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B J Morris

Publications and source records attributed to B J Morris.

At least 55 records · Page 3Linked to original sources
PubMed1999

The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians.

A Gly460Trp variant of the cytoskeletal protein alpha-adducin has recently been implicated in the etiology of essential hypertension (HT) in a study involving southern European whites. We attempted to replicate this finding in a well-characterized, extensively studied group of 112 white Australians with essential HT, with strong family history (two HT parents), early-onset, moderate to severe disease, and of British extraction. Controls were 196 normotensive (NT) white subjects whose parents were both NT older than age 50 years. A mismatch polymerase chain reaction method involving BanII was developed for genotyping. Frequency of the Trp460 allele was 0.23 in the HT and 0.24 in the NT groups (chi2 = 0.2, P = .7). No association was observed with blood pressure, body mass index, age, plasma renin, angiotensinogen, angiotensin converting enzyme, cholesterol, triglycerides, or HDL or LDL cholesterol. Our results therefore provide no support for a role for the alpha-adducin variant in hypertension, at least in our severely affected Anglo-white group with strong family history of HT.

Alleles↗
PubMed1999

Activation of nuclear factor kappaB by nitric oxide in rat striatal neurones: differential inhibition of the p50 and p65 subunits by dexamethasone.

Nitric oxide (NO), an intercellular messenger in the brain, has been implicated in both neuronal plasticity and neurotoxicity. It has been suggested that NO can activate the DNA binding activity of nuclear factor kappaB (NF-kappaB) family proteins in some cell types while having an inhibitory effect in others. In this study we have investigated the effect of acute NO in primary neuronal cultures of rat striatum using immunohistochemistry. Exposure of neurones to the NO-mimetic S-nitroso-n-acetylpenicillamine (SNAP; 200 microM) and to bacterial lipopolysaccharide (LPS; 10 microg/ml) for 30 min increased nuclear protein expression of the p50 subunit of NF-kappaB. SNAP also enhanced nuclear protein expression of the p65 subunit of NF-kappaB. Simultaneously, the cytoplasmic expression of phosphorylated inhibitory protein IkappaB alpha was dramatically increased by SNAP (200 microM), LPS (10 microg/ml), and kainate (50 microM) treatment. In the adult rat, stimulation with NOR-3 (2 mg/kg), a NO donor, increased NF-kappaB DNA binding activity in the striatum after 45 min. Because glucocorticoids inhibit NF-kappaB activity, primary cultures were pretreated with dexamethasone (50 microM) before SNAP, LPS, and kainate treatment, and the effect on the protein expression level of the individual subunits p50 and p65 present in the classical form of the transcription factor NF-kappaB was assessed. Dexamethasone pretreatment resulted in a marked reduction of p65 protein in striatal neurones after SNAP, LPS, and kainate, whereas p50 expression was reduced by dexamethasone pretreatment only after an LPS stimulus. This study indicates that NO-releasing compounds can directly induce nuclear NF-kappaB subunit expression in rat striatum and that glucocorticoids selectively inhibit p65 subunit expression following exposure to NO.

Animals↗
PubMed1999

Influence of angiotensin converting enzyme (ACE) genotype on interpretation of diagnostic tests for serum ACE activity.

BACKGROUND: The discovery that an insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene influences the circulating concentration of ACE may have implications for the proper use of serum ACE activity measurements in screening for sarcoidosis. AIM: To determine whether the sensitivity of the serum ACE test improves if ACE genotype is taken into account. METHODS: A retrospective determination of ACE genotype and clinical diagnosis was done in 54 patients with serum ACE activity above the upper limit of the reference range for the insertion (II) genotype. ACE was measured by radioenzymatic and spectrophotometric techniques, and genotype by PCR. RESULTS: When serum ACE values determined diagnostically were related to the appropriate genotype-specific reference range, sensitivity and specificity for diagnosis of sarcoidosis were 65-70% and 58% respectively, compared to 47-57% and 77% with a reference range unsegregated for genotype. CONCLUSION: ACE genotyping may be helpful in determining the diagnostic significance of mildly elevated serum ACE activity in patients with the II and ID genotypes.

Female↗
PubMed1999

Different frequencies of inducible nitric oxide synthase genotypes in older hypertensives.

