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PubMed2000

CNV and temporal uncertainty with 'ageing' and 'non-ageing' S1-S2 intervals.

OBJECTIVES: Uncertainty about the timing of a known external event is an everyday phenomenon but has been rarely investigated with electrophysiological methods. We studied how the amplitude of the contingent negative variation (CNV) is affected by temporal variation of S2 presentation. Competing hypotheses about the development of CNV during the foreperiod until S2 presentation were that CNV either would follow a monotonic trend, be it increasing or decreasing, or alternatively that the time-course of CNV would be affected by the probability with which S2 was presented at each time-point in a given task. METHODS: The interval between cueing stimulus and imperative stimulus was randomly chosen from 3 different values between 1.3 and 2.6 s, using 3 different probability distributions in separate blocks: an 'ageing', a 'non-ageing' and a 'Gaussian' distribution. RESULTS: As previously shown, reaction times were determined by the probability of the imperative stimulus at the given length of the foreperiod. The same was found for CNV amplitude: the effects of temporal uncertainty on CNV mainly depended on the particular distribution of temporal probabilities used in a block. The relevant parameter was the a posteriori probability of event occurrence, very similar to the effects of this parameter on response times. In fact, the major part of the effect of a posteriori probability on CNV was common variation of CNV and response times. CONCLUSIONS: Thus, under temporal uncertainty the amplitude of CNV reflects the subjective expectancies for the occurrence of a given event, with this variation being related to variations in response times.

Adult↗
PubMed2005

Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: genetic factors.

Insulin-like growth factors (IGFs) play key roles in cell proliferation and apoptosis. Whereas relatively stable within individuals, IGFs vary substantially between individuals, and a large component of this variation may be determined by genetic factors. Several polymorphisms in IGF genes have been identified, although their functional significance is not clear. We evaluated the association of polymorphisms in IGF-1 and IGFBP-3 and circulating levels of IGF-1 and IGFBP-3 in 323 population-based control subjects enrolled in a case-control study of colorectal cancer from September 1999 through February 2002. Total IGF-1 and IGFBP-3 levels were measured using ELISA assays, and all subjects were genotyped for a microsatellite polymorphism in IGF-1 and a single nucleotide polymorphism in IGFBP-3. Multiple linear regression was used to assess the association of genotype with circulating IGFs. IGF-1 levels were unrelated to either polymorphism. IGFBP-3 was significantly associated with IGFBP-3 genotype, with IGFBP-3 levels increasing from CC (1,895 ng/mL) --> GC (2,029 ng/mL) --> GG (2,182 ng/mL), (p-trend < 0.001). Having an IGF-1 genotype other than homozygous for the 19-repeat allele was associated with higher IGFBP-3 levels (1,945 versus 2,052 ng/mL). Furthermore, both IGF-1 and IGFBP-3 genotypes modified the relationship between postmenopausal hormone use and IGFs. This analysis provides evidence that common variation in IGF genes may contribute to the variation in circulating levels observed between individuals.

Adult↗
PubMed1994

Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidaemia.

By using chemical cleavage mismatch analysis and the single strand conformation polymorphism technique, DNA fragments of the apo CIII gene, including the 5' flanking region and all the exons, were screened for sequence changes underlying the observed association between familial combined hyperlipidaemia (FCHL) and the apo AI-CIII-AIV gene cluster in affected individuals from eight FCHL families. A C1100-T transition in the wobble position of codon 14 in exon 3 and a T3206-G transversion in the non-translated region of exon 4 were identified, occurring in four and all probands, respectively. Using these variants and the G-75-A transition in the apo AI promoter, co-segregation of the gene cluster with hyperlipidaemia could be excluded in all eight families (lod score - infinity at theta = 0). No support for co-segregation was obtained using the affected pedigree member method of linkage analysis (overall T = -0.77 for f(p) = 1 [symbol: see text] p). The frequencies of T1100 and G3206 in a group of 55 patients with combined hyperlipidaemia were 0.35 and 0.52, respectively, which were significantly higher compared to 360 controls (0.21, p < 0.01 and 0.35, p < 0.005 respectively). In patients homozygous for the T1100 allele, levels of plasma triglyceride were 2.5-fold higher (868 mg/dl) than those homozygous for the C1100 allele (337 mg/dl), while patients heterozygous for the polymorphism had intermediate values (443 mg/dl) (p < 0.01). A similar association was seen in controls (p < 0.04). The three polymorphisms studied were in strong linkage disequilibrium in both the group of CHL patients and the unrelated individuals. This study confirms the association between common variation in the gene cluster and differences in plasma lipid levels in the general population and in patients with combined hyperlipidaemia, but fails to confirm co-segregation with FCHL, suggesting the role of other genetic or environmental factors in the aetiology of FCHL.

