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PubMedDate not supplied

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster.

Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (P<0.0001) but this pattern was not observed at non-coding sites (P=0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.

Animals↗
PubMed1998

Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection.

A simple, sensitive and accurate method for the simultaneous determination of risperidone (RSP) and its 9-hydroxy metabolite (9-OH-RSP) in human plasma is described. The relationship between dose of RSP and the plasma concentration of RSP and 9-OH-RSP in a clinical situation is discussed. Both compounds were isolated from plasma by a simple one-step liquid-liquid extraction with 15% methylene chloride in pentane. High-performance liquid chromatography separations were made on a cyano column and the compounds were detected by electrochemical detector. The method had sufficient sensitivity to determine RSP and 9-OH-RSP accurately at concentrations as low as 0.25 ng/ml when 1 ml of plasma is used for the analysis. The assay determinations were accurate, precise and consistent with a coefficient of variation less than 15%. Commonly co-administered drugs and other antipsychotics did not interfere with the analysis of either RSP or 9-OH-RSP There were large variations in inter- and intra-individual values of plasma concentrations of RSP and 9-OH-RSP. The 9-OH-RSP appears to be the major circulating active moiety and its plasma concentrations were, on the average 22 fold higher than that of RSP in schizophrenic patients treated with RSP. The ratio of RSP/9-OH-RSP concentrations suggested that three of the patients may have deficiency in cytochrome P450 enzyme CYP 2D6. The plasma concentrations of RSP showed a weak relationship with the administered daily oral dose (r = 0.4684, p = 0.01, n = 215). However, there was a good relationship between the daily dose of RSP and the plasma concentration of 9-OH-RSP (r = 0.6654, p = 0.01, n = 280) or the total active moiety, sum of RSP and 9-OH-RSP concentrations (r = 0.7041, p = 0.0005, n = 280). The measurement of the total active moiety in plasma of schizophrenic patients may be useful for assessing the relationship between dose and plasma concentration and dose and clinical outcome of patients rather than measuring RSP alone.

Antipsychotic Agents↗
PubMedDate not supplied

Building knowledge for quality improvement in healthcare: an introductory glossary.

At the heart of organization-wide quality improvement in healthcare is the need to build knowledge for improvement that complements the subject matter knowledge of healthcare. Dr. W. Edwards Deming, the quality improvement pioneer, has suggested that "profound knowledge," or knowledge required for improvement, consists of four basic dimensions: Knowledge of the organization as a system. At its heart this knowledge is an understanding of the methods of production, the methods of improvement, and the aim of the entire enterprise. This concept was first presented by Deming at Mount Hakone, Japan, in 1950. In his book Out of the Crisis (1986), Deming illustrates the organization as a system. Knowledge of variation. This understanding comes from the awareness that a system of causes is at work producing any result. These sources of the variation, which can be observed in any process, are what must be acted upon to improve the results of the process. Studying the variation in a process can provide clues to the most economical actions that managers can take for improvement. It involves knowledge of the difference between common and special cause variation. Knowledge of psychology. The focus is on an awareness of the power of intrinsic motivation, a sense of self-worth and pride in what is done in the workplace. Theory of knowledge. How is new knowledge built? What is the purpose of knowledge? What is the nature of knowledge? Unless these issues are clear, it will not be easy to build useful knowledge. Deming has provided further insight into this framework in a recent unpublished essay and is currently working to further expand these concepts in additional publications in preparation. This framework helps build the knowledge necessary for the improvement of healthcare. As you work to build that knowledge, however, you will confront a wide variety of terms and a language that may in some ways be unfamiliar. In recognition of that, an introductory glossary is offered for your use and reference. With time, it can, should, and will be replaced by an expanded lexicon. Other sources that interested readers may wish to consult include the references listed at the end of the glossary.

Quality Assurance, Health Care↗
PubMed2000

Problems in interpreting laboratory tests. What do unexpected results mean?

