expressing junB mRNA strongly suggests that induction occurs in striatal projection neurones. A significant increase in the levels of the mRNA encoding another IEG, junD, was also detected after haloperidol treatment. The atypical neuroleptic clozapine (3 mg/kg) did not induce the expression of any of these IEGs in striatal tissue. The results show additional complexity in the pattern of IEG induction after neuroleptic administration and suggest that junB is involved in mediating some of the effects of neuroleptics on striatal gene expression.

Animals↗
PubMed1994

Similarity of blood pressure for each genotype of the insertion/deletion polymorphism of the dipeptidyl carboxypeptidase-1 gene in different age groups of patients with severe, familial essential hypertension.

1. The association of alleles of an insertion/deletion polymorphism (I/D) of the dipeptidyl carboxypeptidase-1 gene with hypertension is controversial. If a particular allele makes a major contribution to blood pressure, then hypertensives homozygous for this allele could be expected to have higher high blood pressure than those homozygous for the alternate allele. 2. The present study examined this hypothesis by comparing pretreatment blood pressures of hypertensives who had been genotypes for the I/D polymorphism. Blood pressures for different age groups (< 50, 50-59 and > or = 60 years) were also examined for each genotype. In addition, several other parameters were examined. 3. Systolic blood pressures were found to be 167 +/- 3, 167 +/- 3 and 170 +/- 6 mmHg (mean +/- s.e.) for the genotypes II, ID and DD, respectively. Diastolic blood pressures were 113 +/- 4, 111 +/- 2 and 111 +/- 4, for the respective genotypes. One-way ANOVA showed that the respective blood pressure values did not differ significantly across genotypes. Blood pressures for different age groups of hypertensives were also similar. 4. In addition, body mass index, mean age and sex did not differ between genotypes, either for the group as a whole or for the different age groups. 5. In conclusion, the present study could find no evidence to support a genetic association between the I/D polymorphism of DCP1 and blood pressure in a group with severe, familial hypertension living in Sydney.

Age Factors↗
PubMed1994

Frequencies of variants of candidate genes in different age groups of hypertensives.

1. In severe, familial hypertension, we have reported that the proportion of patients homozygous for the deletion allele of an insertion/deletion polymorphism of the angiotensin I-converting enzyme gene is markedly decreased in older age groups, suggesting that this genotype is associated with increased risk of premature death. The aim of the present study was to examine the relationship with age, of variants of other genes that encode proteins having an influence on the cardiovascular system. 2. Genotypes of 13 different variants at 12 relevant genetic loci were determined by either Southern blotting, followed by hybridization probing, or polymerase chain reaction techniques, as appropriate, using genomic DNA extracted from blood leukocytes. Genotype numbers were then assigned to the age categories of < 50, 50-59 and > or = 60 years. 3. Polymorphisms at the atrial natriuretic factor, antithrombin III, renin, angiotensinogen, neuropeptide-Y Y1 receptor, insulin, alpha 2-adrenoceptor, beta 1-adrenoceptor, growth hormone, low density lipoprotein receptor, insulin receptor and renal kallikrein gene loci were found to display similar allele frequencies in each age group of hypertensives, as well as in normotensive controls. 4. In conclusion, we were unable to detect any difference with age for a range of variants of genes whose products have cardiovascular significance, suggesting that, like most polymorphisms, they carry no selective survival advantage or disadvantage in the hypertensive and normotensive population groups studied.

Age Factors↗
PubMed1994

Genotypic influence on plasma dipeptidyl carboxypeptidase-1 activity in hypertensives.

1. Plasma dipeptidyl carboxypeptidase-1 (DCP1; angiotensin I-converting enzyme, kininase II; EC 3.4.15.1) tracks with the deletion allele in genotypes of a 287 bp insertion/deletion (I/D) polymorphism of its gene, DCP1, in healthy Caucasian populations. The aim of the present study was to see whether genotype has a similar influence on plasma DCP1 in hypertensives. 2. The study involved 35 Caucasian patients with severe, familial essential hypertension, who were not being treated with DCP1 inhibitors, and 94 normotensives. Genotyping for the I/D polymorphism was performed by polymerase chain reaction and plasma DCP1 activity was measured by rate of hydrolysis of both [3H]-Hip-Gly-Gly and Hip-His-Leu. 3. Plasma DCP1 activity (nmol Gly-Gly/min per mL; mean +/- s.e.m.) was 67 +/- 2, 82 +/- 4 and 91 +/- 6 in II, ID and DD hypertensives, respectively, which was similar to values of 68 +/- 4, 82 +/- 3 and 94 +/- 3 in normotensives (P = 0.0001 by one-way analysis of variance). Results for the His-Leu assay indicated similar tracking with genotype. 4. The Michaelis constant (mumol Hip-Gly-Gly/mL; mean +/- s.e.m., n = 10) for DD subjects was the same as for II subjects (10.6 +/- 1.6 vs 11.1 +/- 2.3; P = 0.86). 5. In conclusion, in severely hypertensive Caucasian subjects, plasma DCP1 activity is subject to a similar genotypic influence in hypertensives as has been reported previously in normotensives. Furthermore, the plasma DCP1 enzyme itself appears to be functionally similar for each genotype.

