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PubMedDate not supplied

Serum complement (C3, BF, C4) types in Swedish Saamis.

Serum complement (C3, BF, C4) types were examined in Swedish Saamis (Lapps). In agreement with previous studies, a very low frequency of the C3*F allele (0.033) was found. Compared to Swedes and other Caucasian populations, Swedish Saamis showed a significantly increased frequency of the BFS, C4A4 and C4B2 variants, and a lower frequency of C4 deficiency. BFS, C4A4 and C4B2 show haplotype associations and thus the frequency of the S-A4-B2 complotype is significantly increased among the Saamis. Although the serum complement constitution of the Saamis shows some similarity with that of Asiatic Mongoloid populations it is unlikely to be due to Asiatic ethnic influence. The marked genetic deviations of the Saamis from all other populations has often been interpreted as a result of the founder effect and genetic drift. In this particular case, however, immunogenetic adaptation appears to be a plausible alternative explanation for the deviations in genetic complement factors.

Adaptation, Biological↗
PubMed1993

A study of sister chromatid exchange and somatic cell mutation in hospital workers exposed to ethylene oxide.

To investigate the risks of exposure to ethylene oxide (EO) at current permissible levels and at past higher levels, an inception cohort of sterilizer operators and supervisors from the Central Processing Department (CPD), respiratory therapists, and engineers exposed to EO were identified at the McMaster University Medical Centre. A comparison group from Nutrition Services (NUTR) were matched with the CPD workers on the basis of sex, age, and smoking habit. The present report is based on genetic test results for the 94 CPD and matched NUTR workers only. Statistical analysis based on the mean SCE frequency in the top 5, top 10, and all cells (50 cells scored per individual) and high frequency cells (HFC) based on the 95th percentile for nonsmoking control subjects showed a direct association with current smoking but not with EO exposure. Similarly, statistical analysis of the somatic cell mutation (SCMT) variant frequencies did not demonstrate an association with EO exposure, nor with smoking. Regression analysis indicated that sex was the only other covariate that significantly affected SCE. Age was weakly associated with SCMT. A statistically significant interaction between occupational exposure and smoking habits was observed only for the mean SCE frequency of the top 5 and top 10 cells when the 11 current CPD/NUTR pairs were not included. Thus, this interaction should be interpreted with caution.

Ethylene Oxide↗
PubMed2000

Mutations in a potential phospholipid binding loop in the C2 domain of factor V affecting the assembly of the prothrombinase complex.

Activated factor V (FVa) serves as a cofactor to activated factor X in the prothrombinase complex. FVa is homologous to activated factor VIII (FVIIIa), the light chains of both proteins being formed by similar domains (A3-C1-C2). Interaction of FVa and FVIIIa with negatively charged phospholipid membranes is crucial for the function of both cofactors. In both proteins, the C2 domains are important for membrane binding but a detailed understanding of the binding mechanisms is missing. Recently, knowledge has been gained into the three-dimensional structures of the C domains facilitating studies of structure-function relationships. Structural analysis of the C2 domain in FVa predicted a surface-exposed loop (K2060, K2061, S2062, W2063, W2064) to be involved in membrane binding. Three double mutants were created, K2060Q-K2061Q, W2063Y-W2064Y and W2063A-W2064A, and expressed in a transient expression system. In addition, a FV variant in which all four residues were mutated, K2060Q-K2061Q-W2063A-W2064A, was produced. Mutagenesis of the two lysines showed no functional consequences, whereas mutagenesis of the two tryptophanes yielded FVa with impaired ability to interact with the phospholipid, as demonstrated by a poor functional activity at limiting phospholipid concentrations. A molecular model of FVa, anchored at the surface of a phospholipid membrane, was developed and used as a template for the interpretation of the mutagenesis experiments.

Animals↗
PubMed1990

[Elements of NOT (Scientific Organization of Labor) in a clinical diagnostic laboratory].

The suggested graphic variants of laboratory forms permit a rapid and accurate assessment of laboratory data, help detect organ abnormalities and relationships between shifts in laboratory characteristics of various systems of the body. These forms are convenient for dynamic assessment of changes in laboratory parameters, they permit a further mathematical processing of the data. Use of such forms will help reduce the number of laboratory analyses at the expense of purposeful laboratory tests, much more rapidly interpreted, thus saving the clinician's time.

