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At least 1,063 records · Page 59Linked to original sources
PubMed2001

African-American heredity prostate cancer study: a model for genetic research.

A genome-wide scan of high-risk prostate cancer families in North America has demonstrated linkage of a particular marker to Chromosome 1q (HPC1). An even greater proportion of African-American families have shown linkage to HPC1. Therefore, investigators at the National Human Genome Research Institute (NHGRI) in collaboration with Howard University and a predominantly African-American group of urologists established the African-American Hereditary Prostate Cancer (AAHPC) Study Network to confirm the suggested linkage of HPC in African Americans with a gene on Chromosome 1. Blood samples from recruited families were sent to Howard University for extraction of DNA. The DNA was sent to NHGRI at NIH where the genotyping and genetic sequence analysis was conducted. Genotype data are merged with pedigree information so that statistical analysis can be performed to establish potential linkage. From March 1, 1998, to June 1, 1999, a total of 40 African-American families have been recruited who met the study criteria. Preliminary results suggest that racial/ethnicity grouping may affect the incidence and extent of linkage of prostate cancer to specific loci. The importance of these findings lays in the future treatment of genetic-based diseases.

Aged↗
PubMed1993

The Os/+ mouse: a genetic animal model of reduced renal mass.

The ROP [Ra/+ (ragged), Os/+ (oligosyndactyly), and Pt/+ (pintail)] mouse possessing the gene for oligosyndactylism (Os) was evaluated as a potential genetic animal model of reduced renal mass. Young male ROP mice that were heterozygotes with respect to the Os gene (Os/+) and their normal homozygote litter mates (+/+) were used in the present study. Approximately 50% fewer nephrons were present in the Os/+ mice than in the +/+ mice. Hypertrophic changes were detected in the epithelial cells in proximal convoluted and proximal straight tubules as well as in cortical collecting ducts in the kidneys of the Os/+ mice. Glomerular hypertrophy was also noted in the kidneys of these mice. After unilateral nephrectomy, further hypertrophic changes occurred in both Os/+ and +/+ mice, but the magnitude of compensatory growth was greater in the +/+ mice. From a functional standpoint, the Os/+ mice appeared to be capable of maintaining normal fluid and electrolyte homeostasis, even after unilateral nephrectomy. The findings from the present study indicate that the ROP Os/+ mouse can be a useful animal model to study the effects of reduced renal mass.

Adaptation, Physiological↗
PubMed1995

Comparison of effects of ACE inhibition with calcium channel blockade on renal disease in a model combining genetic hypertension and diabetes.

The aim of this study was to compare the renal effects of angiotensin converting enzyme (ACE) inhibition with calcium channel blockade in a model combining genetic hypertension with diabetes. Streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). The animals were then randomized to receive no treatment, the ACE inhibitor, perindopril, or the dihydropyridine calcium antagonist lacidipine. Body weight, systolic blood pressure, glycemic control, renal function, and albumin excretion rate (AER) were assessed serially over the 32-week study period. At week 32 the animals were killed and glomerular volume was measured. Both antihypertensive regimens significantly reduced systolic blood pressure in diabetic SHR. There was no significant difference in glycemic control, serum creatinine, or glomerular filtration rate among the three groups at week 32. The ACE inhibitor perindopril significantly reduced AER and glomerular hypertrophy over the 32 weeks, whereas the calcium antagonist lacidipine failed to reduce AER or glomerular hypertrophy. Thus, in contrast to the effects of ACE inhibition, calcium channel blockade with lacidipine, despite significantly reducing blood pressure, failed to reduce renal injury in this model. These results support the hypothesis that antihypertensive regimens may differ in their capacity to protect the diabetic kidney, despite similar effects on systemic blood pressure.

Albuminuria↗
PubMed1985

Description of a new model of genetic obesity: the dbPas mouse.

A new strain of genetically obese mouse, the dbPas mouse, has been studied in terms of fat pad cellularity, serum parameters and thermogenesis. This obesity was observed in the inbred DW strain of mice at the Institut Pasteur-France, and is due to a recessive mutation on chromosome 4 at the diabetes locus. The mice became grossly obese, gaining weight until at least 16 mo of age. By 6 mo of age they exhibited hyperphagia, hypercholesterolemia, severe hyperinsulinemia, hypertrophy and hyperplasia of adipocytes, and impaired fertility. In contrast with other diabetic strains of mice, glycemia was normal in females and slightly elevated in males. This result indicates that the mutation of the db locus does not necessarily lead to a frank diabetes. Body temperature was normal either at 22 degrees C or after a cold exposure at 4 degrees C. GDP (guanosine diphosphate) binding to brown adipose tissue mitochondria was normal in obese mice as compared to lean. These data differentiate this model from other genetic obesities in mice and rats. This new model of genetic obesity offers interesting characteristics for the study of obesity.

