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Biomedical subjects

M A Brown

Publications and source records attributed to M A Brown.

At least 37 records · Page 2Linked to original sources
PubMed2004

A review of the MHC genetics of rheumatoid arthritis.

Rheumatoid arthritis is a common complex genetic disease, and, despite a significant genetic element, no gene other than HLA-DRB1 has been clearly demonstrated to be involved in the disease. However, this association accounts for less than half the overall genetic susceptibility. Investigation of other candidate genes, in particular those that reside within the major histocompatibility complex, are hampered by the presence of strong linkage disequilibrium and problems with study design.

Arthritis, Rheumatoid↗
PubMed2004

Automated self-initiated blood pressure or 24-hour ambulatory blood pressure monitoring in pregnancy?

OBJECTIVE: To determine whether self-initiated and recorded automated blood pressure measurement can provide an accurate estimate of ambulatory blood pressure in pregnant women suspected of having 'white coat hypertension'. DESIGN: A prospective observational study. SETTING: Women's and Children's Health Unit, St George Hospital, a teaching hospital of the University of New South Wales. POPULATION: Pregnant women being assessed for possible 'white-coat hypertension'. METHODS: Sixty-six pregnant women who were undergoing 24 hour ambulatory blood pressure monitoring (ABPM) in their home or work environment also measured their blood pressure six times during this interval using a self-initiated automated blood pressure recorder (Omron HEM 705CP). Agreement between awake ABPM and Omron recorded blood pressures was tested by Bland-Altman analysis. MAIN OUTCOME MEASURE: Limits of agreement between blood pressures measured by each device. RESULTS: Average blood pressures obtained by the two devices were identical (125/77 mmHg) but limits of agreement were wide, -20 to +23 mmHg for systolic blood pressure and -9 to +15 mmHg for diastolic blood pressure. CONCLUSION: The Omron HEM 705CP is a useful device for measuring group average blood pressures in pregnant women suspected of having white coat hypertension but cannot reliably replace ABPM for clinical management of individual pregnant women.

Blood Pressure↗
PubMed2004

A novel human leucocyte antigen-DRB1 genotyping method based on multiplex primer extension reactions.

We have developed and validated a semi-automated fluorescent method of genotyping human leucocyte antigen (HLA)-DRB1 alleles, HLA-DRB1*01-16, by multiplex primer extension reactions. This method is based on the extension of a primer that anneals immediately adjacent to the single-nucleotide polymorphism with fluorescent dideoxynucleotide triphosphates (minisequencing), followed by analysis on an ABI Prism 3700 capillary electrophoresis instrument. The validity of the method was confirmed by genotyping 261 individuals using both this method and polymerase chain reaction with sequence-specific primer (PCR-SSP) or sequencing and by demonstrating Mendelian inheritance of HLA-DRB1 alleles in families. Our method provides a rapid means of performing high-throughput HLA-DRB1 genotyping using only two PCR reactions followed by four multiplex primer extension reactions and PCR-SSP for some allele groups. In this article, we describe the method and discuss its advantages and limitations.

Alleles↗
PubMed2003

The effect of transforming growth factor beta1 gene polymorphisms in ankylosing spondylitis.

OBJECTIVES: To determine whether genetic polymorphisms in or near the transforming growth factor beta1 (TGFB1) locus were associated with susceptibility to or severity of ankylosing spondylitis (AS). METHODS: Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index). RESULTS: A weak association was noted between the rare TGFB1 +1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/+915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent-case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers. CONCLUSION: This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.

Adult↗
PubMed2003

Investigation of the role of ANKH in ankylosing spondylitis.

OBJECTIVE: The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. METHODS: Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. RESULTS: Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude lambda>/=1.4 (logarithm of odds score <-2) (equivalent to a genetic contribution of >10% to the AS sibling recurrence risk ratio) within this area contributing to AS. CONCLUSION: These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.

Adult↗
PubMed2003

Interleukin 10 polymorphisms in ankylosing spondylitis.

