Nonreciprocal Directional Dichroism in Magnetoelectric Spin Glass.

Optical absorption spectra in the visible and near-infrared light were measured for magnetoelectric spin glass Ni_{0.4}Mn_{0.6}TiO_{3} under various field-cooled conditions. Despite the absence of long-range magnetic-dipole order, this spin-glass system exhibits nonreciprocal directional dichroism (NDD) at zero external field after a magnetoelectric field-cooled procedure. This result is distinct from previous studies on NDD in systems with magnetic toroidal moments induced either by long-range magnetic-dipole order or by applying crossed electric and magnetic fields. The present Letter conclusively demonstrates that the observed NDD originates from magnetoelectrically induced ferroic order of magnetic toroidal moments without conventional magnetic-dipole order.

Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

Expression dynamics of CXCL12 and CXCR4 during the progression of mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) classically presents from patch stage to plaque stage over a number of years and finally progresses to tumour stage with nodal or visceral involvement. The mechanism of progression remains incompletely elucidated. Chemokines and their receptors are known to be involved in disease mechanisms, with CXCL12 and CXCR4 playing a critical role in carcinogenesis, invasion and cancer cell migration in various carcinomas. OBJECTIVES: To investigate the expression of CXCL12 and CXCR4 in different cutaneous stages of MF. METHODS: Formalin-fixed, paraffin-embedded skin samples from 40 patients with MF (21 patch stage, 10 plaque stage, nine tumour stage) and 30 non-neoplastic control skin samples were analysed. CXCL12 and CXCR4 were assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining. RESULTS: The expression level of mRNA for CXCL12 in plaque-stage MF was significantly higher than in control skin (P = 0.0035), or patch-stage (P = 0.0108) or tumour-stage disease (P = 0.0089). The CXCR4 mRNA expression level in plaque-stage disease was significantly higher than in control skin (P = 0.0090) or patch-stage disease (P = 0.0387). CXCL12- and CXCR4-positive cell rates in patch-stage and plaque-stage MF were significantly higher than those in control skin (P < 0.0001). CXCL12- and CXCR4-positive cell rates in tumour-stage MF were significantly lower than those in patch- and plaque-stage disease (P = 0.0274 and P = 0.0492, respectively). CONCLUSIONS: Our data suggest that neoplastic T cells in MF are exposed to the microenvironment, given the abundance of CXCL12 during its progression, and also that neoplastic T cells express CXCR4, especially in the pretumour stage. We reveal that the CXCL12-CXCR4 axis plays a critical role in MF progression.

Glasgow Prognostic Score Predicts Survival and Recurrence Pattern in Patients With Hepatocellular Carcinoma After Hepatectomy.

BACKGROUND/AIM: The prognostic significance of the Glasgow Prognostic Score (GPS) on outcomes of liver resection for hepatocellular carcinoma (HCC) remains unclear; the aim of the study was to assess its significance. PATIENTS AND METHODS: A total of 480 patients with HCC who underwent liver resection with curative intent at the Yokohama City University Hospital and Medical Center were enrolled in the study. Patients were classified into three groups: GPS-0, C-reactive protein (CRP) ≤1.0 mg/dl serum albumin ≥3.5 g/dl; GPS-1, CRP >1.0 mg/dl or serum albumin <3.5 g/dl; and GPS-2, CRP >1.0 mg/dl, serum albumin <3.5 g/dl. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. The recurrence pattern was also investigated using GPS. RESULTS: Of the 480 patients, 382 (79.6%), 81 (16.9%), and 17 (3.5%) were assigned to GPS-0, GPS-1, and GPS-2, respectively. Elevated GPS, indocyanine green retention rate at 15 min, and protein induced by vitamin K antagonist-II (PIVKA-II) were significantly associated with a poor OS. Elevated GPS, alpha-fetoprotein, and PIVKA-II were significantly associated with a poor DFS by multivariate analysis. The number of patients with liver-only recurrence in GPS-0, GPS-1, and GPS-2 was 179 (86.1%), 40 (78.4%), and 9 (69.2%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-0, GPS-1, and GPS-2 groups, was 33 (17.9%), 11 (27.5%), and 8 (88.9%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-2 group was significantly higher (p<0.001). CONCLUSION: Preoperative GPS is a useful predictor of OS and recurrence pattern after liver resection with a curative intent for HCC.

Erythroderma as a paraneoplastic cutaneous disorder in systemic anaplastic large cell lymphoma.

