Optimizing insulin sensitivity assessment using the minimal model in chronic heart failure.

BACKGROUND: Minimal model analysis of the intravenous glucose tolerance test (IVGTT) has been used successfully to demonstrate that patients with chronic heart failure (CHF) are insulin-resistant. Continuing experience in minimal model methodology has raised questions about how best to assign basal glucose concentrations during such analyses. METHODS AND RESULTS: IVGTT data from randomly selected patients with CHF (n = 15) and controls (n = 15) were analysed using the minimal model, with the basal glucose concentration (G (b)) assigned the value of fasting plasma glucose concentration (G (fast)), or the value of plasma glucose concentration 180 minutes after the start of the IVGTT (G (180)). Insulin sensitivity (S (I)) was significantly higher with G (b) = G (fast), than with G (b) = G (180) (controls: 5.60 +/- 0.78 vs. 3.36 +/- 0.25/min/muU/ml x 10 (4), p = 0.0017; patients 4.19 +/- 0.54 vs. 2.36 +/- 0.15/min/microU/ml x 10 (4), p = 0.0004). At G (b) = G (fast), CHF patients showed a non-significant 25 % reduction in S (I) in comparison to controls (p = 0.15). In contrast, at G (b) = G (180), CHF patients showed a significant 30 % reduction of S (I) in comparison to controls (p = 0.0018). S (I) estimates derived at G (b) = G (fast) exhibited twice the variability of those estimated using G (b) = G (180) (coefficients of variation of S (I) in patients with CHF were 50.0 % and 24.8 %, respectively). CONCLUSION: In studies of patients with CHF, greater precision and discriminatory power of insulin sensitivity estimates is obtained when the basal glucose concentration is taken as the plasma glucose concentration 180 minutes after the start of the IVGTT.     

Immunoreactive luteinizing hormone, estradiol, progesterone, testosterone, and androstenedione levels during the breeding season and anestrus in Siberian tigers

Seasonal analysis of 1239 captive births of Siberian tigers (Panthera tigris altaica) indicated a peak in April to June (P less than 0.001). Studies on seven animals in Minnesota indicated that behavioral heat cycles and ovarian follicular phase cycles began in late January and ceased in early June. Behavioral observation of 12 heat cycles in four tigers yielded an estrous length of 5.3 +/- 0.2 days and an interestrous interval of 25.0 +/- 1.3 days. Hormone assays on weekly blood samples (N = 180) from three female tigers indicated 16 cycles in two breeding seasons. Peak estradiol-17 beta levels were 46.7 +/- 6.0 pg/ml (N = 17) and interestrous concentrations were 8.7 +/- 0.66 pg/ml (N = 28) during the breeding season. Anestrous estradiol levels were 4.2 +/- 0.5 pg/ml (N = 70). The interestrous interval between estradiol peaks was 24.9 +/- 1.3 days (N = 9) with two outliers of 42 days. Serum progesterone concentrations from February to June were 1.2 +/- 0.15 ng/ml (N = 32), providing no evidence for ovulation or corpus luteum formation. Luteinizing hormone (LH) levels were 0.56 +/- 0.04 ng/ml (N = 180). Serum testosterone (r=0.71, P less than 0.001) and androstenedione levels (r=0.75, P less than 0.001) were correlated with estradiol during the breeding season. The duration of anestrus was 8 mo in two of these tigers. The interval was shortened in one tiger by exposure to a 16L:8D photoperiod. The Siberian tiger appears to be a polyestrous seasonal breeder and an induced ovulator whose breeding season may be synchronized by photoperiod.     

