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PubMed2005

Lack of association of PAX4 gene with type 1 diabetes in the Finnish and Hungarian populations.

We aimed to assess the possible contribution of the PAX4 transcription factor gene to the genetic background of type 1 diabetes. We analyzed four coding polymorphisms of the PAX4 gene in 498 cases with type 1 diabetes and 825 control subjects from Finland and Hungary. All patients were diagnosed under the age of 15 years according to the World Health Organization criteria. All four PAX4 variants (three in exon 9 and one in exon 3) were genotyped using DNA sequencing. In addition, all Finnish subjects were typed for HLA DR-DQ, insulin gene (-23) HphI, and CTLA4 CT60 polymorphisms. The +1,168 C/A coding variant of PAX4 was found to be polymorphic in both populations (P321H, rs712701). No difference was observed in the genotype frequencies between cases and control subjects, nor was any disease association detected when patients were stratified according to age at diagnosis, sex, HLA, insulin gene, or CTLA4 genotypes. Our data indicate that the +1,168 C/A variant of PAX4 gene does not play any essential role in genetic type 1 diabetes susceptibility. The strong coherence between the datasets of the two ethnic groups studied with highly contrasting disease incidence, socioeconomic characteristics, and profoundly diverse environment emphasizes the impact of this finding.

Adolescent↗
PubMed2001

Antidepressant drug discovery in the postgenomic era.

The progress made in genome research raises the question whether the new knowledge bases that have emerged may also lead to better antidepressants. The past has seen many remarkable improvements over traditional drugs, but not a real breakthrough. More recently hypothesis-driven research in depression has focussed upon stress-hormone regulation as a possible target, but validation of new drugs is not yet in sight. In parallel, we see an upsurge of systematic unbiased research in a biotechnology-driven drug discovery effort. This research can only lead to results if clinical research adapts to these new demands by phenotyping depressed patients not only according to psychopathological characteristics but also by utilising functional (e.g. neuroendocrine, neuropsychological, neurophysiological, neuroimaging and clinical drug response) data that are to be correlated with data from genotyping. To achieve the goal of genotype/phenotype-based differential therapy, large-scale efforts with regards to both patient samples and genotyping capacities are needed. In the long term, increasingly detailed patient information, if translated into specific pharmacological treatments, will lead to customized drugs and thus to a partial fragmentation of the antidepressant market. Concurrently, the improved genotyping/phenotyping efforts will also lead to more widely applicable drugs that promise to avoid side effects and refractoriness and also to hasten the time to onset of action. Once these goals are achieved notorious undertreatment of depression may come to an end.

Adrenocorticotropic Hormone↗
PubMed1999

Breeding structure of the sand fly Lutzomyia longipalpis (Lutz & Neiva) in Brazil.

Eleven populations of Lutzomyia longipalpis (Lutz & Neiva), the sand fly vector of Leishmania chagasi, from different areas of Brazil were analyzed for genetic variation at 16 enzyme loci. In this region, the prevalence of visceral leishmaniasis (VL) caused by L. chagasi is spotty and reproductive isolation among populations of Lu. longipalpis has been reported. It is thought that morphologically similar cryptic species with varying vectorial capacity may be responsible for the discontinuous distribution of VL. The aim was to study the genetic structure of populations within this region and to identify demes that may represent sibling species. Genotypic frequencies within populations were in close compliance to Hardy-Weinberg expectations, suggesting there are no sympatric species among these 11 populations. Levels of genetic distance between pairs of populations were very low (< 0.03), consistent with local populations within a single sand fly species. When genotypic frequency data for all populations were pooled, 9 of the 13 polymorphic loci deviated from Hardy-Weinberg expectations, indicating some degree of genetic substructuring. Estimates of effective migration rates (N(e)m) among all populations were low, 2.73, suggesting that gene flow is restricted among populations, which is probably the reason for the observed genetic substructuring.

Alleles↗
PubMed2002

NAD (P) H oxidase p22 phox C242T polymorphism affects LDL particle size and insulin resistance in Japanese subjects.

