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Background No anti-adhesive materials are currently in clinical use for orthopaedic surgery. We developed a hyperdry amniotic membrane (HD-AM) for easy storage and transplantation as amniotic membrane. The purpose of this study was to examine the application of HD-AM to reduce peritendinous adhesions without impairing tendon healing. Methods We randomly divided 3 digits (2nd, 3rd, and 4th digits) from each rabbit into three groups: a tendon repair group; a tendon repair with HD-AM group (HD-AM group); and a control group (cast only). The effects of HD-AM on peritendinous adhesions and tendon healing were examined using microscopic, histological, and mechanical analyses in a rabbit flexor digitorum profundus tendon model. Results Adhesions on macroscopic evaluation of the tendon repair site were significantly smaller in the HD-AM group than in the tendon repair group. Little adhesion formation or foreign body reactions were seen by on histologic evaluation in the HD-AM group. Range of motion following tendon repair was significantly better in the HD-AM group than in the tendon repair group. Maximal tensile strength required to pull the tendon from the site of adhesion was significantly smaller in the HD-AM group than in the tendon repair group. As for tendon repair site, no significant difference was seen between the tendon repair and HD-AM groups. Conclusions HD-AM prevented peritendinous adhesion macroscopically, pathologically, and mechanically without impairing the sutured tendon. HD-AM has already been clinically applied in neurosurgery, ophthalmology, and otolaryngology, and clinical application as an anti-adhesive materials may be achieved in the future.

In the first case, a 60-year-old man who was using continuous subcutaneous insulin infusion (CSII), developed recurrent hypoglycemia due to insulin antibodies. This is the first report of such a case using CSII. In the second case, a 70-year-old man was follow-up case who developed hypoglycemia while using human insulin. In both cases, the hypoglycemia subsided after switching to multiple daily insulin injection and/or insulin preparation. The results of Scatchard analyses of the two cases were similar to those of cases of insulin autoimmune syndrome (IAS) that improved after recovery from hypoglycemia.The clinical characteristics and Scatchard analysis data were essentially the same as those for IAS, except for the presence of insulin administration.

The statin use in patients on hemodialysis remains controversial, and no beneficial effects of statin on the reduction of adverse cardiovascular events have been reported in these patients. This study used stratification analysis to examine the clinical factors in patients on hemodialysis who could benefit from statin for secondary prevention. This prospective multicenter study included 234 consecutive patients on hemodialysis with coronary artery disease who underwent successful reperfusion therapy with percutaneous coronary intervention. The patients were followed up for up to 3 years or until the occurrence of major adverse cardiac events (MACEs; defined as a composite of all-cause death and nonfatal myocardial infarction). Inverse probability of treatment weighting adjustment was used to remove the selection bias. During the median follow-up period of 30 months, MACEs occurred in 55 patients. Patients with MACEs had significantly lower statin therapy (P0.001). Multivariable Cox proportional hazards analysis showed that the patients on statins had a significantly reduced rate of MACE occurrence [adjusted hazard ratio 0.30 (0.11-0.81), P = 0.02]. The stratification analysis of outcomes according to the presence of clinical factors showed that beneficial effects of statin were associated with man, elderly, lower body mass index, lower abdominal circumference, hypertension, diabetes, higher C-reactive protein, symptomatic heart failure, lower left ventricular function, nonacute coronary syndrome, and shorter stent length. Statin was effective for the prevention of MACEs in patients on hemodialysis who underwent percutaneous coronary intervention. We identified specific clinical factors affecting statin effectiveness for secondary prevention.

Pregabalin is a first-line treatment option for neuropathic pain. Recently, some cases of pregabalin-induced hypoglycemia have been reported, which can complicate the treatment of neuropathic pain and worsen patient outcomes. Therefore, a better understanding of the clinical condition of patients with pregabalin-induced hypoglycemia is desirable. In this study, we evaluated the risk of hypoglycemia in patients administered pregabalin, using the Japanese Adverse Drug Event Report database. All patients on pregabalin not taking any antidiabetic agents were screened from April 2004 to July 2020, and data on adverse events related to hypoglycemia, sex, age, weight, and the presence of chronic kidney disease were collected. Gabapentin and duloxetine, which are usually indicated for neuropathic pain, were used for comparison. Among 242,275 patients, 4,287 were administered pregabalin, which included 37 patients who reported hypoglycemic incidents. Disproportionality of hypoglycemia was observed in patients administered pregabalin (reporting odds ratio, 2.25; 95% confidence intervals [CI], 1.16-3.13; P < 0.01), whereas this was not the case in patients taking gabapentin and duloxetine. Multivariate logistic regression showed that hypoglycemia in patients on pregabalin was associated with age ≥ 70 years (odds ratio, 2.76; 95% CI, 1.29-5.91; P < 0.01) and weight < 40 kg (odds ratio, 2.97; 95% CI, 1.32-6.71; P < 0.01). These findings suggest that pregabalin may be associated with a higher risk of hypoglycemia, especially in elderly individuals with low body weight. Healthcare providers may need to be aware of pregabalin-induced hypoglycemia in patients with these risk factors during therapy. This article is protected by copyright. All rights reserved.