Efficiency↗
PubMed2003

Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics.

If the risk of disease is not the same for all germline mutations in a given gene, or if there are other familial modifiers of risk in carriers, then family-history-based estimates of average risk for detected mutations in that gene will depend on how carriers are sampled. Risk may also depend on the site or type of mutation. We studied 51 families with strong histories of breast cancer who attended Australian family cancer clinics and in which a germline mutation in BRCA1 or BRCA2 had been identified (28 and 23 families, respectively). Breast cancer risk in carriers was estimated under maximum likelihood theory, using information from all family members including those not tested, with adjustment for ascertainment by conditioning on genotype of the proband and family phenotype. The average cumulative risk of breast cancer for mutations in either BRCA1 or BRCA2 was 27% (95% confidence interval 16-43%) to age 50 and 64% (44-83%) to age 70. When grouped, the incidence in carriers was on average 17 (10-30) times that in non-carriers, independent of gene or mutation type (hazard ratios: 11 (4-29) for BRCA1, 23 (12-43) for BRCA2 (P for difference = 0.23); 13 (6-29) for protein-truncating mutations, 30 (9-104) for missense mutations and 30 (10-90) for splice-site mutations). For missense mutations, this was equivalent to a cumulative risk to age 70 of 83% (40-100%) and was due in part, but not totally, to the missense mutations 300 T>G in BRCA1 and 4486 G>T in BRCA2, which were individually found to be associated with high risk (P<0.001). Mutations in the central region of BRCA1 may be associated with a lower risk. The issue of the pathogenicity of specific variants may be addressed analytically providing there are one or more suitably informative families with that mutation.

Age Factors↗
PubMed1976

Difficulties and pitfalls in the interpretation of screening tests for the detection of inborn errors of metabolism.

A review of factors which may be responsible for false positive and false negative results in a screening program for the detection of inborn errors of metabolism is presented. Administration of medication, dietary therapy, chemical treatment of specimens, delay in analysis, hypersensitivity of procedures utilized, interfering metabolites and inadequate metabolic development or enzymatic maturation in the patient may all produce results resembling an actual inborn error of metabolism. Inadequate nutritional intake prior to procurement of specimen and loss of material during analytical procedures may produce false negative results. As well, certain less severe variants of inborn errors may present in an unusual manner or may only present during periods of stress to the patient. These factors are discussed in relation to the performance of a metabolic screening program. It is suggested that these progrms should be performed by specialized, central laboratories experienced in the complexities of detection of inborn errors of metabolism.

Anticonvulsants↗
PubMed1998

Structural analysis and evaluation of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene in human essential hypertension.

AIM: Mutations of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive form of hypertension. We therefore investigated the question of whether variants of the 11beta-HSD2 gene can contribute to genetic susceptibility to essential hypertension. SUBJECTS AND METHODS: We performed a linkage study in 162 French hypertensive sibships using the affected sib-pair method on 347 sibling pairs and a polymorphic microsatellite marker that we identified in a 30 kb cosmid clone containing the 11beta-HSD2 gene. The coding sequence, introns 2-4 and 350 bp of the 5'-flanking region of the 11beta-HSD2 gene were screened for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism, and a single polymorphism, Glu178/Glu (G534A), was identified in exon 3, which did not change the encoded amino acid sequence. A case-control study was conducted on 370 hypertensive subjects with a positive family history of hypertension and 783 French subjects with hypertension with or without a family history of hypertension, compared with 313 normotensive control subjects, all of whom were analyzed for the newly identified bi-allelic polymorphism. RESULTS: Statistical analyses using the affected sib-pair method did not show significant linkage between the 11beta-HSD2 microsatellite marker and hypertension. Furthermore, no positive association with hypertension was found with the Glu178/Glu (G534A) polymorphism. CONCLUSION: Our data do not suggest that variants of the 11beta-HSD2 gene contribute substantially to essential hypertension in Caucasians.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Rank-based methods as a non-parametric alternative of the T-statistic for the analysis of biological microarray data.