Elevated cardiovascular risk is associated with an increased number of small, dense low-density lipoprotein (LDL) particles, which exhibit increased susceptibility to lipid oxidation, however, the mechanism determining LDL particle size has never been fully elucidated. We have examined the association between the C242T polymorphism of the p22 phox gene, which is a small subunit of vascular NAD(P)H oxidase, and both LDL particle size and clinical characteristics in 260 healthy subjects. Peak LDL particle diameter (LDL-PPD) was measured by continuous disk polyacrylamide gel electrophoresis. Twenty-one of the 217 subjects with the CC genotype showed pattern B (median LDL-PPD under 25.5 nm), whereas, none of the 43 subjects with TC + TT genotypes showed pattern B. The pattern B fraction was significantly larger in the CC group than in the TC + TT group (p = 0.030). The subjects with the CC genotype also showed a significantly higher fasting glucose level, plasma insulin level, and insulin resistance index of homeostasis model assessment (HOMA-R) than those with the TC + TT genotype. Our data demonstrate that variation in the small NAD(P)H oxidase subunit p22 phox gene substantially influences LDL particle size and may also reflect differences in the insulin sensitivity of non-diabetic subjects.

Adult↗
PubMed1999

[A cluster of patients with puerperal fever in Gouda; a reiteration of the lesson by Semmelweis].

OBJECTIVE: Description of a cluster of 6 patients who developed a puerperal infection with group A haemolytic streptococci (Streptococcus pyogenes, GAS) out of 10 patients who delivered during a 2-day period in the hospital in Gouda, the Netherlands, and of the epidemiological and microbiological search for the source. DESIGN: Descriptive. METHOD: After the report on the fourth patient the suspicion of a hospital infection arose. Hospital staff, family members and environment were screened for GAS. All isolated GAS were serotyped and genotyped. Epidemiological data, like time of admission, delivery and discharge, used delivery room and maternity unit ward, were recorded. All regional midwives and general practitioners were informed and asked to be alert for puerperal endometritis in patients after hospital deliveries. RESULTS: All 6 patients and 2 health care workers proved to have an identical type of GAS. The environmental cultures were negative. By analysing the epidemiological data the most probable cause of this cluster was found to be one health care worker. After stressing the importance of good hand disinfection no additional cases were seen.

Adult↗
PubMed2000

A practical algorithm for optimal inference of haplotypes from diploid populations.

The next phase of human genomics will involve large-scale screens of populations for significant DNA polymorphisms, notably single nucleotide polymorphisms (SNP's). Dense human SNP maps are currently under construction. However, the utility of those maps and screens will be limited by the fact that humans are diploid, and that it is presently difficult to get separate data on the two "copies". Hence genotype (blended) SNP data will be collected, and the desired haplotype (partitioned) data must then be (partially) inferred. A particular non-deterministic inference algorithm was proposed and studied before SNP data was available, and extensively applied more recently to study the first available SNP data. In this paper, we consider the question of whether we can obtain an efficient, deterministic variant of that method to optimize the obtained inferences. Although we have shown elsewhere that the optimization problem is NP-hard, we present here a practical approach based on (integer) linear programming. The method either returns the optimal answer, and a declaration that it is the optimal, or declares that it has failed to find the optimal. The approach works quickly and correctly, finding the optimal on all simulated data tested, data that is expected to be more demanding than realistic biological data.

Algorithms↗
PubMedDate not supplied

[Transgene transfer and inheritance under genetic transformation in maize].

Achievements are discussed regarding in genetic transformation of maize is examined from that point of view what cells, tissues and organs can be the targets for the alien gene transfer. The review of available data on genotypical peculiarities of transgenesis and inheritance of alien genes included in the maize genome are presented.

Gene Transfer Techniques↗
PubMed1975

Tests for association of gene frequencies at several loci in random mating diploid populations.

Methods are outlined for analyzing data on genotype frequencies at several codominant loci in random mating diploid populations. Maximum likelihood (ML) methods are given for estimating chromosomal frequencies. Using these, a succession of models of assumed independence of gene frequency are fitted. These are based on those used in multi-dimensional contigency tables, and tests for association (linkage disequilibrium), made using likelihood ratios. The methods are illustrated with an example.