Evidence on the efficacy and safety of low-dose direct oral anticoagulant (DOAC) in older patients with nonvalvular atrial fibrillation is still scarce. We conducted a single-center prospective registry of patients with nonvalvular atrial fibrillation treated with DOACs: the DIRECT registry (n = 2,216; follow-up, 407 ± 388 days, UMIN000033283). The whole population was divided into 2 groups: the older group (age ≥80 years, n = 548) versus the younger group (age80 years, n = 1,668). Primary safety and efficacy end points were major bleeding according to the International Society on Thrombosis and Haemostasis criteria, and stroke or systemic embolism (SSE), respectively. Effects of known risk factors and low-dose DOAC on major bleeding and SSE were assessed using a multivariable Cox proportional hazards model. In the older group, low-dose DOAC was associated with lower bleeding events (hazard ratio 0.279, 95% confidence interval 0.087 to 0.892, p = 0.031) but was not associated with increased SSE (p = 0.894). In the younger group, low-dose DOAC was neither associated with risk of major bleeding nor SSE (both p 0.05). In conclusion, in older patients, low-dose DOAC was associated with reduced risk of major bleeding without compromising its efficacy.

A 69-year-old woman sustained progressive proptosis for 2 months. The patient had undergone surgery for resection of colon cancer 10 years prior, which was considered to have been completely cured 5 years prior. She was also aware of a hard mass in her left breast, but it had been left untreated. Furthermore, she experienced back pain for a month. Blood examination revealed an elevated level of serum carcinoembryonic antigen, at 17.4 ng/mL (< 5). Computed tomography (CT) revealed a tumor occupying the superolateral part of the right orbit, with intratumoral calcifications and destructive changes in the lateral orbital wall. On magnetic resonance imaging, it appeared as a heterogeneously enhancing, extraconal tumor, 44 mm × 31 mm in maximal dimension, extending into the middle fossa and the adjacent subcutaneous region. Fluorodeoxyglucose positron emission tomography/CT revealed abnormal accumulation in the left breast, T12 vertebra, liver, and lung, in addition to the orbital tumor. The patient underwent total tumor resection through a lateral orbitotomy. Histological examination of the tumor was highly suggestive of a metastatic colon cancer. Late metastasis should be assumed as a differential diagnosis that can be determined only through histological verification.

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here, we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared with normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag-1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, whereas downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag-1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Intraperitoneal injection of a Piezo1 channel blocker, GsMTx4, ameliorated experimental PH in mice. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

A 6-month-old, previously healthy boy presented with poor feeding and vomiting for 2 weeks. At presentation, his left supraorbital vein was found to engorge considerably. A cranial computed tomography (CT) scan revealed a large cyst in the posterior fossa with a prominent left superior ophthalmic vein (SOV). Magnetic resonance imaging delineated the well-demarcated cyst markedly compressing the right cerebellar hemisphere. The patient underwent microscopic fenestration of the cyst wall through lateral suboccipital craniotomy. The cyst wall, comprising multi-layered, opacified membranes, was extensively resected and communicated with the prepontine cistern. The histological appearance of the cyst wall was consistent with an arachnoid cyst. Engorgement of the left supraorbital vein resolved immediately after surgery. A postoperative CT scan did not identify the SOV in the left orbit. In the present case, engorgement of the supraorbital vein might reflect the increased venous pressure of the SOV caused by compression of the contralateral cerebellar hemisphere.

Recent retrospective studies have shown that increased intraoperative blood loss (IBL) during curative gastrectomy for patients with advanced gastric cancer is a negative prognostic indicator for recurrence. However, there are no reliable reports assessing this with a large-scale prospective cohort. This study aimed to evaluate the impact of IBL on long-term outcomes using data from the JCOG1001 phase III trial, which was designed to determine if bursectomy led to improved survival vs. nonbursectomy in patients with cT3/4a gastric cancer. This study included 1203 of the 1204 patients enrolled in the JCOG1001. From the tertiles of IBL (196 ml, 400 ml), we divided the patients into three groups: IBL

Although both cinacalcet and etelcalcetide are calcimimetics that directly inhibit parathyroid hormone (PTH) secretion by activating the calcium (Ca)-sensing receptor (CaSR), their binding sites are different. We report a first case of a hemodialysis (HD) patient with secondary hyperparathyroidism (SHPT), in whom cinacalcet, but not etelcalcetide, could reduce serum intact PTH (i-PTH) levels. A HD patient received total parathyroidectomy (PTx) with auto-transplantation 16 years earlier. Due to SHPT relapse, cinacalcet was started at 7 years after PTx. His i-PTH levels had been controlled with both 75–100 mg of cinacalcet and 4.5 μg/week of calcitriol for a year before switching from cinacalcet to etelcalcetide. At 1 month following the switch, his serum i-PTH level increased to 716 pg/mL. The dose of etelcalcetide was gradually increased and finally reached the maximal dose of 45 mg/week. Because even the maximal dose of etelcalcetide for > 4 months did not reduce his serum i-PTH levels to

PURPOSE To identify the clinical factors resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement (BPE). METHODS We retrospectively surveyed the patient cohort who had been enrolled in the study of dutasteride add-on treatment to alpha-adrenergic antagonist from December 2009 to November 2011. Treatment failure was defined as receiving surgery for BPE or requiring intermittent catheterization or permanent bladder catheter for urinary retention or huge postvoid residual urine. Clinical parameters before dutasteride treatment were compared between the successful and failed group. RESULTS Of 92 patients, 23 (25%) were defined as treatment failure at 7-109 months (mean: 38 months) after dutasteride add-on treatment. In the failed group, the patient' age was younger (71.6 ± 6.8 vs 75.4 ± 8.4, p = 0.033), prostatic volume (PV) was larger (76 ± 41 vs 49 ± 26 ml, p = 0.005), voiding efficiency was lower (54 ± 27 vs 68 ± 24%, p = 0.045) and bladder outlet obstruction index was higher (73 ± 30 vs 48 ± 30, p = 0.015). The cox proportional-hazards model indicated that only intravesical prostatic protrusion (IPP) was associated with treatment failure. Non-failure rate at 3 years after dutasteride add-on treatment was 89% with patients of IPP

