Accurate Scaling Functions of the Scaled Schrödinger Equation. II. Variational Examination of the Correct Scaling Functions with the Free Complement Theory Applied to the Helium Atom.

In a previous paper [Phys. Rev. Lett. 2004, 93, 030403.], one of the authors introduced the scaled Schrödinger equation (SSE), g(H - E)ψ = 0 for atoms and molecules, where the scaling function g is the positive function of the electron-nuclear (e-n) and electron-electron (e-e) distances. The SSE is equivalent to the Schrödinger equation (SE), (H - E)ψ = 0, that governs the chemical world but does not have the divergence difficulty that occurs when we try to solve the SE to obtain the exact solution. The g function is essential not only to prevent this divergence difficulty but also to obtain the exact wave function of the SE or SSE. In paper I of this series [J. Chem. Phys. 2022, 156, 014113.], we introduced five analytical g functions that behave correctly at both the coalescence and asymptotic regions, but we examined them only for the e-e part. In this paper, we examine these correct g functions for both e-n and e-e parts by applying the free complement (complete-element) (FC) theory variationally to the He atom. However, even for the two-electron He atom, the analytical integral formulas were not obtained when we use the correct g functions for both e-n and e-e parts, except for g = 1 - exp(-γr), but we were able to perform variational FC calculations by employing numerical integration schemes. We examined not only the energy and wave function but also the H-square error (defined by eq 14 of the text), energy lower bound, and e-n and e-e cusp properties. For the energy lower bound, we applied our FC wave functions to the method proposed recently by Pollak, Martinazzo, and others and could obtain good results. With the use of the correct-group g functions, the convergence of the FC theory to the exact analytical solution of the SE or SSE became efficient, and the performance was particularly good with the g functions, r/(r + 1/γ), Ei, and 1 - exp(-γr) in this order. These results were always superior to those obtained with g = r.

l-Carnitine pretreatment ameliorates heat stress-induced acute kidney injury by restoring mitochondrial function of tubular cells.

A major complication of heat-related illness is the development of acute kidney injury (AKI) and damage to kidney tubular cells. Because kidney tubular cells use fatty acids as a major energy source, impaired fatty acid oxidation (FAO) may be associated with kidney injury due to heat stress. Carnitine is essential in the transportation of fatty acid into mitochondria for FAO. To date, there has been little attention given to the role of carnitine in heat-related illness and AKI. To evaluate the relationship between carnitine inadequacy and heat-related illness severity or AKI, we examined serum carnitine levels in patients with heat-related illness. We also used heat-stressed mice to investigate the effect of l-carnitine pretreatment on various kidney functions such as mitochondrial activity, proinflammatory changes in kidney macrophages, and histological damage. We observed an elevation in serum acylcarnitine levels, indicating carnitine insufficiency in patients with severe heat-related illness and/or AKI. l-Carnitine pretreatment ameliorated ATP production in murine tubular cell mitochondria and prevented a change in the kidney macrophage population dynamics observed in AKI: a decrease in tissue-resident macrophages, influx of bone marrow-derived macrophages, and change toward proinflammatory M1 polarization. In conclusion, carnitine insufficiency may be closely associated with severe heat-related illness and related AKI. Enhancement of the FAO pathway by l-carnitine pretreatment may prevent heat stress-induced AKI by restoring mitochondrial function.NEW & NOTEWORTHY Enhancing fatty acid oxidation (FAO) after acute kidney injury (AKI) improves renal outcomes. This report shows that carnitine insufficiency, which could inhibit FAO, correlates to severe heat-related illness and AKI in a clinical study. We also demonstrate that administering l-carnitine to mice improves mitochondrial respiratory function and prevents deleterious changes in renal macrophage, resulting in improved renal outcomes of heat-induced AKI. l-Carnitine may be an effective preventive treatment for severe heat-related illness and related AKI.

Potential Energy Curves of the Low-Lying Five 1Σ+ and 1Π States of a CH+ Molecule Based on the Free Complement - Local Schrödinger Equation Theory and the Chemical Formula Theory.