Female↗
PubMed1994

No effect of kinins on DNA synthesis in LNCaP prostate cancer cells.

1. Prostate has kininogenase activity and expresses members of the tissue kallikrein gene family. The present study examined the effect of exogenous and endogenous kinins on growth of LNCaP prostate adenocarcinoma cells. 2. Rate of DNA synthesis was measured by incorporation over 4 h of [3H]-thymidine into a TCA insoluble fraction of LNCaP cells that had been cultured for 24 h. 3. Increased [3H]-thymidine incorporation was seen in response to 10 nmol/L testosterone (+103 +/- 5 s.e.%), dihydrotestosterone (+113 +/- 14%) and R1881 (+64 +/- 10%) (P < or = 0.001; n = 4). 4. In contrast 0.05, 5 and 1000 nmol/L lysyl-bradykinin had no effect (15 +/- 4, 10 +/- 9 and 5 +/- 3 s.e.%, respectively; n = 7). Des-Arg9[Leu8]-bradykinin (a B1 receptor antagonist) and/or D-Arg-[Hyp3,Thi5,8,D-Phe7]-bradykinin (a B2 receptor antagonist), 1 nmol/L, and indomethacin, 5 mumol/L, also had little or no effect. 5. In conclusion, kallidin and endogenous kinins and prostaglandins have little or no effect on DNA synthesis and therefore on the growth of LNCaP cells in comparison to the two-fold stimulation produced by androgens.

Adenocarcinoma↗
PubMed1994

Different frequencies of angiotensin-converting enzyme genotypes in older hypertensive individuals.

The frequency of the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been reported to be elevated in myocardial infarction and other patients. We therefore hypothesized that death rate of DD individuals should be increased in the population as a whole and this should be evident as a decrease in DD frequency with age. This hypothesis was tested in 118 Caucasian subjects who were already at high risk of cardiovascular events by having severe, early onset, familial hypertension (HT). A group of 196 age-, sex- and body mass index-matched normotensives (NTs) was used as a control. In the NT group II, ID, and DD genotype frequencies were similar for different age groups. DD frequency was 0.42 in NTs, but in HTs was 0.28, 0.26, and 0.10 for the age groups < 50, 50-59, and > or = 60 yr, respectively. Corresponding D allele frequencies were 0.52, 0.46, and 0.40 in the respective age groups of HTs, compared with 0.61 in NTs (by chi 2-analysis, P = 0.1, 0.047, and 0.0006, respectively). In HTs aged > or = 60, DD frequency was only 14% of expected. Plasma ACE activity tracked similarly with I/D genotype in HTs (P = 0.027; n = 35) as in NTs (P = 0.0001; n = 94) and Michaelis constant was identical for DD and II. Neither blood pressure, body mass index, nor sex bore any relationship with I/D genotype. In conclusion, in a group of severely HT patients not selected for cardiac pathology, there appeared to be a marked, selective decrease, in subgroups of increasing age, in frequency of the ACE DD genotype. One possibility suggested by this data might be that DD increases risk of premature death, at least in HTs who have two HT parents.

Adult↗
PubMed1994

Insertion variant in intron 9, but not microsatellite in intron 2, of the insulin receptor gene is associated with essential hypertension.

OBJECTIVE: To determine whether a microsatellite polymorphism of the insulin receptor gene (INSR) is associated with essential hypertension, as has been demonstrated previously for an RsaI restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic hypertensive patients whose parents were both hypertensive, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the hypertensive and normotensive groups, or between obese and non-obese subgroups of hypertensives. This is in contrast to the significantly higher frequency seen for the R1- allele of an RsaI RFLP of INSR: 0.71 in the hypertensive group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of hypertensives and did not differ between obese and non-obese subgroups. The non-obese hypertensives also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the hypertension-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the hypertension-associated variants of INSR as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron.

Adult↗
PubMed1993

Cross-sectional analysis of Met235-->Thr variant of angiotensinogen gene in severe, familial hypertension.

