A Novel Xenogeneic Graft-Versus-Host Disease Model for Investigating the Pathological Role of Human CD4+ or CD8+ T Cells Using Immunodeficient NOG Mice.

Graft-versus-host disease (GVHD) is a major complication of allogenic bone marrow transplantation and involves the infiltration of donor CD4+ and/or CD8+ T cells into various organs of the recipient. The pathological role of human CD4+ and CD8+ T cells in GVHD remains controversial. In this study, we established two novel xenogeneic (xeno)-GVHD models. Human CD4+ or CD8+ T cells were purified from peripheral blood and were transplanted into immunodeficient NOD/Shi-scid IL2rgnull (NOG) mice. Human CD8+ T cells did not induce major GVHD symptoms in conventional NOG mice. However, CD8+ T cells immediately proliferated and induced severe GVHD when transferred into NOG mice together with at least 0.5 × 106 CD4+ T cells or into NOG human interleukin (IL)-2 transgenic mice. Human CD4+ T cell-transplanted NOG mice developed skin inflammations including alopecia, epidermal hyperplasia, and neutrophilia. Pathogenic T helper (Th)17 cells accumulated in the skin of CD4+ T cell-transplanted NOG mice. Further, an anti-human IL-17 antibody (secukinumab) significantly suppressed these skin pathologies. These results indicate that pathogenic human Th17 cells induce cutaneous GVHD via IL-17-dependent pathways. This study provides fundamental insights into the pathogenesis of xeno-GVHD, and these humanized mouse models may be useful as preclinical tools for the prevention of GVHD.

Comparison of ultrasonographic joint and tendon findings in hands between early, treatment-naïve patients with systemic lupus erythematosus and rheumatoid arthritis.

Although both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) may lead to joint deformity, SLE arthritis is typically non-erosive and often accompanied by Jaccoud's deformity. Therefore, we examined characteristics of joint and tendon lesions in patients with SLE and RA by ultrasonography. Fifteen treatment-naïve SLE patients and 40 treatment-naïve RA patients with joint symptoms were included in this study. The hand joints and related tendons were ultrasonographically examined using grey-scale (GS) and power Doppler (PD). Joint involvement was comparably observed in patients with SLE and RA (80% versus 95%, p = 0.119). However, tendon involvement was more frequent in SLE than in RA (93% versus 65%, p = 0.045), especially in the wrist joints (73% versus 40%, p = 0.037). When we investigated the intensity of US findings, the joint synovitis score (GS + PD) per affected joint was lower in SLE than RA (2.0 versus 2.6, p = 0.019), while tendon inflammation score was not significantly different (2.1 versus 2.2, p = 0.738). Finally, the examination of concordance between joint and tendon involvement in the same finger revealed that joint lesion appeared in only 49% of fingers having tendon involvement in the SLE group, which was significantly less than 74% in the RA group ( p = 0.010). Thus, as compared with RA, SLE arthropathy is characterized by the predominance of tenosynovitis/periextensor tendon inflammation, which is likely to develop independently from joint synovitis.

Biochemical and hematologic effects of polyvinylpyrrolidone-wrapped fullerene C60 after oral administration.

The fullerene C60 is used in consumer products such as cosmetics owing to its antioxidative effects and is being developed for nanomedical applications. However, knowledge regarding the safety of fullerene C60, especially after oral administration, is sparse. Here, we examined the safety of fullerene C60 in mice after 7 d of exposure to orally administered polyvinylpyrrolidone (PVP)-wrapped fullerene C60 (PVP-fullerene C60). Mice treated with PVP-fullerene C60 showed few changes in the plasma levels of various markers of kidney and liver injury and experienced no significant hematologic effects. Furthermore, the histology of the colon of PVP-fullerene C60-treated mice was indistinguishable from that of control mice. These results suggest that PVP-fullerene C60 lacks toxicity after high-dose oral administration and indicate that PVP-fullerene C60 can be considered safe for oral medication. These data provide basic information that likely will facilitate the production of safe and effective forms of fullerene C60.

ADC Level is Related to DWI Reversal in Patients Undergoing Mechanical Thrombectomy: A Retrospective Cohort Study.

