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PubMed2002

DNA viruses and genetic modification of dendritic cells.

An alternative approach to the use of tumor-peptide-loaded dendritic cells (DC) in immunotherapy would be the use of genetically modified DC using viral vectors expressing tumor-associated antigens (TAA). However, viruses have developed several immune escape mechanisms and, thus, one has to study the interaction between viruses and DC before these viruses can be used as an alternative strategy. Here we report that vaccinia virus (VV) as well as herpes simplex virus type 1 (HSV-1) are able to potently infect monocyte-derived DC, however, this infection leads to the inhibition of the DC-mediated T cell stimulation in vitro.

Animals↗
PubMed2002

Sperm DNA damage and cancer treatment.

Cancer treatments are well known to adversely affect male fertility. Reduction of sperm output arises from the cytotoxic effects of chemo- or radiotherapy upon the spermatogenic epithelium. However, if the epithelium survives there is a hazard to reproduction as the treatments are also mutagenic. The presence of DNA damage in the male genome is shown in animal experiments where there is transgenerational expression as a variety of effects ranging from miscarriage to carcinogenesis. The application of DNA damage methodology to sperm provides the opportunity for direct assessment. The Comet and Chromatin structure assays (SCSA) measure DNA damage by different principles, however, conclusions arising from the data are similar. DNA damage is present in sperm from fertile and infertile men and there is some association with infertility. Both assays detect sperm DNA damage after in vivo treatment with genotoxic agents. In a man treated with chemotherapy for cancer there was increased and persistent DNA damage in sperm. This information is consistent with the generation of human genetic diseases after conception with sperm carrying high loads of DNA damage. Whilst studies have not supported any association between paternal cytotoxic cancer therapy and genetic disease in their children, it would be unwise to discount these observations. The institution of better surveillance of genetic disease in the offspring of men surviving cytotoxic therapies may provide more robust risk assessment.

Antineoplastic Agents↗
PubMed2001

The action of salt and captopril on blood pressure in mice with genetic hypertension.

OBJECTIVE: Does captopril lower blood pressure in genetically hypertensive, normotensive and hypotensive mice under normal and salt-loaded conditions? DESIGN AND METHODS: Groups of inbred mice that were genetically hypertensive, normotensive or hypotensive were given one of the following treatments: (a) captopril in drinking water for 7 days; controls were given water. (b) 0.85% saline to drink for up to 14 days; controls were given water. (c) Water or saline followed by captopril/water or captopril/saline for 7 days. (d) In hypotensive mice only, 0.85% saline, 0.85% saline plus captopril, water or captopril in water. Systolic blood pressures (SBP) were measured by a computerized tail-cuff sphygmomanometer. Results were compared by analysis of variance (ANOVA). RESULTS: Captopril lowered SBP in all strains of mice. When saline was given with captopril, the fall in SBP was slower but the final SBP level was similar to that of mice given captopril in water. Hypotensive mice showed a transient rise in SBP on saline, which was abolished by concurrent treatment with captopril. CONCLUSION: Captopril lowers blood pressure in hypertensive, normotensive and hypotensive mice. Salt-loading retards the captopril-induced fall in SBP, but the final level of SBP achieved is similar to that in mice given captopril with water. The BPL1 strain of mouse was slightly salt-sensitive, and this was abolished by captopril.

Animals↗
PubMed2006

What is intervertebral disc degeneration, and what causes it?