Accounting for competition in genetic analysis, with particular emphasis on forest genetic trials

Available experimental evidence suggests that there are genetic differences in the abilities of trees to compete for resources, in addition to non-genetic differences due to micro-site variation. The use of indirect genetic effects within the framework of linear mixed model methodology has been proposed for estimating genetic parameters and responses to selection in the presence of genetic competition. In this context, an individual’s total breeding value reflects the effects of its direct breeding value on its own phenotype and its competitive breeding value on the phenotype of its neighbours. The present study used simulated data to investigate the relevance of accounting for competitive effects at the genetic and non-genetic levels in terms of the estimation of (co)variance components and selection response. Different experimental designs that resulted in different genetic relatedness levels within a neighbourhood and survival were other key issues examined. Variances estimated for additive genetic and residual effects tended to be biased under models that ignored genetic competition. Models that fitted competition at the genetic level only also resulted in biased (co)variance estimates for direct additive, competitive additive and residual effects. The ability to detect the correct model was reduced when relatedness within a neighbourhood was very low and survival decreased. Selection responses changed considerably between selecting on breeding value estimates from a model ignoring genetic competition and total breeding estimates using the correct model. Our results suggest that considering a genetic basis to competitive ability will be important to optimise selection programmes for genetic improvement of tree species.     

Genetic parameters and responses of performance and body composition traits in pigs selected for high and low growth rate on a fixed ration over a set time

Two lines of Large White pigs of common genetic origin were divergently selected over four years for high and low growth rate during a 6 week post-weaning test period in which all pigs were fed the same total amount of food (80% of estimated ad libitum intake). Genetic parameters and direct and correlated responses in performance and carcass traits were estimated on 2884 pigs with pedigrees comprising a total of 5324 animals, with restricted maximum likelihood and best linear unbiased prediction methods applied to a multi-trait animal model. Estimates of heritability (± SE) were 0.19 ± 0.04 for lifetime daily gain (LDG), 0.16 ± 0.03 for test daily gain (TDG), 0.25 ± 0.04 for ultrasound P2 backfat (UBF) and 0.16 ± 0.03 for food conversion ratio during test (TFC), and 0.15 ± 0.04 for daily carcass weight gain (CDG), 0.43 ± 0.06 for carcass backfat (CFT) and 0.40 ± 0.06 for carcass lean percentage (LEAN). Common litter effects for TDG, UBF and TFC were less than 5% and for LDG, 17% of total phenotypic variance. Genetic correlations between performance and carcass traits were moderately to highly favourable. After four years of divergent selection for growth rate, the selection responses in estimated breeding value (EBV) for TDG were 40.14 and -41.11 g (SED 2.95) for the high and low growth lines, respectively. The regressions of EBV on year of birth, indicate that the annual genetic trend for TDG, was 8.73 g/yr in the high and -8.48 g/yr in the low lines (P < 0.001). Correlated genetic responses in the high and low lines respectively were 5.28 g and -12.40 g (SED 2.09) in LDG, -0.35 mm and 0.56 mm (SED 0.009) in UBF, -0.145 units and 0.185 units (SED 0.012) in TFC, 3.17 g and -10.97 g (SED 1.53) in CDG, -1.13 mm and 1.01 mm (SED 0.155) in CFT and 1.24% and -1.27% (SED 0.150) in LEAN. It was concluded that selection for increased post-weaning daily gain on a ration of fixed amount reduces the age at slaughter and the level of backfat and increases the efficiency of food utilisation, weight and leanness of pig carcasses.     

Natural selection and inheritance of breeding time and clutch size in the collared flycatcher

Many characteristics of organisms in free-living populations appear to be under directional selection, possess additive genetic variance, and yet show no evolutionary response to selection. Avian breeding time and clutch size are often-cited examples of such characters. We report analyses of inheritance of, and selection on, these traits in a long-term study of a wild population of the collared flycatcher Ficedula albicollis. We used mixed model analysis with REML estimation ("animal models") to make full use of the information in complex multigenerational pedigrees. Heritability of laying date, but not clutch size, was lower than that estimated previously using parent-offspring regressions, although for both traits there was evidence of substantial additive genetic variance (h2 = 0.19 and 0.29, respectively). Laying date and clutch size were negatively genetically correlated (rA = -0.41 +/- 0.09), implying that selection on one of the traits would cause a correlated response in the other, but there was little evidence to suggest that evolution of either trait would be constrained by correlations with other phenotypic characters. Analysis of selection on these traits in females revealed consistent strong directional fecundity selection for earlier breeding at the level of the phenotype (beta = -0.28 +/- 0.03), but little evidence for stabilising selection on breeding time. We found no evidence that clutch size was independently under selection. Analysis of fecundity selection on breeding values for laying date, estimated from an animal model, indicated that selection acts directly on additive genetic variance underlying breeding time (beta = -0.20 +/- 0.04), but not on clutch size (beta = 0.03 +/- 0.05). In contrast, selection on laying date via adult female survival fluctuated in sign between years, and was opposite in sign for selection on phenotypes (negative) and breeding values (positive). Our data thus suggest that any evolutionary response to selection on laying date is partially constrained by underlying life-history trade-offs, and illustrate the difficulties in using purely phenotypic measures and incomplete fitness estimates to assess evolution of life-history trade-offs. We discuss some of the difficulties associated with understanding the evolution of laying date and clutch size in natural populations.     

