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PubMedDate not supplied

[The typological analysis of males with alcohol dependence disorder].

The aim of our study was the typological analysis of male alcoholics that was conducted on the basis of the K-means cluster analysis. 296 hospitalized men were examined after a duration of drinking. The results of the statistical analysis let us isolate two and then three types of alcoholics. When dividing the examined into two clusters it appeared that those who belonged to the 1st type had shorter history of addiction, became dependent later and in their case coexistence of psychiatric disorders, somatic diseases and the genetic loading for alcoholism were found less frequently than those from the 2nd type. Thus, early age of dependence onset was connected with the family alcoholism and worse clinical course-i.e.-co-occurrence of psychiatric disorders and somatic diseases. When dividing the patients into three clusters the following variables that differentiate the examined from three types of alcoholics were found: (a)-1st type: late age of dependence onset, rare load of family alcoholism, psychiatric disorders, somatic diseases; (b)-2nd and 3rd type: early age of dependence onset, the load of family-alcoholism, co-occurrence of psychiatric disorders and somatic diseases; (c)-3rd type: patients from the 3rd type were dependent longer than those from the 2nd type. Longer duration of the disease was connected with more frequent occurrence of psychiatric disorders and somatic diseases.

Adult↗
PubMed1998

[Craniological research--an important study method in stomatological pathology].

Reviews 30-year experience in studies of the maxillodental system in ancient and modern residents of Siberia on craniological material. Craniological studies permitted the authors to trace the evolution of the maxillodental system, reveal the genetic relations between ethnic groups, detect the "genetic loading", and disclose the effects of morphological signs on the formation of the maxillodental system.

Craniology↗
PubMed1988

Genetic disorders in children and young adults: a population study.

The data base of an ongoing population-based registry with multiple sources of ascertainment was used to estimate the present population load from genetic disease in more than 1 million consecutive live births. It was found that, before approximately age 25 years, greater than or equal to 53/1,000 live-born individuals can be expected to have diseases with an important genetic component. This total was composed of single-gene disorders (3.6/1,000), consisting of autosomal dominant (1.4/1,000), autosomal recessive (1.7/1,000), and X-linked recessive disorders (0.5/1,000). Chromosomal anomalies accounted for 1.8/1,000, multifactorial disorders (including those present at birth and those of onset before age 25 years) accounted for 46.4/1,000, and cases of genetic etiology in which the precise mechanism was not identified accounted for 1.2/1,000. Previous studies have usually considered all congenital anomalies (ICD 740-759) as part of the genetic load, but only those judged to fit into one of the above categories were included in the present study. Data for congenital anomalies are therefore also presented separately, to facilitate comparison with earlier studies. If all congenital anomalies are considered as part of the genetic load, then greater than or equal to 79/1,000 live-born individuals have been identified as having one or other genetic disorder before approximately age 25 years. These new data represent a better estimate of the genetic load in the population than do previous studies.

Adult↗
PubMed2003

High simian T-cell leukemia virus type 1 proviral loads combined with genetic stability as a result of cell-associated provirus replication in naturally infected, asymptomatic monkeys.

Simian T-cell leukemia virus type 1 (STLV-1) is a primate T cell leukemia virus of the group of oncogenic delta retroviruses. Sharing a high level of genetic homology with human T cell leukemia virus type 1 (HTLV-1), it is etiologically linked to the development of simian T cell malignancies that closely resemble HTLV-1 associated leukemias and lymphomas and might thus constitute an interesting model of study. The precise nature of STLV-1 replication in vivo remains unknown. The STLV-1 circulating proviral load of 14 naturally infected Celebes macaques (Macaca tonkeana) was measured by real-time quantitative PCR. The mean proportion of infected peripheral mononuclear cells was 7.9%, ranging from <0.4% to 38.9%. Values and distributions were closely reminiscent of those observed in symptomatic and asymptomatic HTLV-1 infected humans. Sequencing more than 32 kb of LTRs deriving from 2 animals with high proviral load showed an extremely low STLV-1 genetic variability (0.113%). This paradoxical combination of elevated proviral load and remarkable genetic stability was finally explained by the demonstration of a cell-associated dissemination of the virus in vivo. Inverse PCR (IPCR) amplification of STLV-1 integration sites evidenced clones of infected cells in all infected animals. The pattern of STLV-1 replication in these asymptomatic monkeys was indistinguishable from that of HTLV-1 in asymptomatic carriers or in patients with inflammatory diseases. We conclude that, as HTLV-1, STLV-1 mainly replicates by the clonal expansion of infected cells; accordingly, STLV-1 natural monkey infection constitutes an appropriate and promising model for the study of HTLV-1 associated leukemogenesis in vivo.