STUDY DESIGN: Review and reinterpretation of existing literature. OBJECTIVE: To suggest how intervertebral disc degeneration might be distinguished from the physiologic processes of growth, aging, healing, and adaptive remodeling. SUMMARY OF BACKGROUND DATA: The research literature concerning disc degeneration is particularly diverse, and there are no accepted definitions to guide biomedical research, or medicolegal practice. DEFINITIONS: The process of disc degeneration is an aberrant, cell-mediated response to progressive structural failure. A degenerate disc is one with structural failure combined with accelerated or advanced signs of aging. Early degenerative changes should refer to accelerated age-related changes in a structurally intact disc. Degenerative disc disease should be applied to a degenerate disc that is also painful. JUSTIFICATION: Structural defects such as endplate fracture, radial fissures, and herniation are easily detected, unambiguous markers of impaired disc function. They are not inevitable with age and are more closely related to pain than any other feature of aging discs. Structural failure is irreversible because adult discs have limited healing potential. It also progresses by physical and biologic mechanisms, and, therefore, is a suitable marker for a degenerative process. Biologic progression occurs because structural failure uncouples the local mechanical environment of disc cells from the overall loading of the disc, so that disc cell responses can be inappropriate or "aberrant." Animal models confirm that cell-mediated changes always follow structural failure caused by trauma. This definition of disc degeneration simplifies the issue of causality: excessive mechanical loading disrupts a disc's structure and precipitates a cascade of cell-mediated responses, leading to further disruption. Underlying causes of disc degeneration include genetic inheritance, age, inadequate metabolite transport, and loading history, all of which can weaken discs to such an extent that structural failure occurs during the activities of daily living. The other closely related definitions help to distinguish between degenerate and injured discs, and between discs that are and are not painful.

Animals↗
PubMed1993

Dyspnea sensation and chemical control of breathing in adult twins.

To examine possible genetic influence on the sensation of dyspnea and on load compensation, we conducted a twin study using healthy adult pairs (10 monozygotes, MZ, and 9 dizygotes, DZ). The ventilatory response to progressive hypercapnia (HCVR) was examined under three different conditions: hyperoxia (PETO2 > 150 mm Hg), hypoxia (PETO2 maintained at 50 to 55 mm Hg), and hyperoxia with an inspiratory flow-resistive load (17 mm H2O/L/s), with simultaneous assessment of the dyspnea sensation by visual analog scale (VAS). Although the VDZ/VMZ ratio (VMZ and VDZ are within-pair variances in MZ and DZ, respectively) for the slope value of the minute ventilation-PETCO2 regression line was not different from 1 in hyperoxia either with or without an inspiratory load, it was significantly larger than 1 in hypoxia (F = 5.17, p < 0.05), suggesting that a genetic influence on HCVR existed only in the presence of hypoxia. During 3% CO2 inhalation, the VDZ/VMZ ratio for the tidal volume (VT) was larger than 1 in hyperoxic HCVR with loading (F = 7.89, p < 0.01), and that for respiratory frequency (f) was larger than 1 only in hypoxic HCVR (F = 3.59, p < 0.05). At a PETCO2 of 55 mm Hg, the VT ratio was larger than 1 under all conditions (F = 5.91, p < 0.05; F = 6.99, p < 0.05; F = 3.75, p < 0.05; respectively), and the f ratio was significantly larger than 1 again only in hypoxic HCVR (F = 3.48, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Influence of cytokine and mannose binding protein gene polymorphisms on human T-cell leukemia virus type I (hTLV-I) provirus load in HTLV-I asymptomatic carriers.

Human T-cell leukemia virus type I (HTLV-I) provirus load differs more than 100-fold among carriers and a high provirus load in the peripheral blood mononuclear cells (PBMCs) is regarded as a risk factor for both preleukemic states and inflammatory diseases including HTLV-I-associated myelopathy (HAM). We examined polymorphisms in the genes for tumor necrosis factor (TNF), TNF receptor type 1 and 2, lymphotoxin (LT)-alpha, interleukin (IL)-1beta, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and mannose binding protein (ManBP) in 143 HTLV-I carriers whether these polymorphisms affect the provirus load in the PBMCs of carriers. No significant association was observed between these polymorphisms and the provirus load. Homozygotes for a ManBP-variant allele, however, showed a tendency for the decreased number of provirus load. When combined, the data on the alleles of LT-alpha and MCP-1, HTLV-I carriers having high producer alleles of both genes showed a trend for increased provirus load. These data suggest that inflammation or an active immune response may induce an increased amount of HTLV-I-infected T cells, leading to a high provirus load.

