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PubMedDate not supplied

Continuing education for nurses that incorporates genetics.

BACKGROUND: The discoveries of the Human Genome Project are bringing new knowledge of genetics to health and illness arenas. The nursing profession will need to incorporate these new advances into clinical practice, research, and education. METHOD: A survey of 68 nursing specialty organizations was conducted to determine current and future offerings in genetics to members. RESULTS: Responses from 43 organizations' top administrators who are influential in decisions regarding continuing education offerings revealed that 30% were planning to offer content in genetics in future programming. In contrast, none of the respondents had plans to present consumer perspectives of genetic illnesses. CONCLUSION: The results of this survey alert leaders in continuing education to the urgent need for dissemination of genetic advances to inform nurses in basic and advanced roles in health care delivery.

American Nurses' Association↗
PubMed2001

Phenotypic variations of orpk mutation and chromosomal localization of modifiers influencing kidney phenotype.

The Oak Ridge polycystic kidney (orpk) mutant mouse model resulted from a transgene insertion into the Tg737 gene and exhibits a pleiotropic syndrome with lesions in the kidney, liver, and pancreas. We found marked differences in the phenotypic expression of the orpk mutation when bred on different genetic backgrounds. In the FVB/N background, the phenotype is very severe for kidney, pancreas, and liver lesions. To evaluate better how genetic background might influence the expressivity of the orpk phenotype, we bred the transgene into the C3HeB/FeJLe (C3H) genetic background. We performed a genome-wide scan using backcross and intercross populations with more than 150 markers to map the chromosomal location of the modifier genes that differ in the FVB/N and C3H genetic backgrounds that affect the severity of kidney disease in the orpk mouse. Low-resolution interval mapping was performed using the Map Manager QTb program, with the interval explaining a significant portion of the variance being the distal end of chromosome 4.

Animals↗
PubMed1981

Gametic frequency of second chromosomes of the T-007 type in a natural population of Drosophila melanogaster in Texas.

The T-007 second chromosome, which was isolated from a natural population of Drosophila melanogaster in south Texas in 1970, is known to show, when made heterozygous in males with a standard cn bw second chromosome, a transmission frequency (k) of 0.35-much lower than the theoretically expected 0.5. Natural populations of this species in Texas contain second chromosomes that, against the standard cn bw genetic background, are associated with distorted transmission frequencies comparable to that of the T-007 chromosome. In order to explain how such chromosomes can persist in natural populations in nontrivial frequencies, it has been postulated that, although such chromosomes show reduced k values when tested under the genetic background of a laboratory stock such as cn bw, they may show, on the average, k values larger than 0.5 under natural genetic backgrounds. If this were true, the frequency of chromosomes of the T-007 type (T chromosomes) should be higher in male than in female gametes under natural genetic backgrounds. The present study was conducted to examine this possibility. The results clearly showed that the frequency of such chromosomes was much higher among male than among female gametes, and that the transmission frequency of this type of chromosome was higher than 0.5 under natural genetic backgrounds. These results suggest that T chromosomes behave like Segregation Distorter (SD) chromosomes in natural populations of this species in Texas. A possible relationship between T-007 and SD chromosomes is suggested.

Animals↗
PubMed2005

Drosophila soluble guanylyl cyclase mutants exhibit increased foraging locomotion: behavioral and genomic investigations.

Genetic variation in the gene foraging (for) is associated with a natural behavioral dimorphism in the fruit fly, Drosophila melanogaster. Some larvae, called 'rovers', have increased foraging locomotion compared to others, called 'sitters', and this difference is directly related to for-encoded cGMP-dependent protein kinase (PKG) activity. Here we report that larvae with mutations in the gene dgcalpha1, which encodes a soluble guanylyl cyclase (sGC) subunit, have increases in both PKG activity and foraging locomotion. This is contrary to our original prediction that, based on the role of sGC in the synthesis of cGMP, dgcalpha1 mutant larvae would have deficient cGMP production leading to decreased PKG activation and thus reduced larval foraging locomotion. We performed DNA microarray analyses to compare transcriptional changes induced by a dgcalpha1 mutation in both rover and sitter wildtype genetic backgrounds. In either background, we identified many genes that are differentially transcribed, and interestingly, relatively few are affected in both backgrounds. Furthermore, several of these commonly affected genes are enhanced or suppressed in a background-dependent manner. Thus, genetic background has a critical influence on the molecular effects of this mutation. These findings will support future investigations of Drosophila foraging behavior.

