Everolimus Rescue Treatment for Chronic Rejection After Pediatric Living Donor Liver Transplantation: 2 Case Reports

Ueno T., Hiwatashi S., Saka R., et al. Everolimus Rescue Treatment for Chronic Rejection After Pediatric Living Donor Liver Transplantation: 2 Case Reports. Transplantation Proceedings 50, 2872 (2018); https://doi.org/10.1016/J.TRANSPROCEED.2018.03.079.Chronic rejection (CR) remains a challenging complication after liver transplantation. Everolimus, which is a mammalian target of rapamycin inhibitor, has an anti-fibrosis effect. We report here the effect of everolimus on CR. Case 1 was a 7-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 10 months of age. Liver function tests (LFTs) did not improve after transplantation despite treatment with tacrolimus + mycophenolate mofetil (MMF). Antithymoglobulin (ATG) and steroid pulse therapy were also ineffective. The patient was diagnosed with CR, and everolimus was started with a target trough level of about 5 ng/mL. LFTs improved and pathological examination showed no progression of hepatic fibrosis. Case 2 was a 10-year-old girl with Alagille syndrome who underwent LDLT at 1 year of age. She had biopsy-proven acute cellular rejection with prolonged LFT abnormalities beginning 3 years after transplantation. She was treated with steroid pulse therapy, followed by MMF, tacrolimus, and prednisolone. Her condition did not improve, even after subsequent ATG administration. CR was suspected based on liver biopsy in the fourth postoperative year, and everolimus was introduced. The target trough level was around 5 ng/mL, but was reduced to 3 ng/mL due to stomatitis. Four years have passed since the initiation of everolimus, and LFTs are stable with no progression of liver biopsy fibrosis. We describe 2 cases in which everolimus was administered for CR. In both cases, LFTs improved and fibrosis did not progress, suggesting that everolimus is an effective treatment for CR after LDLT

Pulmonary Arterial Pressure Management Based on Oral Medicine for Pediatric Living Donor Liver Transplant With Portopulmonary Hypertension

Ueno T., Hiwatashi S., Saka R., et al. Pulmonary Arterial Pressure Management Based on Oral Medicine for Pediatric Living Donor Liver Transplant With Portopulmonary Hypertension. Transplantation Proceedings 50, 2614 (2018); https://doi.org/10.1016/J.TRANSPROCEED.2018.03.068.Pediatric living donor liver transplantation (LDLT) in patients with advanced portopulmonary hypertension (PoPH) is associated with poor prognoses. Recently, novel oral medications, including endothelin receptor antagonists (ERAs), phosphodiesterase 5 (PDE5) inhibitors, and oral prostacyclin (PGI2) have been used to treat PoPH. Pediatric patients with PoPH who underwent LDLT from 2006 to 2016 were enrolled. Oral pulmonary hypertension (PH) medication was administered to control pulmonary arterial pressure (PAP). Four patients had PoPH. Their ages ranged from 6 to 16 years, and their original diseases were biliary atresia (n = 2), portal vein obstruction (n = 1), and intrahepatic portal systemic shunt (n = 1). For preoperative management, 2 patients received continuous intravenous PGI2 and 2 oral medications (an ERA alone or an ERA and a PDE5 inhibitor), and 2 received only oral drugs (an ERA and a PDE5 inhibitor). One patient managed only with intravenous PGI2 died. In the remaining 3 cases, intravenous PGI2 or NO was discontinued before the end of the first postoperative week. Postoperative medications were oral PGI2 alone (n = 1), an ERA alone (n = 1), or the combination of an ERA and a PDE5 inhibitor (n = 1). An ERA was the first-line therapy, and a PDE5 inhibitor was added if there was no effect. New oral PH medications were effective and safe for use in pediatric patients following LDLT. In particular, these new oral drugs prevent the need for central catheter access to infuse PGI2

Magnetic structures of RbCuCl_3 in a transverse field

A recent high-field magnetization experiment found a phase transition of unknown character in the layered, frustrated antiferromagnet RbCuCl_3, in a transverse field (in the layers). Motivated by these results, we have examined the magnetic structures predicted by a model of RbCuCl_3, using the classical approximation. At small fields, we obtain the structure already known to be optimal, an incommensurate (IC) spiral with wave vector q in the layers. At higher fields, we find a staircase of long-period commensurate (C) phases (separated initially by the low-field IC phase), then two narrow IC phases, then a fourth IC phase (also with intermediate C phases), and finally the ferromagnetically aligned phase at the saturation field H_S. The three-sublattice C states familiar from the theory of the triangular antiferromagnet are never optimal. The C phases and the two intermediate IC phases were previously unknown in this context. The magnetization is discontinuous at a field \approx 0.4H_S, in qualitative agreement with experiment, though we find much fine structure not reported.Comment: 9 pages, 8 figure

