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Biomedical subjects

A M Martin

Publications and source records attributed to A M Martin.

At least 19 recordsLinked to original sources
PubMed2005

Anomalous quantum reflection of Bose-Einstein condensates from a silicon surface: the role of dynamical excitations.

We investigate the effect of interatomic interactions on the quantum-mechanical reflection of Bose-Einstein condensates from regions of rapid potential variation. The reflection process depends critically on the density and incident velocity of the condensate. For low densities and high velocities, the atom cloud has almost the same form before and after reflection. Conversely, at high densities and low velocities, the reflection process generates solitons and vortex rings that fragment the condensate. We show that this fragmentation can explain the anomalously low reflection probabilities recently measured for low-velocity condensates incident on a silicon surface.

Journal Article↗
PubMed2005

HLA-B*5701 typing by sequence-specific amplification: validation and comparison with sequence-based typing.

Susceptibility to abacavir hypersensitivity (ABC HSR) is strongly associated with alleles carried on the 57.1 ancestral haplotype including HLA-B*5701 and Hsp70 Hom M493T. In one study, prospective testing for HLA-B*5701 and exclusion of individuals carrying this allele, from receiving abacavir, substantially lowered the incidence of ABC HSR to 0% (95% confidence interval 0-0.075%). The presence of HLA-B*5701 is usually detected by standard serological tests and by molecular genetic methods such as sequence-based typing (SBT). While the former test cannot discriminate between HLA-B57 subtypes, the expensive SBT may not be readily available in all laboratories. Hence, an alternate method was developed to detect HLA-B*5701 using allele and group-specific polymerase chain reaction-sequence-specific primers (PCR-SSP) typing. This PCR-SSP-typing method positively amplified all HLA-B*5701 alleles in concordance with their SBT-assigned typing. This multiplexed SSP assay was able to distinguish between HLA-B*5701 (n = 10) and closely related HLA-B57 alleles B*5702 (n = 2), -B*5703 (n = 1), -B*5704 (n = 1) alleles and non-HLA-B*57 alleles (n = 61). In conclusion, this method of HLA-B*5701 detection is a rapid and accurate typing method with high specificity, sensitivity and reproducibility.

Alleles↗
PubMed2004

Absence of BRAF mutations in UV-protected mucosal melanomas.

BACKGROUND: Mutations in BRAF have recently been identified in a significant percentage of primary and metastatic cutaneous malignant melanomas. As ultraviolet (UV) exposure may play a role in the development of cutaneous melanoma lesions with BRAF mutations, BRAF mutation frequency in melanomas arising in sites protected from sun exposure may be lower than those from sun-exposed areas. Thus, we determined the BRAF mutation frequency in a panel of 13 mucosal melanomas and compared those data with data from all currently published series of cutaneous melanomas. METHODS: BRAF exon 15 DNA from 13 archival primary mucosal melanomas (eight vulvar, four anorectal, and one laryngeal) was sequenced using intron-based primers. As archival DNA occasionally produces poor-quality template, results were confirmed with a TspRI restriction fragment length polymorphism (RFLP) that distinguishes wild-type BRAF from the common mutant form V599E. A binomial test was used to compare the mutation frequency in the mucosal melanomas with the published mutation frequency in cutaneous melanomas. RESULTS: None of the 13 mucosal melanomas in this series had an exon 15 BRAF mutation, as compared to 54/165 (33%) primary cutaneous melanomas with BRAF mutations in a compilation of all current published studies (p = 0.006). DISCUSSION: These data suggest that UV exposure, plays a role in the genesis of BRAF mutations in cutaneous melanoma, despite the absence of the characteristic C>T or CC>TT mutation signature associated with UV exposure, and suggests mechanisms other than pyrimidine dimer formation are important in UV-induced mutagenesis.

DNA Mutational Analysis↗
PubMed2003

Model for the voltage steps in the breakdown of the integer quantum Hall effect.

In samples used to maintain the U.S. resistance standard the breakdown of the dissipationless integer quantum Hall effect occurs as a series of dissipative voltage steps. A mechanism for this type of breakdown is proposed, based on the generation of magnetoexcitons when the quantum Hall fluid flows past an ionized impurity above a critical velocity. The calculated generation rate gives a voltage step height in good agreement with measurements on both electron and hole gases. We also compare this model to a hydrodynamic description of breakdown.