Adult↗
PubMed2003

Development of rheumatoid arthritis is not associated with two polymorphisms in the Crohn's disease gene CARD15.

INTRODUCTION: It has been proposed that genetic susceptibility loci for rheumatoid arthritis (RA) may be shared with other autoimmune/inflammatory diseases. Recently, common variation in the CARD15 (NOD2) gene on chromosome 16q12 has been associated with Crohn's disease (CD) in several independent populations. CARD15 is an excellent functional and positional candidate gene for RA. METHODS: Genomic DNA was obtained from 392 RA cases and 471 ethnically matched healthy controls. All samples were genotyped for two polymorphisms in CARD15, 1007fs and R702W, using 5' nuclease reporter assays. Allele frequencies were compared between cases and controls using the chi(2) test. Estimated haplotype frequencies across the two mutations were determined using the EH program. RESULTS: The allele frequency of the 1007fs variant in RA cases was 1.8% compared with 1.6% in normal controls (not significant). The frequency of the R702W variant was 4.0% in both cases and controls. Haplotypes carrying either of the two mutations accounted for 5.6% of possible haplotypes. A haplotype carrying both mutations was rare, with estimated frequency <0.01%. This study provided high power to detect an association of similar magnitude to that in Crohn's disease. These data therefore exclude the possibility that the contribution of these mutations to RA is comparable to that seen in CD. CONCLUSION: Within defined statistical parameters, we excluded a role for the CARD15 1007fs and R702W variants in RA susceptibility. These data do not preclude a role for other polymorphisms in the CARD15 gene in RA susceptibility. Results from other autoimmune and inflammatory diseases will reveal whether the CARD15 gene is in fact a common autoimmune susceptibility locus.

Arthritis, Rheumatoid↗
PubMed1984

Surgical anatomy of the extraparotid distribution of the facial nerve.

The peripheral, extraparotid distribution of the clinically important branches of the facial nerve is described, with common variations, based on the anatomical dissection of 35 cadaver half heads. Methods are suggested for avoiding, isolating, and protecting the facial nerve branches during surgical procedures.

Cadaver↗
PubMed2007

Association of tagSNPs in the urokinase-plasminogen activator (PLAU) gene with Alzheimer's disease and associated quantitative traits.

The gene coding for urokinase-plasminogen activator (PLAU) is a strong biological and positional candidate gene for Alzheimer's disease (AD). Previously some studies have examined the role of common variation in the PLAU gene with AD risk but the results have been inconsistent and this inconsistency could have been due to the use of relatively small sample sizes. In this study we evaluated the distribution of four tagSNPs (rs2227562 in intron 5, rs2227564 in exon 6, rs2227571 in intron 9, and rs4065 in 3'UTR) in the PLAU gene in a large case-control study consisting of up to 1,000 AD patients and 697 white control subjects. We examined the role of these tagSNPs with AD risk and quantitative traits of AD, including age-at-onset (AAO), disease duration, and mini-mental state examination (MMSE) scores. The 3'UTR SNP revealed modest significant association with risk (OR = 0.71, 95% CI: 0.53-0.95; P = 0.02), AAO (P = 0.036) and disease duration (P = 0.04) of AD. In addition, the intron 9 SNP also revealed a significant association with AAO (P = 0.01) and disease duration (P = 0.006). Our data on a large number of AD cases and controls suggest that genetic variation in PLAU may affect the risk and AAO of AD.

3' Untranslated Regions↗
PubMed2003

CFTR genotypes in patients with normal or borderline sweat chloride levels.