It is always important that physicians not overreact to apparently abnormal laboratory values by undertaking inappropriate further investigations or clinical treatments. When confronted with unexpected differing test results from repeat testing in the same individual, physicians should be aware of explanations other than laboratory error and change in the patient's clinical status. While test-related variables may be factors, intraindividual biologic variation is much more common and may be the explanation for discrepant results. For this reason, physicians need to know which laboratory tests are associated with significant intraindividual biologic variation as well as the magnitude of possible changes. Age-associated physiologic changes may significantly alter certain laboratory values in the elderly without constituting a pathologic process. Laboratory values that may appear abnormal in 10% or more of the healthy elderly without necessarily representing a pathologic process include serum alkaline phosphatase, fasting blood glucose, 2-hour postprandial glucose, erythrocyte sedimentation rate, hemoglobin, and a normal serum creatinine level in the face of a markedly decreased creatinine clearance. To ensure proper assessment of the geriatic patient, the clinician needs to be aware of these age-related changes and possible effects on laboratory values. More clinical research is needed to establish appropriate reference ranges, especially for those over the age of 75 years.

Adolescent↗
PubMed2006

Analysis of common CFTR polymorphisms 5T, M470V and R75Q in healthy Serbian population.

Three common CFTR polymorphisms, 5T, M470V and R75Q, have been shown to be relatively frequent in Serbian patients with monosymptomatic CF disorders. Since there is a variation in distribution of common polymorphisms among different populations, it was important to compare their frequencies in patients with the frequencies in healthy population in order to assess the possible role of these polymorphisms in the monosymptomatic CF disorders. Samples obtained from 100 healthy Serbian individuals were analyzed for the presence of CFTR 5T, M470V and R75Q variants by PSM, RFLP and DGGE methods, respectively. Allele 5T was present in two individuals, giving the allelic frequency of 1% (2/200 alleles). The frequency obtained for allele M470 was 45% (90/200 alleles), while V470 allele was present with the frequency of 55% (110/200 alleles). Polymorphism R75Q was present in two individuals, with allelic frequency of 1% (2/200 alleles). Our study has shown that the frequencies of two common polymorphisms, 5T and M470V, differ significantly in Serbian population in comparison with other South European populations. Since it appears that Serbian population has a specific distribution of studied CFTR gene variants, it would also be interesting to analyze other common variants of this gene in our population. Such data can also be potentially useful as anthropogenetic markers in population studies.

Alleles↗
PubMedDate not supplied

Anatomic variation in intrahepatic bile ducts: an analysis of intraoperative cholangiograms in 300 consecutive donors for living donor liver transplantation.

OBJECTIVE: To describe the anatomical variation occurring in intrahepatic bile ducts (IHDs) in terms of their branching patterns, and to determine the frequency of each variation. MATERIALS AND METHODS: The study group consisted of 300 consecutive donors for liver transplantation who underwent intraoperative cholangiography. Anatomical variation in IHDs was classified according to the branching pattern of the right anterior and right posterior segmental duct (RASD and RPSD, respectively), and the presence or absence of the first-order branch of the left hepatic duct (LHD), and of an accessory hepatic duct. RESULTS: The anatomy of the intrahepatic bile ducts was typical in 63% of cases (n=188), showed triple confluence in 10% (n=29), anomalous drainage of the RPSD into the LHD in 11% (n=34), anomalous drainage of the RPSD into the common hepatic duct (CHD) in 6% (n=19), anomalous drainage of the RPSD into the cystic duct in 2% (n=6), drainage of the right hepatic duct (RHD) into the cystic duct (n=1), the presence of an accessory duct leading to the CHD or RHD in 5% (n=16), individual drainage of the LHD into the RHD or CHD in 1% (n=4), and unclassified or complex variation in 1% (n=3). CONCLUSION: The branching pattern of IHDs was atypical in 37% of cases. The two most common variations were drainage of the RPSD into the LHD (11%) and triple confluence of the RASD, RPSD and LHD (10%).

Bile Ducts, Intrahepatic↗
PubMed1988

Population cytogenetics of the malaria vector Anopheles leucosphyrus group.