Animals↗
PubMed2005

Interleukin-10 haplotype associated with total serum IgE in atopic dermatitis patients.

BACKGROUND: The genetic background of atopic dermatitis (AD) is not clearly understood. Interleukin (IL)-10 is a powerful Th-2 cell cytokine produced by lymphoid cells that exerts its function by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines [IL-1, tumour necrosis factor-alpha (TNFA), IL-6, IL-8 and IL-12]. OBJECTIVE: In an effort to discover additional polymorphism(s) in genes whose variant(s) have been implicated in total immunoglobulin E (IgE) level in AD patients, we scrutinized the single nucleotide polymorphisms (SNPs) in the IL10 gene as a potent candidate for contributing to the level of IgE in serum. METHODS: We recruited 334 AD patients and assayed their serum total IgE levels using the LIPA-200 system. Four SNPs in the IL10 gene were genotyped using the single-base extension (SBE) method. Logistic regression analyses were performed with single polymorphisms and haplotypes (ht) to determine their association with the level of serum total IgE. RESULTS: Genetic association analysis of total serum IgE in AD patients revealed that one of the IL10 ht, IL10-ht2, was associated with decreased serum total IgE in gene dose-dependent manner (P = 0.02-0.001). CONCLUSIONS: It was predicted that the inhibition of innate immunity by increased IL-10 production in IL10-ht2-bearing individuals might be associated with decreased total serum IgE levels among AD patients. The greater effects of IL10 ht on decreased total serum IgE levels suggest that the effect of IL-10 polymorphism might be the result of a combined genotype (ht) rather than single polymorphisms.

Adolescent↗
PubMed2003

A tumor necrosis factor gene polymorphism influences the inflammatory response after cardiac operation.

BACKGROUND: The genetic background may influence cytokine release evoked by cardiac operation. Thus we determined the allele frequency and genotype distribution of a bi-allelic tumor necrosis factor (TNF) gene polymorphism and TNF-alpha concentrations in patients undergoing cardiac operations with and without cardiopulmonary bypass (CPB). METHODS: The TNF NcoI gene polymorphism was identified by polymerase chain reaction followed by restriction analysis of the polymerase chain reaction product. Reading the size of the resulting DNA bands from the agarose gel defined the genotype as homozygous or heterozygous for the two alleles TNFB1 and TNFB2. Blood samples to determine TNF-alpha plasma levels were drawn from the patients before induction of general anesthesia after termination of CPB or after finishing coronary revascularization on the beating heart in non-CPB patients and 12 hours postoperatively. RESULTS: The genotype distribution and allele frequencies in 47 patients undergoing cardiac operation with CPB were comparable with those found in 36 patients undergoing cardiac operation without CPB. The TNF-alpha plasma levels over time were comparable in patients with and without CPB. However, patients homozygous for the TNF-B2 allele had significantly higher TNF-alpha plasma levels after termination of the CPB (40.2 +/- 3.5 pg/mL; mean +/- standard error of the mean; n = 28) compared with non-CPB patients (29.8 +/- 2.5 pg/mL; mean +/- standard error of the mean; n = 15) (p < 0.05). CONCLUSIONS: Patients homozygous for the TNF-B2 allele showed significantly higher TNF-alpha plasma levels after termination of CPB compared with non-CPB patients. Therefore preoperative TNF genotyping may be useful as patients with genetically determined increased proinflammatory cytokine expression with multiple comorbidities may in particular benefit from avoiding the use of CPB.

Adult↗
PubMed2005

No MSH6 germline mutations in breast cancer families with colorectal and/or endometrial cancer.

BACKGROUND: The genetic background in breast cancer families with colorectal and/or endometrial cancer is mostly unknown. The functional connection between MSH6 and the known breast cancer predisposition gene product BRCA1 suggests that the MSH6 gene may also play a role in breast cancer predisposition. METHODS: We analysed 38 breast cancer families with colorectal and/or endometrial cancer for germline mutations in MSH6. RESULTS: No disease associated mutations were detected among the breast cancer families. However, mutation analysis revealed a Glu995STOP mutation in an atypical HNPCC family. The same mutation was found in a patient with both breast and colorectal carcinoma in our previous study, and haplotype analysis confirmed a common ancestral origin. The Glu995STOP mutation was further examined in an extensive series of 245 colorectal and 142 breast carcinoma patients with a family history of breast, colorectal, and/or endometrial carcinoma, and in 268 healthy population controls, but none was found to carry the mutation. CONCLUSIONS: Our results suggest that MSH6 may not be the underlying gene in breast cancer families with a history of colorectal and/or endometrial cancer. The Glu995STOP founder mutation is not a familial breast cancer predisposition allele and makes only a limited contribution to colorectal cancer burden in Finland.

