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Biomedical subjects

S Humphries

Publications and source records attributed to S Humphries.

At least 19 recordsLinked to original sources
PubMed2005

RF tumour ablation: computer simulation and mathematical modelling of the effects of electrical and thermal conductivity.

This study determined the effects of thermal conductivity on RF ablation tissue heating using mathematical modelling and computer simulations of RF heating coupled to thermal transport. Computer simulation of the Bio-Heat equation coupled with temperature-dependent solutions for RF electric fields (ETherm) was used to generate temperature profiles 2 cm away from a 3 cm internally-cooled electrode. Multiple conditions of clinically relevant electrical conductivities (0.07-12 S m-1) and 'tumour' radius (5-30 mm) at a given background electrical conductivity (0.12 S m-1) were studied. Temperature response surfaces were plotted for six thermal conductivities, ranging from 0.3-2 W m-1 degrees C (the range of anticipated clinical and experimental systems). A temperature response surface was obtained for each thermal conductivity at 25 electrical conductivities and 17 radii (n=425 temperature data points). The simulated temperature response was fit to a mathematical model derived from prior phantom data. This mathematical model is of the form (T=a+bRc exp(dR) s(f) exp(g)(s)) for RF generator-energy dependent situations and (T=h+k exp(mR)+n?exp(p)(s)) for RF generator-current limited situations, where T is the temperature (degrees C) 2 cm from the electrode and a, b, c, d, f, g, h, k, m, n and p are fitting parameters. For each of the thermal conductivity temperature profiles generated, the mathematical model fit the response surface to an r2 of 0.97-0.99. Parameters a, b, c, d, f, k and m were highly correlated to thermal conductivity (r2=0.96-0.99). The monotonic progression of fitting parameters permitted their mathematical expression using simple functions. Additionally, the effect of thermal conductivity simplified the above equation to the extent that g, h, n and p were found to be invariant. Thus, representation of the temperature response surface could be accurately expressed as a function of electrical conductivity, radius and thermal conductivity. As a result, the non-linear temperature response of RF induced heating can be adequately expressed mathematically as a function of electrical conductivity, radius and thermal conductivity. Hence, thermal conductivity accounts for some of the previously unexplained variance. Furthermore, the addition of this variable into the mathematical model substantially simplifies the equations and, as such, it is expected that this will permit improved prediction of RF ablation induced temperatures in clinical practice.

Catheter Ablation↗
PubMed2002

The 5A6A polymorphism in the promoter of the stromelysin-1 (MMP3) gene as a risk factor for restenosis.

AIMS: Intracoronary ultrasound studies in humans show that chronic remodelling rather than neointimal hyperplasia is the mechanism of restenosis. Stent implantation limits this remodelling process and significantly reduces restenosis. MMP3 (Stromelysin-1), a member of the matrix metalloproteinase family may play a role in this remodelling. We used a functional polymorphism (with alleles designated 5A or 6A) in the promoter of the MMP3 gene to examine the possible role of MMP3 in restenosis. METHODS AND RESULTS: Genotypes were determined in a series of consecutive patients who underwent conventional balloon coronary angioplasty without stenting (n=287) or who also had successful implantation of a Palmaz-Schatz stent (stent) (n=198). For all patients restenosis was estimated at 6 months using quantitative computer-assisted angiography. The minimal luminal diameters before and after the procedures did not differ significantly between genotypes. At follow-up in the patients without stent, those with the 6A6A genotype had an increased degree of restenosis after coronary angioplasty compared to those with one or more 5A alleles, with a greater diameter stenosis (52+/-21% vs 45+/-19%, P=0.012), and a greater late loss (0.58+/-0.59 mm vs 0.38+/-0.59 mm, P=0.038). By contrast, in the stented patients MMP3 genotype was not associated with any angiographically determined measure of vessel dimensions. CONCLUSIONS: These data imply the involvement of MMP3 in chronic remodelling after conventional balloon angioplasty, and suggest that the 6A6A MMP3 genotype is a genetic susceptibility factor for restenosis after angioplasty without stenting.

Aged↗
PubMed2001

Bradykinin B2BKR receptor polymorphism and left-ventricular growth response.

Angiotensin-converting-enzyme (ACE) activity regulates left-ventricular growth. The deletion (D), rather than the insertion (I), ACE gene variant is associated with increased ACE activity and kinin degradation, and the absence (-) rather than the presence (+) of a 9 bp deletion in the gene encoding the bradykinin 2 receptor (B2BKR) is associated with greater gene expression. We determined the ACE and B2BKR genotype of 109 male army recruits, and measured their physiological left-ventricular growth response to a 10-week physical training programme. Mean left-ventricular growth was 15.7 g (SE 3.5) in those with ACE genotype D/D and B2BKR genotype +9/+9, but -1.37 g (4.1) in those with ACE genotype I/I and B2BKR genotype -9/-9 (p=0.003 for trend across genotypes). These results suggest that kinins regulate left-ventricular growth, mediating some of the effects of ACE in this regard.

Adult↗
PubMed2001

Elite swimmers and the D allele of the ACE I/D polymorphism.

