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PubMedDate not supplied

[Comparative analysis of the monopodial and sympodial models of bulb branching in Galanthus L].

We have examined sympodial and monopodial models of bulb branching in Galanthus. The issue of the position of the reduced prophyll is discussed. We proposed a method of formal interpretation: parts of the plant were positioned on diagrams; several variants of axial schemes were matched to each diagram; the schemes were divided into two classes, monopodial and sympodial ones, and stability of each class was estimated. In order to decide about the model of Galanthus bulb branching, we have examined plants with additional inflorescences and plants with additional leaf series. We have shown that the sympodial model predicts the presence of the reduced prophyll at the base of the innovation bud in all studied cases. Consecutive stages of prophyll reduction (prophyll of the innovation bud) can be followed in Amaryllidaceae in the following sequence: Zephyranthes, a well-developed large prophyll with green lamina; Vallota, a developed prophyll with reduced green lamina; Haemanthus, a thin chaffy short-living prophyll. At the end of this sequence is Galanthus with completely reduced prophyll at the innovation bud.

Liliaceae↗

PubMed2000

Pharmacogenetics: a molecular sophistication or a new clinical tool for cardiologists?

The study of genetic risk factors for multifactorial diseases is attracting increasing interest. In particular interest has been focused on the interaction between genetic polymorphisms and environmental factors in determining the risk of disease. Among environmental factors therapeutic approaches should be considered. Therapeutic responses to a given drug, failure of drug efficacy, interindividual variability in side effects and toxicity of drugs could be at least partially accounted for by genetic polymorphisms. This paper summarizes the presently available applications of genetic concepts to some drugs commonly used in patients with cardiovascular disease. Statins and probucol fail to lower cholesterol levels in carriers of specific polymorphisms. The progression of cardiovascular disease is decreased by pravastatin only when certain polymorphisms are present. Induction problems and bleeding complications of warfarin occur in subgroups of populations carrying specific genetic variants of key enzymes in the drug metabolism. A new interpretation of the results of a thrombosis prevention trial will be given in the light of a genetic approach to pharmacology; indeed, prevention and treatment of thrombotic disease could be better focused on the basis of this knowledge. Future clinical trials and cost-effectiveness evaluation of drugs should be conducted taking these gene-drug interactions into account.

Administration, Oral↗

PubMedDate not supplied

Dental gel viscosity parameters and pharmaceutical availability of non-steroidal anti-inflammatory drugs.

Model prescription for dental anti-inflammatory gels with carboxymethylcellulose sodium salt and non-ionic surfactants have been worked out. Viscosity parameters of 10 variant gel forms were investigated and an attempt on their interpretation was undertaken in relation to pharmaceutical availability of non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen sodium). Viscosity tests demonstrated higher pharmaceutical availability of ibuprofen sodium than of diclofenac sodium particularly from model gels with surfactants of low number of oxyethylene segments in the structure. The above has been confirmed by in vitro studies on the kinetics of therapeutic agent penetration into external compartment.

Algorithms↗

PubMedDate not supplied

[Comparative value of molecular forms of prostate-specific antigen in diagnosis of prostatic cancer].

The aim of the study was to compare diagnostic significance of free PSA (fPSA)/total PSA (tPSA) versus PSA complex with alpha1-antichymotrypsin (cPSA) in tPSA level within 4-10 ng/ml in differential diagnosis of prostatic cancer (PC). A complete urological examination (digital rectal test, transrectal ultrasound investigation, serum assay for fPSA and tPSA, multifocal transperineal prostatic biopsy) was made in 108 patients with tPSA blood level 4-10 ng/ ml. Prostatic adenoma (PA) was histologically verified in 61 of 108 patients, fPSA/tPSA was normal. In the other 39 of 108 patients fPSA/tPSA was under 15% while cPSA was in the range 3.8-9.6 ng/ml. A course of etiotropic therapy of chronic prostatic inflammation produced no significant changes in fPSA/tPSA and cPSA in 28 out of 39 patients. Histologically, these 28 patients had PC. In the rest 11 of 39 patients chronic prostatitis treatment fPSA/tPSA significantly rose to 18.2%, on the average. CPSA decreased to 2.4 ng/ml. These 11 patients were found histologically to have PA and signs of chronic inflammation. In 8 of 108 patients fPSA/tPSA was not indicative of PC being 18,2% on the average while cPSA indicated the presence of PC and was 4.2 ng.ml, on the average. PC was verified histologically in these 8 patients. Thus, cPSA in PC suspects is more informative than fPSA/tPSA in PC diagnosis. CPSA in the serum depends on prostatic inflammation making difficult differential diagnosis of PC in interpretation of tPSA, fPSA/tPSA and cPSA. Therefore, estimation of PSA variants and molecular forms in PC suspects and prostatic inflammation should be made after etiotropic therapy.

