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The study was conducted to determine the influence of male-male competition on reproductive performance and male mortality of Cobb 500 broiler breeder flocks following double intra-spiking. Broiler breeders were housed in 3 open-sided houses each accommodating 8,200 females and 820 males. Males of the same age on the same farm were exchanged between the houses (intra-spiking) to stimulate competition thereby changing the social hierarchy of each house. Intra-spiking was performed by replacing 25, 35, and 45% of males between the houses at 40 and 48 weeks of age (WOA), respectively. Eggs were collected from 36 to 55 WOA, when egg fertility and male mortality were recorded. Data was analyzed using repeated measures techniques of SAS 9.4, modeling the covariance structure of the observed data. Male-male competition (intra-spiking), age and their interaction significantly (P < 0.05) influenced egg fertility, hatchability, and male mortality. Average fertility and hatchability were increased in the 45% intra-spiked flocks (P < 0.05) (95.89 and 85.83%) compared with the 35% (95.13 and 86.30%) and 25% (94.42 and 0.23%) intra-spiked flocks. Fertility and hatchability with the 45% double intra-spiked flocks was consistently higher (P < 0.05) over time than the other double intra-spiked flocks. Male mortality was lower (P < 0.05) in the 45% intra-spiked flock (0.23%) than in the 35% (0.40%) and 25% (0.44%) intra-spiked flocks. After double intra-spiking, the male mortality in the 25 and 35% double intra-spiked flocks significantly increased (P < 0.05), whereas that of 45% intra-spiked flocks remained relatively low. Male mortality in the 45% intra-spiked flocks was consistently low over time than other double intra-spike levels from 45 WOA until the end of the trial. Noteworthy, egg fertility and hatchability gradually decreased, and mortality increased with increasing flock age toward the end of the productive life cycle. High level of male-male competition (45%) showed great promise as a tool to slow down the decrease in egg fertility and hatchability, and reduce male mortality in aging broiler breeder flocks., (© 2019 Poultry Science Association Inc.)

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic disorder diagnosed by thrombocytopenia and hemolytic anemia, associated with a deficiency in von Willebrand factor (VWF)-cleaving protease ADAMTS13. Current treatment is based on plasma infusion for congenital TTP, or plasma exchange, often in combination with immunosuppressive agents, for acquired TTP. These treatment methods are not always effective; therefore, new treatment methods are highly necessary. N -acetylcysteine (NAC), an FDA-approved anti-mucolytic agent, is a possible new treatment strategy for TTP, as it was demonstrated to reduce disulfide bonds in VWF, thereby decreasing VWF multimers size and hence their prothrombotic potential. We investigated whether NAC, without concurrent plasma exchange and immunosuppressive therapy, is effective in preventing and resolving TTP signs, using well-established murine and baboon models for TTP. In mice, prophylactic administration of NAC was effective in preventing severe TTP signs. This in vivo finding was supported by in vitro data demonstrating the VWF multimer-reducing properties of NAC in solution. Nonetheless, in both mice and baboons, administration of NAC was not effective in resolving preexisting TTP signs; thrombocytopenia, hemolytic anemia, and organ damage could not be reversed, as thrombus resolution was not achieved. Failure to improve clinical outcome occurred even though a reduction in VWF multimers was observed, demonstrating that NAC was efficient in reducing disulfide bonds in circulating VWF multimers. In conclusion, prophylactic administration of NAC, without concurrent plasma exchange, was effective in preventing severe TTP signs in mice, but NAC was not effective in resolving preexistent acute TTP signs in mice and baboons., (© 2017 by The American Society of Hematology.)

The pathophysiology of thrombotic thrombocytopenic purpura (TTP) can be explained by the absence of active ADAMTS13, leading to ultra-large von Willebrand factor (UL-VWF) multimers spontaneously interacting with platelets. Preventing the formation of UL-VWF-platelet aggregates therefore is an attractive new treatment strategy. Here, we demonstrate that simultaneous administration of the inhibitory anti-VWF monoclonal antibody GBR600 and the inhibitory anti-ADAMTS13 antibody 3H9 to baboons (prevention group) precluded TTP onset as severe thrombocytopenia and hemolytic anemia were absent in these animals. In addition, partial VWF inhibition was not enough to prevent thrombocytopenia, demonstrating the specificity of this therapeutic strategy. GBR600 treatment of baboons during acute TTP (treatment group) resulted in a rapid recovery of severe thrombocytopenia similar to the platelet count increases observed in TTP patients treated by plasma exchange. Baboons in the control group only injected with 3H9 developed early stages of TTP as previously described. Hence, inhibiting VWF-GPIb interactions is an effective way to prevent and treat the early symptoms of acquired TTP in baboons.

ALX-0681 is a therapeutic Nanobody targeting the A1-domain of VWF. It inhibits the interaction between ultra-large VWF and platelet GpIb-IX-V, which plays a crucial role in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). In the present study, we report the efficacy and safety profile of ALX-0681 in a baboon model of acquired TTP. In this model, acute episodes of TTP are induced by administration of an ADAMTS13-inhibiting mAb. ALX-0681 completely prevented the rapid onset of severe thrombocytopenia and schistocytic hemolytic anemia. After induction of TTP, platelet counts also rapidly recovered on administration of ALX-0681. This effect was corroborated by the full neutralization of VWF activity. The schistocytic hemolytic anemia was also halted and partially reversed by ALX-0681 treatment. Brain CT scans and post mortem analysis did not reveal any sign of bleeding, suggesting that complete neutralization of VWF by ALX-0681 under conditions of thrombocytopenia was not linked with an excessive bleeding risk. The results obtained in this study demonstrate that ALX-0681 can successfully treat and prevent the most important hallmarks of acquired TTP without evidence of a severe bleeding risk. Therefore, ALX-0681 offers an attractive new therapeutic option for acquired TTP in the clinical setting.

Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) has been demonstrated, but additional genetic and/or environmental triggers are thought to be required to incite acute illness. Here we report that 4 days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers because injections with an inhibitory monoclonal antibody (mAb) consistently (n = 6) induced severe thrombocytopenia (< 12 × 10(9)/L), microangiopathic hemolytic anemia, and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet- and von Willebrand factor-rich thrombi in kidney, heart, brain, and spleen but not lungs. Prolonged inhibition (14 days, n = 1) caused myocardial ischemic damage and asplenia but not death. Control animals (n = 5) receiving equal doses of a noninhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Furthermore, we present a reliable animal model of this disease as an opportunity for the development and validation of novel treatment strategies.

The processed leaves and stems of Aspalathus linearis contain a new diastereomeric pair of the flavanones, (S)- and (R)-eriodictyol-6-C-beta-D-glucopyranoside, which is also formed via the oxidative cyclization of the dihydrochalcone, aspalathin, under conditions which mimic the fermentation process.

Mushroom tyrosinase catalysed oxidation of three flavan-3-ols, viz. catechin, fisetinidol and mesquitol, was conducted to construct biphenyl bonds. Exposure of the flavan-3-ols to tyrosinase and subsequent trapping of the o-quinone intermediates resulted in the formation of novel flavan-3-ol derivatives, the structures of which were elucidated by mono- and two-dimensional 1H-NMR experiments. Application of the methodology resulted in the improved synthesis of the natural flavan-3-ol dimer, mesquitol-[5-->8]-catechin, previously isolated from Prosopis glandulosa.