Until recently, very little was known of Anopheles species complexes and their relationships to epidemiology and malaria transmission in Southeast Asia. During the past eight years, extensive studies on the genetics of natural populations of anopheline mosquitoes in this region, involving the interdisciplinary efforts of taxonomists, operational entomologists and biologists, have revealed groups of cryptic species of Anopheles vectors, particularly the An. leucos phyrus group. This species group comprise seventeen species and two subspecies widely distributed in the forested areas of Southeast Asia. Among these species. An. dirus Peyton and Harrison, has been shown by cytogenetic and morphological studies to be a complex of at least seven isomorphic species, provisionally designated species A, B, C, D, E, F and takasagoensis, on the Southeast Asian mainland. Cytological identification of these species is based on distinct banding patterns of salivary gland polytene chromosomes as well as heterochromatin differences in mitotic karyotypes. The five species found in Thailand (A-D, F) exhibit distinct geographic distributions. Species A is widespread throughout Thailand except in the south. Species B had been found in sympatry with species C in southern Thailand and both seem to show north-south clinal geographic variation. Species D is common on the west side of southern Thailand and along the Thai-Burmese border in sympatry with species A. Species F, An. nemophilous Peyton and Ramalingam, has been found in a population at the Thai-Malaysian border in this study although it was known to be common in southern and western Thailand and Peninsular Malaysia. Species E is known only from western India. The five species found in Thailand also exhibit seasonal variation in relative abundance and different nocturnal biting cycles. Chromosomal polymorphisms have been observed in mitotic and polytene chromosomes of An. dirus A and D. Species B and C also show heterochromatin variation in the sex chromosomes, but are monomorphic for the standard sequence in polytene chromosomes. These biological characteristics of the An. dirus complex may have implications for understanding the epidemiology of malaria in Southeast Asia. Recent cytogenetic studies of wild-caught samples of An. leucosphyrus from Sumatra, Kalimantan and southern Thailand have revealed the presence of two distinct species within this taxon. Species A is widely distributed in southern Thailand, East Malaysia and Kalimantan, while species B is confined to Sumatra. The two isomorphic species are vectors of human malaria within their range of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2026

Ambrosia beetle invasions are structured by inbreeding, intraspecific hybridisation, and bridgeheads.

When invasive populations establish in regions far from their origin, they may accumulate deleterious mutations that limit population viability and later expansion. Invasions stemming from such bridgehead populations may experience further sequential bottlenecks. However, deleterious mutations can be masked or eliminated when populations outbreed with other lineages. Here, we analyse global invasions of a species complex of persistently inbreeding ambrosia beetles, using genomic data (N=247) from invasive populations in Africa, North America and Australia, and from native populations in Asia. We mostly focus on one species of this complex (Euwallacea fornicatus) which poses a severe threat to tree species worldwide and is rapidly expanding its global range. We uncover a single lineage of this species across California, South Africa, and Western Australia, involving an invasive bridgehead and containing almost no nuclear genetic variation. In South Africa we identify a second lineage that has repeatedly hybridised with the first lineage. Genetic patterns in the native range indicate that such opportunistic outbreeding may be common. Despite lacking nuclear variation, the first lineage contained two CO1 haplotypes that were also observed in every hybrid lineage, pointing to heteroplasmy and possible hybrid origins of this lineage. Native populations had fewer missense mutations than invasive populations, indicating that opportunistic outbreeding may help purge fixed deleterious mutations when local lineage diversity is high. These findings highlight the importance of outbreeding even when inbreeding is common, and they demonstrate the biosecurity threat posed by subsequent gene flow into invasive populations.

Journal Article↗
PubMed2006

The c.43_44insCTG variation in PCSK9 is associated with low plasma LDL-cholesterol in a Caucasian population.

The genetic etiology of familial hypobetalipoproteinemia (FHBL) is unclear in the majority of cases. Mutations in apolipoprotein B (APOB) are the only confirmed causes of FHBL. Recently, loss-of-function mutations of PCSK9 gene have been shown to be associated with the hypocholesterolemia phenotype. Our primary goal was to confirm that mutations in PCSK9 could be another cause of FHBL. Using the sequencing approach, we found that the c.43_44insCTG variation in PCSK9, a common in-frame insertion in both African American and Caucasian populations, is associated with the hypocholesterolemia phenotype in three FHBL families. Then we tested whether this variation could be associated with lower cholesterol levels in the general population. A total of 403 subjects from a Caucasian population, in which hypobetalipoprotein (HBL) and normal groups were classified using standard criteria, were sequenced for this variation. The allele frequency of this variation in the HBL group was 0.186, but was only 0.128 in the normal lipid group. The mean plasma low-density lipoprotein (LDL)-cholesterol level in subjects heterozygous for this variant is significantly lower than that in the normal group (p<0.01). Heterozygous subjects also had higher high-density lipoprotein (HDL)-cholesterol levels (p<0.01). In general, LDL-cholesterol concentration in individuals with PCSK9 c.43_44insCTG variation was approximately 10-15 mg/dL lower than that in normal individuals. We conclude that the c.43_44insCTG variant plays a role in lowering cholesterol in the general population.