The potential energy curves (PECs) of the low-lying five 1Σ+ and 1Π states (X1Σ+, C1Σ+, 31Σ+, A1Π, and D1Π states) of a CH+ molecule, an important interstellar molecule, were calculated by the free complement (FC) - local Schrödinger equation (LSE) theory with the direct local sampling scheme. The FC wave functions were constructed based on the chemical formula theory (CFT), whose local characters correspond to the covalent dissociations: C+(2P°(s2p))) + H(2S) of the X1Σ+ and A1Π states and the ionic dissociations: C(1D(s2p2)) + H+ of the C1Σ+ and D1Π states. All the calculated PECs were obtained with satisfying the chemical accuracy, i.e., error less than 1 kcal/mol, as absolute total energy of the Schrödinger equation without any energy shift. The spectroscopic data calculated from the PECs agreed well with both experimental and other accurate theoretical references. We also analyzed the wave functions using the inverse overlap weights proposed by Gallup et al. with the CFT configurations. For the X1Σ+ and A1Π states, the covalent C+(sp2) and C+(p3) configurations played important roles for bond formation. In the small internuclear distances of the C1Σ+, D1Π, and 31Σ+ states, the covalent character was also dominant as a result of the electron charge transfer from C to H+. Thus, the present FC-LSE results not only are accurate but also can provide chemical understanding according to the CFT.

Novel phenotypical and functional sub-classification of liver macrophages highlights changes in population dynamics in experimental mouse models.

Liver macrophages are critical components of systemic immune system defense mechanisms. F4/80high Kupffer cells (KCs) are the predominant liver-resident macrophages and the first immune cells to contact pathogens entering the liver. F4/80low monocyte-derived macrophages (MoMφs) are essential macrophages that modulate liver immune functions. Here we report a novel method of identifying subpopulations of these two populations using traditional flow cytometry and examine each subpopulation for its putative roles in the pathogenesis of an experimental non-alcoholic steatohepatitis model. Using male C57BL/6 mice, we isolated and analyzed liver non-parenchymal cells by flow cytometry. We identified F4/80high and F4/80low macrophage populations and characterized subpopulations using uniform manifold approximation and projection. We identified three subpopulations in F4/80high macrophages: CD163(+) KCs, CD163(-) KCs, and liver capsular macrophages. CD163(+) KCs had higher phagocytic and bactericidal activities and more complex cellular structures than CD163(-) KCs. We also identified four subpopulations of F4/80low MoMφs based on Ly6C and MHC class II expression: infiltrating monocytes, pro-inflammatory MoMφs, Ly6C(-) monocytes, and conventional dendritic cells. CCR2 knock-out mice expressed lower levels of these monocyte-derived cells, and the count varied by subpopulation. In high-fat- and cholesterol-diet-fed mice, only one subpopulation, pro-inflammatory MoMφs, significantly increased in count. This indicates that changes to this subpopulation is the first step in the progression to non-alcoholic steatohepatitis. The community can use our novel subpopulation and gating strategy to better understand complex immunological mechanisms in various liver disorders through detailed analysis of these subpopulations.

Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.

In vitro study on the effect of fibrinogen γ-chain peptide-coated ADP-encapsulated liposomes on postcardiopulmonary bypass coagulopathy using patient blood.