Antigens, Surface↗

PubMedDate not supplied

[Functional organization of the cortico-reticular system of the brain in response to physical loads].

An estimation was carried out by factor analysis method of informative value of alpha-like rhythm, EEG theta-rhythm, local cerebral blood filling and oxygen tension (pO2) in estimation of functional state of cerebral structures under submaximal physical loads. Experiments were carried out on 35 rabbits with electrodes chronically implanted in the sensorimotor cortex and reticular formation. The obtained values were processed by a variant of factor analysis--a method of main components. For interpretation of factor loads matrix an orthogonal turn of factor axes was carried out according to varimax criterion. It has been established that informative value of the parameters depends on the brain structure where the given parameters were defined. Dynamics of pO2 and the theta-rhythm mostly influence the changes in other parameters. The states of structures before and during the period of physical load after-effect are mostly characterized by the brain local blood filling and less by the theta-rhythm amplitude.

Animals↗

PubMed1997

Pharmacologic intervention for the diagnosis of acute cholecystitis: cholecystokinin pretreatment or morphine, or both?

Recent data and reanalysis of the literature suggest that nonvisualization of the gallbladder on the delayed images of cholescintigraphy is a nonspecific finding. Morphine augmentation has a reasonably good, though imperfect, specificity and positive predictive value, that are significantly better than for delayed imaging, in addition to its logistical advantage (shortening the imaging time). The technique is recommended, therefore, for routine clinical use in patients with nonvisualization of the gallbladder at 1 hr. Further study seems to be necessary to assess the effect of variable or no visible effect of low-dose morphine among patients on the efficacy of morphine-augmented cholescintigraphy. Sincalide pretreatment, when administered at the physiologic rate, is helpful in conditions in which functional resistance to tracer flow into the gallbladder are present. The results from the series by Chen et al. and by Kim et al. suggest that morphine augmentation can further improve the efficacy of the test even after CCK pretreatment. A comparison between the efficacy of delayed imaging and that of imaging for 60-90 min after CCK pretreatment is not available. Therefore, the latter does not obviate the need for delayed imaging when the morphine augmentation technique is not used. Finally, the nuclear medicine physician should use the most optimal technique for the pharmacologic intervention, in other words, the dose and the rate of administration. Certain conditions and medications may affect gallbladder contraction. It is also important to be aware of the various physiologic and pharmacologic effects on imaging findings, not only those findings that are normal but also the undesirable variants. Failure to recognize such effects can lead to incorrect interpretations.

Acute Disease↗

PubMed1997

Complex formation of the spinach chloroplast psbA mRNA 5' untranslated region with proteins is dependent on the RNA structure.

RNA-protein interactions are part of many regulatory pathways in gene expression. In chloroplasts of higher plants and of green algae, gene regulation by posttranscriptional processes such as differential regulation of mRNA stability and control of translation plays a major role during chloroplast development and light-dependent protein expression. Regulation here is mediated by interactions of RNA-binding proteins with the respective mRNAs. In this work, structural requirements for protein-RNA complex formation between the 5' untranslated region of the spinach psbA mRNA (encoding the D1 protein of photosystem II) and stromal proteins are analyzed. For this, a combination of temperature gradient gel electrophoresis and gel shift analysis is employed to study several variants of the psbA 5' untranslated region. Supported by theoretical interpretation of the data and analysis of the structures by chemical probing, we show that a certain structure of the RNA is necessary for protein complex formation. Already very subtle structural changes within the RNA interfere with binding and thereby with the biological activity of the mRNA.