Enhanced individual selection for selecting fast growing fish: the "PROSPER" method,with application on brown trout (Salmo trutta fario)

Growth rate is the main breeding goal of fish breeders, but individual selection has often shown poor responses in fish species. The PROSPER method was developed to overcome possible factors that may contribute to this low success, using (1) a variable base population and high number of breeders (Ne > 100), (2) selection within groups with low non-genetic effects and (3) repeated growth challenges. Using calculations, we show that individual selection within groups, with appropriate management of maternal effects, can be superior to mass selection as soon as the maternal effect ratio exceeds 0.15, when heritability is 0.25. Practically, brown trout were selected on length at the age of one year with the PROSPER method. The genetic gain was evaluated against an unselected control line. After four generations, the mean response per generation in length at one year was 6.2% of the control mean, while the mean correlated response in weight was 21.5% of the control mean per generation. At the 4th generation, selected fish also appeared to be leaner than control fish when compared at the same size, and the response on weight was maximal (≈130% of the control mean) between 386 and 470 days post fertilisation. This high response is promising, however, the key points of the method have to be investigated in more detail.     

Effects of melengestrol acetate and P.G. 600 on fertility in Rambouillet ewes outside the natural breeding season

The effects of melengestrol acetate (MGA) and P.G. 600 on ewe fertility outside the natural breeding season were evaluated. Rambouillet ewes were assigned to one of four groups: (1) control (C; n=92); (2) PG600 (n=86); (3) MGA (n=99); and (4) MGA+PG600 (n=92). A pellet with or without MGA (0.3mg/ewe/d) was fed at 0.15kg/ewe/d for 7d. On the last day of pellet feeding, ewes were given either saline or 5mL of P.G. 600 i.m. (400IU equine chorionic gonadotropin (eCG) and 200IU human chorionic gonadotropin (hCG)). Ultrasonography was performed between Days 20 and 25 of gestation for ewes that were mated during the first 6 d of the breeding period from the MGA (n=15) and MGA+PG600 (n=8) groups, and the number of luteal structures and embryos were counted. During the first 6d of the breeding period, MGA increased (P<0.05) the percentage of ewes that mated and conceived when compared to C and PG600 (24.2% vs. 3.3% and 10.5%, respectively). Relative to MGA, the mean (+/-S.E.M.) number of luteal structures per ewe was enhanced (P<0.03) in MGA+PG600 (1.53+/-0.13 vs. 2.38+/-0.42, respectively), however as pregnancy progressed, the number of embryos (1.5+/-0.13 vs. 1.8+/-0.16, respectively) and lambs born (1.3+/-0.15 vs. 1.5+/-0.27, respectively) did not differ. Treatment with MGA reduced (P<0.01) the interval from ram introduction to lambing relative to groups that did not receive MGA (168+/-0.8d vs. 171+/-0.6d, respectively). In conclusion, treatment with MGA increased the percentage of ewes conceiving early in the breeding period. Although P.G. 600 increased the number of luteal structures present per ewe, it did not significantly enhance ewe prolificacy.     