We have recently introduced a rank-based test statistic, RankProducts (RP), as a new non-parametric method for detecting differentially expressed genes in microarray experiments. It has been shown to generate surprisingly good results with biological datasets. The basis for this performance and the limits of the method are, however, little understood. Here we explore the performance of such rank-based approaches under a variety of conditions using simulated microarray data, and compare it with classical Wilcoxon rank sums and t-statistics, which form the basis of most alternative differential gene expression detection techniques. We show that for realistic simulated microarray datasets, RP is more powerful and accurate for sorting genes by differential expression than t-statistics or Wilcoxon rank sums - in particular for replicate numbers below 10, which are most commonly used in biological experiments. Its relative performance is particularly strong when the data are contaminated by non-normal random noise or when the samples are very inhomogenous, e.g. because they come from different time points or contain a mixture of affected and unaffected cells. However, RP assumes equal measurement variance for all genes and tends to give overly optimistic p-values when this assumption is violated. It is therefore essential that proper variance stabilizing normalization is performed on the data before calculating the RP values. Where this is impossible, another rank-based variant of RP (average ranks) provides a useful alternative with very similar overall performance. The Perl scripts implementing the simulation and evaluation are available upon request. Implementations of the RP method are available for download from the authors website (http://www.brc.dcs.gla.ac.uk/glama).

Algorithms↗
PubMed1989

C7 polymorphism in Japanese: new allele C7*8.

The polymorphism of C7 was investigated in neuraminidase-treated sera from 513 unrelated Japanese individuals using isoelectric focusing followed by an electroimmunoblotting technique. Besides the common phenotypes 5 rare variants including 2 types of new variants were detected. The family analysis suggested the hereditary occurrence of a new allele C7*8. The allele frequencies were: C7*1 = 0.8314, C7*2 = 0.0926, C7*3 = 0.0380, C7*4 = 0.0331, C7*6 = 0.0010, and C7*8 = 0.0039.

Alleles↗
PubMed1978

Ethnic communities in Israel: the genetic blood markers of the Babylonian Jews.

One hundred eighty-eight Jewish individuals who either they or whose both parents were born in Iraq were typed for 7 blood groups (ABO, MNS, Rh, Kell, Duffy, P and Kidd), 12 red cell enzyme systems and 2 serum proteins. Iraqi Jews are characterized by a high frequency of A (in ABO), N (in MNS), low cde (Rh) and low Hp-1. Several rare electrophoretic variants were encountered: PGM1 6-1, PHI 3-1 and PHI 2-1, and an unidentified AK phenotype. No evidence of Negroid admixture was found in their gene pool. Comparisons with results previously obtained in Iraqi Jews show general similarities in frequencies while comparisons with neighboring non-Jewish populations suggest divergence in most systems investigated. The difficulties of assessing relationships on the basis of a few selected differences and the need for careful interpretations of similarities are emphasized.

Blood Group Antigens↗
PubMed1981

An argument for the use of total side frequencies of bilateral nonmetric skeletal traits in population distance analysis: the regression of symmetry on incidence.

In population studies based on frequencies of bilateral nonmetric skeletal traits, the choice between sampling by individuals or by sides should depend less on the exigencies imposed by fragmentary remains than on fundamental assumptions about the biological meaning of symmetry/asymmetry. Though the latter has been interpreted in various ways, little attention has focused on the possibility that bilateral correlation is meaningful in quantifying genetic liability for a trait. Analysis of two independent mandibular features, mylohyoid bridge and suppressed third molar, in Indian and Eskimo population samples (total N congruent to 1,200) reveals a statistically significant pattern of increasing bilateral occurrence with increasing population incidence. This pattern is consistent with the theory that liability for a "quasi-continuous" variant is normally distributed with constant increment between thresholds on an underlying scale. According to theory, phenotypes with more pronounced expression (bilateral occurrence) have greater genetic potential than those with less pronounced expression (unilateral occurrence). Therefore, scoring traits in total left and right sides, by giving greater weight to bilaterally affected individuals, may provide a better estimate of the liability for the trait in the population. Viewed in a theoretical context broader than that of the sampling debate, this pattern of positive regression of symmetry on incidence means that prevalence of unilateral occurrence probably cannot be used to assess the relative strength of genetic versus nongenetic control of threshold variants.

Age Factors↗
PubMed1990

Retardation of metastatic tumor growth after immunization with metastasis-specific monoclonal antibodies.