Breast Neoplasms↗
PubMed2024

Co-expression in tissue-specific gene networks links genes in cancer-susceptibility loci to known somatic driver genes.

BACKGROUND: The genetic background of cancer remains complex and challenging to integrate. Many somatic mutations within genes are known to cause and drive cancer, while genome-wide association studies (GWAS) of cancer have revealed many germline risk factors associated with cancer. However, the overlap between known somatic driver genes and positional candidate genes from GWAS loci is surprisingly small. We hypothesised that genes from multiple independent cancer GWAS loci should show tissue-specific co-regulation patterns that converge on cancer-specific driver genes. RESULTS: We studied recent well-powered GWAS of breast, prostate, colorectal and skin cancer by estimating co-expression between genes and subsequently prioritising genes that show significant co-expression with genes mapping within susceptibility loci from cancer GWAS. We observed that the prioritised genes were strongly enriched for cancer drivers defined by COSMIC, IntOGen and Dietlein et al. The enrichment of known cancer driver genes was most significant when using co-expression networks derived from non-cancer samples of the relevant tissue of origin. CONCLUSION: We show how genes within risk loci identified by cancer GWAS can be linked to known cancer driver genes through tissue-specific co-expression networks. This provides an important explanation for why seemingly unrelated sets of genes that harbour either germline risk factors or somatic mutations can eventually cause the same type of disease.

Humans↗
PubMedDate not supplied

Identification and reciprocal introgression of a QTL affecting body mass in mice.

The aim of this study was to examine the effects of a QTL in different genetic backgrounds. A QTL affecting body mass on chromosome 6 was identified in an F(2) cross between two lines of mice that have been divergently selected for this trait. The effect of the QTL on mass increased between 6 and 10 weeks of age and was not sex-specific. Body composition analysis showed effects on fat-free dry body mass and fat mass. To examine the effect of this QTL in different genetic backgrounds, the high body mass sixth chromosome was introgressed into the low body mass genetic background and vice versa by repeated marker-assisted backcrossing. After three generations of backcrossing, new F(2) populations were established within each of the introgression lines by crossing individuals that were heterozygous across the sixth chromosome. The estimated additive effect of the QTL on 10-week body mass was similar in both genetic backgrounds and in the original F(2) population (i.e., approximately 0.4 phenotypic standard deviations); no evidence of epistatic interaction with the genetic background was found. The 95% confidence interval for the location of the QTL was refined to a region of approximately 7 cM between D6Mit268 and D6Mit123.

Animals↗
PubMed2003

Functional roles of the neuropeptide PACAP in brain and pancreas.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide implicated in a broad variety of physiological processes. To assess PACAP's function in vivo, we recently generated PACAP knockout mice (PACAP(-/-)) and transgenic mice overexpressing PACAP specifically in the pancreas (PACAP-Tg). In PACAP(-/-) mice, we have demonstrated a marked phenotypic changes including a high early mortality rate, increased novelty-seeking behavior and abnormal explosive jumping in a novel environment, as well as reduced female fertility. In this paper, we reevaluated these phenotypes in terms of the genetic background of the mice. Genetic background appears to modulate critically the magnitude but not the general nature of the PACAP-null phenotype. In PACAP-Tg mice, we have recently demonstrated that enhanced glucose-induced insulin secretion with normal glucose tolerance, amelioration of streptozotocin-induced diabetes with increased beta-cell proliferation, and a trend towards an increase in total islet mass with age. Here we show that PACAP(-/-) mice exhibit significantly impaired glucose-induced insulin secretion but still have normal glucose tolerance. These observations suggest that PACAP may play important roles in and beyond the regulation of insulin release. Taken together, the mutant phenotypes revealed both expected and unexpected roles of PACAP in the brain and pancreatic functions.

Animals↗
PubMed2005

Genetic susceptibility to infectious diseases.

The clinical outcome of infectious disease (ID) is determined by a complex interaction between microorganism, host genetic factors and environment. Epidemiological studies have revealed differences within and between populations exposed to the same infectious agent, and in the prevalence or severity of the disease, underlying the relevance of the genetic background. Population genetic studies have estimated the genetic component (susceptibility) in the ID determination and have identified some susceptibility gene(s)/polymorphism(s). This paper describes the methods used in genetic epidemiology. Complex segregation analysis is used to define genetic models. Parametric linkage analysis and association studies are used to identify polymorphisms strongly linked to the disease. Genome-wide scan and microarray technology are used to map and identify major genes for ID. Future developments will identify subgroups of subjects at different risks of developing ID.