Diploidy↗
PubMed2003

Transgenic models of metabolic bone disease: impact of estrogen receptor deficiency on skeletal metabolism.

Estrogen has protective effects on the skeleton via its inhibition of bone resorption. Mechanisms for these effects and the selectivity to the estrogen receptor alpha (ER alpha) or ER beta are unclear. The purpose of our study was to determine the impact of the ER alpha on skeletal metabolism using murine models with targeted disruption of the ER alpha and beta. Mice generated by homologous recombination and Cre/loxP technology yielding a deletion of the ER alpha exon 3 were evaluated and also crossed with mice with a disruption of the exon 3 of the ER beta to result in double ER alpha and ER beta knockout mice. Skeletal analysis of long bone length and width, radiographs, dual X-ray absorptiometry, bone histomorphometry, micro computerized tomography, biomechanical analysis, serum biochemistry, and osteoblast differentiation were evaluated. Male ER alpha knockout mice had the most dramatic phenotype consisting of reduced bone mineral density (BMD), and bone mineral content (BMC) of femurs at 10 and 16 weeks and 8-9 months of age. Female ER alpha knockout mice also had reduced density of long bones but to a lesser degree than male mice. The reduction of trabecular and cortical bone in male ER alpha knockout mice was statistically significant. Male double ER alpha and ER beta knockouts had similar reductions in bone density versus the single ER alpha knockout mice suggesting that the ER alpha is more protective than the ER beta in bone. In vitro analysis revealed no differences in osteoblast differentiation or mineralized nodule formation among cells from ER alpha genotypes. These data suggest that estrogens are important in skeletal metabolism in males; the ER alpha plays an important role in estrogen protective effects; osteoblast differentiation is not altered with loss of the ER alpha; and compensatory mechanisms are present in the absence of the ER alpha and/or another receptor for estrogen exists that mediates further effects of estrogen on the skeleton.

Absorptiometry, Photon↗
PubMed1976

Activation of cytotoxic function in T lymphocytes.

The requirements for activation of cytotoxic function in mouse T lymphocytes were investigated. Initial generation of cytotoxicity in normal lymphocytes was equal in magnitude with either Con A or specific alloantigen, and in either case required DNA synthesis. Cytotoxic function in MLC-primed cells could also be regenerated by Con A, the magnitude and target specificity of the cytotoxicity thus generated being indistinguishable from that recalled by specific alloantigen. Cytotoxicity could also be regenerated by third party-stimulating cells; however, the cytotoxicity evoked by third party cells was always specific only for target cells of the original stimulating cell H-2 genotype. The data presented suggest that there are a number of ways to activate cytotoxicity in effector T cells, and are most consistent with a model for T cell triggering that minimizes a strict informational function of antigen-receptor interactions.

Animals↗
PubMedDate not supplied

[Evaluation of embryological potential of soybean cultivars zoned in forest, steppe, and marshy woodlands of Ukraine as essential stage for the further transformation].

Seven soybean (Glycine max (L.) Merr.) cultivars zoned in forest-steppe and marshy woodlands of Ukraine: "Chernuatka", "Vasylkivska", "Kyivska-91", "Kyivska-27", "Marjana", "Chernobura" and "Altair" were established in vitro for somatic embryogenesis inducing. Cultivars "Marjana" (88%) and "Vasylkivska" (86%) demonstrated the highest embryogenic capacity among all the tested cultivars. During the further plant regeneration cultivars "Marjana" and "Kyivska-91" showed the best capacity to form adult plants despite the fact that embryogenic capability of the cultivar "Kyivska-91" was 71%. According to the obtained data three genotypes were selected for the further investigation of effective methods of biolictic transformation of ukrainian cultivars.

Regeneration↗
PubMed1986

Age related cochlear toxicity from noise and antibiotics--a review.

Laboratory experimental evidence indicates that there is an age related susceptibility to cochlear damage from noise exposure and ototoxic antibiotics. In some rodents there is a critical period of auditory development during which there is greater vulnerability to such damage and, in some species, noise induced damage is influenced by genotype. Available data from patients are inconclusive in this regard. Further careful studies are indicated in this area. All available evidence emphasizes that caution should be exercised in the use of ototoxic drugs during pregnancy, in neonates, young children, and older people.