BACKGROUND AND PURPOSE: In patients with ischemic stroke, DWI lesions can occasionally be reversed by reperfusion therapy. This study aimed to ascertain the relationship between ADC levels and DWI reversal in patients with acute ischemic stroke who underwent recanalization treatment. MATERIALS AND METHODS: We conducted a retrospective cohort study in patients with acute ischemic stroke who underwent endovascular mechanical thrombectomy with successful recanalization between April 2017 and March 2021. DWI reversal was assessed through follow-up MR imaging approximately 24 hours after treatment. RESULTS: In total, 118 patients were included. DWI reversal was confirmed in 42 patients. The ADC level in patients with reversal was significantly higher than that in patients without reversal. Eighty-three percent of patients with DWI reversal areas had mean ADC levels of ≥520 × 10-6 mm2/s, and 71% of patients without DWI reversal areas had mean ADC levels of <520 × 10-6 mm2/s. The mean ADC threshold was 520 × 10-6 mm2/s with a sensitivity and specificity of 71% and 83%, respectively. In multivariate analysis, the mean ADC level (OR, 1.023; 95% CI, 1.013-1.033; P < .0001) was independently associated with DWI reversal. Patients with DWI reversal areas had earlier neurologic improvement (NIHSS at 7 days) than patients without reversal areas (P < .0001). CONCLUSIONS: In acute ischemic stroke, the ADC value is independently associated with DWI reversal. Lesions with a mean ADC of ≥520 × 10-6 mm2/s are salvageable by mechanical thrombectomy, and DWI reversal areas regain neurologic function. The ADC value is easily assessed and is a useful tool to predict viable lesions.

A larger number of L chains (Tac) enhance the association rate of interleukin 2 to the high affinity site of the interleukin 2 receptor.

The IL-2-R is composed of at least two proteins, that is, a 55-kD protein (p55, the L chain, or Tac) and a 75-kD protein (p75, the H chain, or converter). The high affinity binding of IL-2 results in the formation of the ternary complex consisting of IL-2, and the L and H chains. To distinguish the affinity conversion model and the binary complex model we have carried out kinetic studies on the IL-2 binding to the high affinity IL-2-R on T lymphocytes expressing various numbers of L chains and a relatively constant number of H chains. We found that expression of a larger number of L chains accelerated the association of IL-2 to the high affinity receptor. The results are not compatible with the binary complex model that assumes a fixed number of high affinity sites determined by the numbers of a limiting chain. Instead, the results are consistent with the prediction of the affinity conversion model that assumes association of IL-2 to the L chain as the first step of the ternary complex formation and they indicate that the possible role of excess L chains is to accelerate the formation of the ternary complex. The reaction rate constants calculated from the affinity conversion model were reasonably constant.

Pirfenidone in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

Topological metastability supported by thermal fluctuation upon formation of chiral soliton lattice in [Formula: see text].

Topological magnetic structure possesses topological stability characteristics that make it robust against disturbances which are a big advantage for data processing or storage devices of spintronics; nonetheless, such characteristics have been rarely clarified. This paper focused on the formation of chiral soliton lattice (CSL), a one-dimensional topological magnetic structure, and provides a discussion of its topological stability and influence of thermal fluctuation. Herein, CSL responses against change of temperature and applied magnetic field were investigated via small-angle resonant soft X-ray scattering in chromium niobium sulfide ([Formula: see text]). CSL transformation relative to the applied magnetic field demonstrated a clear agreement with the theoretical prediction of the sine-Gordon model. Further, there were apparent differences in the process of chiral soliton creation and annihilation, discussed from the viewpoint of competing between thermal fluctuation and the topological metastability.

Niflumic acid-sensitive ion channels play an important role in the induction of glucose-stimulated insulin secretion by cyclic AMP in mice.