Base Sequence↗

PubMed2026

Integrative post-GWAS analysis prioritizes immune regulatory pathways and candidate effector signals in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) has a complex polygenic architecture, but translating genome-wide association signals into biologically interpretable candidates remains challenging. We applied an integrative post-GWAS framework to refine SLE-associated loci and prioritize candidate regulatory mechanisms. METHODS: European-ancestry SLE GWAS summary statistics from FinnGen and Bentham et al. were meta-analysed, comprising 8417 cases and 354,277 controls. After quality filtering, 6,782,131 SNPs were retained. Downstream analyses included LAVA regional prioritization, Bayesian colocalization with GTEx v8 whole-blood and spleen eQTLs, independent replication in the Julià et al. Spanish cohort, pathway enrichment, bivariate LAVA cross-trait local genetic correlation, and therapeutic annotation. RESULTS: The discovery meta-analysis identified 46 genome-wide significant SLE-associated loci, including putative novel signals requiring database/literature qualification. LAVA identified 14 candidate index variants across 12 high-confidence regions, of which nine index variants were retained as the primary prioritized set based on LAVA support and/or convergent regulatory evidence. The strongest association mapped to the chr6p21.3/MHC region (rs389884), where four genes showed colocalization support, including CLIC1 in whole blood and C4A in spleen. Because the chr6p21.3/MHC rs389884 region lead variant was unavailable for replication and no suitable proxy was identified, this signal was interpreted as an emerging candidate for functional validation rather than a replicated causal signal. Seven available variants replicated with concordant effects. An exploratory Roadmap immune chromatin-state overlap analysis placed 15 of 45 non-MHC lead variants (33.3%) directly, and 34 of 45 (75.6%) within ±10 kb, in active immune enhancer/promoter states. Pathway analyses highlighted type I interferon, JAK-STAT signaling, cytokine regulation, and antigen presentation, while bivariate LAVA analyses supported shared local genetic architecture with rheumatoid arthritis, systemic sclerosis, and Sjögren syndrome. CONCLUSIONS: This integrative post-GWAS analysis refines SLE association signals into biologically interpretable candidate regions and supports interferon and JAK-STAT signaling as central genetically supported pathways in SLE.

CLIC1↗

PubMed2026

SNPannotator: automated functional annotation of genetic variants and linked proxies.

SUMMARY: Genome-wide association studies (GWASs) have identified thousands of genetic variants associated with complex traits and diseases. However, explaining the mechanisms underlying phenotypic variation remains challenging. Here, we introduce SNPannotator, an automated post-GWAS analysis software package designed to streamline the interpretation of GWAS findings. Our pipeline implements a multi-step process that identifies proxy variants in high linkage disequilibrium (LD) with associated lead variants, then queries comprehensive resources (including Ensembl, the GTEx Portal, the eQTL Catalog, and STRING DB) for genomic position, deleteriousness, regulatory annotations, clinical significance, trait associations, expression (eQTLs) and splicing quantitative trait loci (sQTLs), and functional enrichment analyses and compiles the results into user-friendly reports. This package is implemented in the R programming language and includes auxiliary functions for variant lookup and LD exploration. SNPannotator provides a practical framework for efficiently deriving biologically meaningful insights from GWAS data and for assisting researchers in prioritizing candidate variants for functional validation. AVAILABILITY AND IMPLEMENTATION: The SNPannotator package is available from the Comprehensive R Archive Network (CRAN) at https://cran.r-project.org/web/packages/SNPannotator. The development version and tutorial is available on GitHub (https://github.com/omicslaboratory/SNPannotator). The online version of the package is available at https://omicslab.org/snpannotator.

Software↗

PubMed2026

Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.

One of the ongoing challenges in childhood remains the unexplained sudden death. Autopsies identify a subset of cases that harbor rare variants in genes associated with cardiomyopathy in structurally normal hearts, suggesting a concealed cardiomyopathy. Our goal is to interpret all available data in each case to provide answers to unexplained deaths, while also implementing preventative measures for at-risk family members. Our retrospective study included 68 childhood cases of sudden death, classified as inconclusive at autopsy. Molecular autopsy analyzed all genes currently associated with inherited arrhythmogenic syndromes. Variants were reinterpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Seventeen autopsy-inconclusive childhood cases (70.59% males) carried at least one rare variant in any of the cardiomyopathy-susceptibility genes. A definite deleterious variant was identified in seven cases (10.3%), whereas ten (14.7%) carried only variants of uncertain significance. Slight non-diagnostic myocardial alterations were identified in five cases (7.35%), and three of them carried a deleterious variant. Clinical and genetic analyses of all families identified a carrier of deleterious variants with a diagnosis of cardiomyopathy in six of them (8.82%). Our data support the inclusion of a comprehensive analysis of all genes associated with inherited cardiomyopathies in childhood cases of unexpected death. A personalized multidisciplinary interpretation of post-mortem and genetic data, including family assessment, helps to clarify the role of rare variants and determine the most plausible cause of the unexpected death in one-tenth of the childhood individuals.