Journal Article↗
PubMed2003

Creation of solitons and vortices by bragg reflection of Bose-Einstein condensates in an optical lattice.

We study the dynamics of Bose-Einstein condensates in an optical lattice and harmonic trap. The condensates are set in motion by displacing the trap and initially follow simple semiclassical paths, shaped by the lowest energy band. Above a critical displacement, the condensate undergoes Bragg reflection. For high atom densities, the first Bragg reflection generates a train of solitons and vortices, which destabilize the condensate and trigger explosive expansion. At lower densities, soliton and vortex formation requires multiple Bragg reflections, and damps the center-of-mass motion.

Journal Article↗
PubMed2002

Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.

BACKGROUND: The use of abacavir--a potent HIV-1 nucleoside-analogue reverse-transcriptase inhibitor--is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1-positive individuals treated with abacavir. METHODS: MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (p(c)) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined. FINDINGS: HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29-481], p(c)<0.0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20-268], p(c)<0.0001 ). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43-15 675], p(c)<0.0001). Other MHC markers also present on the 57.1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. INTERPRETATION: Genetic susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient.

Adult↗
PubMed2002

The effect of ad libitum ingestion of a caffeinated carbohydrate-electrolyte solution on urinary caffeine concentration after 4 hours of endurance exercise.

The purpose of the present study was to examine the effect of ad libitum ingestion of a carbohydrate-electrolyte solution (CES) with 150 mg x L (-1) caffeine (CAF) on urinary CAF concentration after 4 h of endurance exercise. Fifty-eight healthy and well-trained male subjects ingested ad libitum a 7 % CES with 150 mg x L (-1) CAF during 4 h cycling at 50 % of maximal work capacity. Total fluid consumption (mean +/- SE) was 2799 +/- 72 mL and CAF intake was 420 +/- 11 mg (5.7 +/- 0.2 mg x kg (-1) body weight). The post-exercise urinary CAF concentration (4.53 +/- 0.25 microg x mL (-1)) was below the doping level of the International Olympic Committee (12 microg x mL (-1)) in all subjects (range 1.20 - 10.84 microg x mL (-1)). A highly positive correlation was observed between CAF intake and post-exercise urinary CAF concentration (r = 0.68, p < 0.001). It is concluded that ad libitum ingestion of a CES with 150 mg x L (-1) CAF during 4 h cycling resulted in post-exercise urinary concentration below the doping level in all subjects.

Adult↗
PubMed2001

Germline mutations in BRCA1 and BRCA2 in breast-ovarian families from a breast cancer risk evaluation clinic.

PURPOSE: Data from the Breast Cancer Linkage Consortium suggest that the proportion of familial breast and ovarian cancers linked to BRCA1 or BRCA2 may be as high as 98% depending on the characteristics of the families, suggesting that mutations in BRCA1 or BRCA2 may entirely account for hereditary breast and ovarian cancer families. We sought to determine what proportion of families with both breast and ovarian cancers seen in a breast cancer risk evaluation clinic are accounted for by coding region germline mutations in BRCA1 and BRCA2 as compared to a linkage study group. We also evaluated what clinical parameters were predictive of mutation status. PATIENTS AND METHODS: Affected women from 100 families with at least one case of breast cancer and at least one case of ovarian cancer in the same lineage were screened for germline mutations in the entire coding regions of BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis, a polymerase chain reaction-based heteroduplex analysis, or direct sequencing. RESULTS: Unequivocal deleterious mutations were found in 55% (55 of 100) of the families studied. Mutations in BRCA1 and BRCA2 accounted for 80% and 20% of the mutations overall, respectively. Using multivariate analysis, the strongest predictors of detecting a mutation in BRCA1 or BRCA2 in this study group were the presence of a single family member with both breast and ovarian cancer (P <.0009; odds ratio [OR], 5.68; 95% confidence interval [CI], 2.04 to 15.76) and a young average age at breast cancer diagnosis in the family (P <.0016; OR, 1.69; 95% CI, 1.23 to 2.38). CONCLUSION: These results suggest that at least half of breast/ovarian families evaluated in a high-risk cancer evaluation clinic may have germline mutations in BRCA1 or BRCA2. Whether the remaining families have mutations in noncoding regions in BRCA1, mutations in other, as-yet-unidentified, low-penetrance susceptibility genes, or represent chance clustering remains to be determined.