AIMS/HYPOTHESIS: We have previously reported that glucose-stimulated insulin secretion (GSIS) is induced by glucagon-like peptide-1 (GLP-1) in mice lacking ATP-sensitive K(+) (K(ATP)) channels (Kir6.2(-/-) mice [up-to-date symbol for Kir6.2 gene is Kcnj11]), in which glucose alone does not trigger insulin secretion. This study aimed to clarify the mechanism involved in the induction of GSIS by GLP-1. METHODS: Pancreas perfusion experiments were performed using wild-type (Kir6.2(+/+)) or Kir6.2(-/-) mice. Glucose concentrations were either changed abruptly from 2.8 to 16.7 mmol/l or increased stepwise (1.4 mmol/l per step) from 2.8 to 12.5 mmol/l. Electrophysiological experiments were performed using pancreatic beta cells isolated from Kir6.2(-/-) mice or clonal pancreatic beta cells (MIN6 cells) after pharmacologically inhibiting their K(ATP) channels with glibenclamide. RESULTS: The combination of cyclic AMP plus 16.7 mmol/l glucose evoked insulin secretion in Kir6.2(-/-) pancreases where glucose alone was ineffective as a secretagogue. The secretion was blocked by the application of niflumic acid. In K(ATP) channel-inactivated MIN6 cells, niflumic acid similarly inhibited the membrane depolarisation caused by cAMP plus glucose. Surprisingly, stepwise increases of glucose concentration triggered insulin secretion only in the presence of cAMP or GLP-1 in Kir6.2(+/+), as in Kir6.2(-/-) pancreases. CONCLUSIONS/INTERPRETATION: Niflumic acid-sensitive ion channels participate in the induction of GSIS by cyclic AMP in Kir6.2(-/-) beta cells. Cyclic AMP thus not only acts as a potentiator of insulin secretion, but appears to be permissive for GSIS via novel, niflumic acid-sensitive ion channels. This mechanism may be physiologically important for triggering insulin secretion when the plasma glucose concentration increases gradually rather than abruptly.

Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2.

The role of Lefty2 in left-right patterning was investigated by analysis of mutant mice that lack asymmetric expression of lefty2. These animals exhibited various situs defects including left isomerism. The asymmetric expression of nodal was prolonged and the expression of Pitx2 was upregulated in the mutant embryos. The absence of Lefty2 conferred on Nodal the ability to diffuse over a long distance. Thus, Nodal-responsive genes, including Pitx2, that are normally expressed on the left side were expressed bilaterally in the mutant embryos, even though nodal expression was confined to the left side. These results suggest that Nodal is a long-range signaling molecule but that its range of action is normally limited by the feedback inhibitor Lefty2.

A phase II dose-ranging study of palonosetron in Japanese patients receiving moderately emetogenic chemotherapy, including anthracycline and cyclophosphamide-based chemotherapy.

BACKGROUND: The 5-HT(3) receptor antagonists (RAs) help maintain the standard of care, in various combinations with other agents, for prevention of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a new generation 5-HT(3) RA with indication not only acute but also delayed nausea and vomiting induced by moderately emetogenic chemotherapy (MEC). This study was carried out to determine the optimal dosage of palonosetron in combination with dexamethasone in patients in Japan. PATIENTS AND METHODS: This study evaluated the efficacy and safety of palonosetron in patients receiving MEC combined with dexamethasone. Patients received single doses of 0.075, 0.25, or 0.75 mg of palonosetron before MEC. Dexamethasone was infused before palonosetron, at 20 mg for the patients receiving paclitaxel (Taxol) and 8 mg for the patients not receiving paclitaxel. The primary end point was complete response (CR: no emetic episodes and no rescue medication) in the acute phase (0-24 h). RESULTS: In total, 204 patients (88 men, 116 women; 96 with paclitaxel, 108 without paclitaxel) were assessable for efficacy. No dose-response relationship was observed regarding the CR rate in the acute phase. CR rates increased dose dependently for delayed (24-120 h) and overall (0-120 h) phases in patients receiving anthracyclines and cyclophosphamide combination (AC/EC, n = 80); however, the difference in CR rates among doses was not statistically significant. The most commonly reported adverse events related to palonosetron were constipation and headache, confirming the class safety profile. CONCLUSION: This study indicates a statistically nonsignificant trend for the dose-response relationship for antiemetic protection in the delayed and overall phases in AC/EC patients (the regimen currently considered to be more emetogenic than MEC).

Effect of individual fat areas on early surgical outcomes after open gastrectomy for gastric cancer.

BACKGROUND: Obesity is generally considered a risk factor for postoperative morbidity following open gastrectomy. Body mass index (BMI) is widely accepted as an indicator of obesity, but does not necessarily reflect the distribution of fat. It is unclear how different types of fat may affect the operative procedure and outcome. METHODS: The relationship between fat area (total, visceral and subcutaneous fat, and BMI) and early surgical outcomes (bleeding, operating time, morbidity, hospital death and hospital stay) was investigated in 135 patients who had a curative gastrectomy at the Cancer Institute Hospital, Tokyo, in 2006. RESULTS: Postoperative intra-abdominal infection, which occurred in 13 patients (9.6 per cent), correlated strongly with visceral (P = 0.023) and total (P = 0.037) fat area. Visceral fat area also correlated with hospital death (P = 0.041) and a longer hospital stay (P = 0.001). Subcutaneous fat area and BMI did not correlate with these early surgical outcomes. CONCLUSION: Patients with a high visceral fat area are more likely to develop an intra-abdominal infection after gastrectomy. Assessment of fat area, in particular visceral fat area, should alert surgeons to increased postoperative risks.