A polymorphism of the human angiotensin-1-converting enzyme (ACE) gene has been identified in which the presence (insertion, I allele) of a 287-bp fragment rather than the absence (deletion, D allele) is associated with lower ACE activity. Several recent studies have shown an association of the I allele with endurance performance, it being found with excess frequency in elite distance runners, rowers and mountaineers. Other workers using heterogeneous cohorts of athletes from mixed sporting disciplines have found no such association. An increasing linear trend of I allele frequency with the distance run amongst Olympic runners and an excess of the D allele amongst sprinters led us to examine whether the ratio of I and D alleles in swimmers competing over different distances would also vary. Swimmers (n=120) from the European and Commonwealth championships and an American college team had their ACE genotype determined and their gene and allele frequencies compared with several control groups, the most closely age-matched of which were 1,248 military recruits. Of the 103 Caucasians, there was a significant excess of the D allele compared with this control group only in the truly elite swimmers of the European and Commonwealth championships (P=0.004). This association remained in those competing over shorter distances (P=0.005 for 400 m and below) but not in the longer events. These findings were confirmed in three further large control groups. A population association study testing whether a genetic marker (the ACE I/D polymorphism) occurs more frequently in cases (elite athletes) than in controls therefore requires a homogeneous cohort of subjects from the same sporting discipline.

Adolescent↗
PubMed2000

Radiographic evaluation of surgical clips is better than ultrasound for defining the lumpectomy cavity in breast boost treatment planning: a prospective clinical study.

PURPOSE: Breast radiotherapy (BrRT) often includes a "boost" to the lumpectomy bed. Selection of an appropriate electron energy and field size is based upon the dimensions and location of the surgical cavity. This study was performed to confirm our impression that ultrasound (US) inadequately defines the volume at risk compared to radiographic evaluation of surgical clips placed within the operative bed at the time of lumpectomy. METHODS AND MATERIALS Twenty-nine women treated with BrRT at our institution between 1996-1998 were prospectively identified as having surgical clips within the lumpectomy cavity. These patients underwent both US evaluation and radiographic evaluation of the clips to independently define two sets of transverse (T), longitudinal (L), and depth (D) measurements for each cavity. Volumes (V) were calculated for each method, assuming the cavity to be a box (V = T x L x D). Twenty-one women began BrRT following a median postoperative interval of 6 weeks (Group A), and 8 after 24 weeks (Group B) due to delivery of systemic therapy. RESULTS: Dimensions derived by US were smaller than the clip method in 22/29 of T, 25/29 of L, and 23/29 of D, or 80% of all linear measurements. A paired t-test demonstrated the difference between the methods to be statistically significant: T: p = 0.0004; L: p = 0.0001; D: p = 0.0004; and V: p = 0.0001. This underestimation by US did not fit any predictable pattern. Although the mean difference between methods (clips - US) was only 1.3, 1.9, and 1.1 cm for T, L, and D, respectively, differences ranged up to 5. 7, 9.2, and 5.5 cm for T, L, and D. The bias toward underestimation of V by US was significantly greater for Group B than Group A (p = 0. 03). CONCLUSIONS: US significantly underestimates all three dimensions of the lumpectomy cavity and hence the volume at risk compared to radiographic evaluation of surgical clips. Breast-conserving surgery should include placement of clips at the margins of the lumpectomy cavity (superior, inferior, medial, lateral, and posterior) to aid in radiotherapy treatment planning. US should not be utilized to guide the design of the boost field as it will result in inappropriate selection of lower electron energies and smaller field sizes (geographical miss), particularly among patients who receive chemotherapy prior to breast radiotherapy.

Breast Neoplasms↗
PubMed2000

Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease.

Allelic frequencies of a (CCTTT)(n) pentanucleotide repeat in the NOS2A promoter region were determined in a total of 1393 unrelated individuals from five specific population groups in four continents: Africa, Europe, Asia, and the Caribbean. There were highly significant differences in allele frequencies between the ethnically diverse populations. The repeat variation may have implications for the selective pressure of malaria or other infectious diseases that may operate at the NOS2 locus.

DNA↗
PubMed2000

Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy.

Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 (PAI-1) activity, is common in patients with manifest coronary artery disease (CAD) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator (tPA) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine (4G/5G) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial (LOCAT). A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response (p < 0.05), an association mainly accounted for by progression of diffuse lesions in graft-affected segments (change in per-patient means of average diameters of segments haemodynamically related to bypass grafts). Plasma PAI-1 activity and mass concentration and 4G/5G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group (+11.3% and + 16.4%, respectively, p < 0.001), whereas there was no treatment effect on PAI-1 activity (median change 0.0%). It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations.

Aged↗
PubMed2000

Prothrombin activation is increased among asymptomatic carriers of the prothrombin G20210A and factor V Arg506Gln mutations.

The risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50-61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the time of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G202 IOA and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment FI+2 [mean +/- SD, 0.88 +/- 0.32 nmol/L in men with prothrombin G20210A (p = 0.002) and 0.89 +/- 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 +/- 0.24 among non-carriers for either mutationl. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo.

Blood Coagulation Factors↗
PubMed1999

Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes.

We have produced mice that carry the human Ig heavy (IgH) and both kappa and lambda light chain transloci in a background in which the endogenous IgH and kappa loci have been inactivated. The B lymphocyte population in these translocus mice is restored to about one-third of normal levels, with preferential (3:1) expression of human lambda over human kappa. Human IgM is found in the serum at levels between 50 and 400 microg/ml and is elevated following immunization. This primary human Ab repertoire is sufficient to yield diverse Ag-specific responses as judged by analysis of mAbs. The use of DH and J segments is similar to that seen in human B cells, with an analogous pattern of N nucleotide insertion. Maturation of the response is accompanied by somatic hypermutation, which is particularly effective in the light chain transloci. These mice therefore allow the production of Ag-specific repertoires of both IgM,kappa and IgM,lambda Abs and should prove useful for the production of human mAbs for clinical use.

Animals↗
PubMed1999

Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.

BACKGROUND: The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems. METHODS: We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training. FINDINGS: Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype. INTERPRETATION: II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.

Adipose Tissue↗