Acoustic Stimulation↗
PubMed1994

von Willebrand disease in the RIIIS/J mouse is caused by a defect outside of the von Willebrand factor gene.

An animal model for human type I von Willebrand disease (vWD) has been previously described in the inbred mouse strain RIIIS/J. Murine vWD is characterized by a prolonged bleeding time, normal von Willebrand factor (vWF) multimer distribution, autosomal dominant inheritance, and proportionately decreased plasma vWF antigen, ristocetin cofactor, and factor VIII (FVIII) activities. To study the molecular genetics of murine vWD, a portion of the vWF gene surrounding exon 28 was cloned, sequenced, and used to develop two informative DNA sequence polymorphisms for rapid genotyping by DNA polymerase chain reaction. RIIIS/J mice were crossed with PWK/Ph mice, an inbred line of Mus musculus musculus, and the F1 progeny backcrossed to the parental PWK/Ph strain. vWF antigen levels in F1 mice were not significantly different from the parental RIIIS/J strain but were markedly decreased compared with the parental PWK/Ph mice. Genetic linkage analysis of 104 backcross progeny showed no correlation between vWF antigen level and vWF genotype. These data indicate that murine vWD is caused by a defect at a novel genetic locus, distinct from the murine vWF gene. The distribution of vWF antigen levels among backcross progeny suggests the presence of one major dominant vWD gene in the RIIIS/J mouse with possible modifying contributions from one or more additional minor loci. These observations may provide new insights into the molecular basis and variable expressivity of human vWD.

Amino Acid Sequence↗
PubMed1993

[Typing of methicillin-resistant Staphylococcus aureus strains for epidemiological studies using the polymerase chain reaction].

OBJECTIVE: To determine whether polymerase chain reaction (PCR) fingerprinting can be used to gain insight into the epidemiology of methicillin resistant Staphylococcus aureus (MRSA). DESIGN: Retrospective DNA analysis of MRSA strains. BACTERIAL STRAINS: MRSA strains were collected in two Dutch and one Belgian hospital (Reinier de Graaf Gasthuis, Delft; St. Antonius Ziekenhuis, Nieuwegein; St. Jan Ziekenhuis, Brugge). METHODOLOGY: MRSA DNA was isolated by standard procedures. Differences in genomic organisation were detected with the aid of exponential enzymatic synthesis of intrinsically variable DNA domains. This so-called PCR fingerprinting, a relatively new technique, was performed in direct comparison with phage typing. The latter is the current golden standard for S. aureus typing. RESULTS: The results of both PCR fingerprinting and phage typing appeared to be useful for strain identification. All results were consistent with other epidemiological data. CONCLUSION: Genotyping MRSA with PCR fingerprinting is complementary to phage typing. In some instances PCR fingerprinting is even to be preferred to the other technique. PCR fingerprinting is well suited for the analysis of MRSA spreading.

Aged↗
PubMed1995

Revised European-American Lymphoma Classification.

The recently proposed Revised European-American Lymphoma Classification represents a serious attempt to overcome the controversies that have divided both pathologists and clinicians over the past three decades. It was formulated by 19 experienced hematopathologists, who agreed on a list of clinicopathologic entities, all well known from the literature and daily practice. Compared with previous schemes, the Revised European-American Lymphoma Classification offers the following advantages: 1) it incorporates all nodal and extranodal lymphoid tumors, including Hodgkin's disease; 2) it is histogenetically updated by recognizing new categories (such as the mantle cell category) and grouping tumors that need further validation to be considered as separate entities (eg, diffuse large B-cell lymphomas); 3) it avoids any morphologic grading, the clinical course of lymphomas being influenced by factors other than histology (tumor burden, cell kinetics, apoptotic rate, and so forth) and 4) it includes all molecular data (phenotype, genotype, cytogenetics, and so forth), which can assist in the diagnosis.

Hodgkin Disease↗
PubMedDate not supplied

Comparison of quantitative methods to assess hepatic function: Pugh's classification, indocyanine green, antipyrine, and dextromethorphan.