Background Pancreatic juice is constantly activated by contaminated bile in patients with pancreaticobiliary maljunction (PBM). Here, we report a case of laparoscopic distal pancreatectomy for a patient with PBM and sphincterotomized papilla, resulting in fatal pancreatic fistula. Case presentation A 79-year-old man was diagnosed with pancreatic intraductal papillary mucinous neoplasm and common bile duct stones. Endoscopic sphincterotomy was performed prior to surgery. The pancreatic duct was simultaneously visualized when the contrast agent was injected into the common bile duct. Sudden bleeding was observed from the abdominal drain on postoperative day (POD) 6. Emergent stent graft placement and coil embolization were performed for bleeding from the splenic artery. On POD 9, the drainage fluid changed to yellowish in color with bile contamination. For internal drainage of the digestive fluid, endoscopic retrograde biliary tube and pancreatic drainage tube were placed. On POD 24, second emergent coil embolization was performed for bleeding from the left gastric artery. On POD 25, open abdominal drainage was performed. On POD 32, third emergent coil embolization was performed for bleeding from the gastroduodenal artery. Subsequently, remnant pancreatic resection was performed. On POD 39, massive bleeding was again observed from the abdominal drain. Emergency arterial portography revealed bleeding in the right wall of the superior mesenteric vein. The patient died of hemorrhagic shock on the same day. Conclusions The extreme risk of severe pancreatic fistula after distal pancreatectomy should be considered in patients with PBM and sphincterotomized papilla. In this extraordinary situation, surgeons should promptly decide whether to resect the remnant pancreas to prevent losing the patient.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Objectives After liver transplant, veno-occlusive disease and infectious complications may result from subclinical pulmonary hypertension. In this retrospective study, we investigated whether our preemptive bundle therapy was effective for subclinical pulmonary hypertension and extrasinusoidal platelet aggregation after liver transplant. Materials and methods After January 2014, nutrition therapy with glutamine, synbiotics, phosphodiesterase 3 inhibitors, prostaglandin E1, prostaglandin I2, closedloop artificial pancreas, and sivelestat has been used to reduce bacterialtranslocation, vascular endothelial cell damage, and extrasinusoidal platelet aggregation, which is administered as preemptive bundle therapy for all livertransplantrecipients. In this study, we evaluated the prognosis of 84 liver transplant recipients who underwent liver transplants through 2018. Subclinical pulmonary hypertension was evaluated in 49 adult liver transplant recipients with an evaluable main pulmonary artery trunk cross-sectional area using enhanced computed tomography in the acute phase after transplant, with 14 of these patients receiving preemptive bundle therapy. Results Subclinical pulmonary hypertension was reduced in the preemptive bundle therapy group (n = 14) compared with the nontherapy group (n = 35). The preemptive bundle therapy group showed more rapid recovery of platelet, prothrombin time, and bilirubin levels afterlivertransplant compared with the nontherapy group. The prognosis of patients in the preemptive bundle therapy group was significantly better than in the nontherapy group. Extrasinusoidal platelet aggregation was significantly lower in the preemptive bundle therapy group than in the nontherapy group. Conclusions Preemptive bundle therapy reduced sinusoidal endothelial cell injury, extrasinusoidal platelet aggregation, and subclinical pulmonary hypertension after liver transplant, resulting in good posttransplant recovery.

Methyl-CpG binding domain protein 3 (MBD3) belongs to the methyl-CpG binding protein family. MBD3 facilitates the initiation of neural stem cell reprogramming. Melanoma originates in melanocytes derived from neural crest stem cells; therefore, we investigated the role of MBD3 in melanoma. MBD3 was overexpressed in melanoma compared with pigmented nevi. MBD3 knockdown had no effect on the proliferation of melanoma cells (A375 and A2058 cells). Contrarily, it significantly reduced the migration and invasion of A375 cells, but had no significant effect on A2058 cells. Furthermore, MBD3 knockdown reduced N-cadherin protein levels and matrix metalloproteinase-2 (MMP-2) activity in A375 cells, but had no significant effect on A2058 cells. Based on these results, the MBD3 expression level may be a useful biomarker for the diagnosis of melanoma. Thus, MBD3 has potential as a novel therapeutic target for some melanoma patients.

BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P

BACKGROUND Most surveillance programs for postoperative infection focus on surgical site infections (SSI). However, postoperative remote infections are of emerging clinical importance. Using data from a multicenter survey administered to patients who underwent gastrointestinal surgery, we investigated the incidence of SSI and remote infection after colorectal surgery. METHODS From September 2015 through March 2016, 1,724 patients underwent colorectal surgery in 28 affiliated centers in Japan. We retrospectively recorded patient age, sex, surgical site, surgical approach, wound classification, performance status at discharge, and postoperative infection status. RESULTS Postoperative infection was noted in 236 (13.7%) patients; 150 and 86 patients underwent colon and rectal surgeries, respectively (incidence of postoperative infection: 13.7% and 14.8%). The incidence of postoperative infection was significantly lower after laparoscopic surgery than after open surgery, in colon and rectal surgery (p < 0.001). Among patients with postoperative infections, 211 (89.4%) had a single infection and 25 (10.6%) had multiple infections. Among patients with a single postoperative infection, SSI and remote infection occurred in 143 (60.6%) and 68 (28.8%) patients, respectively. The most common multiple postoperative infections were "incisional and organ/space SSIs" and "organ/space SSI and bacteremia of unknown origin" (n = 3 each). CONCLUSIONS This study revealed the prevalence distributions for postoperative SSI and remote infections. Because of the substantial effect of remote infections on patient quality of life and the associated social burden, prospective periodic surveillance for SSI and remote infection is necessary for careful evaluation and prevention.