Alleles↗
PubMed2006

Elimination of deleterious mutations in plastid genomes by gene conversion.

Asexual reproduction is believed to be detrimental, mainly because of the accumulation of deleterious mutations over time, a hypothesis known as Muller's ratchet. In seed plants, most asexually reproducing genetic systems are polyploid, with apomictic species (plants forming seeds without fertilization) as well as plastids and mitochondria providing prominent examples. Whether or not polyploidy helps asexual genetic systems to escape Muller's ratchet is unknown. Gene conversion, particularly when slightly biased, represents a potential mechanism that could allow asexual genetic systems to reduce their mutation load in a genome copy number-dependent manner. However, direct experimental evidence for the operation of gene conversion between genome molecules to correct mutations is largely lacking. Here we describe an experimental system based on transgenic tobacco chloroplasts that allows us to analyze gene conversion events in higher plant plastid genomes. We provide evidence for gene conversion acting as a highly efficient mechanism by which the polyploid plastid genetic system can correct deleterious mutations and make one good genome out of two bad ones. Our finding that gene conversion can be biased may provide a molecular link between asexual reproduction, high genome copy numbers and low mutation rates.

Base Sequence↗
PubMed2006

Association of a 31 bp VNTR in the CBS gene with postload homocysteine concentrations in the Framingham Offspring Study.

Elevated total plasma homocysteine concentrations (tHcy), both fasting and post-methionine load, have been established as risk factors for vascular disease. Recently, we described the association of a 31 bp variable number of tandem repeats (VNTR) in the cystathionine beta-synthase (CBS) gene with both CBS enzyme activity and tHcy concentrations. In the present study, we determined the 31 bp VNTR genotypes in 2598 individuals of the Framingham Offspring Study and studied the association between this genotype and fasting, 2-h post-methionine load and delta (ie increase upon methionine loading) tHcy concentrations in 1416 subjects. We observed a positive association between the number of repeat units of the CBS 31 bp VNTR and both postload and delta tHcy concentrations. Adjustment for possible effect modifying factors like age, sex and vitamin (B6, B12 and folate) status did not change this observation. We hereby confirm the results of our earlier study, in which we found that this 31 bp VNTR is a genetic determinant of post-methionine load tHcy concentrations. Since also post-methionine load tHcy concentrations are found to be associated with an increased risk for cardiovascular disease (CVD), this 31 bp VNTR may be considered a risk factor for CVD.

Aged↗
PubMed2005

The structure of genetic and environmental risk factors for anxiety disorders in men and women.

BACKGROUND: The anxiety disorders exhibit high levels of lifetime comorbidity with one another. Understanding the underlying causes of this comorbidity can provide insight into the etiology of the disorders and inform classification and treatment. OBJECTIVE: To explain anxiety disorder comorbidity by examining the structure of the underlying genetic and environmental risk factors. DESIGN: Lifetime diagnoses for 6 anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, and situational phobia) were obtained during personal interviews from a population-based twin registry. Multivariate structural equation modeling that allowed for sex differences was performed. SETTING: General community sample. PARTICIPANTS: More than 5000 members of male-male and female-female twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURES: Parameter estimates for best-fitting model. RESULTS: The full model, which contained 2 common genetic, shared environmental, and unique environmental factors plus disorder-specific factors, could be constrained to equality across male and female study participants. In the best-fitting model, the genetic influences on anxiety were best explained by 2 additive genetic factors common across the disorders. The first loaded most strongly in generalized anxiety disorder, panic disorder, and agoraphobia, whereas the second loaded primarily in the 2 specific phobias. Social phobia was intermediate in that it was influenced by both genetic factors. A small role for shared environmental influences was observed owing to a single common factor that accounted for less than 12% of the total variance for any disorder. Unique environmental influences could be explained by a single common factor plus disorder-specific effects. CONCLUSIONS: The underlying structure of the genetic and environmental risk factors for the anxiety disorders is similar between men and women. Genes predispose to 2 broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety vs the specific phobias. The remaining associations between the disorders are largely explained by a unique environmental factor shared across the disorders and, to a lesser extent, a common shared environmental factor.