BACKGROUND: Fibrinogen γ-chain peptide-coated, adenosine 5'-diphosphate (ADP)-encapsulated liposomes (H12-ADP-liposomes) are potent hemostatic adjuvants that promote platelet thrombi formation at bleeding sites. Although we have reported the efficacy of these liposomes in a rabbit model of cardiopulmonary bypass coagulopathy, we are yet to address the possibility of their hypercoagulative potential, especially in human beings. OBJECTIVES: Considering its future clinical applications, we herein investigated the safety of using H12-ADP-liposomes in vitro using blood samples from patients who had received platelet transfusion after cardiopulmonary bypass surgeries. METHODS: Ten patients receiving platelet transfusions after cardiopulmonary bypass surgery were enrolled. Blood samples were collected at the following 3 points: at the time of incision, at the end of the cardiopulmonary bypass, and immediately after platelet transfusion. After incubating the samples with H12-ADP-liposomes or phosphate-buffered saline (PBS, as a control), blood coagulation, platelet activation, and platelet-leukocyte aggregate formation were evaluated. RESULTS: Patients' blood incubated with H12-ADP-liposomes did not differ from that incubated with PBS in coagulation ability, degree of platelet activation, and platelet-leukocyte aggregation at any of the time points. CONCLUSION: H12-ADP-liposomes did not cause abnormal coagulation, platelet activation, or platelet-leukocyte aggregation in the blood of patients who received platelet transfusion after a cardiopulmonary bypass. These results suggest that H12-ADP-liposomes could likely be safely used in these patients, providing hemostasis at the bleeding sites without causing considerable adverse reactions. Future studies are needed to ensure robust safety in human beings.

Antitumor Immunity Exerted by Natural Killer and Natural Killer T Cells in the Liver.

The liver plays crucial roles in systemic immunity and greatly contributes to the systemic defense mechanism. Antitumor immunity in the liver is especially critical for the defense against systemic tumor cell dissemination. To achieve effective defense against metastatic tumor cells, liver immune cells with powerful cytotoxic activities construct a potent defense mechanism. In the liver, as compared with other organs, there is a significantly more intense percentage of innate immune lymphocytes, such as natural killer (NK) and NKT cells. These characteristic lymphocytes survey the portal blood transferred to the liver from the alimentary tract and eliminate malignant cells with their robust cytotoxic ability. Additionally, with their active cytokine-producing capacity, these innate lymphocytes initiate immunological sequences by adaptive immune cells. Therefore, they are crucial contributors to systemic antitumor immunity. These attractive immune cells help conduct a fundamental investigation of tumor immunity and act as a target of clinical measures for cancer therapies. This review discusses the mechanisms of these innate lymphocytes regarding recognition and cytotoxicity against tumor cells and the possibility of clinical applications for therapeutic measures.

Early treatment with C-reactive protein-derived peptide reduces septic acute kidney injury in mice via controlled activation of kidney macrophages.

The mortality rate for acute kidney injury (AKI) due to sepsis remains high, and effective therapies based on its pathogenesis remain elusive. Macrophages are crucial for clearing bacteria from vital organs, including the kidney, under septic conditions. Excessive macrophage activation results in organ injury. C-reactive protein (CRP) peptide (174-185), a functional product of proteolyzed CRP in vivo, effectively activates macrophages. We investigated the therapeutic efficacy of synthetic CRP peptide on septic AKI, focusing on effects on kidney macrophages. Mice underwent cecal ligation and puncture (CLP) to induce septic AKI and were intraperitoneally administered 20 mg/kg of synthetic CRP peptide 1 h post-CLP. Early CRP peptide treatment improved AKI while still clearing infection. Ly6C-negative kidney tissue-resident macrophages did not significantly increase at 3 h after CLP, while Ly6C-positive monocyte-derived macrophages significantly accumulated in the kidney 3 h post-CLP. CRP peptide augmented the phagocytic ROS production in both subtypes of kidney macrophage at 3 h. Interestingly, both subtypes of macrophage increased ROS production 24 h post-CLP compared to the control group, while CRP peptide treatment maintained ROS production at the same level seen 3 h post-CLP. Although bacterium-phagocytic kidney macrophages produced TNF-α, CRP peptide reduced bacterial propagation and tissue TNF-α levels in the septic kidney at 24 h. Although both subsets of kidney macrophages showed populations of M1 at 24 h post-CLP, CRP peptide therapy skewed the macrophages population toward M2 at 24 h. CRP peptide alleviated murine septic AKI via the controlled activation of kidney macrophages and is an excellent candidate for future human therapeutic studies.

Early biomarkers for kidney injury in heat-related illness patients: a prospective observational study at Japanese Self-Defense Force Fuji Hospital.