Adolescent↗
PubMed1999

The emerging importance of genetics in epidemiologic research. I. Basic concepts in human genetics and laboratory technology.

PURPOSE: To define a general framework of current approaches to the discovery of disease-associated genes and the role of genetic factors in influencing disease risk through the integration of genome technology and traditional epidemiologic methods. METHODS: An overview of basic concepts in human genetics, laboratory methodology for measuring genetic variation believed to influence common diseases, and issues concerning preparation and utilization of genetic materials is provided as a foundation for genetic epidemiologic research. RESULTS: Identification and characterization of human genetic variation is providing new risk factors for disease in the form of DNA sequence variation. The availability of genetic material from participants in large epidemiologic studies and appropriate informed consent represents an invaluable resource for exploring genetic and environmental influences on disease risk. CONCLUSIONS: Advances in genome technology coupled with vast amounts of genetic data resulting from the Human Genome Project are broadening the scope of epidemiologic research and providing tools to identify individuals at increased risk of disease. Combining diverse expertise from the fields of epidemiology and human genetics provides unique opportunities to localize disease-susceptibility genes and examine molecular mechanisms of complex disease etiology.

DNA↗
PubMed1989

Pancreaticoduodenectomy. The importance of preserving hepatic blood flow to prevent biliary fistula.

The arterial blood supply to the common bile duct must be preserved during pancreaticoduodenectomy to avoid ischemic breakdown of the biliary-enteric anastomosis. Interruption of this blood supply can occur during operation because of inadvertent division of the common hepatic artery or a hepatic artery variation. Approximately 17 per cent of patients have a hepatic artery variation that could contribute to devascularization of the common bile duct during surgical resection of the pancreatic head. This report discusses these hepatic artery variations and the value of angiography in defining hepatic arterial anatomy prior to surgery. Two cases are presented in which biliary-enteric anastomoses became ischemic and dehisced secondary to interruption of hepatic arterial blood flow.

Aged↗
PubMed2005

Interpopulational variation in recovery time from chill coma along a geographic gradient: a study in the common woodlouse, Porcellio laevis.

Extreme temperatures restrict the performance of terrestrial arthropods and variations in low temperatures on a latitudinal scale influence physiological variables. Recovery time from chill coma is a measure of cold tolerance and it is a good index of climatic adaptation. We tested differences in recovery time of the common woodlouse (Porcellio laevis) exposed to different thermal conditions. Individuals were sampled from four different populations in Chile, spanning a latitudinal range of approximately 10 degrees . Significant differences were found in recovery time among experimental temperatures and among populations, but no interaction between these factors. The results of recovery time in P. laevis showed a positive increment with annual mean minimum temperature, indicating that there is geographical variation in recovery time. While body mass presented interpopulational variation, this variation was not associated with thermal variables or latitude. Overall, our results agree with previous studies in the sense that recovery time from chill coma decreases towards high latitudes, and it is independent of taxa, continent and hemisphere.

Adaptation, Physiological↗
PubMed2006

Common hepatic artery arising from the left gastric artery: a rare anatomic variation identified on a cadaveric liver donor.

Anatomical variations of the arterial supply of the liver are not uncommon. The typical normal "textbook" anatomy of the hepatic artery is found only in approximately half of the cases. Some of the variations such as the presence of a right or left hepatic branch are more common, but other ones are extremely rare. We describe here a rare case in which the common hepatic artery arose from the left gastric artery, found during a cadaveric liver donor harvesting and confirmed with imaging studies. Cases like this one highlight the importance of knowing the hepatic arterial anatomy and the possibility of its numerous variations by the transplant and hepatobiliary surgeon.

Cadaver↗
PubMed2005

UV-induced skin cancer: similarities--variations.

Skin cancer, the most common cancer world wide, encompasses different tumor entities, the keratinocyte-derived basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) as well as the neuroectodermal malignant melanoma (MM) and the neuroendocrine Merkel cell carcinomas (MCC). While knowledge is significantly increasing about genetic changes contributing to BCCs and MMs, our understanding for the development and progression of SCCs and MCCs is still fragmentary. This review, thus, aims, on the one hand to summarize the present knowledge without claiming completeness and, on the other hand, to provide information on the HaCaT in vitro skin carcinogenesis model that is used to evaluate the functional consequence of genetic aberrations believed to play a role in skin cancer development and progression.

