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Biomedical subjects

D Gordon

Publications and source records attributed to D Gordon.

At least 37 records · Page 2Linked to original sources
PubMed2001

Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p11, 8q22 and 11q23-24 in South African Afrikaners.

Utilizing DNA samples from 91 Afrikaner nuclear families with one or more affected children, five genomic regions on chromosomes 2p, 8q, 11q, 20q, and 21q that gave evidence for association with GTS in previous case-control association studies were investigated for linkage and association with GTS. Highly polymorphic markers with mean heterozygosity of 0.77 were typed and resulting genotypes evaluated using single marker transmission disequilibrium (TDT), single marker haplotype relative risk (HRR), and multi-marker "extended" TDT and HRR methods. Single marker TDT analysis showed evidence for linkage or association, with p-values near 0.05, for markers D2S139, GATA28F12, and D11S1377 on chromosomes 2p11, 8q22 and 11q23-24, respectively. Extended, two-locus TDT and HRR analysis provided further evidence for linkage or association on chromosome 2 with p-values of 0.007 and 0.025, and chromosome 8 with p-values of 0.059 and 0.013, respectively. These results provide important additional evidence for the location of GTS susceptibility loci.

Case-Control Studies↗
PubMed2001

A study comparing precision of the maximum multipoint heterogeneity LOD statistic to three model-free multipoint linkage methods.

This study compared the performance of the maximum lod (MLOD), maximum heterogeneity lod (MHLOD), maximum non-parametric linkage score (MNPL), maximum Kong and Cox linear extension (MKC(lin)) of NPL, and maximum Kong and Cox exponential extension (MKC(exp)) of NPL as calculated in Genehunter 1.2 and Genehunter-Plus. Our performance measure was the distance between the marker with maximum value for each linkage statistic and the trait locus. We performed a simulation study considering: 1) four modes of transmission, 2) 100 replicates for each model, 3) 58 pedigrees (with 592 subjects) per replicate, 4) three linked marker loci each having three equally frequent alleles, and 5) either 0% unlinked families (linkage homogeneity) or 50% unlinked families (linkage heterogeneity). For each replicate, we obtained the Haldane map position of the location at which each of the five statistics is maximized. The MLOD and MHLOD were obtained by maximizing over penetrances, phenocopy rate, and risk-allele frequencies. For the models simulated, MHLOD appeared to be the best statistic both in terms of identifying a marker locus having the smallest mean distance from the trait locus and in terms of the strongest negative correlation between maximum linkage statistic and distance of the identified position and the trait locus. The marker loci with maximum value of the Kong and Cox extensions of the NPL statistic also were closer to the trait locus than the marker locus with maximum value of the NPL statistic.

Bias↗
PubMed2001

Two approaches for consolidating results from genome scans of complex traits: selection methods and scan statistics.

This work has two purposes: (i) empirically selecting levels of significance that maximize the fraction of markers close to a gene (hit rate) when performing linkage analyses of simulated data and (ii) evaluating the utility of a previously reported scan statistic on the same data. Genotype data were simulated from a trait model of seven susceptibility genes. For purpose (i), five statistics were evaluated on all marker loci in fifty replicates; two-point lod and heterogeneity lod scores maximized over dominance (mlod, mhlod), a multi-allelic TDT test, an affected sib-pair test (ASP), and a model-free test on all sib-pairs (ALL_SIBS). Within each replicate the fraction of markers (hit rate) significant at specified levels of significance and also (a) within fifty markers of, or (b) on the same chromosome as a major gene was calculated. For purpose (ii), scan statistics of length 15 were calculated for each chromosome and their empirical significance levels estimated on the basis of 500 replicates generated under no linkage. The scan statistic was applied to the mhlod scores from one replicate (Replicate 5). Empirical p-values for the scan statistic were determined by computing mhlod scores on 500 replicates of simulated null data. For purpose (i), significance levels between 0.001 and 0.01 had the greatest hit rate for all five methods and both criteria. For criterion (a) at the 0.001 level of significance, both mlod and mhlod displayed the highest hit rates, approximately 0.4 for each. For criterion (b), all methods but ALL_SIBS and ASP had hit rates ranging between 0.4 and 0.5. For purpose (ii), the scan statistic proved equally or more powerful than the single-locus statistic for two of the seven susceptibility genes while the remaining five genes were not detected.

Chromosome Mapping↗
PubMed2001

Role of urethrocystoscopy in the evaluation of refractory idiopathic detrusor instability.

