BackgroundThe neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) plays pivotal roles in immunity and inflammation. So far, potential immune-modulatory properties of PACAP have not been investigated in experimental ileitis.Methodology/Principal FindingsMice were perorally infected with Toxoplasma (T.) gondii to induce acute ileitis (day 0) and treated daily with synthetic PACAP38 from day 1 to 6 post infection (p.i.; prophylaxis) or from day 4 to 6 p.i. (therapy). Whereas placebo-treated control mice suffered from acute ileitis at day 7 p.i. and succumbed to infection, intestinal immunopathology was ameliorated following PACAP prophylaxis. PACAP-treated mice exhibited increased abundance of small intestinal FOXP3+ cells, but lower numbers of ileal T lymphocytes, neutrophils, monocytes and macrophages, which was accompanied by less ileal expression of pro-inflammatory cytokines such as IL-23p19, IL-22, IFN-γ, and MCP-1. Furthermore, PACAP-treated mice displayed higher anti-inflammatory IL-4 concentrations in mesenteric lymph nodes and liver and higher systemic anti-inflammatory IL-10 levels in spleen and serum as compared to control animals at day 7 p.i. Remarkably, PACAP-mediated anti-inflammatory effects could also be observed in extra-intestinal compartments as indicated by reduced pro-inflammatory mediator levels in spleen (TNF-α, nitric oxide) and liver (TNF-α, IFN-γ, MCP-1, IL-6) and less severe histopathological sequelae in lungs and kidneys following prophylactic PACAP treatment. Strikingly, PACAP prolonged survival of T. gondii infected mice in a time-of-treatment dependent manner.Conclusion/SignificanceSynthetic PACAP ameliorates acute small intestinal inflammation and extra-intestinal sequelae by down-regulating Th1-type immunopathology, reducing oxidative stress and up-regulating anti-inflammatory cytokine responses. These findings provide novel potential treatment options of inflammatory bowel diseases.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is an endogenous neuropeptide with distinct functions including the regulation of inflammatory processes. PACAP is able to modify the immune response by directly regulating macrophages and monocytes inhibiting the production of inflammatory cytokines, chemokines and free radicals. Here, we analyzed the effect of exogenous PACAP on peripheral immune cell subsets upon acute infection with the parasite Toxoplasma gondii (T. gondii) . PACAP administration was followed by diminished innate immune cell recruitment to the peritoneal cavity of T. gondii -infected mice. PACAP did not directly interfere with parasite replication, instead, indirectly reduced parasite burden in mononuclear cell populations by enhancing their phagocytic capacity. Although proinflammatory cytokine levels were attenuated in the periphery upon PACAP treatment, interleukin (IL)-10 and Transforming growth factor beta (TGF-β) remained stable. While PACAP modulated VPAC1 and VPAC2 receptors in immune cells upon binding, it also increased their expression of brain-derived neurotrophic factor (BDNF). In addition, the expression of p75 neurotrophin receptor (p75 NTR ) on Ly6C hi inflammatory monocytes was diminished upon PACAP administration. Our findings highlight the immunomodulatory effect of PACAP on peripheral immune cell subsets during acute Toxoplasmosis , providing new insights about host-pathogen interaction and the effects of neuropeptides during inflammation.

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Background: Since 2012, Associated Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been standing in the limelight of modern liver surgery and numerous questions have been raised regarding this novel approach. On the one hand, ALPPS has proved to be a valuable method in the treatment of hepatic tumors, while on the other hand, there are many controversies, such as high mortality and morbidity rates. Further surgical research is essential for a better understanding of underlying mechanisms and for enhancing patient safety. Summary: Until recently, only 8 animal models have been created with the purpose to mimic ALPPS-induced liver regeneration. From these 7 are rodent (6 rat and 1 mouse) models, while only 1 is a large animal model, which uses pigs. In case of rodent models, portal flow deprivation of 75-90% is achieved via portal vein ligation leaving only the right (20-25%) or left median (10-15%) lobes portally perfused, while liver splitting in general is carried out positioned according to the falciform ligament. As for the swine model, the left lateral and medial lobes (70-75% of total liver volume) are portally ligated, and the right lateral lobe (accounting for 20-24% of the parenchyma) is partially resected in order to reach critical liver volume. Each model is capable of reproducing the accelerated liver regeneration seen in human cases. However, all species have significantly different liver anatomy compared with the human anatomic situation, making clinical translation somewhat difficult. Key Messages: Unfortunately, there are no perfect animal models available for ALPPS research. Small animal models are inexpensive and well suited for basic research, but may only provide limited translational potential to humans. Clinically large animal models may provide more relevant data, but currently no suitable one exists.

Relatively few, and inconsistent, data are available in the literature about the properties of EnSeal®, an electrosurgical tissue-sealing device. For this reason, we conducted control safety tests on experimental pigs. The mean burst pressure of sealed vessels (2-7 mm in diameter) proved to be 873.89 ± 120.57 mmHg (n = 60). Surface temperature increased to 69.25 ± 0.98 °C in average (n = 22). The mean diameter of the collateral microscopic thermal injury zone was found to be 0.28 ± 0.04 mm, and it did not show significant differences among the groups of tissues studied (n = 183). During our studies, the device worked reliably and met the relevant requirements in all cases. It can be established that EnSeal® enables high-safety clinical interventions at high blood pressure values, in different tissues and even at sites adjacent to heat-sensitive tissues, and thus it paves the way for new operative solutions in both human and veterinary surgery. In our opinion, the discrepancies between data reported in the literature arise from differences in the design of studies and in the designated limit values. To ensure standardisation, we recommend the use of the nitroblue-tetrazolium chloride/lactate dehydrogenase (NBTC/LDH) enzyme histochemical technique for studying thermal injury induced by the different performance levels and application times of devices operating with electromagnetic energy.