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Impact of physiological variables and genetic background on myocardial frequency-resistivity relations in the intact beating murine heart.
Conductance measurements for generation of an instantaneous left ventricular (LV) volume signal in the mouse are limited, because the volume signal is a combination of blood and LV muscle, and only the blood signal is desired. We have developed a conductance system that operates at two simultaneous frequencies to identify and remove the myocardial contribution to the instantaneous volume signal. This system is based on the observation that myocardial resistivity varies with frequency, whereas blood resistivity does not. For calculation of LV blood volume with the dual-frequency conductance system in mice, in vivo murine myocardial resistivity was measured and combined with an analytic approach. The goals of the present study were to identify and minimize the sources of error in the measurement of myocardial resistivity to enhance the accuracy of the dual-frequency conductance system. We extended these findings to a gene-altered mouse model to determine the impact of measured myocardial resistivity on the calculation of LV pressure-volume relations. We examined the impact of temperature, timing of the measurement during the cardiac cycle, breeding strain, anisotropy, and intrameasurement and interanimal variability on the measurement of intact murine myocardial resistivity. Applying this knowledge to diabetic and nondiabetic 11- and 20- to 24-wk-old mice, we demonstrated differences in myocardial resistivity at low frequencies, enhancement of LV systolic function at 11 wk and LV dilation at 20-24 wk, and histological and electron-microscopic studies demonstrating greater glycogen deposition in the diabetic mice. This study demonstrated the accurate technique of measuring myocardial resistivity and its impact on the determination of LV pressure-volume relations in gene-altered mice.
Genetic background: patients.
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Effects of age and genetic background on the antibody response in inbred rats.
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The genetic background of developmental language disorders.
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Effects of dietary sodium and genetic background on angiotensinogen and Renin in mouse.
Elements of a renin-angiotensin system expressed along the entire nephron, including angiotensinogen secreted by proximal tubule and renin expressed in connecting tubule, may participate in the regulation of sodium reabsorption at multiple sites of the nephron. The response of this tubular renin-angiotensin system to stepwise changes in dietary sodium was investigated in 2 mouse strains, the sodium-sensitive inbred C57BL/6 and the sodium-resistant CD1 outbred. Plasma angiotensinogen was not affected by sodium regimen, whereas plasma renin increased 2-fold under low sodium. In both strains, the variation in urinary parameters did not parallel the changes observed in plasma. Angiotensinogen and renin excretion were significantly higher under high sodium than under low sodium. Water deprivation, by contrast, induced significant activation in the tubular expression of angiotensinogen and renin. C57BL/6 exhibited significantly higher urinary excretion of angiotensinogen than did CD1 animals under both conditions of sodium intake. The extent to which these urinary parameters reflect systemic or tubular responses to challenges of sodium homeostasis may depend on the relative contribution of sodium restriction and volume depletion.
Previous cardiac abnormalities in subarachnoid hemorrhage may also have background genetic polymorphisms.
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Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings.
To investigate the impact of chloride (Cl(-)) permeability, mediated by residual activity of the cystic fibrosis transmembrane conductance regulator (CFTR) or by other Cl(-) channels, on the manifestations of cystic fibrosis (CF), we determined Cl(-) transport properties of the respiratory and intestinal tracts in Delta F508 homozygous twins and siblings. In the majority of patients, cAMP and/or Ca(2+)-regulated Cl(-) conductance was detected in the airways and intestine. Our finding of cAMP-mediated Cl(-) conductance suggests that, in vivo, at least some Delta F508 CFTR can reach the plasma membrane and affect Cl(-) permeability. In respiratory tissue, the expression of basal CFTR-mediated Cl(-) conductance, demonstrated by 30% of Delta F508 homozygotes, was identified as a positive predictor of milder CF disease. In intestinal tissue, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive (DIDS-insensitive) Cl(-) secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive Cl(-) secretion was observed mainly in more severely affected patients. The more concordant Cl(-) secretory patterns within monozygous twins compared with dizygous pairs imply that genes other than CFTR significantly influence the manifestation of the basic defect.
Chromosome 2 reciprocal congenic strains to evaluate the effect of the genetic background on blood pressure.