Endothelin-mediated vasoconstriction in early atherosclerosis is markedly increased in ApoE-/- mouse but prevented by atorvastatin

We have discovered that endothelin-1 (ET-1) vasoconstriction is significantly enhanced in aortas of young (8-16-week-old) apolipoprotein E-deficient (ApoE-/-) mice devoid of atherosclerotic lesions (maximum response expressed as a percentage of the mean response to 100 mM KCl (E(MAX)) = 55.7% +/- 19.5% KCl, n = 5) compared to age-matched C57BL/6/J control animals (E(MAX) = 12.6% +/- 2.5% KCl, n = 8), indicating that alterations in the endothelin system may contribute to disease progression, at least in this animal model. There was no difference in the potency of ET-1 to contract aorta from the two groups (C57BL/6/J pD2 = 8.74 +/- 0.30; ApoE-/- pD2 = 8.50 +/- 0.15, P > 0.05). This increased response was specific to ET-1, as it was not observed with phenylephrine or U46619, nor was it due to a non-receptor mediated increase in contractile sensitivity, as there was no change in response to KCl between the two groups. [125I]ET-1 bound with subnanomolar affinity (K(D)) to aorta (K(D) = 0.018 +/- 0.002 nM, n = 4) and, with an order of magnitude lower affinity, to heart (K(D) = 0.47 +/- 0.05, n = 5) of C57BL/6/J mice with binding densities (B(MAX)) of 9.3 +/- 2.4 fmol mg(-1)protein and 100 +/- 14 fmol mg(-1) protein, respectively. Alterations in vascular reactivity to ET-1 could not be explained by increased endothelin receptor density or affinity, as these were not altered in aorta (K(D) = 0.011 +/- 0.003 nM; B(MAX) = 10.1 +/- 3.9 fmol mg(-1), n = 4) and heart (K(D) = 0.43 +/- 0.04 nM; B(MAX) = 115 +/- 26 fmol mg(-1), n == 6) of ApoE-/- animals. The ratio of ET(A) to ET(B) receptors in heart of control and ApoE-/- mice was similar, comprising 89% and 85% ET(A) receptors, respectively. In isolated aorta from ApoE-/- mice on the Western diet, which more closely resembled more advanced stages of the disease in man, the augmented ET-1 vasoconstrictor response was maintained (E(MAX) = 25.2% +/- 6.8% KCl, n = 9); however, it was completely prevented in animals that had received 10 weeks of oral atorvastatin (30 mg kg(-1) day(-1)) (E(MAX) = 4.0% +/- 1.5% KCl, n = 5), a concentration that was chosen because it did not affect plasma cholesterol and triglyceride levels. Therefore, this protective prevention of enhanced ET-1 vasoconstriction in ApoE-/- mice by atorvastatin was independent of its lipid-lowering properties.     

Maturational costs of reproduction due to clutch size and ontogenetic conflict as revealed in the invisible fraction

Reproduction is thought to entail costs, but assessing survival costs associated with maturation as organisms express reproductive genes for the first time is problematic because many will die prior to expressing a phenotype. We quantified selection acting on this invisible fraction by measuring selection on predicted breeding values for clutch size estimated from a multigenerational pedigree of side-blotched lizards in which clutch size was heritable (h2=0.25+/-0.04). The survival effects of predicted breeding values for clutch size during maturation, however, differed between males and females indicating ontogenetic conflict. Increased mortality during maturation was associated with lower predicted breeding values for clutch size for females, but higher predicted breeding values for males who do not produce a clutch. Genetic correlations between clutch size and male and female survival were consistent with calculated selection differentials. Experimental yolk removal did not affect progeny survival during maturation, indicating that selection on maturing progeny was not due to confounding yolk-volume maternal effects, and hormone manipulations confirmed clutch size as the target of viability selection during maturation. Such episodes of selection prior to phenotypic expression of the trait will have important consequences for the evolution of reproductive investment.     