Animals↗
PubMed2005

Therapeutic effect of alpha-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells.

The close cooperation of both innate and acquired immunity is essential for the induction of truly effective antitumor immunity. We tested a strategy to enhance the cross-talk between NKT cells and conventional antigen-specific T cells with the use of alpha GalCer-loaded dendritic cells genetically engineered to express antigen plus chemokine, attracting both conventional T cells and NKT cells. DC genetically engineered to express a model antigen, OVA, along with SLC/CCL21 or monokine induced by IFN-gamma/CXCL9, had been generated using a method based on in vitro differentiation of DC from mouse ES cells. The ES-DC were loaded with alpha-GalCer and transferred to mice bearing MO4, an OVA-expressing melanoma, and their capacity to evoke antitumor immunity was evaluated. In vivo transfer of either OVA-expressing ES-DC, stimulating OVA-reactive T cells, or alpha-GalCer-loaded non-transfectant ES-DC, stimulating NKT cells, elicited a significant but limited degree of protection against the i.p. disseminated MO4. A more potent antitumor effect was observed when alpha-GalCer was loaded to ES-DC expressing OVA before in vivo transfer, and the effect was abrogated by the administration of anti-CD8, anti-NK1.1 or anti-asialo GM1 antibody. alpha-GalCer-loaded double transfectant ES-DC expressing SLC along with OVA induced the most potent antitumor immunity. Thus, alpha-GalCer-loaded ES-DC expressing tumor-associated antigen along with SLC can stimulate multiple subsets of effector cells to induce a potent therapeutic effect against peritoneally disseminated tumor cells. The present study suggests a novel way to use alpha-GalCer in immunotherapy for peritoneally

Animals↗
PubMed1998

A genetic and viral load analysis of the simian immunodeficiency virus during the acute phase in macaques inoculated by the vaginal route.

A comparative genetic analysis of SIV-infected female macaques during the first 120 days postinfection was undertaken. The same dose of a macaque-passaged SIVmac239(nef open) was administered to three macaques intravenously (i.v.) and to three macaques intravaginally (i.VAG). Clinical outcomes observed ranged from rapid to nonprogression, while two of the i.v.-infected macaques developed an uncommon hindleg paresis. Analysis of viral load (bDNA assay) determined that both i.v.- and i.VAG-infected macaques had comparable high viral loads at the observed viral peak of 14 days postinfection. A study of viral quasispecies diversity by the heteroduplex mobility assay indicated that (1) the i.v.-infected macaques had a highly heterogeneous quasispecies population similar to the infecting viral stock; and (2) in two of three i.VAG-infected macaques multiple viral genotypes (minimum, three or four) were observed in blood and lymph tissues at early times postinfection, which indicated that limited numbers of viral variants crossed the vaginal mucosa and established infection. Therefore, the route of infection can clearly influence early viral selection and diversity. In addition, a third i.VAG-infected macaque, which was a rapid progressor, did not seroconvert and progressed to AIDS in 120 days. This macaque exhibited a high viral load and heterogeneous quasispecies. These data demonstrate differences in the quasispecies complexity associated with route of infection and rate of disease progression.

Amino Acid Sequence↗
PubMed2005

Regulation of bone mass by mechanical loading: microarchitecture and genetics.

For decades, the processes that couple bone architecture and mass to function have been investigated and characterized. It is well known, and now well accepted, that increases in exercise and loading of bone are associated with increased bone mass, and that disuse induces osteopenia. However, the mechanisms by which disuse leads to bone loss remain poorly understood, even in the 21st century. Clearly, the skeleton is able to perceive and respond to some general input(s) generated, or lost, as a consequence of mechanical unloading of bone that are distinct from habitual activity, so called functional adaptation. It is the focus of this paper to evaluate the evidence underlying roles for genetics, osteocytes, and interstitial fluid flow in mediating disuse osteopenia.