The localisation of quantitative trait loci (QTL) is the first step towards gene identification. This is then verified by the construction of reciprocal congenic strains. The hypertensive SHRSP and normotensive WKY strains were used in a speed congenic approach to confirm the existence of a QTL on rat chromosome 2. Systolic baseline and salt loaded blood pressures were measured by radiotelemetry. Transfer of the chromosome 2 blood pressure QTL region from WKY into an SHRSP background significantly reduced blood pressure, with the increased significance at the salt loaded period, compared to the SHRSP. The reciprocal congenic blood pressure showed a significantly increased baseline systolic pressure compared to the WKY, with no change in significance at the salt loaded period. Thus we have successfully captured a gene(s) which contribute to blood pressure regulation in both congenic strains. This will facilitate further positional cloning of the causative genes first in this model and then in human essential hypertension.
Establishing insulin 1 and insulin 2 knockout congenic strains on NOD genetic background.
As insulin is a major autoantigen in autoimmune diabetes and because the insulin gene region locus in humans has been linked to diabetes risk, we have bred insulin gene knockouts onto the NOD mouse. Mice differ from humans in terms that they express two nonallelic genes of insulin. Insulin 2 is the murine homologue of the human insulin gene and is located on mouse chromosome 7. Insulin 1 is thought to have evolved by a gene duplication event, lacks the second intron of the insulin 2 gene, and is located on mouse chromosome 19. The differential thymic expression of the insulin gene may be important for central tolerance induction. Here, we present the initial establishment of congenic knockouts and characterization of the congenic intervals corresponding to insulin 1 and insulin 2 knockout genes on mouse chromosome 19 and 7, respectively.
The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia.
Steroid sulfurylation represents a potential mechanism for controlling the level of active steroids within a tissue. We have elucidated an inbred strain background-dependent interaction between the diabetes (db) mutation and steroid sulfotransferase (ST) enzymes, potentially modulating the level of active steroid hormones or their precursors in the liver. Gonadectomized mutants were analyzed to correlate how strain- and gender-dependent variation in ST activities interacted with db to achieve diabetogenesis. Both sexes on the C57BL/KsChp (BKs) background developed severe early-onset hyperglycemia, and gonadectomy failed to prevent diabetes. In contrast, C3HeB/FeChp (C3HeB)-db/db males, but not females, were diabetes susceptible, and the male susceptibility was completely dependent upon endogenous testes-derived testosterone. The female resistance, in turn, was dependent upon ovarian sex steroids. The differential requirements of BKs- and C3HeB-db/db males and females for gonadal sex steroids could be explained on the basis of the differential strength of the interaction between the db mutation and hepatic ST activities. Hepatic ST from normal adult females sulfurylated dehydroepiandrosterone (DHEA), whereas this activity disappeared in cytosols of normal adult males by 8 weeks of age. This sexually dimorphic inability to sulfurylate (pre)androgens was controlled by testosterone. Diabetogenic susceptibility in BKs mutant mice of both sexes was associated with marked depression of preandrogen/androgen sulfurylation [female mutants exhibiting at least a 5-fold reduced DHEA sulfurylation at a near-physiological concentration (0.2 microM)]. This reduced preandrogen/androgen sulfurylation occurred concomitant with a 10-fold acceleration of estrone (E1) sulfurylation at a limiting (0.2 microM) concentration, essentially producing a hyperandrogenized hepatic tissue state. These extreme shifts in ST substrate preferences were not observed in the diabetes-resistant C3HeB-db/db females. Kinetic analysis of semipurified hepatic ST from BKs-db/db females showed a 10-fold decrease in Km for E1 (apparent Km = 0.9 microM in mutants vs. 9.0 microM in normals). Whereas the Km for DHEA did not differ from the control value, hepatic ST from BKs-db/db females showed a 10-fold decreased maximal velocity for DHEA sulfurylation (1230 vs. 12750 pmol/mg.h in control preparations). The antihyperglycemic effects of dietary E1 therapy were associated with enhanced androgen sulfurylation in BKs-db/db females and restoration of androgen sulfurylation in BKs-db/db males.(ABSTRACT TRUNCATED AT 400 WORDS)
WKY/Ztm-ter: a new rat inbred strain on the WKY/Ztm genetic background with congenital teratomas.