Adult↗
PubMed2000

Superior tumor protection induced by a cellular vaccine carrying a tumor-specific T helper epitope by genetic exchange of the class II-associated invariant chain peptide.

Efficient loading of MHC class II molecules with a T helper epitope of choice can be achieved through genetic exchange of the MHC class II-associated invariant chain peptide (CLIP) sequence with a sequence encoding the helper peptide. We have now used this method to engineer a cellular vaccine that continuously expresses a tumor-specific helper epitope in a defined costimulatory context. We provide evidence (a) that this cellular vaccine induces peptide-specific helper T cells in vivo that are functional in protecting mice from challenge with a highly aggressive tumor, (b) that this vaccine can directly prime tumor-specific helper T cells in vivo, and (c) that this cellular vaccine is superior compared with similar cells loaded with synthetic T helper peptide in inducing tumor protection. In conclusion, cellular vaccines for activation of antigen-specific helper T cells can be greatly improved by the introduction of invariant chain constructs containing a T helper epitope by class II-associated invariant chain peptide exchange.

Amino Acid Sequence↗
PubMed1993

Genetics and high cognitive ability.

More is known about the genetics of general cognitive ability (g) than any other trait in psychology. Recent findings on the genetics of g include the following three examples: (1) heritability increases throughout the lifespan; (2) heritabilities of performance in cognitive tests are strongly correlated with the tests' loadings on a g factor; and (3) genetic effects on scholastic achievement largely overlap with genetic effects on cognitive ability. This body of genetic research addresses the aetiology of individual differences in the normal range. Much less is known about the genetics of the high end of the distribution. Finding heritability in the normal range of cognitive ability does not imply that high ability is also genetic in origin. However, the first twin study of high IQ children, which uses a new technique that analyses the average difference between extreme groups and the rest of the population, suggests that high IQ is as heritable as individual differences in the normal range. We are currently engaged in a molecular genetic study that attempts to identify specific genes that contribute to high ability.

Adolescent↗
PubMed1990

Quantitation of IgM antibodies to the M. leprae synthetic disaccharide can predict early bacterial multiplication in leprosy.

Quantitative enzyme-linked immunosorbent assays detecting IgM to the soluble Mycobacterium leprae crude sonicate (CD75) and the synthetic disaccharide antigen coupled to bovine serum albumin (ND-BSA) were assessed for their ability to determine early infection in families/household contacts of leprosy patients and employees of a leprosy center working in close contact with leprosy patients. Although IgM to both antigens (CD75 and ND-BSA) correlated with the bacterial index (BI) assessed histologically on skin-biopsy samples, the level of IgM antibodies to ND-BSA was a much more sensitive indicator of low bacterial loads. A 4.4-fold difference in antibody levels was observed between the mean group levels of endemic controls (N = 116) and tuberculoid leprosy patients with a BI of 0 (N = 88), increasing to sevenfold in tuberculoid leprosy patients with a BI of 1 (N = 20). Using a statistical cut off with endemic controls (mean + 2 S.D.), household/family contacts showed 30% seropositivity (N = 180) as compared to staff contacts who showed 17% seropositivity (N = 55). Percent seropositivity in family contacts was not related to the type of leprosy of the index case (lepromatous vs. tuberculoid) or the duration of treatment of the index case. Age of the individual in the family contact group had a significant influence on seropositivity. These results support the hypothesis that, in this community, factors other than the viable bacterial load of the index case, such as genetic susceptibility, may be influencing the high rate of seropositivity in family contacts. IgM ND-BSA antibodies seem to provide a good indicator of low antigenic loads and could prove to be useful in detecting subclinical infection before the onset of disease. Follow-up studies of these seropositive individuals are in progress to understand the relationship between seropositivity and the progress of clinical disease.