Genetic polymorphisms of the IL10 promoter region have been implicated in many autoimmune diseases, including seronegative spondyloarthropathies. We studied three SNPs (IL10-1087, -824, and -597) and two microsatellites (IL10R and IL10G) lying within the promoter region of IL10 for association with susceptibility to and clinical manifestations of ankylosing spondylitis (AS), a common form of spondyloarthritis. Four hundred and sixty-eight individuals from 182 Finnish families affected with AS were studied. No association between individual IL10 promoter region polymorphisms or marker haplotype was observed with susceptibility to AS, but weak association was noted between the IL10-597 and -824 SNPs and age of disease onset (P=0.01 for each SNP). The IL10.G4 allele was associated with BASFI (corrected for disease duration) (P=0.03). We conclude that IL10 promoter polymorphisms have no significant effect on susceptibility to AS, but may play a minor role in determining age of disease onset and disease severity.

Alleles↗
PubMed2003

Osteoclast formation from circulating precursors in osteoporosis.

OBJECTIVE: An imbalance between bone formation and bone resorption is thought to underlie the pathogenesis of reduced bone mass in osteoporosis. Bone resorption is carried out by osteoclasts. which are formed from marrow-derived cells that circulate in the monocyte fraction. The aim of this study was to determine the role of osteoclast formation in the pathogenesis of bone loss in osteoporosis. METHODS: The proportion of circulating osteoclast precursors and their relative sensitivity to the osteoclastogenic effects of M-CSF. 1,25(OH)2D3 and RANKL were assessed in primary osteoporosis patients and normal controls. RESULTS: Although there was no difference in the number of circulating osteoclast precursors in osteoporosis patients and normal controls. osteoclasts formed from osteoporosis patients exhibited substantially increased resorptive activity relative to normal controls. Although no increased sensitivity to the osteoclastogenic effects of 1,25(OH)D3 or M-CSF was noted, increased bone resorption was found in osteoporosis peripheral blood mononuclear cell (PBMC) cultures to which these factors were added. CONCLUSION: Our findings suggest that osteoclast functional activity rather than formation is increased in primary involutional osteoporosis and that dexamethasone acts to increase osteoclast formation.

Aged↗
PubMed2003

Non-inherited maternal HLA alleles are associated with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is strongly associated with a series of HLA-DRB1 alleles that encode a conserved sequence of amino acids ((70)Q/R K/R R A A(74)) in the DRbeta1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE-negative. Exposure to these alleles as non-inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA. METHODS: One hundred families, including the RA proband and both parents, were recruited. HLA-DRB1 genotyping was performed using an allele-specific polymerase chain reaction by standard methods. The frequencies of NIMA and non-inherited paternal antigens (NIPA) were compared using contingency tables and a two-tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined data RESULTS: We identified 36 families in which the proband was DRB1*04-negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non-inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non-inherited SE allele (P=0.03). CONCLUSION: A role for HLA NIMA in RA is suggested by these results.

Alleles↗
PubMed2003

Influence of milk production potential on forage dry matter intake by multiparous and primiparous Brangus females.

Brangus cows (n = 29) were used in three experiments to evaluate the effects of parity (multiparous vs. primiparous) and potential genetic merit for milk production (high vs. low) on forage intake during late gestation, early lactation, and late lactation. Cows were selected for milk production based on their sire's EPD for milk production (MEPD). Cows had ad libitum access to (130% of previous 2-d average intake) low-quality hay (5.3% CP and 76% NDF), and cottonseed meal was supplemented to ensure adequate degradable intake protein. All females were adapted to diets for at least 7 d, and individual intake data were collected for 9 d. During the lactation trials, actual milk production was determined using a portable milking machine following a 12-h separation from calves. During late gestation, multiparous cows consumed 24% more (P = 0.01) forage DM (kg/d) than primiparous cows; however, parity class did not influence forage intake when intake was expressed relative to BW. Furthermore, MEPD did not influence forage intake during late gestation. During early lactation, multiparous cows produced 66% more (P < 0.001) milk than primiparous cows, and high MEPD tended (P = 0.10) to produce more milk than low MEPD. Multiparous cows consumed 19% more (P < 0.0001) forage DM than did primiparous cows when expressed on an absolute basis, but not when expressed on a BW basis. High-MEPD cows consumed 8% more (P < 0.05) forage DM than did low-MEPD cows. During late lactation, multiparous cows produced 84% more milk than primiparous cows, although MEPD did not influence (P = 0.40) milk yield. In addition, multiparous cows consumed 17% more (P < 0.01) forage DM per day than primiparous cows, but when intake was expressed relative to BW, neither parity nor MEPD influenced forage DMI during late lactation. Milk yield and BW explained significant proportions of the variation in forage DMI during early and late lactation. Each kilogram increase in milk yield was associated with a 0.33- and 0.37-kg increase in forage DMI for early and late lactation, respectively. Results suggest that multiand primiparous cows consume similar amounts of low-quality forage DM, expressed per unit of BW, during late gestation and lactation. Selecting beef cows for increased genetic merit for milk production increases forage DMI during early lactation.