Role of adenosine in the hypoxia-induced hypothermia of toads

The concept that hypoxia elicits a drop in body temperature (T(b)) in a wide variety of animals is not new, but the mechanisms remain unclear. We tested the hypothesis that adenosine mediates hypoxia-induced hypothermia in toads. Measurements of selected T(b) were performed using a thermal gradient. Animals were injected (into the lymph sac or intracerebroventricularly) with aminophylline (an adenosine receptor antagonist) followed by an 11-h period of hypoxia (7% O(2)) or normoxia exposure. Control animals received saline injections. Hypoxia elicited a drop in T(b) from 24.8 +/- 0.3 to 19. 5 +/- 1.1 degrees C (P < 0.05). Systemically applied aminophylline (25 mg/kg) did not change T(b) during normoxia, indicating that adenosine does not alter normal thermoregulatory function. However, aminophylline (25 mg/kg) significantly blunted hypoxia-induced hypothermia (P < 0.05). To assess the role of central thermoregulatory mechanisms, a smaller dose of aminophylline (0.25 mg/kg), which did not alter hypoxia-induced hypothermia systemically, was injected into the fourth cerebral ventricle. Intracerebroventricular injection of aminophylline (0.25 mg/kg) caused no significant change in T(b) under normoxia, but it abolished hypoxia-induced hypothermia. The present data indicate that adenosine is a central and possibly peripheral mediator of hypoxia-induced hypothermia.     

Effects of intracerebroventricular administration of D,L-2-amino-5-phosphonovaleric acid, an N-methyl-D-aspartate receptor antagonist, on luteininizing hormone release in ovariectomized lambs.

To determine whether endogenous glutamate and aspartate control LH secretion via N-methyl-D-aspartate (NMDA) receptors in the sheep, we evaluated the effects of the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (AP5) on secretion of LH in ovariectomized lambs. Twelve lambs were ovariectomized and surgically implanted with lateral cerebroventricular cannulae. At the time of the experiment, (38 wk of age) they received intracerebrally 4 injections of either 50 (n = 4), 100 (n = 4), or 200 micrograms (n = 4) of AP5. Blood samples were collected every 10 min for 8 h with animals receiving AP5 at hours 4, 5, 6, and 7. Patterns of LH during the preinjection period were compared to those during the period encompassing AP5 injections. Mean concentrations of LH were lower during AP5 injections than during the preinjection periods, a response that was not influenced by dose (0.87 +/- 0.08 vs. 0.69 +/- .07 ng/ml; p < 0.01). LH pulse amplitude decreased during AP5 treatment relative to the preinjection periods, but this difference was not statistically significant (0.79 +/- 0.11 vs. 0.68 +/- 0.10 ng/ml; p = 0.09). There were no effects of AP5 on LH pulse frequency (1.00 +/- 0.10 vs. 0.83 +/- 0.15 pulses/h for injection and preinjection periods; p > 0.10). A second experiment was done to evaluate a higher dose of AP5. Four animals were chosen to receive 4 injections of 2 mg of AP5 in a design identical to that used in the first experiment.     

Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection

Prior studies have demonstrated the effectiveness of noninvasive transdermal insulin delivery using a cymbal transducer array. In this study the physiologic response to ultrasound mediated transdermal insulin delivery is compared to that of subcutaneously administered insulin. Anesthetized rats (350-550 g) were divided into four groups of four animals; one group representing ultrasound mediated insulin delivery and three representing subcutaneously administered insulin (0.15, 0.20, and 0.25 U/kg). The cymbal array was operated for 60 minutes at 20 kHz with 100 mW/cm2 spatial-peak temporal-peak intensity and a 20% duty cycle. The blood glucose level was determined at the beginning of the experiment and, following insulin administration, every 15 minutes for 90 minutes for both the ultrasound and injection groups. The change in blood glucose from baseline was compared between groups. When administered by subcutaneous injection at insulin doses of 0.15 and 0.20 U/kg, there was little change in the blood glucose levels over the 90 minute experiment. Following subcutaneous administration of insulin at a dose of 0.25 U/kg, blood glucose decreased by 190 +/- 96 mg/dl (mean +/- SD) at 90 minutes. The change in blood glucose following ultrasound mediated insulin delivery was -262 +/- 40 mg/dl at 90 minutes. As expected, the magnitude of change in blood glucose between the three injection groups was dependant on the dose of insulin administered. The change in blood glucose in the ultrasound group was greater than that observed in the injection groups suggesting that a higher effective dose of insulin was delivered.     

