Single-step genomic predictions for crossbred Holstein and Jersey cattle in the United States.

In the dairy cattle sector, the number of crossbred genotypes increased in the last years, and therefore, the need for accurate genomic evaluations for crossbred animals has also increased. Thus, this study aimed to investigate the feasibility of including crossbred genotypes in multibreed, single-step genomic BLUP (ssGBLUP) evaluations. The Council of Dairy Cattle Breeding provided more than 47 million lactation records registered between 2000 and 2021 in purebred Holstein and Jersey and their crosses. A total of 27 million animals were included in the analysis, of which 1.4 million were genotyped. Milk, fat, and protein yields were analyzed in a 3-trait repeatability model using BLUP or ssGBLUP. The 2 models were validated using prediction bias and accuracy computed for genotyped cows with no records in the truncated dataset and at least one lactation in the complete dataset. Bias and accuracy were better in the genomic model than in the pedigree-based one, with accuracies for crossbred cows higher than those of purebreds, except for fat yield in Holstein. Our study shows that genotypes for crossbred animals can be included in a ssGBLUP analysis with their purebred ancestors to estimate genomic estimated breeding values in a single run.

Strategies for choosing core animals in the algorithm for proven and young and their impact on the accuracy of single-step genomic predictions in cattle.

Nowadays, in some populations, the number of genotyped animals is too large to obtain the inverse of the genomic relationship matrix. The algorithm for proven and young animals (APY) can be used to overcome this problem. In the present work, different strategies for defining core animals in APY were tested using either simulated or real data. In particular, core definitions based on random choice or on the contribution to the genomic relationship matrix (GCONTR) calculated using Principal Component Analysis were tested. Core sizes able to explain 90, 95, 98, and 99% of the total variance of the genomic relationship matrix (G) were used. Analyzed phenotypes were three simulated traits for 3 000 individuals, and milkability records for 136 406 Italian Simmental cows. The number of genotypes was 4 100 for the simulated dataset, and 11 636 for the Simmental data, respectively. The GCONTR values in Simmental dataset were moderately correlated with the analyzed phenotype, and they showed a decreasing trend according to the year of birth of genotyped animals. The accuracy increased as the size of the core increased in both datasets. The inclusion in the core of animals with largest GCONTR values led to the lowest accuracies (0.50 and 0.71 for the simulated and Simmental datasets, respectively; average across traits and core sizes). On the contrary, the selection of animals with the lowest rank according to their contribution to the G provided slightly higher accuracies, especially in the simulated dataset (0.68 for the simulated dataset, and 0.76 for the Simmental data; average across traits and core sizes). In real data, particularly for larger sizes of core animals, the criteria of choice appear less important, confirming the results of earlier studies. Anyway, the inclusion in the core of animals with the lowest values of GCONTR led to increases in accuracy. These are preliminary results based on a small sample size that need to be confirmed on a larger number of genotypes.

Technical note: Automatic scaling in single-step genomic BLUP.

Single-step genomic BLUP (ssGBLUP) requires compatibility between genomic and pedigree relationships for unbiased and accurate predictions. Scaling the genomic relationship matrix (G) to have the same averages as the pedigree relationship matrix (i.e., scaling by averages) is one way to ensure compatibility. This requires computing both relationship matrices, calculating averages, and changing G, whereas only the inverses of those matrices are needed in the mixed model equations. Therefore, the compatibility process can add extra computing burden. In the single-step Bayesian regression, the scaling is done by including a mean (µg) as a fixed effect in the model. The parameter µg can be interpreted as the average of the breeding values of the genotyped animals. In this study, such scaling, called automatic, was implemented in ssGBLUP via Quaas-Pollak transformation of the inverse of the relationship matrix used in ssGBLUP (H), which combines the inverses of the pedigree and genomic relationship matrices. Comparisons involved a simulated data set, and the genomic relationship matrix was computed using different allele frequencies either from the current population (i.e., realized allele frequencies), equal among all the loci, or from the base population. For all of the scenarios, we computed bias [defined as the average difference between true breeding values (TBV) and genomic estimated breeding values (GEBV)], accuracy (defined as the correlation between TBV and GEBV), and dispersion (defined as the regression coefficient of GEBV on TBV). With no scaling, the bias expressed in terms of genetic standard deviations was 0.86, 0.64, and 0.58 with realized, equal, and base population allele frequencies, respectively. With scaling by averages, which is currently used in ssGBLUP, bias was 0.07, 0.08, and 0.03, respectively. With automatic scaling, bias was 0.18 regardless of allele frequencies. Accuracies were similar among scaling methods, but about 0.1 lower in the scenario without scaling. The GEBV were more inflated without any scaling, whereas the automatic scaling performed similarly to the scaling by averages. The average dispersion for those methods was 0.94. When µg was treated as random, with the variance equal to differences between pedigree and genomic relationships, the bias was the same as with the scaling by averages. The automatic scaling is biased, especially when µg is treated as a fixed effect. The bias may be small in real data with fewer generations, when traits are undergoing weak selection, or when the number of genotyped animals is large.