Animal Feed↗
PubMed2002

Detection of vitamin K-dependent proteins in venoms with a monoclonal antibody specific for gamma-carboxyglutamic acid.

gamma-Carboxyglutamic acid (Gla) is an unusual amino acid that is synthesized post-translationally from glutamate in a vitamin K-dependent reaction. The dicarboxylic side chain of Gla chelates Ca(2+), a property important for the biological activity of vitamin K-dependent proteins. To date, Gla-containing polypeptides have been identified in venom from two groups of organisms: elapid snakes, and snails of the genus Conus. In certain elapid snakes, a gamma-carboxylated coagulation factor Xa-like protein is a component of the venom whereas cone snails utilize Gla in a range of peptide neurotoxins. Using a monoclonal antibody that specifically recognizes Gla residues, venom samples from various organisms were screened by western blotting and immunofluorescence assays. Amino acid analyses were also performed on most samples. A survey of 21 snake species from 12 genera detected gamma-carboxylated polypeptides only in venom of snakes from the elapid subfamily Acanthophiinae. Gla-containing polypeptides were also observed in cone snail venom but not in venom or toxic salivary secretions from several other organisms. The Gla-specific antibody used here provides a simple immunochemical means to detect gamma-carboxylated polypeptides in venom and may allow new species to be identified that utilize Gla in the biosynthesis of toxic polypeptides.

1-Carboxyglutamic Acid↗
PubMed2002

The F158V polymorphism in FcgammaRIIIA shows disparate associations with rheumatoid arthritis in two genetically distinct populations.

OBJECTIVES: To investigate the association of the FcgammaRIIIA gene with rheumatoid arthritis (RA) in two genetically distinct groups: a white group from the United Kingdom and a northern Indian group. METHODS: The distributions of the two alleles of the FcgammaRIIIA F158V polymorphism were determined in 398 white patients from the United Kingdom and 63 Indian patients with RA and compared with those from 289 United Kingdom and 93 Indian healthy controls, respectively. RESULTS: Among the Indian patients, the frequency of the rare 158V allele and the proportion of 158VV homozygotes were reduced (relative risk (RR)=0.3, 95% confidence interval (95% CI) 0.1 to 1.1, p<0.06), reaching statistical significance for carrying the 158VV phenotype relative to 158FV or FF (RR=0.2, 95% CI 0.05-0.9, p<0.02). Conversely, no significant deviation in allelic frequencies was noted between the patients and controls from the United Kingdom. CONCLUSIONS: The 158VV phenotype showed a weak protective effect against developing RA in the Indian group. However, this sample was small (resulting in a low power for statistical analysis) and no independent confirmation was found in the larger white United Kingdom group. Thus the FcgammaRIIIA locus is unlikely to be of major importance in causing RA.

Alleles↗
PubMed2002

Genetic testing for haemochromatosis in patients with chondrocalcinosis.