OBJECTIVES: To assess the role of diagnostic urethrocystoscopy in the evaluation of women with idiopathic detrusor instability (DI) refractory to conventional pharmacologic management. METHODS: One hundred consecutive women (mean age 62.1 +/- 15.1 years) with idiopathic DI refractory to conventional pharmacologic management were prospectively enrolled. All patients underwent a meticulous evaluation, including a detailed history, urogynecologic questionnaire, micturition diary and pad test, urinalysis and culture, physical examination, and urodynamic studies. Refractory DI was defined as the lack of clinical improvement after at least 6 months of conventional drug therapy. These patients underwent additional evaluation with diagnostic urethrocystoscopy. RESULTS: All patients had a normal urinalysis and negative cytologic findings. Diagnostic urethrocystoscopy revealed isolated bladder tuberculosis in one and transitional cell carcinoma in another. Seven other patients had bladder diverticula (only one of which was also diagnosed by sonographic examination) and 22 had mild-to-moderate bladder trabeculations. CONCLUSIONS: The absence of other alarming signs (ie, recurrent urinary tract infection, hematuria, significant residual urinary volume, positive cytologic findings, or suspicious sonographic findings) cannot confirm the lack of significant lower urinary tract abnormalities among patients with refractory DI. Diagnostic urethrocystoscopy, a simple and safe office procedure, facilitates timely diagnosis and appropriate treatment for these patients.

Cystoscopy↗
PubMed2001

Combined genitourinary prolapse repair and prophylactic tension-free vaginal tape in women with severe prolapse and occult stress urinary incontinence: preliminary results.

OBJECTIVES: Continent patients with a positive stress test demonstrated on repositioning of severe genitourinary prolapse are considered to be at high risk of developing postoperative symptomatic stress urinary incontinence (SUI). Our aim was to evaluate in a prospective study whether a prophylactic, tension-free vaginal tape (TVT) procedure, performed during prolapse repair, may prevent the development of postoperative SUI in these women. METHODS: Thirty consecutive, clinically continent women (mean age 64.5 +/- 9.04 years) with severe genitourinary prolapse and occult SUI were prospectively enrolled. Occult SUI was defined as a positive stress test with repositioning of the prolapse during the preoperative urodynamic studies. All patients had urethral hypermobility; none had intrinsic sphincter deficiency. In addition to genitourinary prolapse repair, these patients underwent concomitant TVT to prevent postoperative SUI. Patients were followed up for at least 1 year. Repeated urodynamic studies were performed at 3 to 6 months postoperatively. The main outcome measures were postoperative SUI, persistent or de novo detrusor instability, and recurrence of prolapse. RESULTS: The mean duration of follow-up was 14.25 +/- 3.08 months (range 12 to 24). None of the patients developed postoperative symptomatic SUI. However, three asymptomatic patients (10%) had a positive stress test during their postoperative urodynamic evaluation. Nine patients (30%) had detrusor instability before surgery, which persisted in six (66%) postoperatively. Postoperative de novo detrusor instability was diagnosed in four other patients (13.33%). None of the patients had recurrent urogenital prolapse, nor did they have clinical evidence of bladder outlet obstruction. CONCLUSIONS: The preliminary results of TVT as a prophylactic procedure in clinically continent women with severe prolapse and occult SUI are encouraging. Long-term follow-up is required to confirm the durability of these results.

Female↗
PubMed2001

The scorpion alpha-like toxin Lqh III specifically alters sodium channel inactivation in frog myelinated axons.

The effects of 1-100 nM Lqh III, an alpha-like toxin isolated from the scorpion Leiurus quinquestriatus hebraeus, were assessed on the nodal membrane potential and ionic currents of single frog myelinated axons. In current-clamped axons, Lqh III increased the duration of action potentials without markedly affecting the peak amplitude and the resting membrane potential. The toxin was less effective when the resting membrane potential of axons was increasingly more positive. The Lqh III-induced increase in action potential duration was not due to the blockade of K(+) channels, since the toxin had no significant effect upon the K(+) current. In contrast, Lqh III inhibited the inactivation of a fraction of the Na(+) current, leading to a maintained late inward Na(+) current which represented about 45% of the peak Na(+) current, as observed during long-lasting depolarisations and in steady-state Na(+) current inactivation-voltage relationships when the pre-pulse potential was more positive than about -30mV. The activation kinetics of the late Na(+) current were well described by a single exponential whose time constant was 8.53+/-0.78 ms (n=3). Finally, Lqh III slowed the time-course of the remaining peak Na(+) current inactivation by altering initial amplitudes (to time zero of depolarisation) and time constants of its fast and slow phases. No significant additional effect was detected during the action of the toxin. In conclusion, we propose that, in frog myelinated axons, the effects of Lqh III are those typically attributed to classical scorpion alpha-toxins.