Adaptation, Physiological↗
PubMed2006

Disease ecology in the Galápagos Hawk (Buteo galapagoensis): host genetic diversity, parasite load and natural antibodies.

An increased susceptibility to disease is one hypothesis explaining how inbreeding hastens extinction in island endemics and threatened species. Experimental studies show that disease resistance declines as inbreeding increases, but data from in situ wildlife systems are scarce. Genetic diversity increases with island size across the entire range of an extremely inbred Galápagos endemic bird, providing the context for a natural experiment examining the effects of inbreeding on disease susceptibility. Extremely inbred populations of Galápagos hawks had higher parasite abundances than relatively outbred populations. We found a significant island effect on constitutively produced natural antibody (NAb) levels and inbred populations generally harboured lower average and less variable NAb levels than relatively outbred populations. Furthermore, NAb levels explained abundance of amblyceran lice, which encounter the host immune system. This is the first study linking inbreeding, innate immunity and parasite load in an endemic, in situ wildlife population and provides a clear framework for assessment of disease risk in a Galápagos endemic.

Animals↗
PubMed2003

Genetic and environmental analysis of behavioral risk factors for adolescent drug use in a community twin sample.

We investigated the etiology of six problem behaviors that might facilitate an understanding of behavioral pathways to substance use and abuse in adolescents. These behavioral measures, classified as Conduct Problems, Hyperactivity, School Problems, Low Self-esteem, Neuroticism, and Social Withdrawal were the result of a previously reported (Siewert et al., 2003) modification of the Drug Use Screening Inventory (DUSI; Tarter, 1990; Tarter & Hegedus, 1991). We developed these measures as interpretable components of risk for substance use and abuse in a community based sample of 633 twin pairs, who were under the legal drinking age of 21 (mean age = 15.0 years). Using multivariate analyses, model comparisons indicated that these six behavioral measures could be thought of as two heritable, and genetically distinct, dimensions of problem behavior. Two closely competing models resulted from our analyses. The best fitting model hypothesized a general genetic factor loading on all 6 behavioral measures with a second genetic factor loading on only the three internalizing behavioral measures with loadings of 0.25-0.59 and 0.26-0.44, respectively. A second model, which fit the data almost as well, hypothesized one genetic factor loading only on the externalizing behavioral measures, and a second genetic factor loading only on the internalizing behavioral measures, with a correlation between the two latent factors of 0.75. Because our analyses show that there are two genetically distinct factors influencing these six problem behaviors, we anticipate that there may be different patterns of relationship of these factors to risk for substance use, abuse, and dependence.

Adolescent↗
PubMed1994

Platelet MAO activity in type I and type II alcoholism.

Lowered activity of the enzyme MAOB in the platelets and other tissues of alcoholics than of nonalcoholics is the most replicated biological finding in genetic research in alcoholism. Data presented here and elsewhere also indicate that the relationship between MAOB activity and alcoholism extends to the clinical subtypes referred to as Type I and Type II alcoholism. A detailed examination of the relationship between in vitro platelet MAOB activity levels, alcoholic subtype, and general mental health status among the relatives of the probands suggests that low MAOB activity is a marker of increased risk overall and that the families of Type II alcoholics have a higher genetic risk loading than do the families of Type I alcoholics. This increased genetic loading is probably due to the classification of Type II alcoholics on the basis of features related to severity of illness and additional psychiatric features such as personality disorders. Although the families of alcoholics tend to have higher levels of psychiatric illness compared to the general population, the overall risk is compounded in the families of Type II alcoholics, and these differences in underlying risk are reflected in the observed differences in MAOB activities. Thus, MAOB is not a biological/genetic marker of alcoholism sensu stricto but is rather a biological/genetic marker of an underlying pathophysiologic process leading to alcoholism and other psychiatric illness. The task now before us is to understand this process and how the activity of MAOB is involved.

Alcoholism↗
PubMed2005

Development of cell-based tuberculosis vaccines: genetically modified dendritic cell vaccine is a much more potent activator of CD4 and CD8 T cells than peptide- or protein-loaded counterparts.