Hereditary haemochromatosis (HH) is the most common lethal monogenic human disease, affecting roughly 1 in 300 white northern Europeans. Homozygosity for the C282Y polymorphism within the HFE gene causes more than 80% of cases, with compound heterozygosity of the C282Y and H63D polymorphism also increasing susceptibility to disease. The aim of this study was to determine the frequency of the C282Y and H63D polymorphisms in the disease, and to assess the risk of HH in heterozygotes for the C282Y polymorphism. 128 patients were recruited because of either radiographic chondrocalcinosis (at least bicompartmental knee disease or joints other than the knee involved) or CPPD pseudogout. Genotyping of the HFE C282Y and H63D mutations was performed using PCR/SSP and genotypes for the C282Y polymorphism confirmed by PCR/RFLP. Historical white European control data were used for comparison. Two previously undiagnosed C282Y homozygotes (1.6%), and 16 C282Y heterozygotes (12.5%), including four (3.1%) C282Y/H63D compound heterozygotes were identified. This represents a significant overrepresentation of C282Y homozygotes (relative risk 3.4, p=0.037), but the number of heterozygotes was not significantly increased. At a cost per test of pound1 for each subject, screening all patients with chondrocalcinosis using the above ascertainment criteria costs only pound64 for each case of haemochromatosis identified, clearly a highly cost effective test given the early mortality associated with untreated haemochromatosis. Routine screening for haemochromatosis in patients with appreciable chondrocalcinosis is recommended.

Adult↗
PubMed2002

Genotype x environmental interaction for mature size and rate of maturing for Angus, Brahman, and reciprocal-cross cows grazing bermudagrass or endophyte infected fescue.

Mature weight and rate of maturing were estimated in 177 Angus, Brahman, and reciprocal-cross cows grazing bermudagrass or endophyte-infected tall fescue over a 4-yr period to evaluate genotype x environment interactions. Data were collected every 28 d until cows were approximately 18 mo of age and then at prebreeding, postcalving, and weaning of calf. All cows with weight data to at least 42 mo of age were included in the analysis. Mature weight and rate of maturing were estimated using the three-parameter growth curve model described by Brody (1945). Data were pooled over year and analyzed by the general linear model procedure of SAS. Included in the models for mature weight and rate of maturing were the independent variables of genotype, environment, and genotype x environment interaction. There was a genotype x environment interaction (P < 0.01) for mature body weight (BW) but not for rate of maturing. Angus cows grazing fescue pastures had greater (P < 0.01) mean mature BW than Angus x Brahman cows grazing bermudagrass (611 +/- 17 vs 546 +/- 16 kg). Angus x Brahman cows grazing bermudagrass had lower (P < 0.05) mean mature BW than Brahman x Angus cows grazing bermudagrass or endophyte-infected fescue and Brahman cows grazing bermudagrass (546 +/- 16 vs 624 +/- 19, 614 +/- 22 and 598 +/- 20 kg, respectively). Brahman cows grazing endophyte-infected fescue had smaller (P < 0.05) mean mature BW than all genotype x forage combinations except for Angus x Brahman cows grazing bermudagrass. Angus cows had a smaller (P < 0.05) mean rate of maturing than Angus x Brahman and Brahman x Angus cows (0.039 +/- 0.002 vs 0.054 +/- 0.002 and 0.049 +/- 0.002%/mo, respectively), respectively, and Angus x Brahman cows had a larger (P < 0.05) mean rate of maturing than Brahman x Angus and Brahman cows (0.054 +/- 0.002 vs 0.049 +/- 0.002 and 0.041 +/- 0.002 %/mo, respectively). There was a direct breed x forage interaction (P < 0.05) for mature BW. These data suggest that the choice of breed type is important in maintaining a crossbreeding program, in that mature BW and rate of maturing are critical to the matching of animal requirements to available production resources.

Animal Feed↗
PubMed2002

Relationship of milk yield and quality to preweaning gain of calves from Angus, Brahman and reciprocal-cross cows on different forage systems.