Action Potentials↗
PubMed2001

Task-related environment alters the cuticular hydrocarbon composition of harvester ants.

Within a colony of harvester ants (Pogonomyrmex barbatus), workers in different task groups differ in the hydrocarbon composition of the cuticle. Foragers and patrollers, which spend extended periods of time outside the nest, have a higher proportion of saturated, unbranched hydrocarbons (n-alkanes) on the cuticle than nest maintenance workers, which spend only short periods of time outside the nest. We tested whether these task-related differences in ant cuticular chemistry arise from exposure to conditions outside the nest. Nest maintenance workers experiencing daily, short-term outside exposure developed a higher proportion of n-alkanes on the cuticle than workers kept inside the lab. Independent manipulations of ultraviolet radiation, relative humidity, and temperature revealed that only the combination of high temperature (ca. 38 degrees C) and low relative humidity (ca. 8%) increased the proportion of cuticular n-alkanes. The results indicate that warm dry conditions, such as those encountered when an ant leaves the nest, trigger changes in cuticular chemistry.

Adaptation, Physiological↗
PubMed2001

Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities.

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.

Arteriosclerosis↗
PubMed2001

UK doctors' attitudes to the General Medical Council's Performance Procedures, 1997-99.

OBJECTIVES: The UK General Medical Council's Performance Procedures were introduced in 1997. This study aimed to assess the changing knowledge and attitudes about the procedures in British doctors at the time of their introduction and in the following 2 years. METHODS: Three questionnaire surveys, of separate representative samples of 800 UK doctors, were carried out in November of 1997, 1998 and 1999. The surveys assessed awareness of Good Medical Practice, attitudes to the Performance Procedures, agreement with Duties of a Doctor as a basis for disciplinary procedures, and attitudes to the Performance Procedures. RESULTS: Although awareness of the procedures increased over the period 1997-99, there was no concurrent increase in agreement with the core principles of the procedures, the Duties of a Doctor, which are spelled out in Good Medical Practice. Of 12 separate attitudes to the procedures, changes were found in eight over the time period, all but two of which were negative, and not in support of the procedures. Nevertheless many doctors were changing their practice as a result of the procedures, and that proportion increased during the period 1997-99. CONCLUSIONS: Although doctors became more aware of the procedures, that increasing awareness was not accompanied by an increasing agreement with the procedures' underlying principles or their wider implications.

Attitude of Health Personnel↗
PubMed2001

Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with type 1 diabetes.

AIM: To determine the plasma levels of enzymes and inhibitors involved in extracellular matrix turnover in patients with Type 1 diabetes with normal renal function. METHODS: Plasma levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in 43 Type 1 diabetic subjects and age- and sex-matched controls. RESULTS: No significant difference in plasma MMP-2 between diabetic patients and controls was observed. MMP-9 was detected in the plasma of 15 diabetic patients (35%), but undetectable in all control subjects (P < 0.015). Plasma TIMP-1 concentrations were significantly elevated (P < 0.001) in diabetic patients compared to controls. There was no correlation observed between MMP-2, MMP-9 and TIMP-1 and similarly between MMP-2, MMP-9 and TIMP-1 and age, duration of diabetes, blood pressure and glycated haemoglobin (HbA1c). CONCLUSIONS: This study has demonstrated alterations in several plasma extracellular matrix modulators in the absence of significant vascular disease.

Adolescent↗
PubMed2001

A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy.

Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP), which stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO). NESP has been shown to be safe and efficacious in patients with chronic renal failure. NESP is biochemically distinct from rHuEPO, due to its increased sialic acid content. NESP has an approximately 3-fold greater half-life. rHuEPO has been shown to be safe and effective for the treatment of chemotherapy-induced anaemia. This study assessed the safety and efficacy of NESP administered once per week, under the supervision of a physician, to patients with solid tumours who were receiving multicycle chemotherapy for up to 12 weeks. Three dose cohorts are presented in this sequential, unblinded and dose-escalating study. Thirteen to 59 patients received NESP (0.5, 1.5 or 2.25 mcg kg(-1)wk(-1)) in each cohort. Patients were monitored for adverse events, including antibody formation to NESP and for effects on haemoglobin. NESP appeared to be well tolerated. Adverse events were similar across all cohorts and were consistent with the population being studied. No antibody formation was detected over the 16-week study period and follow-up. A dose-response relationship was evident for NESP and multiple measures of efficacy, including proportion of patients responding to NESP and the mean change in haemoglobin by week 4 and end of treatment for NESP 0.5, 1.5 and 2.25 mcg kg(-1)wk(-1)cohorts (mean change in haemoglobin at end of treatment was 1.24, 1.73 and 2.15 g dl(-1)respectively). Controlled studies of this agent at higher doses and less frequent schedules of administration are ongoing.