Communicable Diseases↗
PubMed1999

LDL receptor mutations and ApoB mutations are not risk factors for ischemic cerebrovascular disease of the young, but lipids and lipoproteins are.

BACKGROUND: The genetic background for ischemic cerebrovascular disease of the young and the role of lipids and lipoproteins as risk factors are not clear. METHODS: We determined five LDL receptor mutations (Trp23Stop, Trp66Gly, Trp556Ser, 313+1G --> A, 1846-1G --> A) and three apolipoprotein B mutations (Arg3500Gln, Arg3500Trp, Arg3531Cys), and other risk factors for ischemic cerebrovascular disease in 80 patients (36 women, 44 men) with onset of disease before the age of 50 years compared with 3366 individuals from a general population sample within the same age range. RESULTS: None of the patients were carriers of mutations in the LDL receptor (Trp23Stop, Trp66Gly, Trp556Ser, 313+1G --> A, 1846 - 1G --> A) or the apolipoprotein B gene (Arg3500Gln, Arg3500Trp, Arg3531Cys) associated with hypercholesterolemia. However, on univariate analysis as well as on logistic regression analysis allowing for age and gender, plasma cholesterol (OR 1.4; P < 0.0005), HDL-cholesterol (OR 0.4; P < 0.005), diabetes (OR 5.8; P < 0.0001), and hypertension (OR 3.9; P < 0.001) were significant predictors of ischemic cerebrovascular disease. CONCLUSIONS: The five most common LDL receptor mutations in Danish patients with familial hypercholesterolemia and three mutations in the apolipoprotein B gene did not predispose to ischemic cerebrovascular disease of the young. However, cholesterol and HDL-cholesterol are important risk factors for ischemic cerebrovascular disease of the young in the present study. The elevation in cholesterol could in some patients be due to rare LDL receptor mutations not tested for, and could in other patients be multifactorial in origin.

Adult↗
PubMed2003

Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen.

The prevalence of MRSA in the nosocomial setting has been well studied, and its control remains a challenge for infection control professionals. Complicating this problem is the increasing number of reports on the spread of community-acquired MRSA (CA-MRSA). CA-MRSA strains differ from hospital-acquired MRSA (HA-MRSA) strains in that they are generally susceptible to most antibiotics. These strains share the presence of staphylococcal cassette chromosome mec (SCCmec) type IV in their genomes, are frequently virulent, and predominantly cause skin and soft tissue infections. The genome sequence of the prototypic CA-MRSA strain, MW2, revealed the presence of additional virulence factors not commonly present in other S. aureus strains. We determined the genetic relatedness of 30 geographically diverse CA-MRSA isolates clustered based on SCCmec type IV by sequence analysis of the polymorphic repeat region of the protein A gene (spa typing). These results indicated that most strains shared a common spa type (131), identical to MW2. Because this group tends to infect healthy individuals with no known risk factors for nosocomial acquisition of MRSA, we refer to it as CA-MRSA without risk factors. A second group, CA-MRSA with risk factors, consists of two related genotypes, spa types 1 and 7, which differ by one nucleotide change. These strains have caused severe infections in HIV-positive patients in Los Angeles and New York. Although CA-MRSA strains share genetic determinants, they are not clonal but rather are derived from different genetic backgrounds. The genetic characteristics and the epidemiology of CA-MRSA with and without risk factors are discussed.

Communicable Diseases, Emerging↗
PubMed1975

Gerontological data of C57BL/6J mice. I. Sex differences in survival curves.

A group of 1,052 C57BL/6J mice (296 males and 756 females) was kept under well-defined, clean laboratory conditions from the age of 6 weeks until natural death. The survival curves of males and females (computer-produced 3, 4, and 5 parameter curves, Gompertz curve histogram) were established and shown to follow a logistic function. The average life-span amounted to 878 plus or minus 10 days for males and 794 plus or minus 6 days for females. These values distinctly exceed comparable values given in the literature. They are attributed to favorable conditions of animal care and to supposed alterations in genetic background. A genetic drift in sex-dependent mean survival time occurred in the genetically unstable C57BL/6J strain between 1966 and 1970. Before this drift, the males died sooner; after it, they lived longer.

Animal Feed↗
PubMed2003

Strain differences in the development of hypertension and glomerular lesions induced by deoxycorticosterone acetate salt in mice.