In recent years, some patients bearing "atypical" forms of cystic fibrosis (CF) with normal sweat chloride concentrations have been described. To identify the spectrum of mutant combinations causing such atypical CF, we collected the results of CFTR (ABCC7) mutation analysis from 15 laboratories. Thirty patients with one or more typical symptoms of the disease associated with normal or borderline sweat chloride levels and bearing two CFTR mutations were selected. Phenotypes and genotypes of these 30 patients are described. A total of 18 different CFTR mutations were observed in the 60 chromosomes analysed. F508del was present in 31.6 % of the mutated chromosomes and 3849+10kbC>T in 13.3 %. R117H, D1152H, L206W, 3272-26A>G, S1235R, G149R, R1070W, S945L, and the poly-T tract variation commonly called IVS8-5T were also observed. The relative frequency of CFTR mutations clearly differed from that observed in typical CF patients or in CBAVD patients with the same ethnic origin. A mild genotype with one or two mild or variable mutations was observed in all the patients. These findings improve our understanding of the distribution of CFTR alleles in CF with normal or borderline sweat chloride concentrations and will facilitate the development of more sensitive CFTR mutation screening.

Adolescent↗
PubMed1978

Binding of butylated hydroxyanisole to human albumin using a novel dynamic method.

To study the interaction of butylated hydroxyanisole with various body tissues, a fully automated dynamic method was developed for the determination of plasma protein binding constants at 37 degrees, using membrane filtration equipment designed for dissolution rate studies. Appropriate equations were derived for the calculation of the free drug concentration from comparative diffusion rates across sealed dialysis sacs. A monoexponential equation described the diffusion in the absence of proteins, and a biexponential equation was fitted to diffusion from the drug-protein complex. The Scatchard and double-reciprocal plots were developed for butylated hydroxyanisole. A high degree of reproducibility was obtained for the calculation of protein binding constants (K = 2.4 - 2.9 X 10(4) and n = 1.4 - 1.32). The magnitude of these binding-constants suggests that any change in protein binding can have a significant effect on the distribution of butylated hydroxyanisole throughout the body, such as may be brought about by the common variations in the amount ingested.

Anisoles↗
PubMed1994

Comparative pharmacokinetics of morning and evening doses of once-a-day theophylline capsules.

The objective of this study was to determine if the theophylline diurnal variation that has been observed primarily between morning and evening doses of twice-a-day products could be overcome by a once-a-day formulation. Eighteen healthy, nonsmoking, adult male subjects were given 900-mg theophylline doses as three 300-mg once-a-day theophylline capsules in the morning or evening for 5 days in a single-blind fashion. Matching placebo capsules were administered midway between each dose of active drug. Predose theophylline serum levels on day 3-6 were statistically equivalent within each treatment, indicating that approximate steady-state conditions were achieved by day 3. Mean serum level profiles over the 24-h interval following the active dose on day 5 were almost superimposable for the morning and evening treatments. All pharmacokinetic parameters were equivalent between the treatments, except for the time to peak serum level (Tmax), which was significantly shorter for the morning dose. Given the flatness of the serum level curves for both treatments, the Tmax difference was judged to be clinically unimportant. A small peak-trough level fluctuation of about 50% was seen with each treatment. We conclude that by designing a dose form in which drug release was the rate-limiting step in drug absorption, the diurnal variation commonly associated with theophylline formulations may be eliminated.

Adolescent↗
PubMed2002

Reliability of detecting 'onset of pain' and 'submaximal pain' during neural provocation testing of the upper quadrant.