Journal Article↗

PubMed1989

Chromosomal in situ hybridization and Southern blot analyses using c-abl, c-sis, or bcr probe in chronic myelogenous leukemia cells with variant Philadelphia translocations.

The Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myelogenous leukemia (CML). Whereas the majority of Ph-positive CML patients show the standard Ph translocation involving chromosomes 9 and 22, t(9;22)(q34;q11), the minority of cases exhibit a variant type of Ph translocation involving these two and other chromosomes (complex type) or those involving #22 and chromosomes other than #9 (simple type). To get an insight into the nature of variant Ph translocations and the process of their formation, we examined the localization of the c-abl and c-sis oncogenes and the breakpoint cluster region (bcr) gene by chromosomal in situ hybridization in ten variant Ph translocations of CML including five simple and five complex ones as initially interpreted. In situ hybridization showed that c-abl localized to band 9q34 and c-sis localized to band 22q12-q13 were translocated on the Ph and on one of the rearranged chromosomes other than #9, respectively, in all the variant translocations examined. On the other hand, bcr localized to band 22q11 was translocated on various chromosomes but mostly on chromosome 9. Parallel Southern blot analyses on DNA from leukemic cells of five patients including two with simple translocations and three with complex ones revealed rearrangements of bcr with breakpoints occurring mostly in a 5' portion of 5.8-kb BamHI/BglII sequences, which are quite similar to those detected so far in CML cases with the standard Ph translocation. The present findings strongly suggest that variant Ph translocations of CML are all complex, and some of them are formed stepwisely from the standard translocation.

Blotting, Southern↗

PubMedDate not supplied

MR arthrography of the shoulder: variants and pitfalls.

Use of magnetic resonance arthrography to evaluate pathologic conditions of the shoulder is becoming widespread. However, normal anatomy or anatomic variations can cause interpretive errors. The most common variations occur at the origins of the glenohumeral ligaments (GHLs) and the insertion of the joint capsule. Among the GHL variants, common origin of the superior and middle ligaments is the most frequent followed by thinning, thickening, or absence of a ligament, most often the middle one. Absence or thinning of one ligament is sometimes associated with thickening of another or changes in the size and shape of the anterior capsular recesses. Common normal variants of the labrum include foramen sublabrum (detachment of the anterosuperior labrum from the glenoid margin) and the Buford complex (absence of the anterosuperior labrum in association with a thick middle GHL). Pitfalls related to the arthrographic technique include (a) visualization of a deep sulcus between the insertion of the long head of the biceps tendon and the superior labrum and (b) an apparent type III capsular insertion due to overdistention of the capsule by injected contrast material.

Arthrography↗

PubMed2004

Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene.

The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

[Complement fixation reaction for the serologic diagnosis of bovine contagious pleuropneumonia: application and interpretation of the results].

Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides SC (small colony variant), is a disease which has been recognised for a long time. Serological testing is used most often for diagnosing CBPP in live animals. This method is based on a complement fixation test (CFT), the technique recommended by the Office International des Epizooties, which has an important role in detecting infected herds in regions known to be affected by the disease. Although this serological test is the most reliable method currently available, it has some major shortcomings in sensitivity and specificity. The author discusses the reasons for these limitations, which can raise difficulties in the interpretation of CFT results, and the possibilities and potential applications of the test.

Animals↗

PubMed2005

What makes a good genetic association study?

Genetic association studies are central to efforts to identify and characterise genomic variants underlying susceptibility to multifactorial disease. However, obtaining robust replication of initial association findings has proved difficult. Much of this inconsistency can be attributed to inadequacies in study design, implementation, and interpretation--inadequately powered sample groups are a major concern. Several additional factors affect the quality of any given association study, with appropriate sample-recruitment strategy, logical variant selection, minimum genotyping error, relevant data analysis, and valid interpretation all essential to generation of robust findings. Replication has a vital role in showing that associations that are identified reflect interesting biological processes rather than methodological quirks. For an unbiased view of the evidence for and against any particular association, study quality, rather than significance value, needs to play the dominant part.

