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PubMed1998

Genetic variation in paraoxonase-2 is associated with variation in plasma lipoproteins in Canadian Oji-Cree.

We report studies of the association between genetic variation in PON2 and variation in plasma quantitative traits in a sample of 334 non-diabetic Oji-Cree. We detected associations between PON2 variation in codon 148 (Ala --> Gly) and variation in fasting plasma concentrations of total and low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B. In particular, homozygotes for a PON2 allele that encoded A148 had significantly higher plasma total, LDL cholesterol and apo B than subjects having the other two genotypes (p < 0.01). Taken together, our results suggest that common genetic variation on chromosome 7q21.3-22.1 in PON2 is associated with significant variation of intermediate traits in plasma lipoprotein metabolism.

Adult↗
PubMed2003

Evaluation and understanding of myocilin mutations in Indian primary open angle glaucoma patients.

PURPOSE: To screen for mutations in the MYOC gene of patients with Primary Open Angle Glaucoma (POAG) in India and to better understand the mutations using a possible model of myocilin. METHODS: We analyzed DNA for mutations in 107 subjects with POAG and 90 normal control subjects. The exonic sequences of the MYOC gene from all subjects were amplified by Polymerase Chain Reaction (PCR). We carried out Single Strand Conformation Polymorphism (SSCP) for all the PCR products. The DNA samples which showed mobility shift in the banding pattern in SSCP gel were sequenced. We also analyzed the presence of the common mutation Gln368Stop using a specific restriction enzyme Taa 1. The mutations observed here and elsewhere have been mapped onto a possible model built for myocilin using a knowledge-based consensus modeling approach. RESULTS: Two heterozygous mutations Gly367Arg (1099G>A) and Thr377Met (1130C>T) were identified in exon3 of the MYOC gene of probands 40-1 and 51-1 respectively, from material obtained from the 107 unrelated subjects with POAG. These two mutations were not present in the normal controls studied. We identified a Single Nucleotide Polymorphism (SNP) Gly122Gly (366C>T) in exon1 of proband 57-1 as a non-disease causing variation. The common mutation Gln368Stop found in the Western population was not observed in the POAG cases screened in Indian population. The possible structural model for myocilin suggests a predominantly [beta]-strand rich C-terminal region (181-504) which is connected by the [alpha]-helical mid-region (111-180) to the N-terminal region (34-110) which has low secondary structure content. Both the mutations, Gly367Arg and Thr377Met identified in our study, map on to the C-terminal region. These mutations disfavor burial of this region during oligomer formation due to the charged or bulky nature of the mutants. Most of the other mutations known for myocilin also are surface exposed on the C-terminal region. CONCLUSIONS: Our findings indicate that the mutation frequency of the MYOC gene is 2% in the Indian population affected with POAG, which is not a well-studied ethnic group of the Asian continent. The variations identified in our study have been previously reported in the Western population. The nonsense mutation Gln368Stop was not observed in the present study and thereby suggests that it may not be a common disease-causing mutation in the Indian population. Amongst other Asian populations, studies in Japan also didn't report this nonsense mutation. The location of these mutations suggest that a plausible mode of action could be by disruption of dimer or oligomer formation by the C-terminal region allowing greater chances of nucleation of aggregation by the N-terminal region.

Adolescent↗
PubMed1993

Estimation of the genetic variation in complement activity of common carp (Cyprinus carpio L.).

The complement status of hybrid, laboratory raised carp was determined by an in vitro approach of the alternate complement activity (ACH50) and total haemolytic activity (CH50), and by measurement of serum C3 levels. The lysis of target sheep red blood cells (RBC) in the haemolytic assay for CH50 activity depended, amongst others, on the haemolysin concentration in the assay. Rocket electrophoresis showed a mean serum C3 concentration of 0.95 mg ml-1. The variation for both ACH50 and CH50 haemolytic activity was approximately 30%. The degree of genetic determination of the parameters was investigated by estimation of their repeatabilities, which were relatively high for CH50 (0.71) and ACH50 activity (0.72), but lower for C3 levels (0.54). Correlations between ACH50 values and C3 levels were significant, but moderate (0.54-0.58).

Animals↗
PubMed1987

Hemoglobin South Florida: a genetic variant with laboratory recognition of only 20% of its product.