Adipose Tissue↗
PubMed1994

Gene therapy for infectious diseases: the AIDS model.

Genetic manipulation of somatic cells may be of therapeutic value in a variety of infectious diseases, particularly in human immunodeficiency virus (HIV) infection. Stable insertion of custom-designed 'resistance genes' into cells susceptible to HIV could reduce the viral burden in infected individuals and potentially retard the characteristic progressive immune dysfunction. Alternatively, ectopic expression of genes that encode viral antigens might induce potent antiviral immune responses and form the basis for novel prophylactic and therapeutic vaccines. While laboratory studies have proved that the approach works in principle, preclinical and clinical studies will be necessary to evaluate the therapeutic benefit of such gene-based therapies.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Galanin and spinal nociceptive mechanisms: recent results from transgenic and knock-out models.

Genetically modified mice with transgenic overexpression of galanin or depletion of genes for galanin or galanin receptors have become available, providing a new approach for analyzing the role of galanin in nociception. Mice overexpressing galanin had a moderate heat hypoalgesia, reduced spinal sensitization after repetitive C-fiber stimulation and reduced development of neuropathic pain-like behavior after sciatic nerve injury. On the other hand, mice lacking the GALR1 receptor (Galr1-/-) exhibited only slight increase in heat nociception in the hot plate, but not tail flick, test and showed no increase in spinal sensitization. The duration, but not magnitude, of neuropathic pain-like behaviors, was increased in Galr1-/- mice after nerve injury. These results support an inhibitory effect of galanin on nociception, but the physiological role played by galanin via GALR1 receptors needs to be further studied.

Animals↗
PubMed1998

Cholinergic deficiency in Alzheimer's disease. Pathogenic model.

Genetic vulnerability factors are becoming more important in AD, yet only a minority of cases are familial, and of these only a portion are genetically determined. Because, early in the course, neurodegeneration is occurring in vulnerable cholinergically innervated regions and not throughout the brain as a whole, AD may be conceptualized as a corticolimbic system neurodegenerative disorder involving the entorhinal cortex, hippocampus, and amygdala. This conceptualization has obvious implications for the development of therapies since future interventions may be designed to prevent or slow neurodegeneration or improve clinical signs by modulating risk factors, beta-amyloid deposition, and phosphorylation of tau proteins; inhibiting inflammatory or oxidative processes; or enhancing cholinergic function in various ways. The recently reported effects of antioxidants, including vitamin E and selegiline, in prolonging time to institutionalization, death, or significant worsening, is one example of the feasibility of this approach, as are the observations that anti-inflammatory use may reduce AD risk and that long-term cholinesterase inhibitor use may delay nursing home placement. At present, approaches that are focused on neurotransmitter systems may prove more immediately accessible targets for therapeutic intervention.

Aged↗
PubMed1997

Rett syndrome: an analysis using Sartwell's incubation period model.

Evidence suggests that Rett syndrome is a genetic disorder; however, an etiologic genetic model has yet to be identified. The purpose of this study was to apply a statistical model, Sartwell's incubation period model, to estimate the incubation period of Rett syndrome and postulate further on the etiology of Rett syndrome. Sartwell's model was used to test the hypothesis that the age of onset of developmental regression distributions approximate a logarithmic normal model and thus the etiologic factors of Rett syndrome occur in utero or prior to conception. Data from three case-series of Rett syndrome from different geographic regions were used for the analyses. Curves resulting from the analyses demonstrated a good approximation to the logarithmic normal distribution, indicating a good fit of the data to Sartwell's model. In conclusion, the incubation period of Rett syndrome fits the logarithmic normal model, which is consistent with the theory that a major causal factor for Rett syndrome most likely occurs in utero or prior to conception, eg, a defective gene.

Age of Onset↗
PubMed1994

A DeFries and Fulker regression model for genetic nonadditivity.

Parameter estimates from the DeFries and Fulker [(DF) Behav. Genet. 15:462-473, 1985] regression method can be greater than unity or less than zero. This occurs when the monozygotic correlation is greater than twice the dizygotic correlation. Sensible values can be obtained in these cases by fitting a constrained DF model that estimates genetic and nonshared environmental variance components only. In this article I demonstrate that the original Df model yields positively biased heritability estimates and negatively biased estimates of shared environmentality when data are significantly influenced by genetic nonadditivity. The magnitude of the bias is algebraically expressed. I then describe a simple regression equation that provides unbiased estimates of the standardized additive and dominance genetic variance components. Results of a study of 6 million twin pairs from the Monte Carlo Twin Registry demonstrate that the DF additive and dominance genetic parameter estimates are virtually identical to those obtained by maximum-likelihood procedures. Finally, I derive the expectations for the constrained DF model and show that the genetic parameter estimates from this model are negatively biased estimates of broad-sense heritability.