Gene Frequency↗

PubMed2003

Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection.

BACKGROUND: The cause of severe acute respiratory syndrome (SARS) has been identified as a new coronavirus. Whole genome sequence analysis of various isolates might provide an indication of potential strain differences of this new virus. Moreover, mutation analysis will help to develop effective vaccines. METHODS: We sequenced the entire SARS viral genome of cultured isolates from the index case (SIN2500) presenting in Singapore, from three primary contacts (SIN2774, SIN2748, and SIN2677), and one secondary contact (SIN2679). These sequences were compared with the isolates from Canada (TOR2), Hong Kong (CUHK-W1 and HKU39849), Hanoi (URBANI), Guangzhou (GZ01), and Beijing (BJ01, BJ02, BJ03, BJ04). FINDINGS: We identified 129 sequence variations among the 14 isolates, with 16 recurrent variant sequences. Common variant sequences at four loci define two distinct genotypes of the SARS virus. One genotype was linked with infections originating in Hotel M in Hong Kong, the second contained isolates from Hong Kong, Guangzhou, and Beijing with no association with Hotel M (p<0.0001). Moreover, other common sequence variants further distinguished the geographical origins of the isolates, especially between Singapore and Beijing. INTERPRETATION: Despite the recent onset of the SARS epidemic, genetic signatures are emerging that partition the worldwide SARS viral isolates into groups on the basis of contact source history and geography. These signatures can be used to trace sources of infection. In addition, a common variant associated with a non-conservative aminoacid change in the S1 region of the spike protein, suggests that immunological pressures might be starting to influence the evolution of the SARS virus in human populations.

Amino Acid Sequence↗

PubMed2006

Lead, genetic susceptibility, and risk of adult brain tumors.

BACKGROUND: Although few etiologic factors for brain tumors have been identified, limited data suggest that lead may increase the risk of brain tumors, particularly meningioma. The ALAD G177C polymorphism affects the toxicokinetics of lead and may confer genetic susceptibility to adverse effects of lead exposure. METHODS: We examined occupational exposure to lead and risk of brain tumors in a multisite, hospital-based, case-control study of 489 patients with glioma, 197 with meningioma, and 799 non-cancer controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to hospital. ALAD genotype was assessed by a Taqman assay for 355 glioma patients, 151 meningioma patients, and 505 controls. Exposure to lead was estimated using a rigorous questionnaire-based exposure assessment strategy incorporating lead measurement and other occupational data abstracted from published articles and reports. RESULTS: Increased risk of meningioma with occupational lead exposure (estimated by odds ratios and 95% confidence intervals) was most apparent in individuals with the ALAD2 variant allele, for whom risk increased from 1.1 (0.3-4.5) to 5.6 (0.7-45.5) and 12.8 (1.4-120.8) for estimated cumulative lead exposures of 1 to 49 microg/m3-y, 50 to 99 microg/m3-y, and >or=100 microg/m3-y, respectively, compared with unexposed individuals (two-sided P trend = 0.06). This relationship became stronger after excluding occupational lead exposures characterized by a low confidence level or occurring in the 10 years before meningioma diagnosis. Occupational lead exposure was not associated with glioma risk. CONCLUSIONS: Although our results indicate that lead may be implicated in meningioma risk in genetically susceptible individuals, these results need to be interpreted with caution given the small numbers of exposed cases with a variant genotype.

Adolescent↗

PubMed2005

Allele frequencies and the r2 measure of linkage disequilibrium: impact on design and interpretation of association studies.

The design and interpretation of genetic association studies depends on the relationship between the genotyped variants and the underlying functional variant, often parameterized as the squared correlation or r(2) measure of linkage disequilibrium between two loci. While it has long been recognized that placing a constraint on ther(2) between two loci also places a constraint on the difference in frequencies between the coupled alleles, this constraint has not been quantified. Here, quantification of this severe constraint is presented. For example, for r(2) >/= .8, the maximum difference in allele frequency is +/- .06 which occurs when one locus has allele frequency .5. For r(2) >/= .8 and allele frequency at one locus of .1, the maximum difference in allele frequency at the second locus is only +/- .02. The impact on the design and interpretation of association studies is discussed.

Algorithms↗