Merkel cell carcinoma (MCC) is an aggressive neoplasm and patients with metastasis have poor survival outcomes. Recently, avelumab, an anti-programmed death ligand 1 (PD-L1) immune checkpoint inhibitor, was approved for first-line treatment in patients with metastatic MCC. While the administration interval of avelumab is every 2 weeks, the durable effect of a single administration of avelumab is unknown. Additionally, the effect of avelumab in pure MCC or combined MCC concurrent with non-MCC histology has not been fully elucidated. Herein, we report a case of combined MCC concurrent with squamous cell carcinoma; the patient had a complete response after a single administration of avelumab. Although the levels of avelumab were outside the detection limit within 12 weeks, a remarkable efficacy remained for more than 28 weeks after administration. Immunohistochemical analyses revealed that the expression of PD-L1 and Merkel cell polyomavirus large T antigen was almost negative or only partial in the primary tumor lesion of this patient. Conversely, thyroid transcription factor 1 (TTF-1) expression was positive in the primary MCC lesion, which is consistent with a previous report that combined MCC is positive for TTF-1 expression. In conclusion, this case study presents a rare case of TTF-1-positive combined MCC showing complete response after a single administration of avelumab.

In psoriasis, tumor necrosis factor (TNF)-α is a key pro-inflammatory cytokine that activates keratinocytes to produce other inflammatory mediators. In addition, increased serum or plasma TNF-α levels are considered to be biomarkers of psoriasis. Circulating cell-free DNA (cfDNA) originates from apoptotic or necrotic cells and reflects the severity of cellular damage. Although cfDNA has recently attracted attention as a marker in the diagnosis and prognosis of various disorders, there are few reports of its clinical implications in the field of dermatology including psoriasis. The aim of this study was to investigate whether the TNF-α gene is present in the cfDNA, and whether its levels can be utilized as a biomarker for patients with psoriasis. cfDNA was isolated from serum samples of 79 patients with psoriasis vulgaris and 29 with psoriatic arthritis. The levels of TNF-α in the cfDNA were assessed by droplet digital polymerase chain reaction. In this study, we made two novel findings. First, circulating TNF-α DNA levels in the cfDNA were significantly higher in patients with psoriasis than in healthy controls. In addition, the area under the curve was 0.91, suggesting that serum TNF-α DNA levels are effective as a diagnostic biomarker. Second, the levels of TNF-α DNA copies in the cfDNA were positively correlated with the Psoriasis Area and Severity Index (PASI) score in the group of patients with a PASI score higher than 10. Generally, a PASI score of more than 10 is defined as severe psoriasis; therefore, the levels of TNF-α DNA copies in the cfDNA could be a biomarker for severity in patients with severe psoriasis. Further studies are needed to establish serum TNF-α DNA levels as a novel biomarker of psoriasis.

Systemic sclerosis (SSc) is a kind of collagen disease and has an acquired autoimmune activation as represented by the production of autoantibodies. CD27 is a type I glycoprotein and a member of the tumor necrosis factor receptor family. It binds to the CD70 ligand, CD27-CD70 signaling is implicated in the development of various autoimmune diseases, but its role in the regulation of extracellular matrix expression and its contribution to the phenotype of SSc both remain to be elucidated. This study aimed to investigate the associations between CD27 and SSc in the skins and sera. Immunohistochemistry were performed to determine the expression of CD27 in the skin. Enzyme-linked immunosorbent assays were done to the sera of the 54 patients with SSc and 23 normal healthy controls. CD27 expression was significantly increased in the affected regions of the skin and the sera of patients of SSc. Thereafter, we evaluated the correlation between the serum soluble CD27 (sCD27) levels and the clinical symptoms. The study subjects with increased sCD27 levels had a significantly higher ratio of dcSSc and to showed higher modified Rodnan's total skin thickness scores (mRSS) than those with normal sCD27 levels. These results suggest that sCD27 levels might be useful for diagnosis of SSc and its severity.

Immune checkpoint inhibitors improved the survival rate of patients with unresectable melanoma. However, some patients do not respond, and variable immune-related adverse events have been reported. Therefore, more effective and antigen-specific immune therapies are urgently needed. We previously reported the efficacy of an immune cell therapy with immortalized myeloid cells derived from induced pluripotent stem cells (iPS-ML). In this study, we generated OX40L-overexpressing iPS-ML (iPS-ML-Zsgreen-OX40L) and investigated their characteristics and in vivo efficacy against mouse melanoma. We found that iPS-ML-Zsgreen-OX40L suppressed the progression of B16-BL6 melanoma, and prolonged survival of mice with ovalbumin (OVA)-expressing B16 melanoma (MO4). The number of antigen-specific CD8+ T cells was higher in spleen cells treated with OVA peptide-pulsed iPS-ML-Zsgreen-OX40L than in those without OX40L. The OVA peptide-pulsed iPS-ML-Zsgreen-OX40L significantly increased the number of tumor-infiltrating T lymphocytes (TILs) in MO4 tumor. Flow cytometry showed decreased regulatory T cells but increased effector and effector memory T cells among the TILs. Although we plan to use allogeneic iPS-ML in the clinical applications, iPS-ML showed the tumorgenicity in the syngeneic mice model. Incorporating the suicide gene is necessary to ensure the safety in the future study. Collectively, these results indicate that iPS-ML-Zsgreen-OX40L therapy might be a new method for antigen-specific cancer immunotherapy.