Basal Cell Carcinoma↗
PubMed1997

Anatomical variations and sinusitis.

Paranasal sinus anatomy and variations have gained interest with the introduction of functional endoscopic sinus surgery and the concept of the ostiomeatal complex. Anatomical variations can be divided in structural abnormalities, (increased) pneumatization and supplementary openings. Most anatomical variations are equally found in control and sinusitis patients. The anatomical variations which are most commonly associated with sinus pathology are septal deviations, true conchae bullosae and supplementary maxillary ostia but the latter one only when recycling is present. The knowledge of anatomical variations is most important in the surgical management and specifically in the prevention of complications.

Adolescent↗
PubMed1997

Reproducibility of ultrasonographic measurements of different carotid and femoral artery segments in healthy subjects and in patients with increased intima-media thickness.

1. The reproducibility of measurements of the arterial wall thickness in both the carotid and femoral artery was investigated by means of high-resolution B-mode ultrasonography. For this purpose, subjects with normal and increased intima-media thickness were selected. Images were stored on an optical disk and were analysed with a semi-automatic software program by two readers. Individuals were scanned twice by two independent observers. 2. Measurements were performed of the far and near wall of the common carotid artery and bulbous in 30 healthy subjects and 19 patients known to have an increased intima-media thickness. Far-wall measurements were made of the internal carotid artery on both sides and common femoral artery on the right side only. 3. In healthy subjects the mean within-observer coefficient of variation was 1.8% and 3.0% for the far wall in the common carotid artery on the right side and left side, respectively. For the near wall the mean coefficient of variation of the common carotid artery was 2.8% on the right and 3.4% on the left side. The mean coefficient of variation was less than 4% for both far and near wall in the bulbous and far wall in the internal carotid artery. Even in patients with increased intima-media thickness the mean coefficient of variation of each segment was less than 4.5%. In the control subjects the between-observer coefficient of variation of the common carotid artery was 2.8% and 5.1% for the far wall on the right and left side, respectively, and 3.4% and 4.2% for the near wall on the right and left side. In healthy subjects a mean difference of 0.002 mm within observers was found in the right far-wall common carotid artery, with limits of agreement of -0.048 to 0.052 mm. The coefficient of repeatability was 0.050 mm. For patients with increased intima-media thickness the mean difference in this segment was -0.006 mm (-0.094 to 0.082) with a coefficient of repeatability of 0.088 mm. For the near wall in the common carotid artery and far and near wall in the bulbous and internal carotid artery the mean differences were larger, but were all below 0.1 mm. The differences and limits of agreements increased between observers. In patients the between-observer mean difference of the far wall of the common carotid artery was -0.055 mm (-0.255 to 0.145). For the common femoral artery of normal control subjects the within- and between-observer mean differences were 0.005 mm (-0.119 to 0.129) and 0.015 mm (-0.081 to 0.111), respectively. 4. In conclusion, the reproducibility of intima-media thickness measurements in the common carotid artery is reliable, even in patients with increased artery wall thickness. Also in other segments prone to atherosclerosis, such as the bulbous, internal carotid artery and common femoral artery, a good reproducibility was found. To obtain good reproducibility it is highly recommended to use the same ultrasonographer to scan patients in follow-up studies.

Adult↗
PubMed1993

Myofascial pain dysfunction: treatments used by ADA members.

A survey of 10,000 members of the American Dental Association was conducted in order to identify the most commonly used treatments for myofascial pain dysfunction (MPD). A questionnaire was used in which MPD was defined, all treatments (including referral) were listed, and a percentage-of-use estimate for each treatment was requested. Results from 2,544 questionnaires showed that the most commonly used treatments are: flat plane splints with anterior/canine guidance or posterior group function, occlusal equilibration, thermal packs, relaxation/stress management training, diet counseling, and medications with anti-inflammatory (nonopioid) analgesic and muscle relaxant properties. The results also showed considerable variation in the ways common treatments are performed. A call is issued for systematic and careful research on the outcomes of these and other treatments and their major variations.

Adult↗