Interactions of the regression of preweaning ADG on dam milk yield and quality with breed group and forage environment were evaluated in a two-phase study. Phase I consisted of milk yield and quality and calf gain records from 1989 to 1991 for purebred Angus (n = 64) and Brahman (n = 62) cows mated to sires of both breeds. Phase II consisted of milk yield and quality and calf gain records from 1991 to 1997 for Angus (n = 94), Brahman (n = 85), Angus x Brahman (n = 86) and Brahman x Angus (n = 93) mated to Polled Hereford sires. In Phase I, forage environments included common bermudagrass and endophyte-infected tall fescue. In Phase II, forage environments included common bermudagrass and endophyte-infected tall fescue (1991 to 1995) and a rotational system of both forages (1995 to 1997) in which each forage was grazed during its appropriate growing season, usually June through October for bermudagrass and November through May for tall fescue. Milk yield was estimated monthly six times during lactation from spring through fall and converted to a 24-h basis. Milk fat, milk protein, and somatic cell count were analyzed by a commercial laboratory. In Phase I, the relation of preweaning ADG to milk yield, milk fat yield, and protein yield was greater (P < 0.05) in Brahman cows on bermudagrass than Angus on bermudagrass. The regression of preweaning ADG on milk yield in Phase I was greater (P < 0.05) for cows on tall fescue than cows which grazed bermudagrass. In Phase II, the relation of preweaning ADG to milk yield, milk fat yield, and milk protein yield was greater or tended to be greater (P < 0.01, P < 0.11, P < 0.01, respectively) in purebred cows compared to reciprocal-cross cows. The regression of preweaning ADG on milk yield and milk protein yield was greater (P < 0.05) on tall fescue than bermudagrass in Phase II. These results suggest that the influence of milk yield and quality on calf growth may differ among breed types and production system, and the efficacy of genetic improvements in milk traits may depend on the breed type and forage environment.

Animal Feed↗
PubMed2001

Double-stranded RNA regulates IL-4 expression.

dsRNA, as genomic fragment, replicative intermediate, or stem and loop structure in cells infected by viruses, can act to signal the immune system of the presence of viral infections. Although most viral infections are associated with strong Th1 immune responses, Th2-type responses have also been observed. In this study, we characterize the effects of dsRNA on the induction of Th2 responses in human lymphocytes. We report that in addition to the well-known Th1-inducing capabilities of dsRNA, treatment of human lymphocytes with low concentrations of dsRNA (0.1-1 microg/ml) leads to the expression of the prototypic Th2 cytokine IL-4. This induction was accompanied with the concentration-dependent activation of NF-kappaB and NF-AT2 but not NF-AT1. In addition, dsRNA can directly activate an IL-4 promoter-driven chloramphenicol acetyltransferase reporter gene in transiently transfected Jurkat cells. These results are the first demonstration of a non-TCR-associated activator of NF-AT in human cells and suggest that dsRNA directly influences IL-4 gene expression through its effect on NF-AT activation. Our data provide support for the idea that dsRNA at low concentrations in vivo may induce a Th2-dominant response that is not optimal for protective immunity to the virus.

DNA-Binding Proteins↗
PubMed2001

Application of neurosonography to experimental physiology.

When Horsley and Clark invented the stereotaxic technique they revolutionized experimental neurobiology. For the first time it became possible to repeatably place experimental or surgical probes at precise locations within the skull. Unfortunately, variations in the position and size of neuroanatomical structures within the cranium have always limited the efficiency of this technology. Recent advances in diagnostic medical ultrasonography, however, allow for the real-time visualization of anatomical structures, in some cases with resolutions of up to 150 microm. We report here that commercially available ultrasonographs can be used in the laboratory to generate real-time in vivo images of brain structures in both anesthetized and awake-behaving animals. We found that ultrasonic imaging is compatible with many types of experimental probes including single neuron recording electrodes, microinjection pipettes, and electrodes for producing electrolytic lesions. Ultrasonic imaging can be used to place, monitor and visualize these probes in vivo. In our hands, commercially available ultrasonic probes designed for pediatric use allowed us to visualize anatomical structures with sub-millimeter resolution in primate brains. Finally, ultrasonic imaging allowed us to reduce the risk of accidentally damaging major blood vessels, greatly reducing the incidence of stroke as an unintended complication of an experimental neurosurgical procedure. Diagnostic ultrasound holds the promise of reducing the uncertainty associated with stereotaxic surgery, an improvement which would significantly improve the efficiency of many neurobiological investigations, reducing the number of animal subjects employed in this research. While this demonstration focuses on sonographic imaging in non-human primates, similar advances should also be possible for studies in other species, including rodents.

Animals↗