The influence of 4 murine monoclonal antibodies (MAbs) directed against surface determinants of a metastasizing rat adenocarcinoma (BSp73ASML) on metastatic spread was evaluated and compared to their in vivo binding as well as to the induction of a humoral anti-MAb response, especially with respect to the development of anti-idiotypic (ID) antibodies of the internal image type. In a protocol of explicit immunization, all 4 MAbs transiently inhibited metastatic growth. Survival was prolonged only with one MAb (4.4ASML). With another MAb (1.1ASML), directed against a new variant form of CD44, metastatic growth was accelerated after transient retardation. Retardation of metastatic growth correlated with the humoral anti-MAb response. This accounted for the isotype- as well as for the idiotype-specific response. An exception was noted after immunization with MAb 1.1ASML. Rats with high levels of anti-1.1ASML antibodies, which inhibited binding to the tumor cells (internal image-type antibodies) showed accelerated metastatic spread. Data are interpreted to mean that MAb-induced inhibition of metastatic spread may be based on 2 independent mechanisms: blockade of metastasis-associated epitopes (i.e., with MAb 1.1ASML) and induction of an anti-mouse Ig response. In the latter case it was irrelevant whether the response was isotype- or idiotype-specific.

Adenocarcinoma↗
PubMed2004

Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis.

Late onset multiple sclerosis (LOMS), defined as the first presentation of clinical symptoms in patients over 50, is not a rare phenomenon as previously thought, since the prevalence ranges between 4% and 9.6% in different studies. The course of the disease is often primary progressive and pyramidal or cerebellar involvement is observed in 60%-70% of the patients at presentation. LOMS is usually associated with a faster progression to disability compared to young adult multiple sclerosis (MS) patients. Moreover in patients over 50, MS variants and atypical forms which present a difficult diagnostic problem, may be frequently encountered. The differential diagnosis may be sometimes difficult and includes cerebro-spinal vascular syndromes, hypertension-related disorders, compressive myelopathies, primary or secondary vasculitis, metabolic diseases, degenerative and nutritional syndromes. Clinical characteristics, magnetic resonance imaging (MRI) pattern of abnormalities, evoked potential studies and cerebrospinal fluid (CSF) oligoclonal band analysis are of high diagnostic yield in LOMS patients, but expertise in interpreting their results is strongly required.

Age of Onset↗
PubMed2003

Evidence for sequential barriers and obligatory intermediates in apparent two-state protein folding.

Many small proteins fold fast and without detectable intermediates. This is frequently taken as evidence against the importance of partially folded states, which often transiently accumulate during folding of larger proteins. To get insight into the properties of free energy barriers in protein folding we analyzed experimental data from 23 proteins that were reported to show non-linear activation free-energy relationships. These non-linearities are generally interpreted in terms of broad transition barrier regions with a large number of energetically similar states. Our results argue against the presence of a single broad barrier region. They rather indicate that the non-linearities are caused by sequential folding pathways with consecutive distinct barriers and a few obligatory high-energy intermediates. In contrast to a broad barrier model the sequential model gives a consistent picture of the folding barriers for different variants of the same protein and when folding of a single protein is analyzed under different solvent conditions. The sequential model is also able to explain changes from linear to non-linear free energy relationships and from apparent two-state folding to folding through populated intermediates upon single point mutations or changes in the experimental conditions. These results suggest that the apparent discrepancy between two-state and multi-state folding originates in the relative stability of the intermediates, which argues for the importance of partially folded states in protein folding.

Mathematics↗
PubMed1975

Alloimmune cytotoxic T cells: Evidence that they recognize serologically defined antigens and bear clonally restricted receptors.

Murine T cells immunized with allogeneic cells exert a cytotoxic effect on appropriate target cells, as measured by 51-Cr release. Lysis of the 51-Cr-labeled target can be inhibited by addition to the assay of unlabeled cells which bear target antigens. With variants of lymphoid tumors which express different amounts of serologically defined H-2 antigens as competitors in the assay, a positive correlation is shown to exist between the amount of serologically defined antigen and the degree of inhibition of T cell-mediated lysis. The immunized small lymphocytes are shown to be very poor inhibitors of 51-Cr release from target cells which are more susceptible to T cell-mediated lysis. This is interpreted as showing that small lymphocytes are bound very poorly by cytotoxic T cells. With H-2 cross-over strains which carry only the H-2K or H-2D antigens which a cytotoxic population is directed against, it is shown that, 1) approximately equal amounts of cytotoxicity are directed against the K and D antigens, and 2) separate cytotoxic T cells recognize the K and D antigens. Thus, by this criterion, cytotoxic T cells are monospecific and therefore do not acquire their antigen-specific receptors cytophilically.