A locus for essential hypertension has been found recently on chromosome 17 in the general vicinity of the inducible nitric oxide synthase (iNOS) gene (NOS2A at 17cen-q11.2). We therefore tested NOS2A markers for association and linkage with hypertension in affected Australian Anglo-Caucasians. Patients for the association study (n=112) were from our cohort of hypertensives (systolic/diastolic=175+/-25 SD/112+/-19 mm Hg) who were the offspring of 2 hypertensive parents; control subjects (n=164) were normotensives whose parents were both normotensive. The linkage study involved 156 hypertensive sib-pairs. Genotypes for an 8-allele pentameric repeat located 2.6 kb upstream of NOS2A and of a biallelic tetranucleotide repeat 0.7 kb upstream were determined by polymerase chain reaction and automated gene scan analysis. In the association study, the frequency of the minor allele of the biallelic marker was 0.18 in the hypertensives and 0.14 in the normotensives (chi21 df=1.1, P=0.3). Allele frequencies for the multiallelic marker were also similar in each group (chi2 7 df=9.8, P=0.2). Furthermore, no genotypic differences in blood pressure were apparent. In the sib-pair study, SPLINK APM, and MAPMAKERS/SIBS did not indicate excess allele sharing. We also examined genotype as a function of age. In the younger (< 60 years) hypertensives as well as younger or older normotensives, genotype and allele frequency of the biallelic marker was similar (0.12 to 0.14). However, in hypertensives >/=60 years of age, frequency of the minor allele was 0.28 (chi2=7.4, P=0.006). Homozygotes for this allele were rare. Frequency of heterozygotes was 0.19 for normotensives but 0.39 for the older hypertensives (chi2=8.0, P=0.018) and was 0.40 for hypertensive sibs >/=60 years of age with a diastolic pressure >/=100 mm Hg. Furthermore, homozygotes for the major allele were 7 years younger than heterozygotes (P=0.05 by ANOVA). In conclusion, the present study shows (1) no evidence for a role of NOS2A in hypertension and (2) a genotypic difference in frequency of a NOS2A promoter variant in older hypertensives, seen in 2 different cohorts. A possible interpretation of the latter observation is that NOS2A genotype could affect longevity, at least in patients at high risk by having moderate to severe hypertension.

Adult↗
PubMed1999

Association and linkage analyses of glucocorticoid receptor gene markers in essential hypertension.

Suggestive evidence has been obtained in a "4-corners" study for involvement of the glucocorticoid receptor gene (GRL) in genetic variation in blood pressure. Therefore, we tested markers at the GRL locus for association and linkage with essential hypertension (HT). For the association study, we used a well-characterized group of 129 white Australians of Anglo-Celtic extraction who had HT, a strong family history of HT (2 parents with the disease), and early-onset moderate-to-severe disease. Controls were 195 normotensive white subjects whose parents were normotensive past the age of 50 years. For the linkage study, we used 175 sibling pairs of similar ancestry. The case-control groups were genotyped for an Asn363Ser variant in exon 2, a G/T variant in intron 4, and a microsatellite marker (D5S207) tightly linked (<200 kb) to GRL. For the groups as a whole, no association or linkage was observed after analysis of data by a variety of statistical tests. Analysis of sibling-pair data gave an exclusion score of -3.8 for the logarithm of the odds for linkage, indicating significant nonlinkage. However, in females, weak association of the intron 4 polymorphism with HT (P=0.03), as well as with systolic and diastolic blood pressure in all subjects (P=0. 04 and 0.03), was observed, and in the case of the D5S207 marker, association with HT was apparent in males (P=0.0001). Thus, although our results provide no overall support for GRL in HT etiology, apparent gender-specific associations could exist in this genomic region, possibly reflecting correlated occurrence with (an)other metabolic syndrome disorder(s).

Age of Onset↗
PubMed1999

hOGG1 Ser326Cys polymorphism and lung cancer susceptibility.

The human homologue of the yeast OGG1 gene, hOGG1, has been cloned, and its genetic structure has been determined. Several polymorphisms in the hOGG1 gene were detected in the Japanese populations, and among them, the Ser-Cys polymorphism at codon 326 has been shown to have a functional difference in complementation of mutant Escherichia coli that is defective in the repair of 8-hydroxyguanine. Activity in the repair of 8-hydroxyguanine is greater in hOGG1-Ser326 protein than in hOGG1(326) protein. Because many environmental carcinogens produce 8-hydroxyguanine residue and mismatching to this modified base potentially causes oncogenic mutations, the capacity to repair these lesions can be involved in cancer susceptibility in human beings. We, therefore, examined allele distributions of the Ser326Cys polymorphism in a case-control study of male lung cancer in Okinawa. The analyses based on 241 cases and 197 hospital controls disclosed the following findings. (a) Those with the Cys/Cys genotype were at an increased risk of squamous cell carcinoma and nonadenocarcinoma compared to those with the Ser/Cys and those with the Ser/Ser genotypes combined. The odds ratios adjusted for age and smoking history were 3.01 (95% confidence interval, 1.33-6.83) and 2.18 (95% confidence interval, 1.05-4.54), respectively. (b) The odds ratios for other histological subtypes of lung cancer or those in total were not significant. Those for Cys/Cys or Ser/Cys genotype against Ser/Ser did not reach statistical significance in any cell type. (c) The distributions of this polymorphism varied for different populations (Chinese, Japanese, Micronesians, Melanesians, Hungarians, and Australian Caucasians), with much less prevalence of Cys allele in the latter three populations. Although our sample size was limited, these results indicate that the Ser326Cys variant may be related to squamous cell lung cancer susceptibility. The Cys/Cys genotype appears to be more susceptible to squamous cell carcinoma, although the risk is less than that previously reported to be associated with the CYP1A1 gene. Further studies are needed to assess the importance of the interpopulation variation to cancer susceptibility.