BACKGROUND: Paraneoplastic cutaneous disorders (PCDs) or dermadromes are skin conditions that have an association with internal malignancies but are not themselves malignant. We report the first two cases of systemic anaplastic large cell lymphoma (s-ALCL) accompanied by erythroderma and multiple leg ulcers as PCDs. CASE 1: A 52-year-old Japanese man presented with disseminated itchy papular erythemas which he had over his entire body for the preceding 5 years that later exacerbated to erythroderma. Multiple punched-out ulcers also developed on his lower legs. Superficial lymph nodes (LNs) were swollen, and a left axillary LN biopsy demonstrated dense CD30(+) atypical large cell (ALC) infiltration. By contrast, lymphocytes infiltrating into the erythroderma and leg ulcers were CD30(-) , and T-cell receptor ß (TCRß) chain gene rearrangement was negative in skin biopsy specimens. Thus, he was diagnosed with s-ALCL. Not only his s-ALCL but also his erythroderma and leg ulcers responded well to chemotherapy. CASE 2: A 71-year-old Japanese woman presented with erythroderma that persisted for approximately 20 years after mastectomy. At her initial hospital visit, she was diagnosed with s-ALCL by biopsy of swollen left inguinal LNs. Similar to Case 1, CD30(+) ALCs were negative in skin samples with normal TCRß chain gene rearrangement. As the erythrodermic skin lesion responded well to chemotherapy for s-ALCL, it was considered a PCD. CONCLUSION: s-ALCL development may be predicted by the precedence and concurrence of intractable paraneoplastic erythrodermic and ulcerative skin lesions, as reported in our two cases.

Prediction of time-dependent interaction of aspirin with ibuprofen using a pharmacokinetic/pharmacodynamic model.

WHAT IS KNOWN AND OBJECTIVE: Low-dose aspirin is widely used for prevention of thrombosis, but combined use of aspirin with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, reduces the antiplatelet effect of aspirin. However, there has been no report describing the effects of the timing of the ibuprofen dose on the degree of interaction between low-dose aspirin and ibuprofen. The purpose of this study was to predict the time-course of the antiplatelet effect of low-dose aspirin when ibuprofen is administered as a single dose or repeatedly in combination with aspirin at various time intervals. METHODS: We simulated ex vivo platelet aggregation using a previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model. RESULTS AND DISCUSSION: The antiplatelet effect of low-dose aspirin (81 mg) was predicted to be markedly reduced when ibuprofen (200 mg; the usual prescribed dose in Japan) was administered 1 h or less after aspirin, but not when it was administered more than 2 h after the administration of aspirin. Moreover, the administration of ibuprofen up to 12 h before aspirin completely abrogated the antiplatelet effect of aspirin. When ibuprofen (200 mg) was administered three times daily for 3 days (day 1 to day 3) on a background of continuous low-dose aspirin (81 mg) once daily, 2 h after aspirin, no reduction in the antiplatelet effect of aspirin was predicted on day 1, but a reduction is predicted from day 2, with no return to the initial level until more than 3 days after discontinuation of ibuprofen. A marked reduction in the antiplatelet effect of aspirin was also seen on the same schedule when the dosage of ibuprofen was 150 mg, which is the dose used in over-the-counter (OTC) preparations. WHAT IS NEW AND CONCLUSION: This study indicates that the antiplatelet effect of low-dose aspirin can be markedly reduced with combined use of ibuprofen, depending on the timing of co-administration. As even the lower OTC dose of ibuprofen (150 mg) was enough to affect the antiplatelet effect of aspirin, health professionals should take into account patients' use of OTC ibuprofen when prescribing low-dose aspirin.

Surgical Indications for Huge Hepatocellular Carcinoma.

BACKGROUND/AIM: This study aimed to retrospectively analyse adverse predictors to identify patients with huge hepatocellular carcinoma who were not appropriate candidates for hepatic resection. PATIENTS AND METHODS: From 551 patients with hepatocellular carcinoma who underwent hepatectomy between 1992 and 2019, 92 were diagnosed with huge hepatocellular carcinoma (diameter >10 cm) and 115 were diagnosed with large hepatocellular carcinoma (diameter=5-10 cm). Clinical features and overall and disease-free survival rates were compared between the two groups. RESULTS: Cumulative overall survival was significantly worse in the huge group than in the large group (p=0.035). In the huge group, multivariate analyses revealed that liver cirrhosis, multiple intrahepatic metastases (≥4), poor histological grade, and macroscopic portal vein invasion were significantly associated with poor prognosis. CONCLUSION: We identified four adverse predictors of survival and determined that patients with two or more predictors are not appropriate candidates for straightforward hepatic resection.

Efficacy of Adjuvant Chemotherapy Following Curative Resection of Colorectal Cancer Liver Metastases.

