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A suture variation not commonly utilized in dermatologic surgery is helpful in approximating wound edges without the complications of excessive undermining or the scarring of conventional retention sutures. It is especially useful in scalp reduction surgery.
Cardiovascular disease (CVD) is the most important cause of morbidity and mortality in dialysis patients. The high prevalence of CVD is due to the cumulative effects of multiple risk factors from the early stages of chronic kidney disease (CKD). Familial predispositions to CVD, CKD, and their respective risk factors are well known, and it is likely that genetic factors determine the interindividual variability in risks for disease. Advances in genomic technology have facilitated the study of genetic variation--most commonly single nucleotide polymorphisms (SNPs) in candidate genes--and their associations with disease. This review examines CVD in dialysis patients as a model of a complex disease, discusses the approach to gene polymorphism association studies, including the roles of gene-environment and gene-gene interactions and provides an overview of available studies.
BACKGROUND: Implantable medical devices have increasingly large capacities for storing patient data as a diagnostic aid and to allow patient monitoring. Although these devices can store a significant amount of data, an increased ability for data storage was required for chronic monitoring in recent physiological studies. METHOD OF APPROACH: Novel high capacity implantable data recorders were designed for use in advanced physiological studies of canines and free-ranging black bears. These hermitically sealed titanium encased recorders were chronically implanted and programmed to record intrabody broadband electrical activity to monitor electrocardiograms and electromyograms, and single-axis acceleration to document relative activities. RESULTS: Changes in cardiac T-wave morphology were characterized in the canines over a 6 month period, providing new physiological data for the design of algorithms and filtering schemes that could be employed to avoid inappropriate implantable defibrillator shocks. Unique characteristics of bear hibernation physiology were successfully identified in the black bears, including: heart rate, respiratory rate, gross body movement, and shiver An unanticipated high rejection rate of these devices occurred in the bears, with five of six being externalized during the overwintering period, including two devices implanted in the peritoneal cavity. CONCLUSIONS: High capacity implantable data recorders were designed and utilized for the collection of long-term physiological data in both laboratory and extreme field environments. The devices described were programmable to accommodate the diverse research protocols. Additionally, we have described substantial differences in the response of two species to a common device. Variations in the foreign body response of different mammals must be identified and taken into consideration when choosing tissue-contacting materials in the application of biomedical technology to physiologic research.
The gamma variate function, commonly used to analyze time-activity curves obtained in nuclear medicine flow studies, is shown to be related to the solution to the differential equation obtained from a one-dimensional convective dispersive model of blood flow.
(R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-oxazepam (but not R-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-oxazepam glucuronidation. Furthermore, the apparent K(m) for UGT2B15 (29-35 microM) was similar to values determined for HLMs (43-60 microM). In contrast, R-oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent K(m) values for HLMs (256-303 microM) were most similar to UGT2B7 (333 microM) rather than UGT1A9 (12 microM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higher S-oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3alpha-diol. In conclusion, S-oxazepam is stereoselectively glucuronidated by UGT2B15, whereas R-oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-oxazepam glucuronidation in humans.
Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.
Biological adaptive systems share some common features: variation among their constituent elements and continuity of core information. Some of them, such as the immune system, are endowed with memory of past events. In this study we provide direct evidence that evolving viral quasispecies possess a molecular memory in the form of minority components that populate their mutant spectra. The experiments have involved foot-and-mouth disease virus populations with known evolutionary histories. The composition and behavior of the viral population in response to a selective constraint were influenced by past evolutionary history in a way that could not be predicted from examination of consensus nucleotide sequences of the viral populations. The molecular memory of the viral quasispecies influenced both the nature and the intensity of the response of the virus to a selective constraint.
The surgical experience of a sample of people aged 40-64 randomly selected from general practice lists was elicited by means of a postal questionnaire and the results examined in relation to two indicators of socioeconomic status. Eighty per cent of the sample had had one or more surgical operations and women had a higher mean number of operations than men. Those in the more advantaged groups had a higher mean number of operations than those in the less advantaged groups. This difference was, however, mainly accounted for by operations carried out in childhood before the establishment of the National Health Service and by private sector surgery.
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OBJECTIVE: To investigate whether the tau H1 haplotype is a genetic risk factor in Parkinson's disease and to report a meta-analysis on all previously published data METHODS: and results: In a sample of 580 patients with Parkinson's disease and 513 controls there was an increased risk of Parkinson's disease for both the tau H1 haplotype (p<or=0.0064; odds ratio (OR) 1.34 (95% confidence interval (CI), 1.04 to 1.72)) and the H1H1 genotype (p<or=0.0047; OR 1.42 (1.1 to 1.83)). Under a fixed effect model, the summary OR for this showed that individuals homozygous for the H1 allele were 1.57 times more likely to develop Parkinson's disease than individuals carrying the H2 allele (95% CI 1.33 to 1.85; p<0.00001). The population attributable risk for the tau variant, for the main comparison of H1H1 against H2 carriers, was 24.8% for all studies combined. CONCLUSIONS: Homozygosity for the tau H1 is associated with an increased risk of Parkinson's disease. This adds to the growing body of evidence that common genetic variation contributes to the pathogenesis of this disorder.