Alcohol consumption is a major risk factor for esophageal cancer. In Asia, heavy drinkers are considered to have a higher risk of esophageal cancer than nondrinkers and light drinkers. However, no study has shown an association between alcohol reduction and the morbidity of esophageal cancer in Asian heavy drinkers. Therefore, this study investigated the significance of reducing alcohol consumption to prevent esophageal cancer in Asian heavy drinkers by conducting a systematic review and meta-analysis. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 1995 to December 2020. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effects model. I2 statistics were used to detect heterogeneity. This study included 21 articles in the qualitative synthesis. Light drinkers and heavy drinkers were categorized based on alcohol consumption amount as ≤ 25 ethanol g/day and ≥ 66 ethanol g/day, respectively, as described in many previous studies, and five cohort studies were eligible for this meta-analysis. The HR of esophageal cancer among heavy drinkers versus nondrinkers was 4.18 (95% CI 2.34–7.47, I2 = 74%). On the other hand, the HR of esophageal cancer among light drinkers was 1.82 compared with nondrinkers (95% CI 1.57–2.10, I2 = 0%). Heavy drinkers have a higher esophageal cancer incidence than light drinkers and nondrinker. It is possible that alcohol reduction may decrease the risk of esophageal cancer in Asian heavy drinkers.

To report a patient with nonarteritic anterior ischemic optic neuropathy (NA-AION) occurring soon after the COVID-19 vaccination. A 55-year-old woman presented with a 4-day history of inferior visual field disturbance in the right eye 7 days after receiving the first dose of Pfizer-BioNTech COVID-19 vaccine. Examination revealed a best-corrected visual acuity of 20/20 in both eyes. A relative afferent pupillary defect was observed in the right eye. Fundoscopy revealed diffuse optic disc swelling in the right eye, which was prominent above the optic disc. Goldmann visual field testing identified an inferior altitudinal visual field defect with I/2 isopter in the right eye. Although typical complete inferior visual field defect was not detected, a diagnosis of NA-AION was made. The patient was followed without any treatment. During the 2-month follow-up period, the optic disc swelling was gradually improved, and visual acuity was maintained 20/20; however, the optic disc looked diffusely pale in the right eye. Although it is uncertain whether the development of NA-AION after COVID-19 vaccination was consequential or coincidental, we speculate that the close temporal relationship with COVID-19 vaccination suggests the possibility of vasculopathy on the microvascular network of optic nerve head as background of inflammatory or immune-mediated element to the timing of the onset of NA-AION. The aim of this case report is to present this biological plausibility and to elucidate potential ophthalmological complications.

In cryoballoon ablation (CBA), a contrast medium is commonly used to confirm balloon occlusion of the pulmonary veins (PVs). However, a contrast medium cannot always be used in patients with renal dysfunction and allergy. The present study aimed to assess the efficacy and safety of CBA without the use of a contrast medium. We retrospectively examined consecutive patients with paroxysmal atrial fibrillation (PAF) who underwent first-time CBA. We compared the procedural results and outcomes in patients for whom a contrast medium was used (contrast group) and those from whom a contrast medium was not used (non-contrast group). In the non-contrast group, we used saline injection on the intracardiac echocardiography and pressure wave monitoring for PV occlusion. Fifty patients (200 PVs) and 22 patients (88 PVs) underwent CBA with and without a contrast medium, respectively. The success rate of PV isolation with CBA alone was 93% and 90% in the non-contrast and contrast groups, respectively (p = 0.40). The fluoroscopy time and nadir temperature were significantly lower in the non-contrast group as compared to that in the contrast group. The recurrence rate 1 year after ablation did not differ between the two groups (18% vs. 18%, p > 0.99). Furthermore, the number of reconnected PVs in patients with recurrence was significantly lower in the non-contrast group than in the contrast group (6% vs. 36%, p = 0.017). In conclusion, CBA using the intracardiac echocardiography and pressure monitoring approach without the use of a contrast medium was safe and efficient.

Fixed bulky nodal disease in patients with head and neck cancer of unknown primary (HNCUP) remains difficult to treat. This retrospective study evaluated the therapeutic efficacy of selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin for fixed bulky nodal disease in HNCUP. Data from seven consecutive patients with fixed bulky nodal disease in HNCUP who had undergone selective intra-arterial chemoradiotherapy were analyzed. Whole pharyngeal mucosa and all bilateral nodal areas were irradiated (total dose 50 Gy), and bulky nodal lesions were provided an additional 20 Gy. Intra-arterial chemotherapy used a combination of nedaplatin (80 mg/m2) and docetaxel (60 mg/m2). Outcome measures were local control, disease-free survival, overall survival, and adverse events. Statistical analyses were performed using the Kaplan–Meier method. Median follow-up period was 24 months (range 9–64). All patients had extracapsular extension (N3b) on imaging and clinical findings. Symptoms due to bulky disease were neck discomfort (100%), tumor bleeding (43%), tracheal obstruction (14%), and carotid sinus syndrome (28%). Median value for maximum diameter of cervical disease was 84 mm (range 70–107), and 3-year local control, disease-free survival, and overall survival rates were 100, 54, and 64%, respectively. Symptoms due to bulky disease disappeared in all patients after intra-arterial chemoradiotherapy. Grade 4 leukopenia occurred in two patients (28%) as an acute adverse event. No other serious acute adverse events were observed. Selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin can potentially achieve both favorable local control and survival in in HNCUP with fixed bulky nodal disease.