We describe a new rat model for teratomas (WKY/Ztm-ter) which arose through a spontaneous mutation in the inbred WKY/Ztm rat strain. When the tumours of the gonads became clinically apparent, affected males were 14 to 224 days of age, whereas the females only developed tumours between days 21 and 63. Tumour incidence is not gender-dependent. However, almost all females develop bilateral tumours, while 50% of the males show unilateral tumours. Histologically, all examined tumours (n = 65) represent partially undifferentiated teratocarcinomas.
Familial hypercholesterolemia and response to statin therapy according to LDLR genetic background.
Familial hypercholesterolemia is an autosomal dominant disease defined at the molecular level mainly by the presence of mutations in the low-density lipoprotein receptor gene and is characterized by elevated low-density lipoprotein cholesterol, tendon xanthomas and increased risk of early cardiovascular disease. The type of mutation in the low-density lipoprotein receptor gene has been associated with different phenotype expression and response to statins. Several studies have been undertaken to assess the efficacy of statins and evaluate the influence of mutations on the response to treatment with statins. Not all patients respond to statin therapy with a reduction in cardiovascular disease. In this review paper, we will discuss the results available to date that correlate the low-density lipoprotein receptor genotype to the response to statins, and the interest in developing diagnostic systems which will allow identification of patients at increased risk of adverse drug reactions or patients in which a therapeutic effect is lacking.
Effect of genetic background and activating stimulus on the timing of meiotic cell cycle progression in parthenogenetically activated mouse oocytes.
With the aim of investigating the effects of oocyte genotype and activating stimulus on the timing of nuclear events after activation, oocytes collected from hybrid B6D2F1, inbred C57BL/6 and outbred CF-1 and immunodeficient nude (NU/+) females were activated using ethanol or strontium and fixed at various time-points. Meiotic status, spindle rotation and second polar body (PB2) extrusion were monitored by fluorescence microscopy using DNA-, microtubule- and microfilament-selective probes. Although activation efficiency was similar in all groups of oocytes, a significant percentage of CF-1 and NU/+ oocytes treated with ethanol and of C57BL/6 oocytes treated either with ethanol or strontium failed to complete activation and became arrested at a new metaphase stage (MIII) after PB2 extrusion. C57BL/6 oocytes also showed slower release from MII arrest but faster progression to telophase (TII) after ethanol exposure, and they exhibited the most rapid exit from TII under both activation treatments. Strontium caused delayed meiotic resumption, spindle rotation and PB2 extrusion, but rapid TII exit, in B6D2F1, CF-1 and NU/+ oocytes when compared with ethanol. Compared with all other strains, NU/+ oocytes were significantly slower in completing spindle rotation and PB2 extrusion, irrespective of the activating stimulus, and a significant decrease in activation rates and pace of meiotic progression was observed after strontium exposure. Thus, our findings demonstrated that the kinetics of meiosis resumption and completion, spindle rotation and PB2 extrusion following parthenogenetic activation depends on both genotype-specific factors and on the activation treatment applied.
Absence of insulitis and overt diabetes in athymic nude mice with NOD genetic background.
NOD mice spontaneously develop diabetic syndrome similar to that of insulin-dependent diabetes mellitus in man. Insulitis, i.e., lymphocytic infiltration into the pancreatic islets is the etiologic pathological lesion in the development of diabetes mellitus in NOD mice. In the present study, we examined the role of the T cell in the development of insulitis and overt diabetes in NOD mice using NOD athymic and euthymic congenic mice. None of the NOD athymic mice developed insulitis at 9 weeks of age or overt diabetes up to 30 weeks of age. In contrast, NOD euthymic littermates showed almost the same incidences of insulitis and overt diabetes as those of NOD mice. These observations suggest that T cells are essential for the development of insulitis and overt diabetes in NOD mice.
The genetic background of circadian and ultradian rhythm patterns of 17-hydroxycorticosteroids: a cross-twin study.