Genetically modified dendritic cell (DC)-based vaccines have not been explored for immunization against tuberculosis. A gene-modified DC vaccine expressing Mycobacterium tuberculosis (M.tb) antigen 85A (Ag85A) was developed by using a recombinant replication-deficient adenoviral gene transfer vector (AdAg85A). AdAg85A-transduced DC vaccine (AdAg85/DC) expressed higher levels of IL-12 and was much more immunogenic than Ag85 protein-loaded (pro/DC) or CD4/CD8 T cell peptide-loaded (pep/DC) DC vaccines. Compared to pro/DC or pep/DC, AdAg85/DC elicited a remarkably higher level of ex vivo IFN-gamma production by CD4 and CD8 T cells at weeks 2, 6, and 12 postimmunization, which was coupled with higher frequencies of antigen-specific T cells. By an in vivo CD8 or CD4 T cell cytotoxicity (CTL) assay, AdAg85/DC was shown to provoke much higher and more sustained levels of CD8 and CD4 CTL activity up to 12 weeks postimmunization. Intramuscular (im) AdAg85/DC immunization was more potent than the iv route of AdAg85/DC immunization. Such stronger immunogenicity of im AdAg85/DC vaccination was corroborated with better protection from M.tb challenge. Our results thus suggest that genetically modified DC-based TB vaccine is superior to subunit DC vaccines and has the potential for therapeutic applications.

Adenoviridae↗
PubMed1998

From "magic bullet" to "specially engineered shotgun loads": the new genetics and the need for individualized pharmacotherapy.

Steady progress in the identification of human pharmacogenetic variants and new discoveries of disease susceptibility genes makes the old notion of one disease/one drug untenable. Advances in the ability to rapidly identify these variants, when coupled with appropriate drug delivery systems, should revolutionize pharmacotherapy.

Genetic Predisposition to Disease↗
PubMed2000

Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease.

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Bone's early responses to mechanical loading differ in distinct genetic strains of chick: selection for enhanced growth reduces skeletal adaptability.

Bone's functional competence is established and maintained, at least partly, by mechanisms involving appropriate adaptation to mechanical loading. These appear to fail in chickens selectively bred either for maximum egg (Egg-type) or meat (Meat-type) production, which show high rates of fracture and skeletal abnormality, respectively. By measuring several early strain-induced responses in cultured embryonic tibiotarsi from commercially bred (Egg-type and Meat-type) and wild-type (Wild-type) chicks, we have investigated the possibility that these skeletal failures are the product of a compromised ability to respond appropriately to loading-induced mechanical strain. Axial loads engendering peak dynamic (1 Hz) longitudinal strains of between -1300 microepsilon and -1500 microepsilon (for 10 minutes) in vitro in tibiotarsi from the three types of 18-day-old chicks increased periosteal osteoblast glucose 6-phosphate dehydrogenase (G6PD) activity in both Wild-type (26%, p < 0.01) and Egg-type (49%, p < 0.001) chicks in situ, while Meat-type chicks did not show any significant changes (11%). Load-induced increases in medium nitrite accumulation (stable nitric oxide [NO] metabolite) were produced in Egg-type and Wild-type tibiotarsi (82 +/- 12%, p < 0.01; 39 +/- 8%, p < 0.01), respectively. In contrast, loading produced no change in NO release from Meat-type chick tibiotarsi. These changes in NO release correlated with load-related increases in G6PD activity (R2 = 0.98, p < 0.05) in the different chick types. Wild-type and Meat-type tibiotarsal periosteal osteoblasts responded in a biphasic manner to exogenous prostacyclin (PGI2), with maximal stimulation of G6PD activity at 10(-7) M and 10(-6) M PGI2. However, Egg-type chick osteoblasts showed smaller, progressive increases up to 10(-5) M PGI2. These results indicate that early phases of the adaptive response to loading differ in different genetic strains of embryonic chick; that skeletal abnormalities which develop in genetically selected, high growth rate chicks may reflect a compromised ability to respond to load; and that load-induced increases in osteoblastic G6PD activity appear to be closely associated with increased rates of NO release. It is probable that similar genetically related differences in bones' responsiveness to mechanical loading occur in other species.

Adaptation, Physiological↗