BACKGROUND: The genetic background may exert important modifying effects on the course and severity of experimental kidney diseases in mice. We investigated its influence on the development of hypertension and renal injury following treatment with deoxycorticosterone acetate (DOCA) salt in several mouse strains. METHODS: Four mouse strains were used for comparison: 129/Sv, C57BL/6 and F1 and F2 intercrosses of 129/Sv x C57BL/6. Male mice were uninephrectomized and DOCA hypertension was induced for 6 weeks. DOCA animals and controls received 1% NaCl for drinking. Renal damage was evaluated following measurements of blood pressure, urine albumin and renal matrix expansion. RESULTS: DOCA-induced blood pressure increase, glomerulosclerosis, interstitial fibrosis and albuminuria were markedly higher in 129/Sv than in C57BL/6 mice. F1 and F2 intercrosses displayed intermediate blood pressure, glomerular and interstitial fibrosis comparable to C57BL/6 but albuminuria as high as 129/Sv mice. CONCLUSIONS: 129/Sv mice are more susceptible to the development of DOCA-induced high blood pressure and renal damage than C57BL/6 mice. Intercrosses of both strains show a complex and non-uniform segregation of the susceptibility to DOCA-salt hypertension and nephrosclerosis.

Analysis of Variance↗
PubMed2006

The psychological impact of genetic testing on parents.

AIM AND OBJECTIVES: The aim of this descriptive study was to explore the psychological impact of genetic testing on parents whose children have been referred for genetic testing. BACKGROUND: Genetic tests enable individuals to be informed about their health status and to have the opportunity of early diagnosis and treatment of their diseases. However undergoing genetic testing and receiving a positive test result may also cause stress and anxiety. STUDY DESIGN AND METHOD: This descriptive study was carried out at the genetic departments of two university hospitals in Ankara. The sample of this study consisted of 128 individuals whose children have been referred for chromosomal analysis. Data were collected through using a semi-structured interview method with a data collection form and the anxiety inventory and analysed using the percentages and independent samples t-test. RESULTS: The majority of our participants experienced distress before genetic testing. Their general trait anxiety score before receiving the test results was 47.38, and following the test results the state anxiety score was 50.65. Having a previous child with an abnormality, a positive test result, and being a mother elevated the anxiety of individuals. CONCLUSION: This paper supports the findings of previous studies, which indicated that genetic test results might lead to anxiety in individuals and reveals the importance of genetic counselling. RELEVANCE TO CLINICAL PRACTICE: As the results of this study indicated, genetic testing causes distress and anxiety in individuals. Nurses can play an important role in minimizing anxiety of parents whose children undergo genetic testing by providing information about genetic testing and by taking part in the counselling process.

Adult↗
PubMedDate not supplied

Murine models of renal disease: possibilities and problems in studies using mutant mice.

The elucidation of the pathogenesis of human renal disease at the molecular level has been facilitated by the growing field of gene targeting and the development of mouse strains with single-gene deletions - the 'knock-out' mice. Experimental nephrology, therefore, requires well-characterized and reliable models of human renal disease that can be induced reproducibly in mice. Today surgical procedures for the induction of renal ischemia, chronic renal failure, and ureter obstruction are feasible in mice. Models of mesangioproliferative or crescentic glomerulonephritis, glomerulosclerosis, and tubulointerstitial disease are readily available; however, these depend heavily on the mouse genetic background. Attention to the genetic background and appropriate backcrossing are, therefore, of great importance in the design and interpretation of experimental studies, especially in transgenic mice. Simple murine models displaying the clinical features of other human renal diseases such as IgA nephropathy, membranous glomerulonephritis, and renal vasculitis are still lacking. Mouse strains that spontaneously develop distinct renal pathologies similar to lupus nephritis and focal-segmental glomerulosclerosis can be intercrossed with transgenic mice to study the impact of single-gene deletions on the renal phenotype. The present review provides a survey about currently available spontaneous and inducible murine models of renal disease with special attention to problems and future perspectives for their use in transgenic animals.

Acute Kidney Injury↗
PubMed1999

Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women.

Background-The genetic background of hereditary hemochromatosis (HH) is homozygosity for a cysteine-to-tyrosine transition at position 282 in the HFE gene. Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death. Methods and Results-We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182 976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3. 5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3. 3%, 8.8%, and 4.0%, respectively. In addition, we found evidence for effect modification by hypertension and smoking. Conclusions-We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors.

Aged↗