BACKGROUND AND PURPOSE: Conflicting results have been reported with regard to the reliability of neural tissue provocation tests and it is unclear whether repeated testing affects the test results. In the present study, the stability and reliability of the occurrence of 'onset of pain' and 'submaximal pain' throughout the range of motion during neurodynamic testing was analysed, in both a laboratory and a clinical setting. METHOD: A repeated-measures study design within and between sessions was used. In the laboratory and clinical settings, the base neurodynamic test for the median nerve was performed during a single session on a total of 27 patients with neurogenic cervico-brachial pain. In addition, the base test and three common variations were performed on two occasions by two examiners on 10 asymptomatic subjects in laboratory conditions only. Patients indicated the moment of 'submaximal pain' occurrence, whereas asymptomatic subjects indicated 'onset of pain' and 'submaximal pain'. Corresponding angles at the elbow were recorded by use of an electrogoniometer. RESULTS: In the asymptomatic group, the intra- and inter-tester reliability within the same session was excellent (intraclass correlation coefficient (ICC2.1 > or = 0.95; standard error of measurement (SEM) < or = 4.9 degrees). Reliability after a 48-hour interval was moderate (ICC2.1 > or = 0.69; SEM < or = 9.9 degrees). The reliability coefficients for the symptomatic group within the same session were comparable with the excellent results of the asymptomatic group, for both the laboratory (ICC2.1 = 0.98; SEM = 2.8 degrees) and clinical settings (ICC2.1 > or = 0.98; SEM < or = 3.4 degrees). Consequently, from a statistical perspective, improvements in range of motion as small as approximately 7.5 degrees may be interpreted meaningfully. No significant trend due to repeated testing could be observed when three consecutive repetitions were analysed. CONCLUSIONS: Pain provocation during neurodynamic testing is a stable phenomenon and the range of elbow extension corresponding with the moment of 'pain onset' and 'submaximal pain' may be measured reliably, both in laboratory and clinical conditions.

Adult↗
PubMed1982

Successful streptokinase treatment of a thrombosed, ectopic coronary artery: a case report.

Early reperfusion of a thrombosed, ectopically arising coronary artery was accomplished by selective streptokinase infusion therapy. Familiarity with the most common variations of coronary artery orifices and/or divisions of major branches is important for the angiographer to ensure that selective catheterization of the involved artery can be accomplished promptly.

Aged↗
PubMed1998

[Measuring changes in subjective quality of life in chronic schizophrenic patients].

Subjective quality of life in a group of chronic schizophrenia outpatients was assessed within 1 1/2 years (n = 50) and 4-6 weeks (n = 47) using the Berliner Lebensqualitätsprofil (German version of the Lancashire Quality of Life Profile). There had been no systematic therapeutic interventions meanwhile. Stability and constancy for the longer interval was similar to results in the general population. The statistics for the shorter interval justify in particular use of the profile's total score and general well-being for the measurement of change. In contrast to cross-sectional data and the longer observation period, no significant common variation between psychopathological symptoms and subjective quality of life could be found for the shorter period.

Adaptation, Psychological↗
PubMed2004

Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes.

AIMS/HYPOTHESIS: The Pro12Ala polymorphism of peroxisome proliferator-activated receptor (PPAR)gamma has been consistently associated with Type 2 diabetes. The rare Ala12 variant is estimated to reduce the risk of developing Type 2 diabetes by 20 percent. This variant is in linkage disequilibrium with another common variant, T1431. Both have opposing associations with body weight. We therefore examined the association of specific haplotypes marked by these two variants with susceptibility to Type 2 diabetes. METHODS: We determined the PPARG genotype of a large Scottish cohort of Type 2 diabetic patients ( n=1997) and compared allele frequencies with a cohort of local children ( n=2444) and a middle-aged, population-based cohort from Scotland ( n=1061). RESULTS: Frequency of the Ala12 allele was slightly lower in the Type 2 diabetic cohort than in the children [odds ratio (OR)=0.91, p=0.1]. In contrast, the Ala12 variant was under-represented in the Type 2 diabetic population when compared with similarly aged non-diabetic adults (OR=0.74, p=0.0006). When the Ala12 variant was on a haplotype not bearing the 1431T variant, it conferred greater protection (OR=0.66, p=0.003). However, when it was present in haplotypes containing the 1431T variant (70% of Ala12 carriers), this protection was absent (OR=0.99, p=0.94). CONCLUSIONS/INTERPRETATION: We replicated the finding that the Ala12 variant of PPARgamma affords protection from Type 2 diabetes, and suggest that this protection is modulated by additional common variation at the PPARG locus.

Adult↗
PubMed1999

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials.

OBJECTIVE: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. SUBJECTS AND METHODS: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5-97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. RESULTS: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5-97.5% interval for each laboratory parameter. CONCLUSION: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.

Adult↗
PubMed2004

Branching patterns of the facial nerve and its communication with the auriculotemporal nerve.