Background Deteriorated skeletal muscle condition, including sarcopenia, is a risk factor for disability in older adults. Promoting physical activity is a useful treatment for sarcopenia. However, optimal intensity of physical activity according to sarcopenia characteristics is unclear. Methods This longitudinal cohort study enrolled 2149 community‐dwelling older adults (women 55.7%, mean age: 75.5 ± 4.0 years). Five‐year disability incidence defined by Japanese long‐term care insurance certification and accelerometer‐measured physical activities (light‐intensity physical activity [LPA] and moderate‐to‐vigorous intensity physical activity [MVPA]), which were adjusted for potential confounders, was analysed using cox‐proportional hazard model stratified by sarcopenia characteristics based on the diagnostic algorithm by the Asian working group for sarcopenia (robust, low physical function, low muscle mass, and sarcopenia). The sarcopenia group was defined as low muscle mass and low physical function (weakness and/or slowness). The low muscle mass and low physical function groups were each defined by these characteristics alone. Muscle mass was analysed via bioelectrical impedance analysis. Each intensity of physical activity times was divided by median values. Results The disability incidence rate was 15.4%, excluding those who could not be followed up. Mean LPA times were 43.8 ± 18.0, 45.6 ± 17.5, 45.4 ± 16.6, 40.8 ± 18.6, and 41.4 ± 18.5 min/day and MVPA times were 24.6 ± 17.6, 26.3 ± 18.3, 27.2 ± 17.3, 21.6 ± 16.3, and 21.5 ± 16.4 min/day in all participants, the robust, low muscle mass, low physical function, and sarcopenia groups, respectively. For all participants, higher MVPA was associated with disability incidence [hazard ratios (HR), 0.63; 95% confidence interval (95% CI), 0.49–0.81; P

Mucoepidermoid carcinoma (MEC) of the lacrimal gland (LG) is a rare entity. A 47-year-old woman was aware of periorbital swelling for 3 months. At presentation, the patient showed periorbital swelling in the right eye. CT scan showed an isodense mass in the anterior superolateral part of the orbit. MRI delineated the mass as enhancing, extra-conal tumor appearing isointense on T1-weighted sequences, and to be of mixed intensity on T2-weighted sequences. The tumor was totally resected. Microscopically, the tumor tissue was comprised of squamous, epithelioid cells, and cells with plump and clear cytoplasm. Necrosis, neural invasion, or mitotic figures were not observed. Immunohistochemical examination revealed intense staining for cytokeratin 7. A subset of the cells was positively stained with periodic acid–Schiff and mucicarmine stains. Genetic analysis revealed the presence of the CRTC1-MAML2 fusion. The CRTC1-MAML2 fusion may be a useful indicator for the prognosis and planning of adjuvant therapy.

Background Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare and fatal disease characterized by uncontrolled immune cell activation that can lead to a cytokine storm. Unfortunately, this condition can occur even during pregnancy, threatening both maternal and fetal lives. Case presentation A 23-year-old nulliparous woman at 26 weeks of gestation presented with continuous fever, coughing, and sore throat. Upon arrival at our hospital, her temperature was >38°C and laboratory findings indicated cytopenia (neutrophil count, 779/μL; hemoglobin level, 10.2 g/dL; platelet count, 29,000/μL), elevated ferritin level (1,308 ng/mL), and elevated soluble interleukin-2 receptor level (11,200 U/mL). Computed tomography showed marked splenomegaly. Bone marrow examination revealed hemophagocytosis, and blood examination showed a plasma Epstein–Barr virus (EBV) DNA level of 8.9 × 105 copies/μg. The monoclonal proliferation of EBV-infected T cells was confirmed by Southern blotting, and the patient was diagnosed with chronic active EBV-associated sHLH and T-cell lymphoproliferative disease. Immediately after admission, the patient’s condition suddenly deteriorated. She developed shock and disseminated intravascular coagulation, requiring endotracheal intubation along with methylprednisolone pulse and etoposide therapy. Although the patient recovered, she delivered a stillborn baby. After delivery, she was treated with reduced-dose dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) and steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapies. Five months after diagnosis, she received human leukocyte antigen-haploidentical allogeneic bone marrow transplantation from her sister. She remains in remission for 5 months from the time of transplantation to the present. Conclusions sHLH, which may cause maternal and fetal death, should be carefully considered in critically ill pregnant women, particularly those presenting with continuous fever and cytopenia.

Background Preeclampsia (PE) is a hypertensive disorder specific to pregnancy that can cause severe maternal-neonatal complications. The International Society for the Study of Hypertension in Pregnancy revised the PE criteria in 2018; a PE diagnosis can be established in the absence of proteinuria when organ or uteroplacental dysfunction occurs. The initial findings of PE (IFsPE) at the first diagnosis can vary considerably across patients. However, the impacts of different IFsPE on patient prognoses have not been reported. Thus, we investigate the predictors of pregnancy complications and adverse pregnancy outcomes based on IFsPE according to the new criteria. Methods This retrospective study included 3729 women who delivered at our hospital between 2015 and 2019. All women were reclassified based on the new PE criteria and divided into three groups based on the IFsPE: Classification 1 (C-1), proteinuria (classical criteria); Classification 2 (C-2), damage to other maternal organs; and Classification 3 (C-3), uteroplacental dysfunction. Pregnancy complications and adverse pregnancy outcomes were assessed and compared among the three groups. Results In total, 104 women with PE were included. Of those, 42 (40.4%), 28 (26.9%), and 34 (32.7%) were assigned to C-1, C-2, and C-3 groups, respectively. No significant differences in maternal characteristics were detected among the three groups, except for gestational age at PE diagnosis (C-1, 35.5 ± 3.0 weeks; C-2, 35.2 ± 3.6 weeks; C-3, 31.6 ± 4.6 weeks, p C-3 group compared to the C-1 and C-2 groups. Additionally, the composite adverse pregnancy outcomes of the C-3 group compared with C-1 and C-2 represented a significantly higher number of patients. Conclusions PE patients with uteroplacental dysfunction as IFsPE had the most unfavorable prognoses for premature birth, FGR, acidosis, and composite adverse pregnancy outcomes.