Modulation of luteinizing hormone pulse amplitude by the frequency of luteinizing hormone-releasing hormone stimulation and by testosterone in castrated, hypothalamic-lesioned male rats

The frequency of spontaneous luteinizing hormone (LH) pulses is thought to be a direct result of the frequency of luteinizing hormone-releasing hormone (LHRH) pulses from the hypothalamus. By contrast, the amplitude of spontaneous LH pulses may be controlled by several factors other than the amplitude of LHRH pulses. We tested two hypotheses: 1) that LH pulse amplitude is determined in part by the frequency of LHRH pulses of constant magnitude, and 2) that testosterone (T) exerts a direct feedback effect on the pituitary gland to regulate LH pulse amplitude. Gonadal feedback was eliminated by castrating adult male rats (n = 20). Endogenous LHRH secretion was eliminated by lesioning the medial basal hypothalamus. Serum LH levels (0.19 +/- 0.04 ng/ml RP-2, mean +/- SEM) and T levels (0.15 +/- 0.02 ng/ml), measured several weeks after hypothalamic lesioning, confirmed the hypogonadotropic hypogonadal state of the animals. During a 8-h period, unanesthetized, unrestrained animals were injected with 40-ng pulses of LHRH via catheters into the jugular vein, and blood samples for LH measurement were drawn at 10-min intervals. The LHRH pulse interval was 20 min during the first 4 h in all animals. The pulse interval was doubled to 40 min in half of the animals (n = 10) during the next 4 hours; in the other 10 animals, the pulse interval was maintained constant at 20 min throughout the study. Within both of these groups, one-half of the animals (n = 5) were infused with T to achieve a physiological level of T in serum (2.46 +/- 0.36 ng/ml at 4 h), while the other half received vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension

Advanced hypertension (HT), associated with left ventricular hypertrophy (LVH), impairs myocardial microvascular function and structure and leads to increased myocardial hypoxia and growth factor activation. However, the effect of HT on microvascular architecture and its relation to microvascular function, before the development of LVH (early HT), remains unclear. By way of method, pigs were studied after 12 wk of renovascular HT (n = 7) or control (n = 7) animals. Myocardial microvascular function (blood volume and blood flow at baseline and in response to adenosine) was assessed by using electron beam computed tomography (CT). Microvascular architecture was subsequently studied ex vivo using micro-CT, and microvessels (diameter, <500 microm) were counted in situ in three-dimensional images (40-microm on-a-side cubic voxels). Myocardial expression of vascular endothelial growth factor, basic fibroblast growth factor, and hypoxia-inducible factor-1alpha were also measured. By way of results, left ventricular muscle mass was similar between the groups. The blood volume response to intravenous adenosine was attenuated in HT animals compared with normal animals (+7.4 +/- 17.0 vs. +46.2 +/- 12.3% compared with baseline, P = 0.48 and P = 0.01, respectively). Microvascular spatial density in HT animals was significantly elevated compared with normal animals (246 +/- 26 vs. 125 +/- 20 vessels/cm2, P < 0.05) and correlated inversely with the blood volume response to adenosine. Growth factors expression was increased in HT animals compared with control animals. In conclusion, early HT elicits changes in myocardial microvascular architecture, which are associated with microvascular dysfunction and precede changes in muscle mass. These observations underscore the direct and early effects of HT on the myocardial vasculature.     

Should genetic groups be fitted in BLUP evaluation? Practical answer for the French AI beef sire evaluation