A recent cross-sectional study of HTs in Salt Lake City and Paris has reported a significant association of a T704-->C (Met235-->Thr) variant in exon 2 of the angiotensinogen gene (AGT) with essential hypertension (HT). The present study used a new, direct PCR technique to detect this variant in 92 Caucasians with severe hypertension (HT) and two HT parents and 94 normotensive (NT) controls. Although frequency of the variant in HTs (0.42) was higher than in NTs (0.39), the difference was not significant (chi 2 = 0.24; P = 0.63). Plasma angiotensinogen showed a weak, nonsignificant relationship with AGT genotype in females and no genotypic relationship was apparent for blood pressure. Thus, if the Met235-->Thr variant of AGT is involved in essential HT, then its contribution may be, at best, much weaker in other HT groups.

Alleles↗
PubMed1993

Neuropeptide-Y Y1 receptor gene polymorphism: cross-sectional analyses in essential hypertension and obesity.

Neuropeptide Y increases blood pressure and appetite, disorders of which have a genetic component. The present study examined the neuropeptide-Y Y1 receptor gene (NPYY1R) for involvement in essential hypertension (HT) and obesity. Frequency of alleles of the only known variant, involving a point mutation in intron 1, was determined by PCR and PstI digestion. Minor allele frequency was 0.37 in 75 HT offspring of two HT parents, compared with 0.35 in 86 normotensives (NTs) ( chi 2 = 0.11; P = 0.73). In obese and lean HTs frequency was 0.40 and 0.35 (chi 2 = 0.51; P = 0.46); and was 0.38 and 0.34 in obese and lean NTs (chi 2 = 0.16; P = 0.69). In conclusion, variant(s) in linkage disequilibrium with the NPYY1R RFLP are not involved in HT or obesity.

Alleles↗
PubMed1993

Simple microwave and thermal cycler boiling methods for preparation of cervicovaginal lavage cell samples prior to PCR for human papillomavirus detection.

Sample preparation is an important step in the detection of viral DNA by the polymerase chain reaction (PCR) technique. The method used should achieve release of cellular DNA with the minimum of manipulation steps so as to reduce the possibility of contamination. The present report demonstrates that either microwaving or 20 min of boiling in the heating block of a thermal cycler lead to satisfactory results in the detection by PCR of human papillomavirus in cervicovaginal epithelial cell specimens obtained by lavage. Since each of these methods uses only one step the possibility of contamination is greatly reduced compared to the widely used proteins K/nonionic detergent extraction procedure.

Carcinoma in Situ↗
PubMed1993

Independent, marked associations of alleles of the insulin receptor and dipeptidyl carboxypeptidase-I genes with essential hypertension.

1. There is evidence to suggest that essential hypertension is a polygenic disorder and that it arises from yet-to-be-identified predisposing variants of certain genes that influence blood pressure. The cloning of various hormone, enzyme, adrenoceptor and hormone receptor genes whose products are involved in blood pressure control and the identification of polymorphisms of these has permitted us to test their genetic association with hypertension. 2. Cross-sectional analyses of a number of candidate gene markers were performed in hypertensive and normotensive subjects who were selected on the basis of both parents being either hypertensive or normotensive, respectively, and the difference in total alleles on all chromosomes for each polymorphism between the hypertensive and normotensive groups was tested by chi 2 analysis with one degree of freedom. 3. A marked association was observed between hypertension and insertion alleles of polymorphisms of the insulin receptor gene (INSR) (P < 0.0040) and the dipeptidyl carboxypeptidase-1 (angiotensin I-converting enzyme; kininase II) gene (DCP1) (P < 0.0018). No association with hypertension was evident, however, for polymorphisms of the growth hormone, low-density lipoprotein receptor, renal kallikrein, alpha 2- and beta 1-adrenoreceptor, atrial natriuretic factor and insulin genes. 4. All but one of the hypertensive subjects had at least one of the hypertension-associated alleles, and although subjects homozygous for both were three times more frequent in the hypertensive group, examination of the nine possible genotypes suggested that the INSR and DCP1 alleles are independent markers for hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Identification of essential hypertension genes.

OBJECTIVES: To review approaches used to identify genetic loci having aetiological involvement in essential hypertension and to highlight the advantages and limitations of each. CONTENTS: Cross-sectional analyses are reasonably powerful, require no knowledge of mode of transmission and have been used to show the association of variants of the insulin receptor, dipeptidyl carboxypeptidase-1 and glucocorticoid receptor genes with hypertension, using relatively low numbers of subjects having a strong genetic component to their elevated blood pressure. Association methods test only a minute portion of the genome, however, and rely heavily on 'linkage disequilibrium' between the marker and causative locus. Approaches involving linkage analysis are not so constrained. Obtaining suitable large affected families in a complex, polygenic, quantitative disease such as hypertension is, however, difficult, and this is compounded by the late onset of the disease, its unknown penetrance, variable phenotype and the influence of environmental factors. The use of only affected pedigree members is more straightforward, requires fewer assumptions and has been used to implicate the angiotensinogen gene in hypertension. CONCLUSION: Cross-sectional and sib-pair approaches show promise in identification of human hypertension genes.