Animals↗
PubMedDate not supplied

US of neurovascular occlusive disease: interpretive pearls and pitfalls.

Ultrasonography (US) of the head and neck is a convenient but operator-dependent screening tool for detection and diagnosis of neurovascular occlusive disease. In US examination of the extracranial carotid arteries, stenosis is most commonly graded according to the peak systolic Doppler velocity in the region of maximal luminal narrowing rather than according to the percentage of atheromatous plaque occupying the lumen. However, the peak systolic velocity is not always reliable in estimation of the degree of stenosis. General diagnostic pitfalls include technical difficulties with scanning, failure to review the spectral waveform patterns, the presence of additional stenotic lesions, and anatomic variants. Specific examples of pitfalls include tandem lesions, differentiation of pseudo-occlusion from true total occlusion, pseudonormalization of velocities in cases of very severe stenosis, lesions of the carotid artery origin or aortic valve, progression of subclavian steal, underestimation of severe stenosis due to heavily calcified plaque, a persistent trigeminal artery, and contralateral carotid artery stenosis. Although conventional angiography remains the standard of reference for assessment of carotid artery disease, recognition of these common sources of error in US can improve the accuracy of this noninvasive test in diagnosis of carotid artery occlusion.

Arterial Occlusive Diseases↗
PubMed2004

Evolution of an arbitrary sequence in solubility.

We have investigated the evolvability of an insoluble random polypeptide, RP3-34, to a soluble form through iterative mutation and selection with the aid of the green fluorescent protein (GFP) folding reporter. To assess the solubility of the polypeptides in the selected clones of each generation, the polypeptide genes were detached from the GFP fusions and expressed with a His(6) tag. The solubility of the variant random polypeptides increased in each generation within the scope of the evolutionary process, and the polypeptides assumed a soluble form from the fourth generation. Analysis of the synonymous and nonsynonymous mutations found in the deduced amino acid sequence of the selected polypeptides revealed that selection had accelerated the evolutionary rate. The solubility and hydrophobicity of the polypeptides and the 25 arbitrarily chosen random polypeptides found in a previously prepared library were determined, analyzed, and interpreted from the landscape on the protein sequence space. This study showed the evolvability of an insoluble arbitrary sequence toward a soluble one, hence, it provides a new perspective on the field of artificial evolution.

Amino Acid Sequence↗
PubMed1988

Spectra of molecular changes induced in DNA of Drosophila spermatozoa by 1-ethyl-1-nitrosourea and X-rays.

Mutations induced in Drosophila spermatozoa at the alcohol dehydrogenase Adh locus by 1-ethyl-1-nitrosourea (ENU) were compared to X-ray-induced mutations using genetic tests for complementation, southern blotting, western blotting and northern blotting. 8 of 10 ENU-induced mutations complemented all known adjacent loci and were presumed to be intragenic. In contrast, 8 of 30 X-ray-induced mutations were intragenic. Southern blot analysis showed that 2 of 7 intragenic mutations induced by X-rays were altered at the Adh locus, whereas all 8 intragenic ENU mutants appeared normal. Western blot analysis showed 4 of 7 intragenic mutants induced by X-rays produced a detectable polypeptide; 1 of the 4 had normal molecular weight and charge. In contrast, 7 of the 8 intragenic mutants induced by ENU produced a polypeptide of normal molecular weight and charge. One ENU and two X-ray-induced mutants, which had normal southern blots and no detectable polypeptide, produced normal molecular weight mRNA by northern blots. The interpretation of these results is that in spermatozoa X-rays induce primarily deletions that either produce deficiencies of the Adh locus or nonsense mutations within the locus, whereas ENU induces primarily missense mutations. This forward mutation assay based on loss of enzymatic activity efficiently recovered a broad spectrum of mutations ranging from missense to intragenic deletions and multi-locus deficiencies. Only 3 of these 40 mutations produced a polypeptide detectable as an electrophoretic variant.

Alcohol Dehydrogenase↗