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Biomedical subjects

A Murray

Publications and source records attributed to A Murray.

At least 145 records · Page 8Linked to original sources
PubMed1999

Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study--preliminary data.

The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.

Adolescent↗
PubMed1999

Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides.

MUC1 mucin is a large complex glycoprotein expressed on normal epithelial cells in humans and overexpressed and under or aberrantly glycosylated on many malignant cancer cells which consequently allows recognition of the protein core by antibodies. In order to understand how glycosylation may modulate or regulate antibody binding of mucin protein core epitopes, we have analyzed the antibody C595 (epitope RPAP) for its structure, stability, and its binding to a series of synthetic peptides and glycopeptides by a number of spectroscopic methods. Thermal and pH denaturation studies followed by changes in the CD spectrum of the antibody indicate critical involvement of specific residues to the stability of the antibody. Fluorescence binding studies indicate that alpha-N-acetylgalactosamine (GalNAc) glycosylation of a MUC1 mucin synthetic peptide TAPPAHGVT9SAPDTRPAPGS20T21APPA at threonine residues 9 and 21 and serine residue 20 enhanced the binding of antibody. The structural effects of GalNAc glycosylation on the conformation of the MUC1 peptide were studied. CD of the peptides and glycopeptides in a cryogenic mixture cooled to approximately -97 degrees C revealed that a left-handed polyproline II helix (PPII) is adopted by the peptides in solution, which appears to be further stabilized by addition of the GalNAc residues. Consistent with the PPII helical structure, which has no intra-amide hydrogen bonds, high-field NMR spectroscopy of the glycopeptide revealed no sequential dNN, medium-range, or long-range nuclear Overhauser effect (NOE) connectivities. These studies indicate that stabilization of the PPII helix by GalNAc glycosylation present the epitope of C595 antibody with a favorable conformation for binding. Furthermore, they illustrate that glycosylation of the MUC1 tumor marker protein with a simple O-linked saccharide expressed in many cancers, can enhance the binding of the clinically relevant C595 antibody.

Amino Acid Sequence↗
PubMed1999

Linear and non-linear analysis of the surface electrocardiogram during human ventricular fibrillation shows evidence of order in the underlying mechanism.

Ventricular fibrillation (VF) is a poorly understood yet potentially lethal cardiac arrhythmia. The electrocardiogram (ECG) time series of VF is investigated by comparison of the linear and non-linear features of VF time series and surrogates in which internal correlations have been destroyed. From 40 ECG time series of human VF and 40 surrogate time series, three quantities are evaluated: the percentage of the linear time-frequency distribution (TFD) exceeding a threshold, the non-linear coarse-grained correlation dimension (Dcg), and the percentage of diagonal lines in the non-linear recurrence plot longer than 10 elements (D10). It is found that the mean (SD) percent threshold TFD and Dcg are higher for the surrogates (6.7% (1.3) and 5.3 (0.6)) than the VF time series (5.6% (0.7) and 3.8 (0.9)), whereas the mean D10 is higher for the VF time series (49% (13)) than the surrogates (32% (7)). All of these differences are significant (p < 0.0001) and indicate greater order in the VF time series than in the surrogates. It is therefore shown that both linear and non-linear signal analysis demonstrate order in the ECG time series of VF.

Electrocardiography↗
PubMed1999

Production and characterization of an anti-(MUC1 mucin) recombinant diabody.

A recombinant diabody fragment based on the anti-MUC1 monoclonal antibody, C595 has been produced in a bacterial expression system. Substitution of a 7-amino-acid linker sequence (Gly6Ser) for the original single-chain (sc)Fv 15-amino-acid linker (Gly4-Ser)3, using polymerase-chain-reaction-based strategies, forces variable heavy (V(H)) and light (V(L)) domains to pair with complementary domains on neighbouring scFv molecules, forming a scFv dimer (diabody). This recombinant protein shows similar binding characteristics to the parental C595 monoclonal antibody. The ability to bind to MUC1 mucin on carcinoma cell surfaces will allow its potential as a diagnostic and therapeutic reagent of clinical utility to be investigated.

Amino Acid Sequence↗
PubMed1999

Coherence between body surface ECG leads and intracardiac signals increases during the first 10 s of ventricular fibrillation in the human heart.