Genes, Dominant↗
PubMed2005

Genetic mouse models of parkinsonism: strengths and limitations.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Patients with PD display a combination of motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability that worsen over time. These motor symptoms are related to the progressive loss of dopamine neurons in the substantia nigra pars compacta. PD patients also suffer from nonmotor symptoms that may precede the cardinal motor symptoms and that are likely related to pathology in other brain regions. Traditional toxin models of PD have focused on the nigrostriatal pathway and the loss of dopamine neurons in this region, and these models have been important in our understanding of PD and in the development of symptomatic treatments for the disease. However, they are limited in that they do not reproduce the full pathology and progression seen in PD, thus creating a need for better models. The recent discovery of specific genes causing familial forms of PD has contributed to the development of novel genetic mouse models of PD. This review discusses the validity, benefits, and limitations of these new models.

Animals↗
PubMed1989

Level of expression and chromosome mapping of the mouse cholecystokinin gene: implications for murine models of genetic obesity.

Cholecystokinin (CCK) is a neuropeptide which is present in brain and intestine and which stimulates gall bladder contraction and pancreatic secretion. Additional studies have demonstrated an appetite-suppressing effect of CCK in vivo. These data have aroused speculation that the physiology of this hormone could be relevant in the pathogenesis of the mouse obesity mutations ob on chromosome 6 and db on chromosome 4. In order to determine whether abnormalities of this hormone could be the primary defect in these obesity mutations, we have used three separate approaches to map the mouse Cck gene to distal chromosome 9, where it is part of a syntenic group between mouse chromosome 9 and human chromosome 3. These data therefore exclude cholecystokinin as the etiologic factor in the pathogenesis of any of the known mouse obesity syndromes. In order to exclude the possibility that there are differences in mutant animals in the level of CCK RNA, we have used an S1 nuclease protection assay as well as a novel radioimmunoassay that detects the CCK precursor, to show that there are no gross differences in CCK mRNA or protein precursor levels between ob/ob and wild-type animals.

Alleles↗
PubMed2005

Age-dependent alterations of striatal calretinin interneuron density in a genetic animal model of primary paroxysmal dystonia.

Various types of hereditary dystonia are regarded as a basal ganglia disorder, but the underlying mechanisms are still unknown. In the dt hamster, a genetic animal model of age-dependent paroxysmal dystonia, recent studies demonstrated a reduced density of striatal parvalbumin-immunoreactive (PV) GABAergic interneurons at an age of maximum severity of dystonia in comparison with age-matched nondystonic controls. So far, alterations of other types of striatal interneurons in dt hamsters cannot be excluded. Therefore, we determined the density of calretinin-immunoreactive (CR) interneurons in the dt mutant at an age of maximum severity and after spontaneous remission of dystonia in comparison with age-matched nondystonic controls using an image analysis system and a stereologic counting method in a blinded fashion. At an age of maximum severity of dystonia, CR interneuron density was significantly lower in dt hamsters in comparison with controls (-20%), whereas no significant differences between the animal groups could be detected after spontaneous remission of dystonia. The comparison of CR interneuron density between young hamsters with those at an age of > 90 days revealed a significant ontogenetic decrease of CR interneurons in both animal groups (dt hamsters: -38%, controls: -54%). These results demonstrate that alterations of striatal interneuron density in dt mutants are not restricted to PV ones. A deficit of CR interneurons that coexpress GABA may contribute to previous findings of disinhibition of striatal projection neurons in the dt mutant at an age of maximum expression of dystonia.

Age Factors↗
PubMed2004

Biodynamic modeling and simulation of multistage cell mutations.

The aim of this study is to present a mathematical computer simulation model for multistage carcinogenesis. The population genetic model is developed based on the reaction diffusion, logistic behavior, and Hollings Type II interactions between normal, benign, and premalignant cells. The simple form of the Fisher-Haldane-Wright equation of the genetic model of tumor suppressor gene and oncogenes is used to describe this type of interaction. Through computer simulation, we observe the behavior, stability, and traveling wave solution of the premalignant stage mutation as well as its survival under natural selection pressure. As a simple case of this model, the interaction between normal and tumor cells with one or two stages of mutations is analyzed.