Adult↗
PubMed2001

Antibody recognition of melphalan adducts characterized using immobilized DNA: enhanced alkylation of G-Rich regions in cells compared to in vitro.

The bifunctional alkylating agent, melphalan, forms adducts on DNA that are recognized by two previously described monoclonal antibodies, MP5/73 and Amp4/42. Immunoreactivity to MP5/73 was lost when alkylated DNA was exposed to alkaline pH, while Amp4/42 only recognized the structures formed after the alkali treatment. Competitive enzyme-linked immunoadsorbent assays (ELISAs) indicated that in 0.01 and 0.1 M NaOH, loss of immunoreactivity to MP5/73 occurred with half-lives that were at least 2-fold longer than half-lives for gain of immunoreactivity to Amp4/42. This supported previously published evidence that Amp4/42 did not simply recognize all the products formed by alkali treatment of adducts that were initially recognized by MP5/73. Adducts recognized by MP5/73 on RNA were considerably more stable at 100 degrees C and pH 7 than adducts on DNA. This was consistent with the hypothesis that immunorecognition involved N7 guanine adducts and ruled out the involvement of phosphotriesters in immunoreactivity. Synthetic oligodeoxyribonucleotides, covalently immobilized onto 96-well plates, were reacted with melphalan and incubated for various periods with alkali, and then the levels of adducts recognized by each antibody in replicate wells were assayed by a direct binding ELISA. Adducts formed on oligodeoxyguanylic acid were recognized very weakly by Amp4/42, unlike other DNA sequences that were tested. Retention of immobilized DNA during alkali treatment was confirmed by immunoassay of cisplatin adducts. Poor recognition by Amp4/42 of adducts in oligodeoxyguanylic acid was confirmed by a competitive ELISA. Amp4/42, unlike MP5/73, efficiently recognized adducts resulting from alkylation of DNA with chlorambucil. It is concluded that the two antibodies recognized melphalan adducts in different DNA sequence environments and that this explains (a) the different alkali stability of immunoreactive adducts and (b) previous results which showed that, in DNA from melphalan-treated cells, adducts recognized by Amp4/42 formed a smaller proportion of total adducts compared to DNA alkylated in vitro. The results presented here indicate that this was caused by a marked cellular influence on the overall sequence-dependent pattern of DNA alkylation or repair.

Alkylation↗
PubMed2001

Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11-14 weeks of gestation.

OBJECTIVE: To examine the value of uterine artery Doppler at 11-14 weeks of gestation in the identification of women at risk of developing pre-eclampsia and fetal growth restriction. METHODS: Uterine artery Doppler was carried out at 11-14 weeks in 3324 consecutive singleton pregnancies attending for routine care in three London hospitals. The right and left uterine arteries were identified using color flow mapping and velocity waveforms were obtained using pulsed Doppler. The mean pulsatility index of the two arteries was determined and the predictive value of a mean pulsatility index > the 95th centile in the prediction of pre-eclampsia and/or fetal growth restriction was calculated. RESULTS: Satisfactory flow velocity waveforms were obtained from both uterine arteries in 3195 (96.1%) of the 3324 pregnancies examined and complete outcome information was obtained for 3045 (95.3%) of these women. The 95th centile of the uterine artery mean pulsatility index was 2.35 and did not change significantly with gestational age. The pregnancy was complicated by pre-eclampsia in 63 (2.1%) cases and by fetal growth restriction in 290 (9.5%) cases. The sensitivity of a mean pulsatility index > 2.35 for pre-eclampsia (with or without fetal growth restriction) was 27.0% but for fetal growth restriction alone it was 11.7%. The respective sensitivities for these complications requiring delivery before 32 weeks of gestation were 60.0% and 27.8%, respectively. CONCLUSION: Uterine artery Doppler at 11-14 weeks of gestation identifies a high proportion of women who develop severe pre-eclampsia and/or fetal growth restriction.