Ventricular fibrillation (VF) in the human heart is not well understood. The aim of this study was to measure changes in the phase relationship between the body surface ECG and intracardiac electrograms recorded during the first 10 s of human VF. We studied 11 episodes of VF and measured the coherence of (a) ECG lead I and ECG lead V1, (b) ECG lead V1 and the right ventricular apex (RVA) electrogram, and (c) ECG lead V1 and the smoothed RVA electrogram. Each coherence measurement was the average of the magnitude squared coherence function in the range 0-60 Hz, and measurements were made 1, 3, 5, 7 and 9 s after the onset of VF. Overall, the mean (SD) coherence was 31(6)% between ECG leads I and V1, 17(3)% between ECG lead V1 and the RVA electrogram, and 20(4)% between ECG lead V1 and the smoothed RVA electrogram. All three measurements of coherence increased significantly between 1 and 9 s with mean (SD) rates of 0.97(1.01)% s(-1), 0.8(1.18)% s(-1) and 0.82(1.19)% s(-1) respectively. These results show that propagation in human VF becomes more organized during the first 10 s of VF. This may be an optimal window for defibrillation.

Cardiac Catheterization↗
PubMed1999

Modelling the relationship between peripheral blood pressure and blood volume pulses using linear and neural network system identification techniques.

The relationships between peripheral blood pressure and blood volume pulse waveforms can provide valuable physiological data about the peripheral vascular system, and are the subject of this study. Blood pressure and volume pulse waveforms were collected from 12 normal male subjects using non-invasive optical techniques, finger arterial blood pressure (BP, Finapres: Datex-Ohmeda) and photoelectric plethysmography (PPG) respectively, and captured to computer for three equal (1 min) measurement phases: baseline, hand raising and hand elevated. This simple physiological challenge was designed to induce a significant drop in peripheral blood pressure. A simple first order lag transfer function was chosen to study the relationship between blood pressure (system input) and blood volume pulse waveforms (system output), with parameters describing the dynamics (time constant, tau) and input-output gain (K). Tau and K were estimated for each subject using two different system identification techniques: a recursive parameter estimation algorithm which calculated tau and K from a linear auto-regressive with exogenous variable (ARX) model, and an artificial neural network which was trained to learn the non-linear process input-output relationships and then derive a linearized ARX model of the system. The identification techniques allowed the relationship between the blood pressure and blood volume pulses to be described simply, with the neural network technique providing a better model fit overall (p < 0.05, Wilcoxon). The median falls in tau following the hand raise challenge were 26% and 31% for the linear and neural network based techniques respectively (both p < 0.05, Wilcoxon). This preliminary study has shown that the time constant and gain parameters obtained using these techniques can provide physiological data for the clinical assessment of the peripheral circulation.

Adult↗
PubMed1999

Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women.

It is now recognized that female carriers of fragile X premutations are at increased risk of premature ovarian failure. We have studied 51 premenopausal women from fragile X families, to determine whether premutation carriers have variations in the hormonal markers of menopause, compared to full mutations and controls. We found a significant increase in serum follicle stimulating hormone in premutation carriers, suggesting that as a group they will enter menopause before full mutation carriers and unaffected controls. These results have important implications for fertility in these women.

Adolescent↗
PubMed1999

Recent developments in clinical photography.

A system comprising a clinical camera, specialized retractors, and a new occlusal mirror are described to maximize the quality of both intra-oral and extra-oral photography in the multi-user situation.

Equipment Design↗
PubMed1999

Microdeletions in FMR2 may be a significant cause of premature ovarian failure.

Genetic causes of premature ovarian failure (POF) include X chromosome deletions and fragile X (FRAXA) premutations. While screening a cohort of women with POF for FRAXA premutations, a more distal trinucleotide repeat, FRAXE, was also tested. We found an unexpected excess of FRAXE alleles with apparently fewer than 11 repeats in the POF group. However, sequence analysis of these alleles showed that the excess was caused by three females who carry cryptic deletions in FMR2, the gene associated with FRAXE. We propose that microdeletions within FMR2 may be a significant cause of premature ovarian failure, being found in 1.5% of women with the condition, and in only 0.04% of the general female population. The deletions may affect transcription of either FMR2 or an adjacent gene.