High-degree atrioventricular block (HAVB) or complete heart block (CHB) is a common complication associated with transcatheter aortic valve replacement (TAVR). However, some patients with HAVB/CHB recover with time. The results of electrophysiological studies (EPSs) using permanent pacemaker implantation (PPI) in patients with suspicious HAVB/CHB are considered controversial.This study aimed to evaluate whether HAVB/CHB induction at the bedside using a temporary pacemaker can predict recurrence in patients who had recovered from HAVB/CHB after TAVR.We enrolled a total of 11 patients who had recovered from HAVB/CHB and evaluated their electrophysiology using right ventricular pacing and/or procainamide administration.HAVB/CHB induction was positive. Three patients tested positive for HAVB/CHB, whereas 8 tested negative. The ejection fraction and the interval between HAVB/CHB onset and EPS were found to be significant. HAVB/CHB positive patients underwent PPI. A patient with a balloon-expandable valve tested positive just before recovery of CHB, but tested negative 5 days later and was included in the negative group. The 4 patients who tested negative received a cardiovascular implantable electric device (CIED). We observed HAVB/CHB in 2 patients who had previously tested positive after 3 months. Among those who tested negative, those with CIED had no HAVB/CHB, and others showed neither HAVB/CHB on electrocardiogram nor experienced syncope or sudden death.Our EPS revealed that HAVB/CHB induction may predict HAVB/CHB recurrence after TAVR. Valve type and EPS timing may affect the results.

INTRODUCTION With regard to short-term outcome in atrial fibrillation (AF), the benefit of cryoballoon ablation (CBA) by pressing a balloon against the earliest pulmonary vein (PV) potential site during PV isolation (earliest potential [EP]-guided CBA) has been previously demonstrated. The present study aimed to evaluate the long-term outcome of the EP-guided CBA. METHODS AND RESULTS This study included 136 patients from two randomized studies, who underwent CBA for paroxysmal AF for the first time. Patients were randomly assigned to the EP-guided and conventional CBA groups in each study. In the EP-guided CBA group, we pressed a balloon against the EP site when the time-to-isolation (TTI) after cryoapplication exceeded 60 and 45 s in the first and second studies, respectively. We compared the clinical outcomes for 1 year after the procedure between the EP-guided CBA group (68 patients) and the conventional CBA group (68 patients). The primary endpoint was the recurrence of atrial arrhythmia after ablation. No significant differences in baseline characteristics were observed between the two groups. Compared with the conventional CBA group, the EP-guided CBA group had a significantly higher success rate at TTI ≤ 90 s (98.5% vs. 90.0%, p

STUDY DESIGN A prospective nutritional intervention study for adult spinal deformity (ASD) patients. OBJECTIVE To investigate how a nutritional intervention affects the incidence of postoperative medical complications and the nutritional status. SUMMARY OF BACKGROUND DATA The medical complication rate in ASD surgery is very high, and one risk factor is malnutrition. Nutritional intervention may improve the patient's nutritional status and reduce risk, but this is unexplored regarding ASD surgery. METHODS Malnourished patients (i.e., a Prognostic Nutritional Index (PNI) score of

Background Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. Methods This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. Results RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. Conclusion RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.

Pulmonary arterial hypertension is a progressive and fatal disease and rodents with experimental pulmonary hypertension (PH) are often used to study pathogenic mechanisms, identify therapeutic targets, and develop novel drugs for treatment. Here we describe a hands-on set of experimental approaches including ex vivo lung angiography and histology and in vivo right heart catheterization (RHC) to phenotypically characterize pulmonary hemodynamics and lung vascular structure in normal mice and mice with experimental PH. We utilized Microfil polymer as contrast in our ex vivo lung angiogram to quantitatively examine pulmonary vascular remodeling in mice with experimental PH, and lung histology to estimate pulmonary artery wall thickness. The peripheral lung vascular images were selected to determine the total length of lung vascular branches, the number of branches and the number of junctions in a given area (mm −2 ). We found that the three parameters determined by angiogram were not significantly different among the apical, middle, and basal regions of the mouse lung from normal mice, and were not influenced by gender (no significant difference between female and male mice). We conducted RHC in mice to measure right ventricular systolic pressure, a surrogate measure for pulmonary artery systolic pressure and right ventricle (RV) contractility (RV ± dP/dt max ) to estimate RV function. RHC, a short time (4–6 min) procedure, did not alter the lung angiography measurements. In summary, utilizing ex vivo angiogram to determine peripheral vascular structure and density in the mouse lung and utilizing in vivo RHC to measure pulmonary hemodynamics are reliable readouts to phenotype normal mice and mice with experimental PH. Lung angiogram and RHC are also reliable approaches to examine pharmacological effects of new drugs on pulmonary vascular remodeling and hemodynamics.

BACKGROUND/AIM In order to produce an animal model for oral mucositis induced by anticancer drugs, it is necessary to maintain an immunosuppressive state. We determined the optimal dose and frequency of 5-fluorouracil for a model mouse production. In addition, we used this model to investigate the effect of GGsTop® gelation on the therapeutic effect of oral mucositis. MATERIALS AND METHODS Changes in body weight and white blood cell count were measured to determine the optimal dosing schedule. The therapeutic effect of GGsTop® gel using chitosan was evaluated by observing changes in the ulcer area for three weeks and measuring collagen and glutathione concentrations in oral mucosal tissue. RESULTS The optimal dose and frequency of 5-fluorouracil were found to be 50 mg/kg every four days. It was revealed that the therapeutic effect of GGsTop® was enhanced by gelation. CONCLUSION GGsTop® gel is suggested to be a promising formulation for the treatment of oral mucositis.