BACKGROUND: Since heatstroke-induced acute kidney injury (AKI) can progress to chronic kidney disease, it would be useful to detect heatstroke-induced AKI and severe heat-related illness in the early phase. We studied the epidemiology of heat-related illness among patients in the Japanese Ground Self-Defense Force and evaluated the relationship between heat-related illness severity and early urinary biomarkers for AKI. METHODS: We enrolled patients who were diagnosed with heat-related illness at the Self-Defense Force Fuji Hospital from 1 May to 30 September 2020. We compared the urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin levels according to the severity of heat-related illness as defined by positive scores for the Japanese Association of Acute Medicine Heatstroke Working Group (JAAM-HS-WG) criteria (0, mild; 1, moderate; ≥2, severe). RESULTS: Of the 44 patients, kidney injury, defined as serum creatinine (sCr) ≥1.2 mg/dL, was seen in 9 (20.5%) patients. Urinary NAG, NGAL and L-FABP levels were significantly higher in the ≥2 JAAM-HS-WG criteria group than in the 0 group. Furthermore, urinary L-FABP levels were positively correlated with sCr levels. In contrast, the urinary KIM-1 levels showed the best correlation with serum cystatin C (sCysC) among these biomarkers. CONCLUSIONS: We conclude even mild to moderate heatstroke could lead to AKI. Urinary L-FABP is useful for detecting heatstroke-induced AKI and patients with severe heat-related illness requiring immediate treatment. Urinary KIM-1 may detect heatstroke-induced AKI in terms of sCysC, although it was not related to the severity of heat-related illness.

Pioglitazone Modifies Kupffer Cell Function and Protects against Escherichia coli-Induced Bacteremia in Burned Mice.

Infectious complications and subsequent sepsis in severely burned patients lead to high morbidity and mortality in response to uncontrolled innate immune responses mediated by macrophages. Peroxisome proliferator-activated receptor gamma (PPARγ) has anti-inflammatory activity and acts as a master regulator of macrophage polarization. In this study, we investigated whether the administration of a PPARγ agonist could modulate the Kupffer cell phenotype and thereby ameliorate the dysregulated innate response during post-burn bacterial infection. C57BL/6 mice were subjected to severe burns and randomized to receive either the PPARγ agonist, pioglitazone, or the vehicle control five days after injury, followed by the subsequent analysis of hepatic macrophages. Survival from the bacterial infection was monitored for seven days. Pioglitazone protected burned mice against bacterial infection. A single treatment with pioglitazone significantly enhanced phagocytosis, phagosome acidification, bacterial clearance, and reduction in inflammatory mediators in Kupffer cells. In conclusion, PPARγ activation by pioglitazone prevents clinical deterioration due to post-burn bacterial infection and improves survival. Our findings suggest that pioglitazone may be an effective therapeutic candidate for post-burn infectious complications.

Potential curves of the lower nine states of Li2 molecule: Accurate calculations with the free complement theory and the comparisons with the SAC/SAC-CI results.

The free-complement (FC) theory proposed for solving the Schrödinger equation of atoms and molecules highly accurately was applied to the calculations of the potential curves of the lower nine states of the Li2 molecule. The results were compared with the accurate experimental Rydberg-Klein-Rees potential curves available. They overlap completely with each other without any shift everywhere for all the states of Li2. At all the calculated points on the seven potential curves ranging between -14.83 and -15.00 hartree, the average difference was only 0.0583 kcal/mol and the maximum difference was only +0.165 kcal/mol. For the vertical excitation energies from the ground state curve to the seven excited states, the differences between theory and experiment were 0.000 645 eV in average and their maximum difference was -0.007 20 eV. The potential properties calculated with the FC theory also agreed well with the experimental values. These results show a high potentiality of the FC theory as a highly predictive quantum chemistry theory. For comparison, as an example of the Hartree-Fock based theory popular in modern quantum chemistry, we adopted the symmetry-adapted-cluster (SAC)-configuration-interaction (CI) theory using a highly flexible basis set. While the FC theory gave the absolute agreements with experiments, the SAC-CI potential curves compare reasonably well with experiments only after shifting-down of the SAC-CI curves by 5.727 kcal/mol. The differences in the excitation energies between SAC-CI and experiments were 0.004 28 eV on average, and the maximum difference was +0.109 67 eV. The SAC-CI results reported in 1985 were less accurate but still reasonable.