Adult↗
PubMed1998

The LCC15-MB human breast cancer cell line expresses osteopontin and exhibits an invasive and metastatic phenotype.

We have characterized the LCC15-MB cell line which was recently derived from a breast carcinoma metastasis resected from the femur of a 29-year-old woman. LCC15-MB cells are vimentin (VIM) positive, exhibit a stellate morphology in routine cell culture, and form penetrating colonies when embedded in three-dimensional gels of Matrigel or fibrillar collagen. They show high levels of activity in the Boyden chamber chemomigration and chemoinvasion assays, and like other invasive human breast cancer (HBC) cell lines, LCC15-MB cells activate matrix-metalloproteinase-2 in response to treatment with concanavalin A. In addition, these cells are tumorigenic when implanted subcutaneously in nude mice and recolonize bone after arterial injection. Interestingly, both the primary lesion and the bone metastasis from which LCC15-MB were derived, as well as the resultant cell line, abundantly express the bone matrix protein osteopontin (OPN). OPN is also expressed by the highly metastatic MDA-MB-435 cells, but not other invasive or noninvasive HBC cell lines. Expression of OPN is retained in the subcutaneous xenograft and intraosseous metastases of LCC15-MB as detected by immunohistochemistry. Both VIM and OPN expression have been associated with breast cancer invasion and metastasis, and their expression by the LCC15-MB cell line is consistent with its derivation from a highly aggressive breast cancer. These cells provide a useful model for studying molecular mechanisms important for breast cancer metastasis to bone and, in particular, the implication(s) of OPN and VIM expression in this process.

Adult↗
PubMed1998

FRAXA and FRAXE: evidence against segregation distortion and for an effect of intermediate alleles on learning disability.

There have been several claims of segregation distortion (meiotic drive) for loci associated with diseases caused by trinucleotide repeats, leading us to test for this phenomenon in a large study of the X-linked loci FRAXA and FRAXE. We found no evidence of meiotic drive in females and no convincing evidence in males, where the limitation of risk to daughters creates a testing bias for alleles of interest. Alleles for pre- and full mutation, intermediate alleles, and common alleles were analyzed separately, with the same negative results that are extended in the discussion to claims of meiotic drive for other diseases. On the other hand, an excess risk of learning difficulties was confirmed for intermediate FRAXA alleles (relative risk, 2.58 +/- .74) and suggested for intermediate FRAXE alleles. The penetrance of learning difficulty is low, the risk being estimated as .039 for FRAXA common alleles and .101 for intermediate alleles. Because of their lower gene frequency, full mutations are a less frequent cause of learning difficulty than intermediate alleles, which contribute .0020 to total prevalence and .0012 to attributable prevalence of learning difficulty.

Alleles↗
PubMed1998

The home and school background of young drivers involved in traffic accidents.

The following study investigates the home and school background of young drivers in Sweden involved in traffic accidents leading to injury. The research sample consists of all young drivers born in 1972 who had been involved in one or several traffic accidents with injury registered by the police during the period of 1988-1994 (age 16-22). In all, 2,980 male and 1,054 female drivers were investigated, classified by the transport mode of car, lorry and bus, motorcycle, moped and bicycle. Information about the family composition and the socioeconomic status of the parents of the young drivers was added from the national census of 1990 and 1985, respectively. The young drivers' school marks in their leaving certificate from compulsory school (at age 16) and educational attainment (at age 20) were obtained from national educational registers. The home and school background of the drivers were compared to a nationally representative sample of men and women of the same age cohort. Estimated risk exposure (driving distance) for car drivers and cyclists from a national travel survey were related to the accident data. The home background of the investigated drivers did not deviate much from the nationally representative sample in the comparison group. The school achievement and school attainment deviated more. The school marks in the school-leaving certificate from compulsory school (at age 16) of all male motor vehicle drivers involved in accidents were below average and men with compulsory education only, and men with a vocational upper secondary education were over-represented among these drivers. Female car drivers involved in accidents also had lower school marks and lower educational attainment than for the male car drivers. The over-representation of low-educated men and women among drivers involved in car accidents could not be explained by a higher risk exposure (driving distances). Thus, educational achievement and attainment were found to be powerful variables explaining accident risk.

Accidents, Traffic↗