Maturation of the medaka immune system depends on reciprocal interactions between the microbiota and the intestinal tract.

The interactions between the host immune system and intestinal microorganisms have been studied in many animals, including fish. However, a detailed analysis has not been performed in medaka, an established fish model for biological studies. Here, we investigated the effect of immunodeficiency on the microbiota composition and the effect of gut bacteria on intestinal epithelial development and immune responses in medaka. Chronological analysis of the intestinal microbiota of interleukin 2 receptor subunit gamma (il2rg) mutant medaka showed a gradual decrease in the evenness of operational taxonomic units, mainly caused by the increased abundance of the Aeromonadaceae family. Exposure of wild-type medaka to high doses of an intestine-derived opportunistic bacterium of the Aeromonadaceae family induced an inflammatory response, suggesting a harmful effect on adult il2rg mutants. In addition, we established germ-free conditions in larval medaka and observed large absorptive vacuoles in intestinal epithelial cells, indicating a block in epithelial maturation. Transcriptome analysis revealed a decrease in the expression of genes involved in the defense response, including the antimicrobial peptide gene hepcidin, whose expression is induced by lipopolysaccharide stimulation in normal larvae. These results show that reciprocal interactions between the microbiome and the intestinal tract are required for the maturation of the medaka immune system.

Accuracy of Cardiac Output Measured by Fourth-Generation FloTrac and LiDCOrapid, and Their Characteristics Regarding Systemic Vascular Resistance in Patients Undergoing Cardiac Surgery.

OBJECTIVES: The clinical use of less-invasive devices that calculate the cardiac output from arterial pressure waveform is increasing. The authors aimed to evaluate the accuracy and characteristics of the systemic vascular resistance index (SVRI) of the cardiac index measured by 2 less-invasive devices, fourth-generation FloTrac (CIFT) and LiDCOrapid (CILR), compared with the intermittent thermodilution technique, using a pulmonary artery catheter (CITD). DESIGN: This was a prospective observational study. SETTING: This study was conducted at a single university hospital. PARTICIPANTS: Twenty-nine adult patients undergoing elective cardiac surgery. INTERVENTIONS: Elective cardiac surgery was used as an intervention. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters, CIFT, CILR, and CITD, were measured after the induction of general anesthesia, at the start of cardiopulmonary bypass, after completion of weaning from cardiopulmonary bypass, 30 minutes after weaning, and at sternal closure (135 measurements in total). The CIFT and CILR had moderate correlations with CITD (r = 0.62 and 0.58, respectively). Compared with CITD, CIFT, and CILR had a bias of -0.73 and -0.61 L/min/m2, limit of agreement of -2.14-to-0.68 L/min/m2 and -2.42-to-1.20 L/min/m2, and percentage error of 39.9% and 51.2%, respectively. Subgroup analysis for evaluating SVRI characteristics showed that the percentage errors of CIFT and CILR were 33.9% and 54.5% in low SVRI (<1,200 dyne×s/cm5/m), 37.6% and 47.9% in moderate SVRI (1,200-1,800 dyne×s/cm5/m), 49.3% and 50.6% in high SVRI (>1,800 dyne·s/cm5/m2), respectively. CONCLUSIONS: The accuracy of CIFT or CILR was not clinically acceptable for cardiac surgery. Fourth-generation FloTrac was unreliable in high SVRI. LiDCOrapid was inaccurate across a broad range of SVRI, and minimally affected by SVRI.

Self-assembled polydopamine nanoparticles improve treatment in Parkinson's disease model mice and suppress dopamine-induced dyskinesia.

Although Levodopa (l-DOPA), a dopamine precursor, exhibits a high risk of dyskinesia, it remains the primary treatment in Parkinson's disease (PD), a progressive neurodegenerative disorder. In this study, we designed poly(l-DOPA)-based self-assembled nanodrug (NanoDOPA) from amphiphilic block copolymer possessing poly(l-DOPA(OAc)2), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatment, the poly(l-DOPA(OAc)2) in the block copolymer was hydrolyzed to liberate l-DOPA gradually. Using the MPTP-induced PD mouse model, we observed that mice treated with NanoDOPA demonstrated a significant improvement of PD symptoms compared to the l-DOPA treatment. Interestingly, the NanoDOPA treatment did not cause the dyskinesia symptoms, which was clearly observed in the l-DOPA-treated mice. Furthermore, NanoDOPA exhibited remarkably lower toxicity in vitro compared to l-DOPA, in addition with no noticeable NanoDOPA toxicity observed in the treated mice. These results suggested that self-assembled NanoDOPA is a promising therapeutic in the treatment of PD. STATEMENT OF SIGNIFICANCE: In this study, we proposed a therapeutic approach for the effective treatment of Parkinson's disease (PD) using newly designed poly(l-DOPA)-based self-assembled nanodrug (NanoDOPA) prepared from amphiphilic block copolymers possessing poly(l-DOPA(OAc)2), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatments, NanoDOPA was hydrolyzed to liberate l-DOPA gradually, improving the pharmacokinetic value of l-DOPA. The mice treated with NanoDOPA significantly improved PD symptoms compared to the l-DOPA treatment in a neurotoxin-induced PD mouse model. Interestingly, NanoDOPA treatment did not cause dyskinesia symptoms, which was observed in the l-DOPA-treated mice. The obtained results in this study suggested that self-assembled NanoDOPA is a promising therapeutic in the treatment of PD.