Heat acclimation ameliorated heat stress-induced acute kidney injury and prevented changes in kidney macrophages and fibrosis.

Heatstroke can cause acute kidney injury (AKI), which reportedly progresses to chronic kidney disease. Kidney macrophages may be involved in such injury. Although heat acclimation (HA) provides thermal resilience, its renoprotective effect and mechanism remain unclear. To investigate heat stress-induced kidney injuries in mice and the mitigating effect of HA on them, male C57/BL6J mice were exposed to heat stress (40°C, 1 h) with or without 5-day HA (38°C, 3 h/day) prior to heat stress. Heat stress damaged kidney proximal tubules with an elevation of urinary kidney injury molecule-1. Kidney fibrosis was observed on day 7 and correlated with urinary kidney injury molecule-1 levels on day 3. Kidney resident macrophages decreased on day 1, whereas the number of infiltrating macrophages in the kidney did not change. Both subsets of macrophages polarized to the proinflammatory M1 phenotype on day 1; however, they polarized to the anti-inflammatory M2 phenotype on day 7. HA significantly ameliorated heat stress-induced proximal tubular damage and kidney fibrosis. HA substantially increased heat shock protein 70 expression in the tubules before heat stress and reduced the elevation of cleaved caspase-3 expression after heat stress. HA also induced heat shock protein 70 expression of resident macrophages and prevented heat stress-induced changes in both subsets of kidney macrophages. These results provide pathophysiological data supporting the renoprotective effect of HA. Further studies are needed to confirm that HA can prevent kidney damage due to heat stress in humans.NEW & NOTEWORTHY Heat stress could induce acute kidney injury. Although heat acclimation (HA) reportedly provides thermal tolerance, its effect on heat stress-induced kidney damage remains unclear. This study showed that 5-day HA ameliorates mouse kidney tubular damage and subsequent fibrosis caused by heat stress. It also demonstrated that HA enhances intracellular heat shock protein 70 expression in tubular cells and prevents a decrease in kidney resident macrophages, which explains the renoprotective effect of HA.

Mouse Liver B Cells Phagocytose Streptococcus pneumoniae and Initiate Immune Responses against Their Antigens.

Recent studies have revealed that mammalian B cells ingest particulate Ags, such as bacteria, although little is known about the effect of this function on acquired immunity. We investigated the role of bacterium-phagocytosing B cells in acquired host immune responses. Cultured mouse liver B cells substantially phagocytosed serum-opsonized Streptococcus pneumoniae and produced IgM. On adoptive transfer of liver B cells that phagocytose S. pneumoniae labeled with pHrodo Red succinimidyl ester, recipient mice showed elevated plasma levels of IgG specific for bacterial Ags. In particular, the levels of IgG2a and IgG2b specific for pneumococcal surface protein A, as well as IgG3 for pneumococcal polysaccharide, were markedly increased compared with total IgG specific for each Ag. When phagocytic liver B cells were cultured with spleen CD4+ T cells obtained from mice primed with heat-killed S. pneumoniae 7 d before, they induced IL-2 production and proliferation of the CD4+ T cells, along with Th1 cytokine production. However, they induced neither the CD4+ T cell production of IL-21, a suggested marker promoting B cell proliferation and differentiation, nor the expression of genes important for somatic hypermutation or isotype switching; such responses were particularly evident when splenic B cells merely capturing S. pneumoniae without processing them were cultured with spleen CD4+ T cells. These findings suggest that phagocytic liver B cells may be involved in acquired immune responses by presenting derivative peptides to CD4+ T cells without their own somatic hypermutation or isotype switching.

Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy.