Hemoglobin South Florida is a recently identified hemoglobin variant that is not associated with any clinical disorder. The standard electrophoretic procedures routinely utilized to identify hemoglobin variants did not recognize hemoglobin South Florida. The acetylated form of this hemoglobin co-eluted with hemoglobin A1c on a Bio-Rex 70 column. The quantity of this hemoglobin component was consistent with the amount of hemoglobin A1c associated with uncontrolled diabetes mellitus. The affected individuals did not have diabetes. This observation led to the characterization of a hemoglobin variant that otherwise would have gone unrecognized. This is an example of a variant peptide that was unrecognized for two generations in one family. It is likely that this type of unrecognized peptide variation is common in mammals. These silent structural alterations may be responsible for the variable physical responses occurring in humans exposed to the same environmental agents.

Adolescent↗
PubMed2004

Surfactant protein C gene variation in the Finnish population - association with perinatal respiratory disease.

Surfactant protein C (SP-C) is a small hydrophobic protein component of alveolar surfactant, a lipid-protein complex lining the alveolar surface of the lung. Surfactant deficiency is the main cause of respiratory distress syndrome (RDS) in premature infants. RDS is a major risk factor of a chronic lung disease called bronchopulmonary dysplasia (BPD). The dominant mutations of the SP-C gene have recently been associated with interstitial lung diseases. However, the common genetic variation in the surfactant protein C gene has not been studied in detail. In the present study, the exonic variation of the SP-C gene in the Finnish population (n=472) was defined, and the association of the allelic variants with the susceptibility to RDS and BPD was examined. Conformation-sensitive gel electrophoresis (CSGE) was used to determine the extent of exonic variation in the SP-C gene. Methods of genotyping were generated for three biallelic polymorphisms of the SP-C gene's exons 1, 4 and 5, which encode proSP-C. The frequencies of these polymorphisms were evaluated in a study population consisting of 158 DNA samples from full-term infants. In addition, the linkage disequilibrium between the SP-C alleles was evaluated by haplotype analysis of parent-infant triplets. The role of SP-C gene variation in RDS and in BPD was evaluated in a high-risk population of 245 premature infants. According to the present results, the SP-C polymorphisms were associated with RDS and with very premature birth. The strength of allelic associations differed according to the gender of the premature infants.

Base Sequence↗
PubMed2002

Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8.

Single-nucleotide polymorphisms (SNPs) at some gene loci are useful as markers of individual risk for adverse drug reactions or susceptibility to complex diseases. We have been focusing on identifying SNPs in and around genes encoding drug-metabolizing enzymes and transporters, and have constructed several high-density SNP maps of such regions. Here we report SNPs at additional loci, specifically 13 genes belonging to the superfamily of ATP-binding cassette transporters ( ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8). Sequencing a total of 416 kb of genomic DNA from 48 Japanese volunteers identified 605 SNPs among these 13 loci: 14 in 5' flanking regions, 5 in 5' untranslated regions, 37 within coding elements, 529 in introns, 8 in 3' untranslated regions, and 12 in 3' flanking regions. By comparing our data with SNPs deposited in the dbSNP database of the National Center for Biotechnology Information (US) and with published reports, we determined that 491 (81%) of the SNPs reported here were novel. We also detected 107 genetic variations of other types among the loci examined (insertion-deletions or mono- di-, or trinucleotide polymorphisms). The high-density SNP maps we constructed on the basis of these data should provide useful information for investigating associations between genetic variations and common diseases or responsiveness to drug therapy.

ATP-Binding Cassette Transporters↗
PubMed2006

Genetic variation of Cytochrome P450 1B1 (CYP1B1) and risk of breast cancer among Polish women.

Four single nucleotide polymorphisms (SNPs) in CYP1B1 (Ex2 + 143 C > G, Ex2 + 356 G > T, Ex3 + 251 G > C, Ex3 + 315 A > G) cause amino acid changes (R48G, A119S, L432V and N453S, respectively) and are associated with increased formation of catechol estrogens; however, epidemiologic evidence only weakly supports an association between these variants and breast cancer risk. Because genetic variability conferring increased susceptibility could exist beyond these putative functional variants, we comprehensively examined the common genetic variability within CYP1B1. A total of eight haplotype-tagging (ht)SNPs (including Ex3 + 315 A > G), in addition to two putatively functional SNPs (Ex2 + 143 C > G and Ex3 + 251 G > C), were selected and genotyped in a large case-control study of Polish women (1995 cases and 2296 controls). Haplotypes were estimated using the expectation-maximization algorithm, and overall differences in the haplotype distribution between cases and controls were assessed using a global score test. We also evaluated levels of tumor CYP1B1 protein expression in a subset of 841 cases by immunohistochemistry, and their association with genetic variants. In the Polish population, we observed two linkage disequilibrium (LD)-defined blocks. Neither haplotypes (global P-value of 0.99 and 0.67 for each block of LD, respectively), nor individual SNPs (including three putatively functional SNPs) were associated with breast cancer risk. CYP1B1 was expressed in most tumor tissues (98%), and the level of expression was not related to the studied genetic variants. We found little evidence for modification of the estimated effect of haplotypes or individual SNPs by age, family history of breast cancer, or tumor hormone receptor status. The present study provides strong evidence against the existence of a substantial overall association between common genetic variation in CYP1B1 and breast cancer risk.