Regulatory mechanisms of growth hormone secretion are sexually dimorphic.

Sexually dimorphic growth hormone (GH) secretory pattern is important in the determination of gender-specific patterns of growth and metabolism in rats. Whether GH secretion in humans is also sexually dimorphic and the neuroendocrine mechanisms governing this potential difference are not fully established. We have compared pulsatile GH secretion profiles in young men and women in the baseline state and during a continuous intravenous infusion of recombinant human insulin-like growth factor I (rhIGF-I). During the baseline study, men had large nocturnal GH pulses and relatively small pulses during the rest of the day. In contrast, women had more continuous GH secretion and more frequent GH pulses that were of more uniform size. The infusion of rhIGF-I (10 microg/kg/h) potently suppressed both spontaneous and growth hormone-releasing hormone (GHRH)-induced GH secretion in men. In women, however, rhIGF-I had less effect on pulsatile GH secretion and did not suppress the GH response to GHRH. These data demonstrate the existence of sexual dimorphism in the regulatory mechanisms involved in GH secretion in humans. The persistence of GH responses to GHRH in women suggests that negative feedback by IGF-I might be expressed, in part, through suppression of hypothalamic GHRH.

Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin.

To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.

Differential autoantibody responses to thyroid peroxidase in patients with Graves' disease and Hashimoto's thyroiditis.

In order to examine the specificity of the autoantibody response to thyroid peroxidase (TPO, previously identified as thyroid microsomal antigen) in autoimmune thyroid disease, we examined reactivity of sera from 45 Hashimoto's and 48 Graves' patients to native thyroid microsomes, denatured and reduced human TPO and several recombinant fragments of human TPO corresponding to amino acids 457-933 of the native protein. Both Graves' and Hashimoto's sera bound native, denatured and reduced TPO at significantly greater rate than normal controls, and no differences were noted between the two disorders in binding to these forms of the autoantigen. Binding was also noted to two recombinant fragments of TPO, corresponding to amino acids 513-633 and 633-933 in TPO. The frequency of autoantibodies to the TPO AA(633-933) region was not significantly different in Hashimoto's vs. Graves' disease patients (58% vs. 65% respectively), and appeared to relate to evidence of glandular inflammation in the Graves' patients (presence of anti-thyroglobulin antibodies and elevated anti-microsomal antibody levels). In contrast, antibodies to the TPO AA(513-633) fragment were significantly more common and of higher titer in Hashimoto's vs. Graves' disease patients, and did not correlate with any measure of glandular inflammation. These results identify two specific regions of TPO autoantibody binding and indicate that there are differences in the autoantibody response to TPO in Hashimoto's and Graves' diseases.

Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.