INTRODUCTION: In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs), and triggers their activation. METHODS: We orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of L-carnitine on kidney mitochondrial reactive oxygen species (mtROS) production, circulating mtDNA content, and kidney CD11bhigh/CD11blow Mφ functions. RESULTS: In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11blow Mφs; both Mφ types showed enhanced TLR9 expression. L-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11blow Mφs (p < 0.01), with improved SOD2 expression in the kidney (p < 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p < 0.01), thereby lowering tumor necrosis factor-α production in CD11bhigh Mφs (p < 0.05) and ROS production by CD11blow Mφs (p < 0.01). Collectively, these changes alleviated DN symptoms. CONCLUSION: The positive effects of L-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.

Accurate scaling functions of the scaled Schrödinger equation.

The scaling function g of the scaled Schrödinger equation (SSE) is generalized to obtain accurate solutions of the Schrödinger equation (SE) with the free complement (FC) theory. The electron-nuclear and electron-electron scaling functions, giA and gij, respectively, are generalized. From the relations between SE and SSE at the inter-particle distances being zero and infinity, the scaling function must satisfy the collisional (or coalescent) condition and the asymptotic condition, respectively. Based on these conditions, general scaling functions are classified into "correct" (satisfying both conditions), "reasonable" (satisfying only collisional condition), and "approximate but still useful" (not satisfying collisional condition) classes. Several analytical scaling functions are listed for each class. Popular functions riA and rij belong to the reasonable class. The qualities of many electron-electron scaling functions are examined variationally for the helium atom using the FC theory. Although the complement functions of FC theory are produced generally from both the potential and kinetic operators in the Hamiltonian, those produced from the kinetic operator were shown to be less important than those produced from the potential operator. Hence, we used only the complement functions produced from the potential operator and showed that the correct-class gij functions gave most accurate results and the reasonable-class functions were less accurate. Among the examined correct and reasonable functions, the conventional function rij was worst in accuracy, although it was still very accurate. Thus, we have many potentially accurate "correct" scaling functions for use in FC theory to solve the SEs of atoms and molecules.

Mobile endovascular therapy for acute treatment of ruptured vertebral artery dissecting aneurysm in multiple hospitals.

BACKGROUND: The patients with ruptured vertebral artery dissecting aneurysm (rVADA) should be treated as early as possible because VADA carries extremely high risk of rebleeding in the acute phase. We have established a mobile endovascular strategy for the patients with rVADA between our flagship center and its affiliated local hospitals. We introduced and reviewed our mobile endovascular therapy in this study. METHODS: We retrospectively evaluated 98 consecutive patients who underwent endovascular surgery for rVADA from 2000 to 2018 at our institution or five affiliated hospitals. When each patient was initially transported to the local affiliated hospitals, neuroendovascular surgeons traveled directly to the affiliated hospital from the flagship center in order to treat the patient there. Clinical outcomes using modified Rankin Scale at 6 months after treatment, radiological results, and procedure-related complications were reviewed to justify our mobile endovascular strategy. RESULTS: All aneurysms were cured successfully by internal trapping. Favorable outcome was achieved in 61 patients (62.2%) even though 53 patients (54.1%) had presented with severe subarachnoid hemorrhage. Overall mortality rate, treatment-related mortality rate, and treatment related complication rate were 18.4% (18/98), 0%, and 16% (16/98), respectively. There were no differences in clinical and radiological outcomes between the patients treated in the flagship center and those who treated in the affiliated hospitals. Treatment in the affiliated hospital was not a predictive factor of unfavorable outcome in our multivariate analysis, and elderly age (≥ 60) was negatively associated with favorable outcome. CONCLUSIONS: Our results prove the efficacy and safety of mobile endovascular therapy for the treatment of rVADA in the ultra-acute stage. Mobile endovascular therapy may work well in the acute treatment of rVADAs in the certain circumstance.

Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice.