Adult↗
PubMed2026

Antivenomic and Proteomic Assessment of Inter- and Intrapopulation Venom Variations in Nikolsky's Adder Vipera nikolskii: Comparison to Common Adder Vipera berus.

Snake venom variation has important clinical implications, yet individual-level venomics remains limited. We investigated inter- and intrapopulation variability in forest-steppe adder Vipera nikolskii and its recognition by commercial V. berus antivenom using proteomic and immunological approaches. Venoms from 12 individual V. nikolskii specimens representing two geographically distinct populations (BG and KM), together with three pooled V. nikolskii and one pooled V. berus samples were analyzed by LC-MS/MS, ELISA, Western blot, and pull-down assays. Multivariate analysis revealed relative homogeneity in BG and pronounced heterogeneity in KM venoms. Area-based proteomics revealed V. berus venom enrichment in PLA2 (34.6%), SVMP (14.6%), and CRiSP (15.6%), whereas V. nikolskii venoms were more variable. Pooled V. nikolskii venoms showed SVMP abundance (35.2-41.1%), contrasting with lower levels in individual samples. Antivenom binding was stronger for V. berus but weaker and more variable across individual and pooled V. nikolskii samples. Antivenom targeted PLA2/VEGF, CRiSP (only in V. berus), and Kunitz-type proteins. In vivo neutralization assay demonstrated strong protection against V. berus but not V. nikolskii venom. These findings reveal substantial compositional and antigenic variability in V. nikolskii venoms, highlight discrepancies between pooled and individual ones, and underscore the need for region-specific and functionally validated antivenom evaluation.

Animals↗
PubMed2002

Comparative analysis of growth rings in perennial forbs grown in an Alpine restoration experiment.

Recent studies have demonstrated that growth rings are widespread in the roots of forbs, and there is evidence that the rings are formed annually. However, the annual nature and development of the growth rings has not yet been examined in comparative experimental studies. In this study growth rings were analysed in the main roots of four alpine forbs (Lotus alpinus, Trifolium thalii, Silene willdenowii and Potentilla aurea) that were grown in an alpine restoration experiment for 6 years. All individuals of L. alpinus and T. thalii, and some individuals of S. willdenowii showed six clearly demarcated growth rings, demonstrating that the rings were formed annually. P. aurea did not show distinguishable growth rings. In L. alpinus and T. thalii there were fluctuations in growth ring width that were consistent between individuals and also between species, and matched variations in climatic growth conditions. Results of the present study indicate that conclusions drawn from previous studies suggesting that growth rings in the roots of forb species are most likely formed annually are also valid for alpine plants. In terms of annual ring width patterns, this study also provides the first strong evidence for consistent responses of different forb species and individuals to commonly experienced variations in habitat conditions.

Altitude↗
PubMed2002

Reproducibility of evaluation of the uterus by transvaginal sonography, hysterosonographic examination, hysteroscopy and magnetic resonance imaging.

BACKGROUND: The aim was to evaluate and compare inter-observer reproducibility by magnetic resonance imaging (MRI), transvaginal ultrasonography (TVS), hysterosonographic examination (HSE) and hysteroscopy (HY). METHODS: Different observers consecutively evaluated MRI, TVS, HSE and HY independently in 51 pre-menopausal women, who underwent hysterectomy for benign diseases. RESULTS: Inter-observer agreement (kappa) was as follows: Exclusion of uterine cavity abnormalities: MRI 0.97, TVS 0.68, HSE 0.48 and HY 0.63; submucous myomas: MRI 0.97, TVS 0.59, HSE 0.60 and HY 0.67; polyps: MRI 0.49, TVS 0.48, HSE 0.35 and HY 0.50; identification of myometrial myomas: MRI 0.97, TVS 0.74; adenomyosis: MRI 0.73 and TVS 0.38. Mean difference between observers in number of observed myomas was (absolute values) MRI 0.58, TVS 0.93. Agreement on evaluation of abnormalities in the uterine cavity, submucous myomas, number of myomas and adenomyosis was significantly greater by MRI than by any of the other techniques, whereas agreement was in line by TVS, HSE and HY. CONCLUSIONS: Inter-observer disagreement reached substantial levels only for exclusion of uterine cavity benign abnormalities by HY, TVS and HSE. Strategies should be adopted to reduce observer variation of common gynaecological imaging techniques or the less observer-dependent MRI technique could be favoured.