Some analytical and simulated criteria were used to determine whether a priori genetic differences among groups, which are not accounted for by the relationship matrix, ought to be fitted in models for genetic evaluation, depending on the data structure and the accuracy of the evaluation. These criteria were the mean square error of some extreme contrasts between animals, the true genetic superiority of animals selected across groups, i.e. the selection response, and the magnitude of selection bias (difference between true and predicted selection responses). The different statistical models studied considered either fixed or random genetic groups (based on six different years of birth) versus ignoring the genetic group effects in a sire model. Including fixed genetic groups led to an overestimation of selection response under BLUP selection across groups despite the unbiasedness of the estimation, i.e. despite the correct estimation of differences between genetic groups. This overestimation was extremely important in numerical applications which considered two kinds of within-station progeny test designs for French purebred beef cattle AI sire evaluation across years: the reference sire design and the repeater sire design. When assuming a priori genetic differences due to the existence of a genetic trend of around 20% of genetic standard deviation for a trait with h² = 0.4, in a repeater sire design, the overestimation of the genetic superiority of bulls selected across groups varied from about 10% for an across-year selection rate p = 1/6 and an accurate selection index (100 progeny records per sire) to 75% for p = 1/2 and a less accurate selection index (20 progeny records per sire). This overestimation decreased when the genetic trend, the heritability of the trait, the accuracy of the evaluation or the connectedness of the design increased. Whatever the data design, a model of genetic evaluation without groups was preferred to a model with genetic groups when the genetic trend was in the range of likely values in cattle breeding programs (0 to 20% of genetic standard deviation). In such a case, including random groups was pointless and including fixed groups led to a large overestimation of selection response, smaller true selection response across groups and larger variance of estimation of the differences between groups. Although the genetic trend was correctly predicted by a model fitting fixed genetic groups, important errors in predicting individual breeding values led to incorrect ranking of animals across groups and, consequently, led to lower selection response.     

Impaired load dependence of diaphragm relaxation during congestive heart failure in the rabbit.

The load dependence (LD) of relaxation was studied in the diaphragm of rabbits with congestive heart failure (CHF). CHF (n = 15) was induced by combined chronic volume and pressure overload. Aortic insufficiency was induced by forcing a catheter through the aortic sigmoid valves, followed 3 wk later by abdominal aortic stenosis. Six weeks after the first intervention, animals developed CHF. Sham-operated animals served as controls (C; n = 12). Diaphragm mechanics were studied in vitro on isolated strips, at 22 degrees C, in isotonic and isometric loading conditions. Contractility was lower in the CHF group, as reflected by lower total tension: 1.11 +/- 0.10 in CHF vs. 2.38 +/- 0.15 N/cm(2) in C in twitch (P < 0.001) and 2.46 +/- 0.22 in CHF vs. 4.90 +/- 0.25 N. cm(-2) in C in tetanus (P < 0.001). The index LD was used to quantify the load dependence of relaxation: LD is <1 in load-dependent muscles and tends toward 1 in load-independent muscles. LD was significantly higher in CHF than in C rabbits, in both twitch (0.99 +/- 0.01 vs. 0.75 +/- 0.03; P < 0. 001) and tetanus (0.95 +/- 0.02 vs. 0.84 +/- 0.02; P < 0.001). In the CHF rabbits' diaphragm, the fall in total tension was linearly related to the fall in load dependence of relaxation. The decrease in load dependence of relaxation in CHF animals suggests sarcoplasmic reticulum abnormalities. Impairment of the sarcoplasmic reticulum may also partly account for the decrease in contractile performance of diaphragm in CHF animals.     

Acute hypoxia modulates 5-HT receptor density and agonist affinity in fetal and adult ovine carotid arteries

In light of recent observations that receptor-ligand binding and coupling are physiologically regulated, the present study examined the hypothesis that the direct effects of hypoxia on vascular contractility involve modulation of pharmacomechanical coupling via changes in agonist affinity and/or receptor density. Because the direct effects of hypoxia on vascular smooth muscle contractility can vary with age, we carried out these experiments using both fetal and adult arteries. In common carotid arteries from near-term fetal and adult sheep, hypoxia (PO(2) = 9-12 Torr for 30 min) reduced the maximum responses to potassium by 17.8 +/- 3.5% (fetus) and 20.5 +/- 2.2% (adult), significantly reduced the pD(2) for 5-HT in the fetus (7.01 +/- 0.1 to 6.3 +/- 0.2) but not the adult (6.1 +/- 0.1 to 6.0 +/- 0.1), and significantly reduced 5-HT-induced maximum contractions (as % maximum response to 120 mM K(+)) not in the fetus (from 114 +/- 7 to 70 +/- 10%, not significant) but only in the adult (from 83 +/- 15 to 25 +/- 7%, P < 0.05) arteries. Hypoxia significantly attenuated 5-HT binding affinity (pK(A), determined by partial irreversible blockade with phenoxybenzamine) in both fetal (from 6.5 +/- 0.2 to 6.0 +/- 0.2) and adult arteries (from 6.2 +/- 0. 2 to 5.7 +/- 0.1) and also decreased receptor density (fmol/mg protein, determined by competitive binding with ketanserin and mesulergine) in adult (from 18.3 +/- 1.1 to 10.9 +/- 1.0) but not in fetal (21.0 +/- 1.0 to 23.2 +/- 1.4) arteries. These results suggest that acute hypoxia modulates receptor-ligand binding via age-dependent modulation of agonist affinity and receptor density. These effects may contribute to hypoxic vasodilatation and help explain why the effects of hypoxia on vascular contractility differ between fetuses and adults.     