The nuclear receptors liver X receptor α (LXRα) and LXRß are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/ß in hepatic NKT cells remains unknown. In this study, we examined the role of LXRα and LXRß in NKT cells using mice deficient for LXRα and/or LXRß, and found that hepatic invariant NKT (iNKT) cells are drastically decreased in LXRα/ß-KO mice. Cytokine production stimulated by the iNKT cell activator α-galactosylceramide was impaired in LXRα/ß-KO hepatic mononuclear cells and in LXRα/ß-KO mice. iNKT cell-mediated antitumor effect was also disturbed in LXRα/ß-KO mice. LXRα/ß-KO mice transplanted with wild-type bone marrow showed decreased iNKT cells in the liver and spleen. The thymus of LXRα/ß-KO mice showed a decreased population of iNKT cells. In conclusion, LXRα and LXRß are essential for NKT cell-mediated immunity, such as cytokine production and hepatic antitumor activity, and are involved in NKT cell development in immune tissues, such as the thymus.

Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy.

The pathogenesis of diabetic nephropathy (DN) is related to macrophage (Mφ) recruitment to the kidneys, tumor necrosis factor-α (TNF-α) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney Mφs in DN model (db/db) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 wk; changes in Mφ distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11bhigh (BM-Mφ) and tissue-resident CD11blow Mφs (Res-Mφ) were identified in the mouse kidneys. As DN progressed, the BM-Mφ number, TLR9 expression, and TNF-α production increased significantly. In Res-Mφs, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-Mφ abundance, TLR9 expression, and TNF-α production by BM-Mφs and ROS production by Res-Mφs. Both increased activation of BM-Mφ via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating Mφs and their TLR9 expression by INCB3344 is a potential therapeutic strategy for DN.NEW & NOTEWORTHY We classified kidney macrophages (Mφs) into bone marrow-derived Mφs (BM-Mφs) expressing high CD11b and tissue-specific resident Mφ (Res-Mφs) expressing low CD11b. In diabetic nephropathy (DN) model mice, Toll-like receptor 9 (TLR9) expression and TNF-α production via TLR9 activation in BM-Mφs and ROS production in Res-Mφs were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-Mφs and their function and the ROS production by Res-Mφs, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.

Variations and management for patients with craniocervical junction arteriovenous fistulas: Comparison of dural, radicular, and epidural arteriovenous fistulas.

BACKGROUND: Craniocervical junction arteriovenous fistulas (CCJAVFs) are known to be rare, but variations and clinical behaviors remain controversial. METHODS: A total of 11 CCJAVF patients (M: F=9:2, age 54-77 years) were investigated. Based on the radiological and intraoperative findings, they were categorized into three types: dural AVF (DAVF), radicular AVF (RAVF), and epidural AVF (EDAVF). RESULTS: There were four symptomatic patients (subarachnoid hemorrhage in two, myelopathy in one, and tinnitus in one) and seven asymptomatic patients in whom coincidental CCJAVFs were discovered on imaging studies for other vascular diseases (arteriovenous malformation in one, intracranial DAVF in two, ruptured cerebral aneurysm in two, and carotid artery stenosis in two). Of these 11 patients, 2 (18.2%) had multiple CCJAVFs. Of 14 lesions, the diagnoses were DAVF in 5, RAVF in 3, and EDAVF in 6 (C1-C2 level ratio =5:0, 2:1, 3:3). Patients with DAVF/RAVF in four lesions with intradural venous reflux underwent surgery, although an RAVF remained in one lesion after embolization/radiation. Since all six EDAVFs, two DAVFs, and one RAVF had neither feeder aneurysms nor significant symptoms, no treatment was provided; of these nine lesions, one DAVF and one RAVF remained unchanged, whereas six EDAVFs showed spontaneous obliteration within a year. Unfortunately, however, one DAVF bled before elective surgery. CONCLUSION: CCJAVFs have many variations of shunting site, angioarchitecture, and multiplicity, and they were frequently associated with coincidental vascular lesions. For symptomatic DAVF/RAVF lesions with intradural drainage, surgery is preferred, whereas asymptomatic EDAVFs without dangerous drainage may obliterate during their natural course.