Tbx5 and the retinotectum projection.

Dorsal and ventral aspects of the eye are distinct from the early stages of development. The developing eye cup grows dorsally, and the choroidal fissure is formed on its ventral side. Retinal axons from the dorsal and ventral retina project to the ventral and dorsal tectum, respectively. Misexpression of the Tbx5 gene induced dorsalization of the ventral side of the eye and altered projections of retinal ganglion cell axons. Thus, Tbx5 is involved in eye morphogenesis and is a topographic determinant of the visual projections between retina and tectum.

A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis.

In order to identify a gene(s) susceptible to idiopathic pulmonary fibrosis (IPF), we conducted a genome-wide association (GWA) study by genotyping 159 patients with IPF and 934 controls for 214 508 tag single-nucleotide polymorphisms (SNPs). We further evaluated selected SNPs in a replication sample set (83 cases and 535 controls) and found a significant association of an SNP in intron 2 of the TERT gene (rs2736100), which encodes a reverse transcriptase that is a component of a telomerase, with IPF; a combination of two data sets revealed a p value of 2.9 x 10(-8) (GWA, 2.8 x 10(-6); replication, 3.6 x 10(-3)). Considering previous reports indicating that rare mutations of TERT are found in patients with familial IPF, we suggest that the common genetic variation within TERT may contribute to the risk of sporadic IFP in the Japanese population.

Allograft airway fibrosis in the pulmonary milieu: a disorder of tissue remodeling.

Obliterative bronchiolitis (OB) is thought to be a form of chronic allograft rejection. However, immunosuppressive therapy is not effective once fibrosis has developed. We hypothesize that disordered tissue remodeling is a mechanism for the pathogenesis of OB. We examined allograft airway fibrosis in an intrapulmonary tracheal transplant model of OB. Allograft airways were completely obliterated at day 21 by fibrotic tissue; however, tissue remodeling continued thereafter, as demonstrated by the change of collagen deposition density, shift from type I to type III collagen, shift from fibroblasts to myofibroblasts and shift of expression profiles and activities of matrix metalloproteinases (MMPs). We then used a broad-spectrum MMP inhibitor, SC080, to attempt to manipulate tissue remodeling. Administration of the MMP inhibitor from day 0 to day 28 reduced airway obliteration, without inhibiting T-cell activation. MMP inhibition from day 14 to day 28 showed similar effects on airway obliteration. MMP inhibition from day 21 to day 35 did not reverse the airway obliteration, but significantly reduced the collagen deposition, type III collagen and myofibroblasts in the lumen. We conclude that tissue remodeling plays a critical role in the development and maintenance of fibrosis after transplantation.

Eosinophilia in bronchoalveolar lavage fluid and architectural destruction are features of desquamative interstitial pneumonia.

AIMS: Desquamative interstitial pneumonia (DIP) is a rare pattern of diffuse parenchymal lung disease known to overlap with respiratory bronchiolitis-interstitial lung disease (RB-ILD). The aim was to review biopsy-proven cases of DIP to investigate further the clinical, imaging and histological features of this disease. METHODS AND RESULTS: Twenty patients fulfilled the pathological criteria: 19 men and one woman with a mean age of 54 years. Clinical features, bronchoalveolar lavage (BAL) data, radiological findings, pathological findings other than criteria, effect of therapy and outcome were examined. The BAL data for 17 cases revealed marked eosinophilia (mean 18%) and moderate neutrophilia (mean 11%). Computed tomography in 17 patients showed peripheral involvement in all cases with a clear margin in 64% and thin-walled cysts in 35% of cases. Additional pathological features were a distinct lobular distribution (70%) and architectural destruction (70%) with cyst formation (55%). Eighteen of the 19 patients (95%) improved under steroid pulse and/or oral therapy. Sixteen subjects (80%) are alive, three died of other diseases and one died of DIP 74 months after the diagnosis. Percent vital capacity increased significantly and new thin-walled cysts appeared in one case. CONCLUSIONS: BAL eosinophilia, lobular distribution and architectural destruction with cyst formation are characteristic features of DIP.