Adult↗
PubMed1998

Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus.

Induction of long-term potentiation (LTP) in the hippocampus is associated with changes in expression of a variety of different proteins and is thought to be the mechanism which underlies synaptic plasticity. The 25 kDa synaptosomal-associated protein (SNAP-25) is a presynaptic protein which is involved in neurotransmitter exocytosis at the nerve terminal. Two isoforms of SNAP-25 have so far been identified (a and b) which differ in their distribution and developmental regulation. Using in situ hybridization, we demonstrated that the mRNA levels of the two isoforms of this protein are increased 2 h after the induction of LTP in granule cells of the dentate gyrus following high frequency stimulation of the perforant path in vivo. These observations further demonstrate the involvement of both isoforms of SNAP-25 in functional synaptic plasticity, although their exact roles have yet to be fully determined.

Animals↗
PubMed1998

Increased expression of dendritic mRNA following the induction of long-term potentiation.

A small number of mRNAs, including Ca2+/calmodulin-dependent protein kinase II alpha-subunit (CamKIIalpha) mRNA and microtubule-associated protein 2 (MAP2) mRNA, are present in the dendrites of neurones as well as in the cell bodies. We show here that the induction of long-term potentiation (LTP) in the hippocampal perforant path/granule cell synapses in anaesthetised rats is associated with increased levels of CamKIIalpha mRNA and MAP2 mRNA in the granule cell dendrites after 2 h. Similarly, induction of LTP in the Schaffer collateral/CA1 pyramidal cell synapses in hippocampal slices maintained in vitro also results in elevated dendritic levels of CamKIIalpha mRNA and MAP2 mRNA 2 h later. In both models, the levels of various other mRNA species restricted to the cell body region were unaffected by the induction of LTP. Increased expression of dendritic CamKIIalpha mRNA and MAP2 mRNA appears to be a general feature of hippocampal plasticity, since it occurs following LTP induction in both the dentate gyrus and the CA1 region. The elevation of mRNA levels in a restricted region close to the afferent synapses would allow a highly-localised enhancement of the synthesis of the corresponding proteins, providing an elegant mechanism for protein-synthesis-dependent synaptic plasticity to maintain a high degree of anatomical specificity.

Animals↗
PubMed1998

Insulin receptor exon 11+/- isoform mRNA in spontaneously hypertensive and adrenocorticotropin-hypertensive rats.

OBJECTIVE: To test the hypothesis that insulin resistance of the spontaneously hypertensive rat (SHR) and adrenocorticotropin-hypertensive rat is related to a difference in the proportion of the functionally different, alternatively spliced exon 11 isoforms of the insulin receptor. DESIGN: We determined the proportions of mRNA for the exon 11+ and exon 11- isoforms in various tissues of SHR and Wistar-Kyoto rats aged 3, 6, 9 and 12 weeks, which span the pre-hypertensive phase through to established hypertension, as well as in Sprague-Dawley rats with adrenocorticotropin-induced hypertension and Sprague-Dawley controls. METHODS: Detection of mRNA involved a reverse-transcriptase polymerase chain reaction technique specific for each isoform and quantification was by slot and dot blot hybridization. RESULTS: Mean proportions of exon 11+ mRNA in SHR, Wistar-Kyoto rats, adrenocorticotropin-hypertensive rats and Sprague-Dawley control rats at each age were 95% for liver, 82% for adipose tissue, 77% for kidney, 66% for adrenal, 53% for heart, 26% for cerebral cortex, 23% for hypothalamus, and 3% for skeletal muscle. There was also no difference in concentration of total insulin receptor mRNA. CONCLUSIONS: The absence of any difference in proportions of insulin receptor mRNA isoforms argues against the hypothesis that an alteration of differential splicing plays a role in the models of hypertension studied.