Molecular and hormone-binding properties of a partially purified preparation of androgen receptors from the liver of male rats

Liver cytosol of mature male rats was found to contain androgen receptors (AR). These AR were purified 7--10-fold, and their molecular and hormone-binding properties were investigated. It was found that the AR molecules have a sedimentation coefficient of 9.3 +/- 0.15 and 4.7 +/- 0.11 S, Stokes radius of 6.5 +/- 0.25 and 3.2 +/- 0.08 nm, Mr of 263000 and 65700 Da and friction coefficient ratio of 1.55 and 1.22 for low and high ionic strength media, respectively. The values of rate constants of [3H]methyltrienolone (R1881) association with AR and for the dissociation of the complexes formed are equal to (0.66 +/- 0.29). .10(5) M-1 s-1 and to (0.68 +/- 0.08).10(-5) s-1, respectively, whereas those of equilibrium association constant--to (1.4 +/- 0.3).10(9) M-1 at 0-4 degrees C. It was shown that R1881, 5 alpha-dihydrotestosterone and testosterone strongly compete with 3H-R1881 for the binding with AR (as can be judged from the relative competitive activity of 35 nonlabeled hormonal agents); 19-nortestosterone and delta1-testosterone are more weak, whereas 5 alpha-androstandiols, some hydroxy derivatives of testosterone, cyproterone acetate, estradiol and progesterone are moderate competitors. Other natural testosterone, estradiol and progesterone metabolites as well as corticosteroids do not compete or weakly compete with 3H-R1881 for the binding to AR. It is concluded that the properties of AR are similar to those of classical type AR and that they can intermediate most of the direct effects of androgens on the liver.     

Effective Size of Populations under Selection

Equations to approximate the effective size (N(e)) of populations under continued selection are obtained that include the possibility of partial full-sib mating and other systems such as assortative mating. The general equation for the case of equal number of sexes and constant number of breeding individuals (N) is N(e) = 4N/[2(1 - α(I)) + (S(k)(2) + 4Q(2)C(2)) (1 + α(I) + 2α(O))], where S(k)(2) is the variance of family size due to sampling without selection, C(2) is the variance of selective advantages among families (the squared coefficient of variation of the expected number of offspring per family), α(I) is the deviation from Hardy-Weinberg proportions, α(O) is the correlation between genes of male and female parents, and Q(2) is the term accounting for the cumulative effect of selection on an inherited trait. This is obtained as Q = 2/[2 - G(1 + r)], where G is the remaining proportion of genetic variance in selected individuals and r is the correlation of the expected selective values of male and female parents. The method is also extended to the general case of different numbers of male and female parents. The predictive value of the formulae is tested under a model of truncation selection with the infinitesimal model of gene effects, where C(2) and G are a function of the selection intensity, the heritability and the intraclass correlation of sibs. Under random mating r = α(I) = -1/(N - 1) and α(O) = 0. Under partial full-sib mating with an average proportion β of full-sib matings per generation, r & β and α(O) & α(I) & β/ (4 - 3β). The prediction equation is compared to other approximations based on the long-term contributions of ancestors to descendants. Finally, based on the approach followed, a system of mating (compensatory mating) is proposed to reduce rates of inbreeding without loss of response in selection programs in which selected individuals from the largest families are mated to those from the smallest families.