Antibodies, Bacterial↗
PubMed1989

Developmental delay in offspring of parents with affective disorders and depression: psycho-social sequels or a constitutional state?

At an early age, offspring of parents with affective disorders and long-lasting depression exhibited elevated rates of psychomotor and language delay, behavior problems and a greater need for somatic psychiatric care compared to matched control children (Harjan 1988, I, II, III). The present report analyses the problem of these children regarding psychomotor and language delay (PMLD) seen in a great number of children and somewhat more often in boys compared with those without this handicap. The study shows that children with PMLD of parents with affective disorders and long-lasting depression differ from those without PMLD with respect to early behavior problems, need for child psychiatric care during latency, and they are loaded by more broken homes and longer stay in pediatric wards. The two groups are similar in aspects of low social standing, mean parental age, perinatal risk factors, delayed somatic growth, incidence of psychiatric registrations and rate and nature of somatic disorders. The developmental delay may be a hereditary disturbance either related to affective disorder or to a concomitant factor, or the developmental delay may relate to the adverse environmental situation. It is also obvious that simultaneous parental illness, social breakdown and genetic constitution form a critical multifactoral loading on the child. The high rate of developmental delay among offspring of parents with affective disorders stresses the importance of giving attention to the children of parents with affective disorders and long-lasting depression. The developmental delay per se is an important disorder for early behavior problems and need for child and youth psychiatric care.

Adolescent↗
PubMed2006

The genetic architecture of life span and mortality rates: gender and species differences in inbreeding load of two seed-feeding beetles.

We examine the inbreeding load for adult life span and mortality rates of two seed beetle species, Callosobruchus maculatus and Stator limbatus. Inbreeding load differs substantially between males and females in both study populations of C. maculatus--life span of inbred females was 9-13% shorter than the life span of outbred females, whereas the life span of inbred males did not differ from the life span of outbred males. The effect of inbreeding on female life span was largely due to an increase in the slope of the mortality curve. In contrast, inbreeding had only a small effect on the life span of S. limbatus--life spans of inbred beetles were approximately 5% shorter than those of outbred beetles, and there was no difference in inbreeding load between the sexes. The inbreeding load for mean life span was approximately 0.4-0.6 lethal equivalents per haploid gamete for female C. maculatus and approximately 0.2-0.3 for both males and females of S. limbatus, all within the range of estimates commonly obtained for Drosophila. However, contrary to the predictions of mutation-accumulation models, inbreeding load for loci affecting mortality rates did not increase with age in either species, despite an effect of inbreeding on the initial rate of increase in mortality. This was because mortality rates decelerated with age and converged to a mortality plateau for both outbred and inbred beetles.

Animals↗
PubMed2002

The genetic structure of Cloninger's seven-factor model of temperament and character in a Japanese sample.

Theoretical assumptions regarding the genetic and environmental structure of personality proposed in Cloninger's seven-factor model of temperament and character were verified in a Japanese sample by using the twin method. The Temperament and Character Inventory (TCI) was administered to 296 twin pairs ranging in age from 14 to 28 years old. Among four temperament dimensions (novelty seeking [NS], harm avoidance [HA], reward dependence [RD], and persistence [PS]), HA and PS showed significant additive genetic contributions and no shared environmental effect, supporting the original theoretical assumption. NS and RD could be explained by either genetic or shared environmental factors with nonshared environment. All three character dimensions (cooperativeness [CO], self-directedness [SD], and self-transcendence [ST]) could be explained exclusively by additive contributions and no shared environmental effect. Multivariate genetic analysis indicated that there were no significant associations between NS, HA, and RD, as the theory predicts, and the genetic components of PS, SD, and CO were derived from those of the temperament dimensions. The fourth genetic component, which had a substantial load specifically on ST and overlapped with PS, was identified. Although most of the nonshared environmental effects were trait-specific, the phenotypic correlation between NS and HA could be explained by nonshared environmental overlap.