In a double-blind randomized trial, the hemodynamic events following the administration of propranolol (n = 51) or a placebo (n = 51) were prospectively studied in cirrhotic patients with esophageal varices. The hepatic venous pressure gradient, heart rate, and variceal size were determined at the baseline and 3, 12, and 24 months after the beginning of therapy. Baseline values were similar in both groups. At 3 months, the hepatic venous pressure gradient decreased significantly in propranolol-treated patients (from 18.1 +/- 4.2 to 15.7 +/- 3.4 mm Hg; P less than 0.05) but not in patients receiving the placebo (19.6 +/- 6.8 to 17.5 +/- 5.3 mm Hg; NS). At subsequent time intervals this gradient decreased significantly from the baseline value in both groups. Heart rate decreased significantly in the propranolol-treated group at all times (P less than 0.001). Variceal hemorrhage occurred in 13 patients (11 placebo-, 2 propranolol-treated; P less than 0.01), all of whom had a hepatic venous pressure gradient greater than 12 mm Hg. In 21 patients (14 propranolol-, 7 placebo-treated) the hepatic venous pressure gradient decreased to less than or equal to 12 mm Hg; none of them bled from esophageal varices, and their mortality rate also decreased. Because most of the bleeding events occurred during the first year (10 placebo-, 1 propranolol-treated; P less than 0.01), propranolol seems to have its protective effect during the period associated with the largest reduction in the hepatic venous pressure gradient. Because a reduction in the hepatic venous pressure gradient to less than 12 mm Hg protects from variceal bleeding and increases the rate of survival, this should be the aim of the pharmacological therapy of portal hypertension.

Short-term effects of propranolol on portal venous pressure.

The present study was designed to investigate the effect of propranolol on portal pressure of patients with alcoholic cirrhosis and portal hypertension and to correlate these effects with clinical and laboratory parameters. The mean baseline hepatic venous pressure gradient in the 50 patients studied was of 18.2 +/- 4.1 mm Hg. It decreased significantly 2 hr after the oral administration of 40 mg of propranolol to 15.7 +/- 4.2 mm Hg (a mean reduction of 13.4 +/- 17%). This reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure. There was no correlation between the decrease in hepatic venous pressure gradient and the decrease in heart rate. When results were analyzed individually, only 15 (30%) showed a large decrease in hepatic venous pressure gradient (greater than 20%), 15 (30%) showed a moderate decrease (10 to 19%), and in 20 patients (40%) there was no reduction or an increase in hepatic venous pressure gradient. Comparison of "responders" (those that reduced hepatic venous pressure gradient greater than 10%) and "nonresponders" (hepatic venous pressure gradient reduction less than 10%) showed no significant differences in baseline laboratory and hemodynamic parameters, in the severity of the liver disease, in the heart rate and blood pressure response to propranolol, nor in the propranolol plasma levels achieved 2 hr after propranolol administration. Propranolol plasma levels correlated with the reduction in heart rate but not with the reduction in hepatic venous pressure gradient. Of 14 nonresponders to 40 mg of propranolol who received additional doses, six showed a reduction in hepatic venous pressure gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

[Assay of serum apolipoprotein A-II by electro-immunodiffusion on ready-for-use plates. Clinical applications]. / Dosage de l'apolipoprotéine A-II sérique par électro-immunodiffusion sur plaques prêtes à l'emploi. Applications cliniques.

Few papers have been devoted to the study of apolipoprotein A-II (apo A-II), one of the major peptides contained in HDL, probably because of the methodological difficulties associated with its assay. The aim of this study is to provide the clinical biochemist with a simply easy to use assay technique. We have been able to demonstrate the practical value of apo A-II assay in hepatology and in the detection of excessive drinkers. On the other hand, our results indicate that apo A-II is not a parameter of choice for the detection of coronary atherosclerosis.

Chemical and pharmacological studies of anorectic drugs with phenylpiperazinyl structure.

Chemical and pharmacological properties of potent anorectic compounds with phenylpiperazinyl structure were studied. Among them, the three derivatives having the most interesting anorectic activity are product VI obtained by pharmacomodulation from amfepramone and the compounds IV and V, analogs of GABA. The derivative VI possesses an anorectic activity very similar to that of fenfluramine, namely: modification of feeding behaviour in treated rats, wasting away and decrease of adipose tissue. The two other compounds and more particularly compound V seem to be effective even when treatment is over. Perhaps this is in relation with metabolic effects modifying the regulation of feeding behaviour in the central nervous system. In fact, these compounds have substituents able to interfere with GABA systems.