Cell Transformation, Neoplastic↗
PubMed2001

HbA(1c) levels are genetically determined even in type 1 diabetes: evidence from healthy and diabetic twins.

HbA(1c), a measure of blood glucose regulation, reflects glucose levels in the preceding months. In diabetes, HbA(1c) levels predict the risk of microvascular complications. The aim of this study was to determine whether genetic factors could influence HbA(1c) levels in normal subjects and type 1 diabetic patients. We performed a classical twin study of HbA(1c) in healthy nondiabetic female twins and 42 monozygotic (MZ) and 47 dizygotic (DZ) pairs. Interclass correlations (r) were higher in MZ (r = 0.77) compared with DZ (r = 0.53) twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62% (95% CI 47-75) of population variance in HbA(1c); the remainder was attributable to the influence of unique environment (23% [15-36]) and age (14% [5-28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA(1c) heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA(1c) levels were correlated in 33 MZ twins concordant for diabetes (r = 0.68; P < 0.001) but also in 45 MZ twins discordant for the disease (r = 0.52; P < 0.001). These significant correlations for HbA(1c) in both concordant and discordant pairs indicate a diabetes-independent familial effect. Thus, HbA(1c) levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA(1c) levels.

Adult↗
PubMed2001

Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins.

Twin studies of dementia have typically used relatively simple 2 x 2 contingency tables with one threshold to estimate the relative importance of genetic variance for liability to disease. These designs are inadequate for addressing issues of age at onset, censoring of data, and distinguishing shared environmental effects from age effects. Meyer and Breitner [1998: Am J Med Genet 81:92-97] applied a multiple-threshold model to the NAS-NRC Twin Panel (average age of onset, 63.5 years) and report that additive genetic effects and shared environmental effects account for 37% and 35% of the variation, respectively, in age of onset for Alzheimer disease. We apply a modified version of their model to the Study of Dementia in Swedish Twins (average age of onset, 75 years) and find that genetic effects account for 57%-78% of the variance, whereas shared environmental effects are of no importance. Heritability is lower when thresholds are freely estimated rather than fixed to the population prevalences. We interpret the findings to suggest that models with free thresholds confound influences on longevity with influences for the disease. Multiple-threshold models, however, do not confound age effects with shared environmental influences.

Age of Onset↗
PubMed2001

Optimal sibship selection for genotyping in quantitative trait locus linkage analysis.

In this paper we present a novel method for selecting optimally informative sibships of any size for quantitative trait locus (QTL) linkage analysis. The method allocates a quantitative index of potential informativeness to each sibship on the basis of observed trait scores and an assumed true QTL model. Any sample of phenotypically screened sibships can therefore be easily rank-ordered for selective genotyping. The quantitative index is the sibship's expected contribution to the non-centrality parameter. This expectation represents the weighted sum of chi(2) test statistics that would be obtained given the observed trait values over all possible sibship genotypic configurations; each configuration is weighted by the likelihood of it occurring given the assumed true genetic model. The properties of this procedure are explored in relation to the accuracy of the assumed true genetic model and sibship size. In comparison to previous methods of selecting phenotypically extreme sibships for genotyping, the proposed method is considerably more efficient and is robust with regard to the specification of the genetic model.

Chromosome Mapping↗
PubMed1989

Linkage studies on NIDDM and the insulin and insulin-receptor genes.

Twenty Black families in which at least two siblings had non-insulin-dependent diabetes mellitus (NIDDM) were typed for restriction-fragment-length polymorphisms at the insulin (INS), insulin-receptor (INSR), and HLA-DR beta loci. Evidence for linkage between NIDDM and these loci was assessed with various genetic models for the transmission of NIDDM and with the affected-sib-pair approach, which does not require assumptions concerning a genetic model for NIDDM. Tight linkage between NIDDM and any of the loci was unlikely under all of the genetic models examined. Similarly, for all three of the loci, the distribution of affected sib pairs sharing 2, 1, or 0 genes identical by descent was not significantly different from (and was very similar to) that expected if the locus were unrelated to disease susceptibility. There was no evidence for linkage heterogeneity for any of the loci when families were grouped according to obesity or age at onset or when considering families individually. We conclude that the INS and INSR loci can be ruled out as major susceptibility loci for NIDDM in most Black families segregating this disorder, but we recognize that defects at either of these loci may cause or contribute to NIDDM in some patients. In addition, it is possible that variation at the INS and/or INSR loci may contribute to NIDDM susceptibility by modifying susceptibility due primarily to another major gene(s) or as part of an overall polygenic component to NIDDM.

Black People↗