BACKGROUND/AIM: Routine use of adjuvant chemotherapy (AC) following hepatectomy for colorectal liver metastases (CRLM) is not universally practiced because of the lack of supporting evidence. Therefore, we investigated the efficacy of AC following curative CRLM resection. PATIENTS AND METHODS: Among the 742 patients who underwent their first hepatectomy for CRLM at our institution, 335 were stratified into surgery alone (SA; n=162) and AC (n=173) groups. Poor prognostic factors for SA were identified using multivariate logistic regression analysis. Propensity score matching was used to compare the clinical outcomes between SA and AC groups according to the number of prognostic factors. RESULTS: Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) levels (≥10 ng/ml; p=0.01), primary lymph node metastases (≥1; p=0.0001), and the number (n≥4; p=0.01) and maximum diameter (≥5 cm; p=0.00001) of CRLM tumours were independent poor prognostic factors for overall survival (OS) in the SA group. Patients with ≥3 risk factors were categorized as being high risk. After propensity score matching, the 5-year OS rate was significantly higher in the AC group (n=13) than that in the SA group (n=15; 47.9% vs. 7.3%; p=0.03) among high-risk patients. CONCLUSION: Adjuvant chemotherapy after curative CRLM resection may improve the prognosis of patients with three or more risk factors including preoperative CEA levels ≥10 g/ml, primary lymph node metastases ≥1, number (≥4) and maximum diameter (≥5 cm) of CRLM tumours.

Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports.

OBJECTIVE: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). CASE SUMMARIES: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable". DISCUSSION: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. CONCLUSION: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.

Revascularization by percutaneous transluminal angioplasty improved abruptly deteriorated ischaemic symptoms in cutaneous polyarteritis nodosa.

We report a patient with cutaneous polyarteritis nodosa, who had a 3-year history of recurrent leg and foot ulcers. Symptoms of ischaemia in the left foot, including severe pain, coldness, paraesthesia and violaceous discoloration, deteriorated abruptly, because of complete occlusion of the left anterior tibial artery. The occluded segment was revascularized by percutaneous transluminal angioplasty, resulting in a dramatic improvement in the ischaemic symptoms.

Increased circulating Th17 frequencies and serum IL-22 levels in patients with acute generalized exanthematous pustulosis.

BACKGROUND/OBJECTIVE: Acute generalized exanthematous pustulosis (AGEP) is a diffuse pustular disorder that usually begins in intertriginous folds with widespread erythema. The causes in the majority of the cases are drugs. T cells and interleukin (IL)-8 play roles in the development of AGEP, but the mechanism remains to be elucidated. We investigated the involvement of Th17 cells and their cytokine IL-22 in the pathogenesis. METHODS: Three patients with AGEP were enrolled in this study. The percentages of IL-17(+) Th17 cells, interferon γ(+) T cells and IL-4(+) T cells were measured in the patients' peripheral blood lymphocytes by intracellular cytokine staining and flow cytometry. The concentration of IL-22 in the sera was measured by enzyme-linked immunosorbent assay. RESULTS: The percentages of Th17 cells were markedly higher in all three patients than healthy control individuals. The frequencies of interferon γ(+) T cells were slightly high in the patients compared with the control, and there was no definite tendency in IL-4(+) T-cell frequencies. The concentration of IL-22 was remarkably high in all patients when compared with normal subjects with levels under detection. CONCLUSION: Th17 cells and their produced cytokine IL-22 were elevated in the peripheral blood of patients with AGEP. As IL-17 and IL-22 cooperatively stimulate keratinocytes to produce IL-8, IL-8 may contribute to the accumulation of neutrophils in the lesional epidermis of AGEP.

Warfarin and miconazole oral gel interactions: analysis and therapy recommendations based on clinical data and a pharmacokinetic model.