Adolescent↗
PubMed2006

Who's afraid of the big bad Wolff?: "Wolff's law" and bone functional adaptation.

"Wolff's law" is a concept that has sometimes been misrepresented, and frequently misunderstood, in the anthropological literature. Although it was originally formulated in a strict mathematical sense that has since been discredited, the more general concept of "bone functional adaptation" to mechanical loading (a designation that should probably replace "Wolff's law") is supported by much experimental and observational data. Objections raised to earlier studies of bone functional adaptation have largely been addressed by more recent and better-controlled studies. While the bone morphological response to mechanical strains is reduced in adults relative to juveniles, claims that adult morphology reflects only juvenile loadings are greatly exaggerated. Similarly, while there are important genetic influences on bone development and on the nature of bone's response to mechanical loading, variations in loadings themselves are equally if not more important in determining variations in morphology, especially in comparisons between closely related individuals or species. The correspondence between bone strain patterns and bone structure is variable, depending on skeletal location and the general mechanical environment (e.g., distal vs. proximal limb elements, cursorial vs. noncursorial animals), so that mechanical/behavioral inferences based on structure alone should be limited to corresponding skeletal regions and animals with similar basic mechanical designs. Within such comparisons, traditional geometric parameters (such as second moments of area and section moduli) still give the best available estimates of in vivo mechanical competence. Thus, when employed with appropriate caution, these features may be used to reconstruct mechanical loadings and behavioral differences within and between past populations.

Adaptation, Physiological↗
PubMed1988

Evolution of sex in RNA viruses.

The distribution of deleterious mutations in a population of organisms is determined by the opposing effects of two forces, mutation pressure and selection. If mutation rates are high, the resulting mutation-selection balance can generate a substantial mutational load in the population. Sex can be advantageous to organisms experiencing high mutation rates because it can either buffer the mutation-selection balance from genetic drift, thus preventing any increases in the mutational load (Muller, 1964: Mut. Res. 1, 2), or decrease the mutational load by increasing the efficiency of selection (Crow, 1970: Biomathematics 1, 128). Muller's hypothesis assumes that deleterious mutations act independently, whereas Crow's hypothesis assumes that deleterious mutations interact synergistically, i.e., the acquisition of a deleterious mutation is proportionately more harmful to a genome with many mutations than it is to a genome with a few mutations. RNA viruses provide a test for these two hypotheses because they have extremely high mutation rates and appear to have evolved specific adaptations to reproduce sexually. Population genetic models for RNA viruses show that Muller's and Crow's hypotheses are also possible explanations for why sex is advantageous to these viruses. A re-analysis of published data on RNA viruses that are cultured by undiluted passage suggests that deleterious mutations in such viruses interact synergistically and that sex evolved there as a mechanism to reduce the mutational load.

Models, Genetic↗
PubMed1992

House dust mite sensitivity: interaction of genetics and allergen dosage.

Pairwise analysis of siblings from 21 families showed that house dust mite (HDM) sensitive children were exposed to higher concentrations of Der p I allergen in their mattress (P = 0.005) and bedding (P = 0.04), but not bedroom floor (P = 0.33), than their atopic sibling who was not sensitive to HDM antigens. There was no difference in the exposure to HDM numbers/100 mg of dust in the mattress (P = 0.61) or bedroom floors (P = 0.09). In contrast, pairwise analysis of siblings from 15 families showed that HDM sensitive children were not exposed to significantly different concentrations of Der p I in the mattress (P = 0.96), bedding (P = 0.11) or bedroom floor (P = 0.70) nor HDM numbers/100 mg of dust in the mattress (P = 0.12) and bedroom floor (P = 0.98) than their non-atopic siblings. These findings were identical when absolute allergen load was compared in these pairs. Genetic linkage studies in these families suggest the tendency to atopic IgE responses is conferred by a putative atopy locus on chromosome 11q. These results together suggest that differences in allergen levels in beds, among siblings with a comparable genetic tendency to atopy, play a significant role in determining the development of HDM allergy.

Allergens↗