Adrenocorticotropic Hormone↗
PubMed1998

Scanning the genome for essential hypertension loci.

1. Essential hypertension occurs in people with an underlying genetic predisposition who subject themselves to adverse environmental influences. The number of genes involved is unknown, as is the extent to which each contributes to final blood pressure and the severity of the disease. 2. In the past, studies of potential candidate genes have been performed by association (case-control) analysis of unrelated individuals or linkage (pedigree or sibpair) analysis of families. These studies have resulted in several positive findings but, as one may expect, also an enormous number of negative results. 3. In order to uncover the major genetic loci for essential hypertension, it is proposed that scanning the genome systematically in 100-200 affected sibships should prove successful. 4. This involves genotyping sets of hypertensive sibships to determine their complement of several hundred microsatellite polymorphisms. Those that are highly informative, by having a high heterozygosity, are most suitable. Also, the markers need to be spaced sufficiently evenly across the genome so as to ensure adequate coverage. 5. Tests are performed to determine increased segregation of alleles of each marker with hypertension. The analytical tools involve specialized statistical programs that can detect such differences. Non-parametric multipoint analysis is an appropriate approach. 6. In this way, loci for essential hypertension are beginning to emerge.

Chromosomes, Human↗
PubMed1998

G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension.

-Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein beta3 subunit gene (GNB3) induces formation of a splice variant (Gbeta3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (chi2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105+/-7, 109+/-16, and 128+/-28 mm Hg (mean+/-SD) for CC, CT, and TT, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein beta3 subunit gene in the causation of essential hypertension.

Age of Onset↗
PubMed1998

Association of Ile462Val (Exon 7) polymorphism of cytochrome P450 IA1 with lung cancer in the Asian population: further evidence from a case-control study in Okinawa.

Okinawa, a group of islands that lie between the East China Sea and the Pacific Ocean, 2000 km south of the Japanese main islands, has a different profile of diseases, ethnicities, and cultures than does the rest of Japan. We examined an Ile462Val polymorphism (CYP1A1*2 allele) of cytochrome P450 IA1 in a hospital-based case-control study of lung cancer patients (247 cases and 185 controls) in Okinawa to ascertain the association of this variant with lung cancer. In addition, the distribution of this genotype was studied in populations from different areas of Japan, including Tokyo (n = 69) and Iwate (northern part of Japan; n = 81), as well as in a Chinese group from the Jiangsu province (n = 39) and in an Australian Caucasian group (n = 146). Genotype frequency in controls was not significantly different from area to area in Japan. In Okinawa, however, the genotype encoding Val/Val was associated with a significantly higher risk of lung cancer (odds ratio = 3.32, P = 0.013), especially of squamous cell carcinoma and small cell carcinoma (odds ratio = 4.85 and 9.35, respectively). The Val-encoding allele was less frequent in the Chinese population and was rare in Australian Caucasians. Thus, this study gives support to the value of the cytochrome P450 IA1 Ile462Val polymorphism as a practical high-risk marker of lung cancer in populations, especially those in southeast Asia, in which this variant is more common.

Adult↗
PubMed1997

Long-term potentiation in perforant path/granule cell synapses is associated with a post-synaptic induction of proenkephalin gene expression.

Enkephalin peptides released from hippocampal mossy fibres lower the threshold for the generation of long-term potentiation (LTP) at the mossy fibre synapses. High frequency stimulation of the hippocampal dentate gyrus, sufficient to induce mossy fibre LTP, is associated with increased expression of the proenkephalin gene in the granule cells. We show here that a similar elevation in proenkephalin mRNA levels is observed, in anaesthetised rats, following stimulation of the perforant path sufficient to induce LTP in the perforant path/granule cell synapses. This strengthens the evidence implicating granule cell enkephalins as mediators of functional plasticity in the hippocampus. Furthermore. the results hint at a form of 'domino plasticity', where potentiation of transmission at the perforant path/granule cell synapses is subsequently followed by an enkephalin-mediated potentiation of transmission at the mossy fibre synapses.

Action Potentials↗
PubMed1997

Transactivation of the human renin promoter by the cyclic AMP/protein kinase A pathway is mediated by both cAMP-responsive element binding protein-1 (CREB)-dependent and CREB-independent mechanisms in Calu-6 cells.