Adult↗
PubMed1986

Prevalence of depressive symptoms and depression in elderly Finnish home nursing patients and home help clients.

Depressive symptoms in a population (N = 419) aged 65 years or over and receiving home nursing, home help or both were assessed by postal questionnaires including the Zung self-rating depression scale (SDS). Eighty-six percent participated, and 38 percent of both men and women scored 45 raw sumpoints or more in the SDS. The mean of the raw sumpoints was 42.1 (+/- 9.6) for men (N = 100) and 41.4 (+/- 9.0) for women (N = 238, the difference being nonsignificant. Home help clients scored less than home nursing patients or patients receiving both home nursing and home help. The population scoring 45 raw SDS sumpoints or more was investigated by a general practitioner, and the diagnosis of depression was made according to DSM III-criteria. The clinical investigations showed 26 percent of both men and women who participated to be depressive. Chronic depression was the most common class, followed by atypical depression. About two thirds of the depressive men and half of the depressive women were 'new' cases in that it had not been realized earlier that they suffer from depression. Atypical depression was the class where underdiagnozing was most evident. Among elderly men psychomotor retardation, libido loss, anorexia and indecisiveness and among elderly women psychomotor retardation, indecisiveness, emptiness and diurnal variation were common symptoms of depression.

Aged↗
PubMed2004

Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment.

BACKGROUND: Reliable assessment of severity in psoriasis is essential to document treatment responses in clinical research. The reliability of current clinical outcome measures is uncertain. OBJECTIVE: To quantify the relative variation in commonly used outcome measures (the Psoriasis Area and Severity Index [PASI] and one version of the Psoriasis Global Assessment [PGA]), and a newer measure, the Lattice System Physician's Global Assessment (LS-PGA). METHODS: Physicians who were experienced (53%; 9/17) or inexperienced (47%; 8/17) in using PASI and PGA evaluated 35 patients with psoriasis in random order twice with each rating system. We assessed the variation in scoring psoriasis severity within (intrarater) and among (interrater) physicians. RESULTS: PASI, PGA, and LS-PGA were highly correlated (r > 0.8 for all comparisons) and had high overall reliability (Cronbach's alpha > 0.9 for each). PGA and LS-PGA had lower intrarater variation than PASI. LS-PGA had a 55% higher concordance coefficient between the two evaluations than did PGA. Interrater variation was lower for PGA and LS-PGA than for PASI both before and after correction for measurement error. Experience was beneficial in reducing variation in PASI scores but was not required with PGA or LS-PGA. CONCLUSION: The LS-PGA, which is standardized, does not require experience, and provides discrete word-based scores with intrinsic meaning, is a reliable measure of therapeutic effect in psoriasis, and would allow comparisons across different clinical trials.

Adult↗
PubMed2003

Multiple origins of cultivated radishes as evidenced by a comparison of the structural variations in mitochondrial DNA of Raphanus.

Configurations of mitochondrial coxI and orfB gene regions were analysed by polymerase chain reaction (PCR) in three wild and one cultivated species of Raphanus. A total of 207 individual plants from 60 accessions were used. PCR with five combinations of primers identified five different amplification patterns both in wild and cultivated radishes. While the mitochondrial DNA (mtDNA) type of Ogura male-sterile cytoplasm was distinguishable from the normal type, the mtDNAs of normal radishes were further classified into four types. The variations were common to wild and cultivated radishes, although contrasting features were found depending on the region of cultivation. These results provide evidence that cultivated radishes have multiple origins from various wild plants of Raphanus.

Biological Evolution↗
PubMed2006

Diversity and variation in biomechanical exposure: what is it, and why would we like to know?