This study examines the anatomic relationships and variability of the facial nerve trunk and its branches, with emphasis on the intraparotid connections between the divisions. Microdissections were performed on 30 Korean half-heads, and the facial nerve trunks and branches were exposed. The average depth of the stylomastoid foramen from the skin surface was 21.0 +/- 3.1 mm, and the distance between the stylomastoid foramen and the bifurcation of the temporofacial (upper) and cervicofacial (lower) divisions was 13.0 +/- 2.8 mm. In 26 of 30 dissections (86.7%), the facial nerve trunk bifurcated into two main divisions, and a trifurcation pattern was seen in the other four cases (13.3%). According to the origin of the buccal branches, we classified the branching patterns of the facial nerve into four categories. In type I (13.8% of cases), the buccal branches arose from the two main divisions of the trunk but not from other branches of the facial nerve. In type II (44.8% of cases), the buccal branches arising from the two main divisions were interconnected with the zygomatic branch. In type III (17.3% of cases), the marginal mandibular branch sent nerve twigs to the buccal branch, which originated from the upper and lower divisions. In type IV (17.3% of cases), the nerve twigs from the zygomatic and marginal mandibular branches merged to the buccal branch arising from the two main divisions. Communications between the facial and auriculotemporal nerve branches, which are known as "communicating auriculotemporal nerves," were observed in 28 of the 30 cases (93.3%). Familiarity with these common variations in the facial anatomy provides useful information for the surgeon in careful dissection, preservation of the facial nerve, and complete removal of the tumors in parotidectomies.

Adult↗
PubMed2004

Iatrogenic pseudoaneurysm in a hemodialysis patient: the hidden hazard of a high radial artery origin.

High origin of the radial artery is the most common variation in the arterial network of the upper extremities in humans. A 36-year-old Japanese woman undergoing chronic hemodialysis presented with a pseudoaneurysm originating from the brachial portion of the radial artery and associated with a high radial artery origin. Recognition of variants of the arterial network in the upper extremities is crucial for clinicians because their superficial position at the elbow joint may make these vessels vulnerable to injury.

Adult↗
PubMed2004

Genetic approaches to solving common diseases.

The pathway to solving simple Mendelian inherited neurological disease is now well established. Barely a month goes by without new linkage data or mutations in a novel gene being reported. These developments are giving insights into a range of neurological conditions from the cortex to the muscle. However, most of these diseases are individually rare, and one of the major challenges facing neuroscience is to devise methods to find the genetic variants that confer risk of common diseases and differential response to treatment. This latter area is an important emerging field known as pharmacogenomics. Unlike Mendelian genetics where effective strategies are well established, the strategies for detecting moderate genetic effects in populations have been problematic. It is likely that a combination of techniques will be used, involving both linkage analysis and linkage disequilibrium mapping. In this review we consider some of the approaches that can be taken to resolve the common genetic variation underlying common disease.

Chromosome Mapping↗
PubMed2000

Relationship between E-selectin L/F554 polymorphism and blood pressure in the Stanislas cohort.

We investigated the relationship between polymorphisms of the E-selectin gene SELE (L/F554, S/R128 and 98G/T), a cell adhesion molecule, and interindividual variability in blood pressure and changes over time. The study population was extracted from the Stanislas cohort (1006 families), a cohort of nuclear families volunteering for a free health check-up and recruited by the Center of Preventive Medicine in Nancy (CMP) between 1993 and 1994. For this specific study 359 men and 337 women were selected from families who had already visited the CMP 11 years before recruitment of the Stanislas Cohort. Measurements of blood pressure 11 years before (t(-11)) and at the time of recruitment (t(0)), and all other measurements necessary for the analysis (body mass index, lipids, SELE genotypes) were available. Pregnant women or subjects taking antihypertensive, lipid-lowering, or anti-inflammatory medications were excluded from the study. During the follow-up period systolic and diastolic blood pressures were lower in SELE F554 allele carriers than in those with the L/L554 genotype (P<0.05), but longitudinal changes were not related to any SELE polymorphism. Multiple regression analysis showed that at t(-11) SELE L/F554 polymorphism was associated with both systolic and diastolic blood pressure levels (P<0.01 and P<0.05, respectively). However, these associations were no longer present at t(0). Our results suggest an age-specific effect of the SELE L/F554 polymorphism on blood pressure levels. If confirmed in other studies, these findings would suggest that assessment of common variation in an adhesion molecule could be useful in predicting blood pressure.

Adult↗