Chromosome Mapping↗
PubMed1993

Renin messenger RNA, detected by polymerase chain reaction, can be switched on in rat atrium.

OBJECTIVE: The aim of the present study was to use a highly sensitive, polymerase chain reaction (PCR) technique to examine the controversial question of renin gene expression in the heart and to determine whether expression in cardiac tissue can be stimulated. DESIGN: The study involved female Wistar rats fed either a normal-sodium diet or a low-sodium diet, together with an angiotensin I converting enzyme inhibitor, enalapril, orally for 1 week. METHODS: RNA was extracted from atrium, ventricle, kidney (positive control) and submandibular gland (negative control) and, after reverse transcription into complementary DNA, was used in a 35-cycle PCR. Reaction products were visualized after electrophoresis by ethidium bromide staining and hybridization probing with [32P]-labelled target oligonucleotide. RESULTS: Atrial RNA from sodium-replete rats gave little or no renin messenger (m)RNA PCR product on ethidium bromide-stained gels. After DNA transfer, followed by hybridization probing and extended autoradiography, a faint band was seen. In sharp contrast, atrial extracts from sodium-depleted enalapril-treated rats displayed a pronounced band of hybridization, corresponding in size to that expected for renin mRNA. No band was seen for ventricle. CONCLUSION: The present PCR study has shown that in the normal sodium-replete rat, atrial tissue has only very low renin gene expression, but that after a low-sodium diet + treatment with enalapril, expression is switched on in atrium. Ventricular tissue does not express the renin gene in either state.

Animals↗
PubMed1993

Chromosome 17q23: a locus for cardiovascular disease.

1. The gene for dipeptidyl carboxypeptidase 1 (angiotensin I-converting enzyme, kininase II; DCP1), located on chromosome 17q23, has been implicated in hypertension in rats. In humans associations have been found for the insertion allele of a bi-allelic insertion/deletion polymorphism of DCP1 with hypertension and the deletion allele with myocardial infarction. Other hypertension studies have, however, failed to find a relationship. 2. Mathematical predictions based on DCP1 association data suggest that high sib-pair numbers may be needed to achieve statistical significance by this approach, although differences in the severity of hypertension in different study groups could account for the disparate findings. 3. No association was found between DCP1 allele or genotype frequencies and obesity in essential hypertensives.

Animals↗
PubMed1993

Species differences in binding of submandibular nuclear proteins to renin promoter DNA.

1. Renin is highly expressed in submandibular gland (SMG) of mouse, which has two genes, Ren-1d and Ren-2d, but not at all in rat SMG. Differences in nuclear protein binding to renin promoter DNA were, therefore, explored. 2. Rat -169 to +23 renin DNA formed complexes with both mouse and rat extract, whereas a corresponding fragment of mouse Ren-1d DNA (-121 to +4) bound with rat extract, but much less so with mouse extract. Rat extract bound a -704 to -450 fragment of the Ren-1d promoter. For Ren-2d -578 to -383 and -786 to -718 DNA bound with mouse extract and -383 to +11 and -664 to -578 DNA bound with rat extract. 3. The results support a role for differences in presence or binding of species-specific trans-acting factors in the differential regulation of the renin gene in SMG of mouse and rat. Strong binding near the rat RNA polymerase II binding site could repress transcription in rat SMG, and binding peculiar to the Ren-2d B2 element might contribute to high expression in mouse SMG.

Animals↗
PubMed1993

Short report: insertion variant in intron 9, but not microsatellite in intron 2, of the insulin receptor gene is associated with essential hypertension.

OBJECTIVE: To determine whether a microsatellite polymorphism of the insulin receptor gene (INSR) is associated with essential hypertension, as has been demonstrated previously for an Rsal restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic hypertensive patients whose parents were both hypertensive, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the hypertensive and normotensive groups, or between obese and non-obese subgroups of hypertensives. This is in contrast to the significantly higher frequency seen for the R1- allele of an Rsal RFLP of INSR: 0.71 in the hypertensive group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of hypertensives and did not differ between obese and non-obese subgroups. The non-obese hypertensives also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the hypertension-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the hypertension-associated variants of INSR as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron.

Adult↗