Pharmacokinetics of immunosuppressive agents during hemoperfusion in a sheep model.

Introduction: Hemoadsorption shows promising signals in organ preservation and post lung transplantation. However, its potential impact on the pharmacokinetics of immunosuppressant drugs (ID) is still unknown. Methods: In this interventional study, CytoSorb® hemoperfusion was tested in healthy sheep (n = 5) against a sham extracorporeal circuit (n = 3). Seven different ID (tacrolimus (TAC), cyclosporin A (CYA), mycophenolate mofetil (MMF), everolimus (EVER), basiliximab (BAS), methylprednisolone (MP) and prednisolone (PRED)) were administered in clinically relevant doses and combinations. Their levels were measured repeatedly in blood samples from the extracorporeal circulation over 6 h following administration. Population pharmacokinetic modeling analysis (NONMEM® 7.5) was performed. Results: Negligible clearance was observed for PRED and BAS. For all other substances, a saturable adsorption sub-model with linear decrease of the adsorption effect over the adsorbed amount best described the measured concentrations. The maximum absolute adsorbed amounts (95% CI) for TAC, CYA, MMF, EVER, and MP were 0.040 (0.028-0.053), 1.15 (0.39-1.91), 4.17 (2.00-6.35), 0.0163 (0.007-0.026), and 53.4 mg (20.9-85.9), respectively, indicating an adsorption of less than 5% of the daily administered dosages for all investigated substances. Discussion: In this large animal model, CytoSorb® hemoperfusion appears to have a limited effect on the clearance of tested ID.

Attraction of female house mice to male ultrasonic courtship vocalizations depends on their social experience and estrous stage.

Male house mice (Mus musculus) produce complex ultrasonic vocalizations (USVs), especially during courtship and mating. Playback experiments suggest that female attraction towards recordings of male USVs depends on their social experience, paternal exposure, and estrous stage. We conducted a playback experiment with wild-derived female house mice (M. musculus musculus) and compared their attraction to male USVs versus the same recording without USVs (background noise). We tested whether female attraction to USVs is influenced by the following factors: (1) social housing (two versus one female per cage); (2) neonatal paternal exposure (rearing females with versus without father); and (3) estrous stage. We found that females showed a significant attraction to male USVs but only when they were housed socially with another female. Individually housed females showed the opposite response. We found no evidence that pre-weaning exposure to a father influenced females' preferences, whereas estrous stage influenced females' attraction to male USVs: females not in estrus showed preferences towards male USVs, whereas estrous females did not. Finally, we found that individually housed females were more likely to be in sexually receptive estrous stages than those housed socially, and that attraction to male USVs was most pronounced amongst non-receptive females that were socially housed. Our findings indicate that the attraction of female mice to male USVs depends upon their social experience and estrous stage, though not paternal exposure. They contribute to the growing number of studies showing that social housing and estrous stage can influence the behavior of house mice and we show how such unreported variables can contribute to the replication crisis.

Use of CytoSorb© Hemoadsorption in Patients on Veno-Venous ECMO Support for Severe Acute Respiratory Distress Syndrome: A Systematic Review.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality. Adjunct hemoadsorption is increasingly utilized to target underlying hyperinflammation derived from ARDS. This article aims to review available data on the use of CytoSorb© therapy in combination with V-V ECMO in severe ARDS, and to assess the effects on inflammatory, laboratory and clinical parameters, as well as on patient outcomes. A systematic literature review was conducted and reported in compliance with principles derived from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. When applicable, a before-and-after analysis for relevant biomarkers and clinical parameters was carried out. CytoSorb© use was associated with significant reductions in circulating levels of C-reactive protein and interleukin-6 (p = 0.039 and p = 0.049, respectively). Increases in PaO2/FiO2 reached significance as well (p = 0.028), while norepinephrine dosage reductions showed a non-significant trend (p = 0.067). Mortality rates in CytoSorb© patients tended to be lower than those of control groups of most included studies, which, however, were characterized by high heterogeneity and low power. In an exploratory analysis on 90-day mortality in COVID-19 patients supported with V-V ECMO, the therapy was associated with a significantly reduced risk of death. Based on the reviewed data, CytoSorb© therapy is able to reduce inflammation and potentially improves survival in ARDS patients treated with V-V ECMO. Early initiation of CytoSorb© in conjunction with ECMO might offer a new approach to enhance lung rest and promote recovery in patients with severe ARDS.

Multiple paternity in wild house mice (Mus musculus musculus): effects on offspring genetic diversity and body mass.

Multiple mating is common in many species, but it is unclear whether multiple paternity enhances offspring genetic diversity or fitness. We conducted a survey on wild house mice (Mus musculus musculus), and we found that in 73 pregnant females, 29% of litters had multiple sires, which is remarkably similar to the 23-26% found in feral populations of Mus musculus domesticus in the USA and Australia, respectively. The question is: How has selection maintained multiple mating in these subspecies since the evolutionary divergence, ca. 2800-6000 years ago? We found no evidence that multiple paternity enhanced females' litter size, contrary to the fertility assurance or genetic benefits hypotheses. Multiple paternity was associated with reduced mean and variance in offspring body mass, which suggests that females allocate fewer resources or that there is increased intrauterine conflict in multiple-versus single-sired litters. We found increased allelic diversity (though not heterozygosity) in multiple-sired litters, as predicted by the genetic diversity hypothesis. Finally, we found that the dams' heterozygosity was correlated with the mean heterozygosity of their offspring in single-and multiple-sired litters, suggesting that outbred, heterozygous females were more likely to avoid inbreeding than inbred, homozygous females. Future studies are needed to examine how increased genetic diversity of litters and smaller mean (and variance) offspring body mass associated with multiple paternity affect offspring fitness.

Effects of chronic stress during pregnancy on maternal performance in the guinea pig (Cavia aperea f. porcellus).

Stress experienced during pregnancy can have persistent impact on the female's physiology and behaviour not only during but even beyond pregnancy. The present study aimed to evaluate such long-term effects of stress in terms of repeated strobe light exposure during early to mid gestation on behavioural aspects of mothering activities and lactational effort in lactating guinea pigs. We found that maternal behaviour was negatively affected by stress experience during pregnancy with treatment females developing a higher level of offspring-directed aggression than controls. In addition, our measure of lactational performances showed tendencies of lowered milk supply and longer pup suckling durations in stressed females. We suggest that this may represent a strategy to advance infant weaning following demanding conditions caused by chronic stress experience during pregnancy.

Sex-specific impact of prenatal stress on growth and reproductive parameters of guinea pigs.

Body condition and reproductive maturation are parameters of reproductive success that are influenced by sexual hormones rising in the circulation during the time of puberty. Various endocrine systems can be programmed by conditions experienced during early life. Stress for instance is supposed to be capable of influencing fetal development, leading to adjustments of offspring's later physiology. We examined whether prenatal stress (induced by exposure to strobe light) during early- to mid-gestation was capable of affecting later reproductive parameters in guinea pigs (Cavia aperea f. porcellus). Therefore, we measured the levels of testosterone and progesterone from the age of day 12-124 in prenatally stressed (PS, n = 20) and unaffected control animals (n = 24). Furthermore, we determined the timing of puberty and growth. Body weight development revealed significantly faster growth in PS females compared to control animals. The onset of first estrus was slightly earlier in PS females, however not significantly so. Cycle lengths and levels of progesterone differed between groups over the course of time with higher progesterone levels and more constant cycles among PS females compared to control females who displayed marked differences between first and subsequent cycles. Levels of testosterone did not differ between groups. We conclude that prenatal stress accelerates growth and maturity in females, but not in males.