Adult↗
PubMed2000

Association of HPC2/ELAC2 genotypes and prostate cancer.

HPC2/ELAC2 has been identified as a prostate cancer (CaP) susceptibility gene. Two common missense variants in HPC2/ELAC2 have been identified: a Ser-->Leu change at amino acid 217, and an Ala-->Thr change at amino acid 541. Tavtigian et al. reported that these variants were associated with CaP in a sample of men drawn from families with hereditary CaP. To confirm this report in a sample unselected for family history, we studied 359 incident CaP case subjects and 266 male control subjects that were frequency matched for age and race and were identified from a large health-system population. Among control subjects, the Thr541 frequency was 2.9%, and the Leu217 frequency was 31.6%, with no significant differences in frequency across racial groups. Thr541 was only observed in men who also carried Leu217. The probability of having CaP was increased in men who carried the Leu217/Thr541 variants (odds ratio = 2.37; 95% CI 1.06-5.29). This risk did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of CaP in the general population of inference. These results suggest that common variants at HPC2/ELAC2 are associated with CaP risk in a sample unselected for family history or other factors associated with CaP risk.

Adult↗
PubMed2000

Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing.

The frequency of genomic rearrangements in BRCA1 was assessed in 42 American families with breast and ovarian cancer who were seeking genetic testing and who were subsequently found to be negative for BRCA1 and BRCA2 coding-region mutations. An affected individual from each family was tested by PCR for the exon 13 duplication (Puget et al. 1999a) and by Southern blot analysis for novel genomic rearrangements. The exon 13 duplication was detected in one family, and four families had other genomic rearrangements. A total of 5 (11. 9%) of the 42 families with breast/ovarian cancer who did not have BRCA1 and BRCA2 coding-region mutations had mutations in BRCA1 that were missed by conformation-sensitive gel electrophoresis or sequencing. Four of five families with BRCA1 genomic rearrangements included at least one individual with both breast and ovarian cancer; therefore, 4 (30.8%) of 13 families with a case of multiple primary breast and ovarian cancer had a genomic rearrangement in BRCA1. Families with genomic rearrangements had prior probabilities of having a BRCA1 mutation, ranging from 33% to 97% (mean 70%) (Couch et al. 1997). In contrast, in families without rearrangements, prior probabilities of having a BRCA1 mutation ranged from 7% to 92% (mean 37%). Thus, the prior probability of detecting a BRCA1 mutation may be a useful predictor when considering the use of Southern blot analysis for families with breast/ovarian cancer who do not have detectable coding-region mutations.

BRCA2 Protein↗
PubMed2000

Analysis of Qa-1(b) peptide binding specificity and the capacity of CD94/NKG2A to discriminate between Qa-1-peptide complexes.

The major histocompatibility complex class Ib protein, Qa-1(b), serves as a ligand for murine CD94/NKG2A natural killer (NK) cell inhibitory receptors. The Qa-1(b) peptide-binding site is predominantly occupied by a single nonameric peptide, Qa-1 determinant modifier (Qdm), derived from the leader sequence of H-2D and L molecules. Five anchor residues were identified in this study by measuring the peptide-binding affinities of substituted Qdm peptides in experiments with purified recombinant Qa-1(b). A candidate peptide-binding motif was determined by sequence analysis of peptides eluted from Qa-1 that had been folded in the presence of random peptide libraries or pools of Qdm derivatives randomized at specific anchor positions. The results indicate that Qa-1(b) can bind a diverse repertoire of peptides but that Qdm has an optimal primary structure for binding Qa-1(b). Flow cytometry experiments with Qa-1(b) tetramers and NK target cell lysis assays demonstrated that CD94/NKG2A discriminates between Qa-1(b) complexes containing peptides with substitutions at nonanchor positions P4, P5, or P8. Our findings suggest that it may be difficult for viruses to generate decoy peptides that mimic Qdm and raise the possibility that competitive replacement of Qdm with other peptides may provide a novel mechanism for activation of NK cells.