We examined the DNA sequence and transcription factor requirements for cAMP-induced transactivation of the human renin promoter using Calu-6 cells that express human renin mRNA endogenously. A series of constructs containing 896 base pairs of human renin 5'-flanking DNA fused to the luciferase gene and containing either the native, a consensus, or a nonfunctional cAMP response element (CRE) were used to assess DNA sequence requirements mediating the cAMP response. Expression vectors encoding the CREB-1 transcription factor, a dominant negative mutant form of CREB-1, and the catalytic subunit of protein kinase A (PKA) were used to assess transcription factor requirements mediating the cAMP response. Forskolin treatment alone only caused a 2-3-fold activation of the HREN promoter in Calu-6 cells, but nearly a 10-fold activation in JEG-3 cells, which do not express renin but are highly responsive to cAMP. Gel shift assays revealed the binding of five specific DNA-protein complexes consisting of the ATF-1 and CREB-1 transcription factors, one of which was an ATF-1.CREB-1 heterodimer suggesting the potential for regulation of CREB-1 activity by ATF-1. However, over-expression of CREB-1 did not significantly enhance forskolin-induced human renin transcriptional activity. Transfection of both Calu-6 and JEG-3 cells with a PKA expression vector resulted in a 10-fold induction of human renin transcriptional activity in constructs containing the native or consensus CRE and 5-fold activation in a construct containing a nonfunctional CRE. We confirmed that the PKA response has both a CREB-dependent and CREB-independent component by demonstrating that the PKA response was abolished by co-transfection of a dominant negative mutant form of CREB-1 into cells containing the native or consensus CRE construct but not in cells containing the nonfunctional CRE construct. We therefore conclude that the human renin promoter can be transcriptionally activated in a renin expressing cell line through the cAMP-PKA pathway and is mediated by both a CREB-dependent and CREB-independent mechanism.

Activating Transcription Factor 1↗
PubMed1997

Association analyses of S(A) gene variant in essential hypertensives.

A gene designated S(A) has been implicated in hypertension (HT) in rat genetic models and Japanese HT patients. However, a linkage study in whites was negative. Because of the limitations of genetic analyses, confirmation in different settings is imperative. Therefore, we conducted a cross-sectional case-control study involving 106 HT and 96 normotensive (NT) white subjects. A polymerase chain reaction technique was developed for PstI restriction fragment length polymorphism (RFLP) determination. We could find no association of this RFLP with HT (frequency of minor allele, A2 = 0.11 in HTs v 0.07 in NTs). However, A2 displayed an association with increase in body mass index in HTs: for a body mass index mean of 26 kg/m2 or more, A2 = 0.17 compared to 0.06 for body mass index of less than 26 kg/m2 (chi2 = 6.4, P = .01; odd ratio 3.4, 95% confidence interval 1.2 to 10.0); for a body mass index of 28 kg/m2 or more, A2 = 0.20 (chi2 = 10.4, P = .001; odds ratio 4.0, 95% confidence interval 1.5 to 10.5). Furthermore, A2 tracked significantly with elevation in body mass index in the HTs (F = 4.8, P = .01 by one-way ANOVA). In conclusion, we could find no association of S(A) genotype with HT, but obtained preliminary evidence for a possible association with variation in body mass index in a severely affected HT group with a strong family history of HT.

Alleles↗
PubMed1997

Association of a low density lipoprotein receptor microsatellite variant with obesity.

OBJECTIVE: To determine whether a microsatellite polymorphism located towards the 3' end of the low density lipoprotein receptor gene (LDLR) is associated with obesity. DESIGN: A cross-sectional case-control study. SUBJECTS: One hundred and seven obese individuals, defined as a body mass index (BMI) > or = 26 kg/m2, and 163 lean individuals, defined as a BMI < 26 kg/m2. MEASUREMENTS: BMI, blood pressure, serum lipids, alleles of LDLR microsatellite (106 bp, 108 bp and 112 bp). RESULTS: There was a significant association between variants of the LDLR microsatellite and obesity, in the overall tested population, due to a contributing effect in females (chi 2 = 12.3, P = 0.002), but not in males (chi 2 = 0.3, P = 0.87). In females, individuals with the 106 bp allele were more likely to be lean, while individuals with the 112 bp and/or 108 bp alleles tended to be obese. CONCLUSIONS: These results suggest that in females, LDLR may play a role in the development of obesity.

Alleles↗
PubMed1997

Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension.

The renin-angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A-->C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT1R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross-sectional case-control study of the A1166C variant in a well-characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/BfrI restriction fragment length polymorphism analysis. Frequency of the C1166 allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (chi 2 = 13, P = 0.0015) and allele (chi 2 = 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA + AC = 7.3 [95% CI, 1.9-31.9). The present results implicate the AT1R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.

Adult↗