Adult↗
PubMed2001

Diversification of neurotoxins by C-tail 'wiggling': a scorpion recipe for survival.

The structure of bioactive surfaces of proteins is a subject of intensive research, yet the mechanisms by which such surfaces have evolved are largely unknown. Polypeptide toxins produced by venomous animals such as sea anemones, cone snails, scorpions, and snakes show multiple routes for active site diversification, each maintaining a typical conserved scaffold. Comparative analysis of an array of genetically related scorpion polypeptide toxins that modulate sodium channels in neuronal membranes suggests a unique route of toxic site diversification. This premise is based on recent identification of bioactive surfaces of toxin representative of three distinct pharmacological groups and a comparison of their 3-dimensional structures. Despite their similar scaffold, the bioactive surfaces of the various toxins vary considerably, but always coincide with the molecular exterior onto which the C-tail is anchored. Superposition of the toxin structures indicates that the C-tails diverge from a common structural start point, which suggests that the pharmacological versatility displayed by these toxins might have been achieved along evolution via structural reconfiguration of the C-tail, leading to reshaping of new bioactive surfaces.

Amino Acid Sequence↗
PubMed2001

Evaluation of female lower urinary tract symptoms: overview and update.

Female lower urinary tract symptoms are nonspecific, and a thorough clinical evaluation is required to establish the correct diagnosis. Such evaluation should consist of a structured micturition history or questionnaire, physical examination with full bladder, micturition diary, pad test and urodynamic evaluation. The urodynamic evaluation should consist at least of cystometry, detrusor pressure/uroflow study, simple ('free') uroflowmetry, assessment of the relative contribution of urethral hypermobility and intrinsic sphincter deficiency, and estimation of postvoid residual urine by ultrasound or catheterization. Recent studies regarding the role of pad tests, micturition diaries and urodynamic studies in the evaluation of female voiding dysfunction are presented. Factors that are associated with the use of transurethral catheter during pressure-flow studies and current controversies regarding the diagnosis of female bladder outlet obstruction are reviewed and discussed. Although the urodynamic study is considered to be the best diagnostic tool in assessment of lower urinary tract function, some practitioners believe that urodynamic evaluation is not routinely warranted and prefer to employ a symptom-based empirical management strategy. Lower urinary tract symptoms are nonspecific, however, and should be used mainly to identify what bothers the patient. Urodynamic studies define the underlying pathophysiology. We believe that treatment of the underlying pathophysiology facilitates better treatment of symptoms.

Female↗
PubMed2001

Automated finishing with autofinish.

Currently, the genome sequencing community is producing shotgun sequence data at a very high rate, but finishing (collecting additional directed sequence data to close gaps and improve the quality of the data) is not matching that rate. One reason for the difference is that shotgun sequencing is highly automated but finishing is not: Most finishing decisions, such as which directed reads to obtain and which specialized sequencing techniques to use, are made by people. If finishing rates are to increase to match shotgun sequencing rates, most finishing decisions also must be automated. The Autofinish computer program (which is part of the computer software package) does this by automatically choosing finishing reads. Autofinish is able to suggest most finishing reads required for completion of each sequencing project, greatly reducing the amount of human attention needed. sometimes completely finishes the project, with no human decisions required. It cannot solve the most complex problems, so we recommend that Autofinish be allowed to suggest reads for the first three rounds of finishing, and if the project still is not finished completely, a human finisher complete the work. We compared this Autofinish-Hybrid method of finishing against a human finisher in five different projects with a variety of shotgun depths by finishing each project twice--once with each method. This comparison shows that the Autofinish-Hybrid method saves many hours over a human finisher alone, while using roughly the same number and type of reads and closing gaps at roughly the same rate. Autofinish currently is in production use at several large sequencing centers. It is designed to be adaptable to the finishing strategy of the lab--it can finish using some or all of the following: resequencing reads, reverses, custom primer walks on either subclone templates or whole clone templates, PCR, or minilibraries. Autofinish has been used for finishing cDNA, genomic clones, and whole bacterial genomes (see http://www.phrap.org).