Fluctuation-induced phase in CsCuCl3 in transverse magnetic field: Theory

CsCuCl3 is a quantum triangular antiferromagnet, ferromagnetically stacked, with an incommensurate (IC) structure due to a Dzyaloshinskii-Moriya interaction. Because of the classical degeneracy caused by the frustration, fluctuations in CsCuCl3 have extraordinarily large effects, such as the phase transition in longitudinal magnetic field (normal to the planes, parallel to the IC wavenumber q) and the plateau in q in transverse field (perpendicular to q). We argue that fluctuations are responsible also for the new IC phase discovered in transverse field near the Neel temperature T_N, by T. Werner et al. [Solid State Commun. 102, p.609 (1997)]. We develop and analyse the corresponding minimal Landau theory; the effects of fluctuations on the frustration are included phenomenologically, by means of a biquadratic term. The Landau theory gives two IC phases, one familiar from previous studies; properties of the new IC phase, which occupies a pocket of the temperature-field phase diagram near T_N, agree qualitatively with those of the new phase found experimentally.Comment: 12 pages, revtex, 4 postscript figures, submitted to J. Phys: Condens. Matte

Oblique triangular antiferromagnetic phase in CsCu1−x_{1-x}Cox_xCl3_3

The spin-1/2 stacked triangular antiferromagnet CsCu$_{1-x}$Co$_x$Cl$_3$ with $0.015<x<0.032$ undergoes two phase transitions at zero field. The low-temperature phase is produced by the small amount of Co$^{2+}$ doping. In order to investigate the magnetic structures of the two ordered phases, the neutron elastic scattering experiments have been carried out for the sample with $x\approx 0.03$. It is found that the intermediate phase is identical to the ordered phase of CsCuCl$_3$, and that the low-temperature phase is an oblique triangular antiferromagnetic phase in which the spins form a triangular structure in a plane tilted from the basal plane. The tilting angle which is 42$^{\circ}$ at $T=1.6$ K decreases with increasing temperature, and becomes zero at $T_{\rm N2} =7.2$ K. An off-diagonal exchange term is proposed as the origin of the oblique phase.Comment: 6 pages, 7 figure

Electronic structure of Co_xTiSe_2 and Cr_xTiSe_2

The results of investigations of intercalated compounds Cr_xTiSe_2 and Co_xTiSe_2 by X-ray photoelectron spectroscopy (XPS) and X-ray emission spectroscopy (XES) are presented. The data obtained are compared with theoretical results of spin-polarized band structure calculations. A good agreement between theoretical and experimental data for the electronic structure of the investigated materials has been observed. The interplay between the M3d--Ti3d hybridization (M=Cr, Co) and the magnetic moment at the M site is discussed. A 0.9 eV large splitting of the core Cr2p{3/2} level was observed, which reveals a strong exchange magnetic interaction of 3d-2p electrons of Cr. In the case of a strong localization of the Cr3d electrons (for x<0.25), the broadening of the CrL spectra into the region of the states above the nominal Fermi level was observed and attributed to X-ray re-emission. The measured kinetic properties are in good accordance with spectral investigations and band calculation results.Comment: 14 pages, 11 figures, submitted to Phys.Rev.

Duplication and Diversification of the Hypoxia-Inducible IGFBP-1 Gene in Zebrafish

Gene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes.We report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1). IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker.These results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic conditions

Hypoxia Impairs Primordial Germ Cell Migration in Zebrafish (Danio rerio) Embryos

Background: As a global environmental concern, hypoxia is known to be associated with many biological and physiological impairments in aquatic ecosystems. Previous studies have mainly focused on the effect of hypoxia in adult animals. However, the effect of hypoxia and the underlying mechanism of how hypoxia affects embryonic development of aquatic animals remain unclear. Methodology/Principal Findings: In the current study, the effect of hypoxia on primordial germ cell (PGC) migration in zebrafish embryos was investigated. Hypoxic embryos showed PGC migration defect as indicated by the presence of mis-migrated ectopic PGCs. Insulin-like growth factor (IGF) signaling is required for embryonic germ line development. Using real-time PCR, we found that the mRNA expression levels of insulin-like growth factor binding protein (IGFBP-1), an inhibitor of IGF bioactivity, were significantly increased in hypoxic embryos. Morpholino knockdown of IGFBP-1 rescued the PGC migration defect phenotype in hypoxic embryos, suggesting the role of IGFBP-1 in inducing PGC mis-migration. Conclusions/Significance: This study provides novel evidence that hypoxia disrupts PGC migration during embryonic development in fish. IGF signaling is shown to be one of the possible mechanisms for the causal link between hypoxia and PGC migration. We propose that hypoxia causes PGC migration defect by inhibiting IGF signaling through the induction of IGFBP-1