Trends in global working life suggest that the occurrence of jobs characterized by long-lasting low-level loads or repetitive operations is increasing. More physical "variation" is commonly believed to be a remedy against musculoskeletal disorders in such jobs. One aim of the present paper was to shortly review the validity of this conviction. An examination of the available epidemiologic literature pointed out that the effectiveness of initiatives like job rotation or more breaks is weakly supported by empirical evidence, and only for short-term psychophysical outcomes. Only a limited number of studies have been devoted to physical variation, and concepts and metrics for variation in biomechanical exposure are not well developed. Thus, as a second objective, the paper proposes a framework for investigating and evaluating aspects of exposure variation, based on explicit definitions of variation as "the change in exposure across time" and diversity as "the extent that exposure entities differ". Operational methods for assessing these concepts are also discussed.

Biomechanical Phenomena↗
PubMed1993

Variability in the embryotoxicity and fetotoxicity of vanadate with the day of exposure.

The aim of this study was to assess the variability in the developmental toxicity of vanadate with the day of administration during gestation. Single ip injections of 25 mg sodium metavanadata/kg were given to albino Swiss mice on one of the days 9-12 of gestation. Dams were killed on day 18 of pregnancy, and fetuses were examined for external, internal and skeletal malformations and variations. The number of dead or resorbed fetuses/litter, as well as the percentage of postimplantation loss, were significantly increased with injections on days 9-12 of gestation. However, the most sensitive time for the induction of metavanadate embryotoxicity was gestational day 12. Metavanadate treatment on day 12, but not days 9-11, resulted in a significant decrease in the fetal body weight/litter. There were no external, internal or skeletal malformations, whereas the most common skeletal variations were a reduced ossification in the parietal bone, metatarsals and metacarpals, bipartite sternebrae and fused ribs. The highest percentage of total skeletal defects was found on day 12 (82.3%). Gestational day 12 is the most sensitive time for metavanadate-induced developmental toxicity in mice.

Animals↗
PubMed2002

Itraconazole (Sporanox®) for seborrheic dermatitis.

Seborrheic dermatitis is a common superficial dermatosis, characterized by red, flaking areas of the skin, which may in some cases be covered with yellowish flakes. The most commonly affected areas are the nasolabial folds, ears, eyebrows, scalp and chest. While seborrheic dermatitis may be easy to recognize clinically, the variability of the lesions in both appearance and location may complicate the diagnosis. Seborrheic dermatitis has been described as resembling psoriasis (in which case, the condition may be called "sebopsoriasis") and, when affecting the eyes or ears, has also been described as blepharitis and otitis, respectively. Seborrheic dermatitis tends to be chronic, though seasonal variation is common, with lesions worsening in the dry, winter months.

Antifungal Agents↗
PubMed1982

Small-area variations in the use of common surgical procedures: an international comparison of New England, England, and Norway.

We examined the incidence of seven common surgical procedures in seven hospital service areas in southern Norway, in 21 districts in the West Midlands of the United Kingdom, and in the 18 most heavily populated hospital service areas in Vermont, Maine, and Rhode Island. Although surgical rates were higher in the New England states than in the United Kingdom or Norway, there was no greater degree of variability in the rates of surgery among the service areas within the three New England states. Hernia repair was more variable in England (P less than 0.05) and hysterectomy in Norway (P less than 0.05) than in the other countries. There was consistency among countries in the rank order of variability for most procedures: tonsillectomy, hemorrhoidectomy, hysterectomy, and prostatectomy varied more from area to area than did appendectomy, hernia repair, or cholecystectomy. The degree of variation generally appeared to be more characteristic of the procedure than of the country in which it was performed. Thus, differences among countries in the methods of organizing and financing care appear to have little relation to the intrinsic variability in the incidence of common surgical procedures among hospital service areas in these countries. Despite the differences in average rates of use, the degrees of controversy and uncertainty concerning the indications for these procedures seem to be similar among clinicians in all three countries.

Appendectomy↗
PubMed2006

Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.

Depressive disorders account for a large and increasing global burden of disease. Although the condition of many patients improves with medication, only a minority experience full remission, and patients whose condition responds to one medication may not have a response to others. Individual variation in antidepressant treatment outcome is, at present, unpredictable but may have a partial genetic basis. We searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) study and were prospectively assessed. In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. We detected significant and reproducible association between treatment outcome and a marker in HTR2A (P range 1 x 10(-6) to 3.7 x 10(-5) in the total sample). Other markers in HTR2A also showed evidence of association with treatment outcome in the total sample. HTR2A encodes the serotonin 2A receptor, which is downregulated by citalopram. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants. The A allele may contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.

Adult↗