Contig Mapping↗
PubMed2001

Assembly, annotation, and integration of UNIGENE clusters into the human genome draft.

The recent release of the first draft of the human genome provides an unprecedented opportunity to integrate human genes and their functions in a complete positional context. However, at least three significant technical hurdles remain: first, to assemble a complete and nonredundant human transcript index; second, to accurately place the individual transcript indices on the human genome; and third, to functionally annotate all human genes. Here, we report the extension of the UNIGENE database through the assembly of its sequence clusters into nonredundant sequence contigs. Each resulting consensus was aligned to the human genome draft. A unique location for each transcript within the human genome was determined by the integration of the restriction fingerprint, assembled genomic contig, and radiation hybrid (RH) maps. A total of 59,500 UNIGENE clusters were mapped on the basis of at least three independent criteria as compared with the 30,000 human genes/ESTs currently mapped in Genemap'99. Finally, the extension of the human transcript consensus in this study enabled a greater number of putative functional assignments than the 11,000 annotated entries in UNIGENE. This study reports a draft physical map with annotations for a majority of the human transcripts, called the Human Index of Nonredundant Transcripts (HINT). Such information can be immediately applied to the discovery of new genes and the identification of candidate genes for positional cloning.

Alleles↗
PubMed2001

BICAV: a block-iterative parallel algorithm for sparse systems with pixel-related weighting.

Component averaging (CAV) was recently introduced by Censor, Gordon, and Gordon as a new iterative parallel technique suitable for large and sparse unstructured systems of linear equations. Based on earlier work of Byrne and Censor, it uses diagonal weighting matrices, with pixel-related weights determined by the sparsity of the system matrix. CAV is inherently parallel (similar to the very slowly converging Cimmino method) but its practical convergence on problems of image reconstruction from projections is similar to that of the algebraic reconstruction technique (ART). Parallel techniques are becoming more important for practical image reconstruction since they are relevant not only for supercomputers but also for the increasingly prevalent multiprocessor workstations. This paper reports on experimental results with a block-iterative version of component averraging (BICAV). When BICAV is optimized for block size and relaxation parameters, its very first iterates are far superior to those of and more or less on a par with ART. Similar to CAV, BICAV is also inherently parallel. The fast convergence is demonstrated on problems of image reconstruction from projections, using the SNARK93 image reconstruction software package. Detailed plots of various measures of convergence, and reconstructed images are presented.

Algorithms↗
PubMed2001

Assessment and management of single nucleotide polymorphism genotype errors in genetic association analysis.

Single nucleotide polymorphisms (SNP) may be used in case-control designs to test for association between a marker (the SNP) and a disease. However, such designs usually assume that the genotype data are reported without error. We propose a method, the reduced penetrance model method (RPM) that allows for errors in a case-control design, as compared to the full penetrance model method (FPM), that assumes data are errorless. Pearson's chi 2 applied to a 2 x 2 contingency table is the test statistic considered. Additionally, we provide a likelihood method to estimate error rates using SNP genotype data in CEPH pedigrees. We test our method (RPM) against the standard method (FPM) using simulated data. All SNP loci are assumed to have two alleles, coded 1 and 2. We consider three pairs of error rates, two different sample sizes, and two sets of allele frequencies for the SNP locus. SNP genotype data in two populations are simulated under a null hypothesis (allele frequencies equal in both populations) and under an alternative hypothesis (allele frequencies differ between two populations). The total number of simulations is 24; 12 simulations under the null hypothesis, and 12 simulations under the alternative. The significance level threshold is 5%. For the null case, 9/12 (75%) of the simulations show no increase in type I error under RPM, while 3/12 (25%) show a slight increase (rejecting the null for at most 7% of the replicates). There is no increase in the type I error rate for FPM method, which can also be shown analytically. For the alternative case (power), there is a consistent increase in power for the RPM method as compared to FPM method, and average increase of 0.02 for the simulations considered. When sample sizes are large there is virtually no difference in power between RPM and FPM methods. Also, the RPM method provides consistently more accurate allele frequency estimates for the various populations. Our likelihood method to estimate error rates with CEPH pedigrees provides good estimates on average. The largest difference between a true error rate and our average estimated error rate is 0.006. However, there is a fair amount of variability in the estimates, suggesting the need for multiple experiments or larger numbers of CEPH pedigrees. Researchers may use the methods presented in this paper to (1) estimate error rates for their automated genotyping process, and (2) allow for such errors in association analyses, thereby increasing power to detect differences between allele frequencies in case and control populations when errors are present.

Alleles↗