Genetic determination of mortality rate in Danish dairy cows: A multivariate competing risk analysis based on the number of survived lactations.

Dairy cow mortality has been steadily increasing during the last 2 decades in Denmark. This study aims to verify whether genetic mechanisms might be contributing to this increase. To do so, the records of 880,480 Holstein, 142,306 Jersey, and 85,206 Red Danish dairy cows calving from 1990 to 2006 were retrieved from the Danish Cattle register. Two causes of culling of cows were considered: death and slaughtering. Bivariate competing risk genetic models with a sire model structure were used to describe the death and the slaughtering rates simultaneously. The models included 2 random components: a sire random component with pedigree representing the sire genetic effects and a herd-year-season component. Moreover, the level of heterozygosity and the sire breed proportions were included in the models as covariates to account for potential nonadditive genetic effects due to the massive introduction of genetic material from other populations. The correlations between the sire components for death rate and slaughter rate were negative and small for the 3 populations, suggesting the existence of specific genetic mechanisms for each culling reason and common concurrent genetic mechanisms. In the Holstein population, the effects of the changes in the level of heterozygosity, breed composition, and the increasing genetic trend acted in the same direction, increasing the death rate in recent years. In the Jersey population, the effects of the level of heterozygosity and the breed proportion were small, and only the increasing genetic trend can be pointed as a genetic cause to the observed increase in the mortality rate. In the Red Danish population, neither the time-development pattern of the genetic trend nor the changes in the level of heterozygosity and breed composition could be causing the observed increase in the mortality; thus, nongenetic factors must be causing this negative development.

A remarkable depletion of both naïve CD4+ and CD8+ with high proportion of memory T cells in an IPEX infant with a FOXP3 mutation in the forkhead domain.

IPEX is a rare X-linked syndrome, with immune dysfunction, polyendocrinopathy and enteropathy. We describe an infant who died at the age of 11 months after developing eczema, severe diarrhoea, diabetes, hypothyroidism, thrombocytopenia and four episodes of septicaemia. Immunophenotyping of peripheral blood at 8 months revealed normal CD3+ T, CD4+ T and CD8+ T cell numbers, with low NK and B cells. CD4+ and CD8+ T lymphocytes showed remarkably low numbers and percentages of naïve cells and high numbers of memory CD4 and CD8 cells. At autopsy, an intense depletion of immune cells in thymus, spleen and lymph nodes was observed. No Hassall's corpuscles were found in thymus. Lymphocytic pancreatitis and intense villous atrophy with mucosal lymphocytic infiltration in small bowel were also seen. FOXP3 gene studies revealed a: C-->G substitution 3 bp upstream of exon 10, which prevents splicing between exons 9 and 10, likely resulting in a functionally altered or deficient protein. Florid clinical findings are usually observed in association of forkhead DNA-binding domain mutations. The intense depletion of naïve T cells we report suggest that depletion of immune cells might take place due to uncontrolled activation due to the absence of regulatory T cells.