Animals↗
PubMed2000

Genetic and hormonal risk factors in breast cancer.

Breast cancer poses a serious public health problem, and it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention efforts. Two breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germline mutations in these genes are thought to account for between 5% and 10% of all breast cancer cases. Current findings suggest that mutations in other highly penetrant genes may play an important role in breast cancer susceptibility, and studies aimed at the isolation of these genes are under way. In addition, common variants in a number of gene classes are thought to act as low-penetrance susceptibility alleles, and efforts to identify and characterize these variants are under way. This review discusses the genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models.

Alcohol Drinking↗
PubMed2000

The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster.

Natural killer (NK) immunoglobulin-like receptors (KIRs) are a family of polymorphic receptors which interact with specific motifs on HLA class I molecules and modulate NK cytolytic activity. In this study, we analyzed a recently sequenced subgenomic region on chromosome 19q13.4 containing eight members of the KIR receptor repertoire. Six members are clustered within a 100-kb continuous sequence. These genes include a previously unpublished member of the KIR gene family 2DS6, as well as 2DL1, 2DL4, 3DL1, 2DS4, 3DL2, from centromere to telomere. Two additional KIR genes, KIRCI and 2DL3, which may be located centromeric of this cluster were also analyzed. We show that the KIR genes have undergone repeated gene duplications. Diversification between the genes has occurred postduplication primarily as a result of retroelement indels and gene truncation. Using pre- and postduplication Alu sequences identified within these genes as evolutionary molecular clocks, the evolution and duplication of this gene cluster is estimated to have occurred 30-45 million years ago, during primate evolution. A proposed model of the duplication history of the KIR gene family leading to their present organization is presented.

Alleles↗
PubMed2000

The mouse as a model for the effects of MHC genes on human disease.

As mice are often used to model human major histocompatibility complex (MHC)-associated diseases, it is important to understand how their MHC regions differ at the DNA level. The sequencing of the mouse MHC (H2 region) has enabled a detailed map of this region to be assembled for comparison with the human MHC. Here, Richard Allcock and colleagues outline the similarities between the human and mouse MHC regions and discuss notable differences that might affect disease models.

Animals↗
PubMed1999

Divalent metal dependence of site-specific DNA binding by EcoRV endonuclease.

Measurements of binding equilibria of EcoRV endonuclease to DNA, for a series of base-analogue substrates, demonstrate that expression of sequence selectivity is strongly enhanced by the presence of Ca2+ ions. Binding constants were determined for short duplex oligodeoxynucleotides containing the cognate DNA site, three cleavable noncognate sites, and a fully nonspecific site. At pH 7.5 and 100 mM NaCl, the full range of specificity from the specific (tightest binding) to nonspecific (weakest binding) sites is 0.9 kcal/mol in the absence of metal ions and 5.8 kcal/mol in the presence of Ca2+. Precise determination of binding affinities in the presence of the active Mg2+ cofactor was found to be possible for substrates retaining up to 1.6% of wild-type activity, as determined by the rate of phosphoryl transfer. These measurements show that Ca2+ is a near-perfect analogue for Mg2+ in binding reactions of the wild-type enzyme with DNA base-analogue substrates, as it provides identical DeltaDeltaG degrees bind values among the cleavable noncognate sites. Equilibrium dissociation constants of wild-type and base-analogue sites were also measured for the weakly active EcoRV mutant K38A, in the presence of either Mg2+ or Ca2+. In this case, Ca2+ allows expression of a greater degree of specificity than does Mg2+. DeltaDeltaG degrees bind values of K38A toward specific versus nonspecific sites are 6.1 kcal/mol with Ca2+ and 3.9 kcal/mol with Mg2+, perhaps reflecting metal-specific conformational changes in the ground-state ternary complexes. The enhancement of binding specificity provided by divalent metal ions is likely to be general to many restriction endonucleases and other metal-dependent nucleic acid-modifying enzymes. These results strongly suggest that measurements of DNA binding affinities for EcoRV, and likely for many other restriction endonucleases, should be performed in the presence of divalent metal ions.

Alanine↗