Over the past two decades, detailed studies of mitochondrial DNA and the Y chromosome have increased our understanding of the history and population genetics of Native American populations. Variation in autosomal DNA has also been investigated, but to a more limited extent. A low level of genetic diversity in Native American populations is a robust finding from all lines of evidence. In contrast to the previous multiple migration scenarios for the Pleistocene peopling of the Americas, it now seems that a single migration satisfactorily explains the genetic data. Native Americans show greater genetic similarity to populations in east central Asia than they do to the current easternmost Siberian populations. Recent studies on the Y chromosome indicate a date of entry (about 17,000 years ago) into the Americas roughly consistent with the archaeological record. Native Americans experienced two episodes of reduced population size: one with the peopling of the Americas and the other with European contact. The former is the more important determinant for the number of gene lineages and founding haplotypes seen in populations. It may also be an important determinant of the genetic variation underlying common complex diseases, and especially diabetes. The tribal structure of contemporary Native American populations is relevant to the distribution of rare Mendelian disorders because most tribes constitute relatively small, semi-independent gene pools. This leads us to expect that the allelic spectrum for Mendelian diseases will be simple within individual tribes but complex for Native Americans as a whole.
Osteoporosis is a metabolic bone disease characterized by low bone mass and deterioration of bone tissue that leads to bone fragility and an increase in fracture risk. It is a disease with a complex etiology that includes genetic and environmental contributors. Environmental factors that influence bone density include dietary factors-such as intakes of calcium, alcohol, and caffeine-and lifestyle factors-such as exercise and smoking. Ethnic differences in the propensity to nontraumatic bone fracture suggest that genetic factors are important. Recently, common allelic variations in he vitamin D receptor gene have been found to be associated with bone mineral density in racially diverse population groups, as well as in prepubertal girls, young adult and postmenopausal women, and men. However, many studies have not been able to find this association. Additional approaches, such as sib-pair analysis, will probably be necessary in the future to identify the important determinants of osteoporosis.
We sought to determine whether common genetic variations at the beta2 (beta2-AR, Gln27Glu) and beta3 (beta3-AR, Trp64Arg) adrenergic receptor gene loci were associated with cardiovascular (CV) hemodynamics during maximal and submaximal exercise. CV hemodynamics were assessed in 62 healthy postmenopausal women (20 sedentary, 22 physically active, and 20 endurance athletes) during treadmill exercise at 40, 60, 80, and 100% maximal O2 uptake using acetylene rebreathing to quantify cardiac output. The beta2-AR genotype and habitual physical activity (PA) levels interacted to significantly associate with arteriovenous O2 difference (a-vDO2) during submaximal exercise (P = 0.05), with the highest submaximal exercise a-vDO2 in sedentary women homozygous for the beta2-AR Gln allele and no genotype-dependent differences in submaximal exercise a-vDO2 in physically active and athletic women. The beta2-AR genotype also was independently associated with a-vDO2 during submaximal (P = 0.004) and approximately 100% maximal O2 uptake exercise (P = 0.006), with a 1.2-2 ml/100 ml greater a-vDO2 in the Gln/Gln than in the Glu/Glu genotype women. The beta3-AR genotype, independently or interacting with habitual PA levels, was not significantly associated with any CV hemodynamic variables during submaximal or maximal exercise. Thus it appears that the beta2-AR genotype, both independently and interacting with habitual PA levels, is significantly associated with a-vDO2 during exercise in postmenopausal women, whereas the beta3-AR genotype does not appear to be associated with any maximal or submaximal exercise CV hemodynamic responses in postmenopausal women.
The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.
Human phosphoserine phosphatase (E.C. 3.1.3.3) (PSP), a phosphohydrolase, participates in the biosynthesis of serine from carbohydrates (Moro-Furlani et al., 1980). Starch gel electrophoresis has identified isoenzymes and rare allelic variants. More common electrophoretic variation is thought to be due to secondary nongenetic modification. Using starch gel electrophoresis of interspecific somatic cell hybrids, we have been able to assign the gene for this enzyme to human chromosome 7.
Morphometric evaluation of the infralabyrinthine approach to the internal auditory canal (IAC) was performed using 20 fresh human temporal bones in order to assess the exposure limitations, inherent risks and technical difficulties that may arise due to common anatomic variations of this region. While performing the infralabyrinthine approach to the IAC, minor problems such as an anteriorly placed sigmoid sinus were easily managed. However, in 50% of the specimens, this approach was limited due to variations of the jugular bulb, restricting access to the IAC. Sacrificing the endolymphatic duct in these specimens did not significantly improve the surgical access to the eighth nerve. Furthermore, it was noted that this approach puts the facial nerve and cochlea under the risk of inadvertent damage during drilling. The authors conclude that vestibular nerve sectioning using the infralabyrinthine approach may be performed only in few selected cases and extreme care is needed in order not to damage the structures that limit this approach.
Although clinical coronary heart disease and many cardiovascular risk factors are well known to aggregate within families, the heritability of carotid artery intima-media thickness (IMT) is less well documented. We report IMT heritability estimates in Mexican American, Salvadoran American, or Guatemalan American (all referred to as Latino) families ascertained through a hypertensive proband. IMT and cardiovascular risk factors (age, sex, blood pressure, body mass index, lipids, fasting glucose, and insulin sensitivity) were measured in 204 adult offspring of 69 hypertensive probands, along with 82 parents (54 probands and 28 spouses). In the offspring, variance component analysis revealed a heritability for IMT of 64% (P< 0.0001) after adjustment for significant cardiovascular risk factors. Genetic factors accounted for 50% of the total variation in IMT, whereas significant cardiovascular risk factors explained 22% (14% were due to age). For offspring and parents combined, adjusted IMT heritability was less, 34% (P=0.0005), with genetic factors accounting for 18% of the total IMT variation, whereas significant cardiovascular risk factors explained 46% (38% were due to age). We conclude that variation in common carotid artery IMT is heritable in Latino families with a hypertensive proband. Heritability is particularly evident in younger family members, suggesting that acquired factors contribute progressively to IMT variability with aging.
Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.