WHAT IS KNOWN AND OBJECTIVE: Miconazole is a strong inhibitor of CYP2C9, one of the main enzymes involved in the metabolism of warfarin. Concurrent use of the two drugs leads to potentially serious adverse effects. Although it is often assumed that use of the oral miconazole gel is acceptable with concomitant warfarin, because of the low bioavailability following buccal administration, drug-drug interactions have been reported following such use. We aimed to investigate case reports of such interactions and develop a pharmacokinetic model to model such interactions. METHODS: The Medline database from 1966 to October 2010 was used for literature search. Case reports of the potentiation of the anticoagulant effects of warfarin, such as the elevation of prothrombin time (INR), by concomitant administration of warfarin and miconazole oral gel were collected. We quantitatively estimated the extent of inhibition of warfarin metabolism by orally administered miconazole gel and compared our findings with case reports. RESULTS AND DISCUSSION: Metabolism of (S)-warfarin is inhibited potently following administration of a standard dose (200-400 mg/day in Japan) of miconazole gel. This may lead to in an increase in the blood concentration of warfarin and lead to serious adverse effects. The literature reports of clinical interactions with concomitant use of those drugs show that other factors may amplify the effects of any increase in blood concentration. WHAT IS NEW AND CONCLUSION: We summarize all reported, clinically significant, cases of drug interaction between miconazole oral gel and warfarin. Pharmacokinetic modelling shows that concomitant administration of warfarin and miconazole oral gel can lead to substantial increase in warfarin concentration. However, our PK/PD model fails to capture the dramatic increases seen in INR values, and hence bleeding complications, reported in the literature. Taken together, the evidence suggests that concomitant use of miconazole gel and warfarin should be avoided. Even over-the-counter products containing miconazole should be used with caution by patients receiving warfarin.

Adenovirus tumor-specific transplantation antigen is a function of the E1A early region.

Viable recombinant adenoviruses that carry a portion of the type 12 E1A and E1B transcription units in a type 5 background were used to identify genes controlling expression of the adenovirus tumor-specific transplantation antigen (TSTA). The TSTA immunity is not crossreacting between the group A and group C adenovirus serotypes. Viruses carrying the E1A region (sub370-12E1A), or both E1A and E1B (sub370-12E1AB) regions of Ad12, induce a strong transplantation immunity against tumors induced by syngeneic cells transformed with adenovirus 12, but fail to induce any protection against syngeneic cells transformed with adenovirus 2. Immunization with the virus carrying only the E1B region (sub370-12E1B) of adenovirus 12 induces no immunity to adenovirus 12 transformed cell line, but confers a strong protection against cells transformed with adenovirus 2. These results provide strong evidence that the adenovirus tumor-specific transplantation antigen is a function of the E1A early region.

Pharmacokinetic modeling of the dosing interval dependency for the interaction between itraconazole and triazolam.

OBJECTIVE: Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A with an elimination half-life of more than 30 hours. Therefore, itraconazole may cause persistent CYP3A inhibition. Triazolam is primarily metabolized by CYP3A and its plasma concentration is increased remarkably by itraconazole. Although separating their dosages by 24 hours has been shown to reduce the interaction, an appropriate dosage interval remains to be determined. The aim of this study was to identify an appropriate dosage schedule to avoid their interaction. MATERIALS AND METHODS: We developed a pharmacokinetic model based on the assumption that both itraconazole and hydroxyitraconazole competitively and reversibly inhibit the first-pass metabolism and systemic elimination of triazolam. The developed model was simultaneously fitted to the plasma concentration profiles of triazolam, taken from the literature, by using the plasma concentration-time profiles of itraconazole and hydroxyitraconazole as input functions to estimate their in vivo Ki values. Subsequently, we simulated the plasma concentration profiles of triazolam administered after itraconazole therapy with various dosing intervals. RESULTS: The model could explain and simulate the interaction between itraconazole-triazolam using a variety of dosage intervals between the administrations. CONCLUSIONS: The developed model may provide useful information with regard to the appropriate interval for triazolam administration during itraconazole therapy.

Ontogenetic changes in schooling behaviour during larval and early juvenile stages of Pacific bluefin tuna Thunnus orientalis.

Schooling was first observed at 25-27 days after hatching (26. 2-33. 8 mm, total length) in the Pacific bluefin tuna Thunnus orientalis. At this time, the mode of swimming changed from intermittent sprinting to continuous cruising, and this allowed the fish to adjust to an inertial hydrodynamic environment.

Development of visual cells in the Pacific bluefin tuna Thunnus orientalis.

The development of rod and cone photoreceptor cells was investigated in the retinas of Pacific bluefin tuna larvae and juveniles, using RET-P1 monoclonal antibody labeling to identify photoreceptors. At 60 h after hatching, which was about when feeding began, opsin (presumably green opsin (Rh2)) was expressed in the outer segments of cone cells. At 15 days after hatching (dah), although many labeled cone cells were observed in the dorsal retina, the same type of cone cells had partially appeared in the ventral retina. The presence of rod cell bodies was confirmed by the expression of Rh1 opsin at 15 dah. At 21 dah, the presence of outer segments of rod cells was confirmed by the expression of Rh1 opsin and by morphology. The observations suggest that the cone cells were substantially operable upon the development of their outer segment at around the beginning of the post-larval stage, and the rod cells began to function at around 15 to 21 dah, before and during metamorphosis.