STUDY OBJECTIVES: To compare three quantitative metabolic markers used to assess hepatic function, indocyanine green (ICG), a high-extraction marker; antipyrine, a low-extraction marker; and dextromethorphan, a P-450IID6 marker, with the clinically used Pugh's classification. DESIGN: Comparison of 12 healthy controls with 12 age- and sex-matched patients with different degrees of liver disease. SETTING: Research center in a university-affiliated teaching hospital. PATIENTS: The 12 patients had different degrees of liver disease: 4 mild (Pugh's score 6 or 7); 4 moderate (Pugh's score 8 or 9); and 4 severe (Pugh's score > or = 10). Each level had an equal number of men and women subjects. MEASUREMENTS AND MAIN RESULTS: Clearance of ICG detected mild alterations in hepatic function as efficiently as it did for moderate and severe impairment, but it lacked the specificity to distinguish among the classification groups. In contrast, antipyrine was effective in identifying moderate and severe hepatic impairment; however, its clearance was not reduced in mild liver disease. Pugh's classification appears to be a clinically useful method of assessing the global degree of hepatic impairment in patients with chronic disease, and there was a significant correlation between it and antipyrine clearance (r = 0.67, p = 0.0003) and ICG clearance (r = 0.86, p = 0.0001). Four of eight patients with a Pugh's score greater than 8 had a dextromethorphan metabolic ratio expression reflective of a poor metabolizer phenotype based on 0- to 4-hour urine collection, but only two of those eight patients were classified as poor metabolizers based on 4- to 12-hour urine collection. These percentages of poor metabolizers are substantially higher than for historical controls (8.5-10.4%) and most likely reflect a decrease in the P-450IID6 functional ability with progression of liver disease. However, due to small sample size and lack of knowledge of the patients' genotypes, these data are only suggestive. CONCLUSION: Pugh's classification appears to be a reliable indicator of the degree of chronic liver disease and could be employed as a drug development research classification tool; however, it does not replace quantitative metabolic markers, especially isozyme-specific markers.

Adult↗
PubMed1995

[DNA polymorphisms of the apolipoprotein AI-CIII-AIV gene cluster in coronary artery disease].

Two polymorphic sites of the apolipoprotein AI (ApoAI) gene, PstI and SstI, were examined in a sample of 43 unrelated Chinese patients with coronary artery disease (CAD) and 60 unrelated healthy individuals. Allele frequencies were compared between patients and controls and their impact on lipid and oxygen free radicals metabolism were also studied. The frequencies of the uncommon P2 and S2 alleles in CAD cases were found as 0.14 and 0.22 respectively, which were significantly higher than 0.05 and 0.13 in controls. The more the number of vessel disease in CAD cases, the higher the frequencies of S2 alleles which were the highest in the group of 3 vessel diseases. Some serum lipid and oxygen free radicals levels differed between CAD cases of different genotypes. These data suggest that genetic variation in P2 and S2 alleles of APOAI gene may contribute to the development and extent of CAD in Chinese subjects.

Alleles↗
PubMed1997

Central nervous system lipoproteins in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the United States and has been associated with APOE genotype. Apolipoprotein (apo) E along with apoAI serve as the major apolipoproteins in the central nervous system; however, we are unaware of any study addressing lipoprotein metabolism in AD. We tested the hypothesis that lipoprotein metabolism is altered in patients with AD by isolating and characterizing ventricular fluid (VF) lipoproteins obtained during a rapid autopsy protocol from patients with AD and age-matched nondemented control patients. Our results demonstrated abnormalities in the protein and lipid constituents of VF lipoproteins from AD patients. Apolipoprotein concentration was reduced by half in AD patients relative to controls; however, there was no selective reduction in apoE or apoAI. In addition, cholesteryl ester fatty acids, but not phospholipid fatty acids, from AD patients demonstrated a significant reduction in some polyunsaturated fatty acids (18:2 and 22:6) and an enrichment in 18:0. None of these changes were directly related to APOE genotype. Our data indicate that VF lipoprotein composition is altered, at least terminally, in AD patients, and that these changes are not associated with APOE. These findings suggest that altered VF lipoprotein metabolism may be a component of AD pathogenesis.

Aged↗