Circadian and ultradian rhythms in urinary excretion of 17-hydroxycorticosteroids were documented individually during an 8-day span in two pairs of young male twins. Studies were performed once at the age of 6 years for dizygotic twins and twice at the ages of 4.3 and 10.3 years for monozygotic twins. Four different methods were used for time-series analyses: chronograms (raw data), best-fitting curves resulting from cosinor analyses, power spectra and correlations of time-qualified data. Estimates of rhythm parameters (prominent periods, acrophases, etc.) as well as shapes of curves were closer in mono- than in dizygotic twins. Both similarities and small differences in rhythm characteristics of monozygotic twins were detected at both ages considered.
The influence of genetic background on the expression of mutations at the diabetes locus in the mouse IV. Male lethal syndrome in CBA/Lt mice.
To assess whether db-induced pathogenetic changes in beta-cells were restricted to mice with H-2d haplotype, the db gene from BL/Ks was transferred into the CBA/Lt subline (H-2k). A marked sexual dimorphism was observed in the diabetes syndrome in db/db animals. Young adult db/db males exhibited an early onset and completely lethal diabetes (100% mortality by 6 mo). At 3 mo db/db males were moderately obese (43 +/- 4 g) but severely hyperglycemic (475 +/- 69 mg/dl blood glucose) and hyperglucagonemic. Islets were atrophic, showing variable leukocytic infiltration. Although hyperinsulinemic at 2 mo, mutant males had only normal or below normal plasma insulin at 4 mo. Electron microscopic examination confirmed beta-cell necrosis and the appearance, in prenecrotic beta-cells, of numerous intracisternal type A (retrovirus) particles (IAP). In contrast, db/db females became increasingly obese with age but remained healthy, suffering no mortality in 6 mo. These mice were only transiently hyperglycemic and were able to sustain hyperinsulinemia. Light and electron microscopy revealed beta-cell hypertrophy that was not accompanied by increased numbers of IAP or by necrosis. Retrovirus infection therefore seemed a consequence rather than a cause of hyperglycemia. Ovariectomy coupled with testosterone injection failed to induce severe diabetes in females; castration failed to moderate male diabetes. Instead, biweekly injections of 25 micrograms each of 17 beta-estradiol and progesterone effected complete diabetes remission in males. Experiments using cultured CBA/J islet cells did not support the hypothesis that ovarian steroids were directly protective at the beta-cell level. This study shows that db gene-induced pathogenesis is not restricted to mice with the H-2d haplotype, and that sex steroids are important modifiers of syndrome severity.
Growth and muscle development of feedlot cattle of different genetic backgrounds.
The effects of crossbreeding, cattle type and dietary energy level on semitendinosus muscle (ST) development, feedlot performance, daily carcass protein and fat gain and serum anabolic hormone concentrations were studied. Over 3 consecutive years, 176 feedlot steers representing four cattle types - unselected Hereford (UH), selected Hereford (SH), Angus x Hereford x Charolais (AHC) and Angus x Hereford x Holstein (AHH) - were fed either an all-corn silage (HS) or a high grain (HG) diet. Steers were slaughtered on day 1 and at the end of the feedlot trial, and ST muscles were removed rapidly. During years 2 and 3, single blood samples were obtained from steers on days 1, 29, 57, 113 and 169, and analyzed for insulin and growth hormone (GH). Steers fed HG had a higher (P less than .005) average daily gain (ADG) than steers fed HS, and cattle type had an effect (P less than .005) on ADG. Cattle type and HG affected (P less than .005) daily carcass protein and fat gain. Weight of ST muscle and total muscle RNA, DNA and protein content increased with frame size, and HS steers had heavier (P less than .05) ST muscles than the HG steers. Steers fed HG had higher (P less than .01) serum insulin concentrations than steers fed HS, but there were no consistent cattle type effects. Serum GH concentrations were not affected by cattle type or diet. Serum insulin concentrations, combined across diet and cattle types, were correlated (P less than .01) with ADG; however, serum GH, assessed on the same basis, was not related to ADG. Average daily protein and fat gain were positively related to serum insulin and were negatively related to serum GH.