Acupuncture is practiced as a complementary medicine worldwide. Although it is considered a safe practice, pneumothorax is one of its most common serious complications. However, there have been few reports of deaths due to pneumothorax after acupuncture treatment, especially focused on electroacupuncture. We report an autopsy case of a man in his 60s who went into cardiopulmonary arrest and died immediately after receiving electroacupuncture. Postmortem computed tomography (PMCT) showed bilateral pneumothoraces, as well as the presence of numerous gold threads embedded subcutaneously. An autopsy revealed two ecchymoses in the right thoracic cavity and a pinhole injury on the lower lobe of the right lung, suggesting that the needles had penetrated the lung. There were marked emphysematous changes in the lung, suggesting that rupture of bullae might also have contributed to bilateral pneumothoraces and fatal outcome. The acupuncture needles may have been drawn deeper into the body than at the time of insertion due to electrical pulses and muscle contraction, indicating the need for careful determination of treatment indications and technical safety measures, such as fail-safe mechanisms. This is the first case report of fatal bilateral pneumothoraces after electroacupuncture reported in the English literature. This case sheds light on the safety of electroacupuncture and the need for special care when administering it to patients with pulmonary disease who may be at a higher risk of pneumothorax. This is also the first report of three-dimensional reconstructed PMCT images showing the whole-body distribution of embedded gold acupuncture threads, which is unusual.

OBJECTIVE: In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on β-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels. METHODS: Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on β-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose. RESULTS: The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR. CONCLUSIONS: The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00523-4.

Hyponatremia is a potential risk factor for the development of coronary artery lesions (CALs) identified after acute Kawasaki disease (KD). However, the serum sodium distribution corresponding to the reference intervals differs between infants ( 1 year of age) and older children. We hypothesized the association of serum sodium level with CAL complications differs between infants and older patients with KD.We analyzed 21,610 population-based patients who developed KD throughout Japan during 2013-2014. We performed multivariable logistic regression analyses to evaluate the association between serum sodium and CAL complications. Additionally, we stratified the serum sodium distribution associated with CAL complications by infants and older patients.CALs were identified in 158 (3.6%) infants and 302 (1.8%) older patients. Infants were more likely to develop CALs when within the normal sodium range compared with older patients (75% vs. 29%), whereas most older patients developed CALs with a sodium level lower than the reference interval. Serum sodium ≤ 130 mEq/L indicated significantly higher risk for development of CALs in both groups (adjusted odds ratio [95% confidence intervals] = 3.21 [1.65-6.25] in infants and 1.74 [1.18-2.57] in older patients).Serum sodium distribution associated with CAL complications differed greatly between infants and older patients. Older patients developed CALs with sodium levels lower than the reference interval; however, among infants, hyponatremia was not necessarily a risk factor for developing coronary artery lesion. When considering risk assessments for CALs using serum sodium levels, infants with KD should be distinguished from older patients. Key Points • Hyponatremia is a potential risk factor for the development of coronary artery lesions (CALs) among patients with Kawasaki disease. • However, the serum sodium distribution corresponding to the reference intervals differs between infants ( 1 year of age) and older children. • Most infants developed CALs within the normal sodium range, whereas older patients developed at a range lower than the reference interval. • These findings highlight that when considering risk assessments for CALs using serum sodium levels, infants should be distinguished from older patients.

Evaluation of in-stent restenosis (ISR) by computed tomography coronary angiography (CTCA) is less invasive but often impossible. We aimed to create a scoring model for predicting which drug-eluting stents (DES) cannot be evaluated with CTCA. We enrolled 757 consecutive implanted DES assessed with CTCA. Non-diagnostic evaluation was defined as poor/not evaluative by two different observers. These stents were randomly divided into a derivation (n = 379) and validation (n = 378) group. In the derivation group, we assessed predictors using logistic regression analysis and created a scoring model that would stratify non-diagnostic evaluation of DES-ISR. The validity of this scoring model was evaluated in the validation group using receiver-operating characteristic analysis. The percentage of non-diagnostic stents was 19/21% in the derivation/validation group (p = 0.71). Non-diagnostic evaluation was independently associated with implanted stent diameter (2.25–2.5. vs. 2.5–3 vs. > 3.0 mm), severe calcification, stent-in-stent lesion, and type of DES (stainless vs. CoCr vs. PtCr) in the derivation group. The predicting system of implanted DES non-diagnostic by CTCA (PIDENT) for non-diagnostic evaluation, including these four baseline factors, was derived (C-statistic = 0.86 in derivation group, cutoff: 8 points). The PIDENT score had a high predictive value for non-diagnostic DES in the validation model (C-statistic = 0.87, sensitivity 86%, specificity 74%, cutoff 8 points, p

Nonalcoholic fatty liver disease is a hepatic disorder with deposition of fat droplets, and has a high risk of progression to steatosis-related hepatitis and irreversible hepatic cancer. Metronidazole (MNZ) is an antiprotozoal and antimicrobial agent widely used to treat patients infected with anaerobic bacteria and intestinal parasites; however, MNZ has also been shown to induce liver tumors in rodents. To investigate the effects of MNZ on steatosis-related early-stage hepatocarcinogenesis, male rats treated with N-nitrosodiethylamine following 2/3 hepatectomy at week 3 were received a control basal diet, high fat diet (HFD), or HFD containing 0.5% MNZ. The HFD induced obesity and steatosis in liver, accompanied by altered expression of Pparg and Fasn, genes related to lipid metabolism. MNZ increased nuclear translocation of lipid metabolism-related transcription factor peroxisome proliferator-activated receptor gamma in hepatocytes, together with altered liver expression of lipid metabolism genes (Srebf1, Srebf2, Pnpla2). Furthermore, MNZ significantly increased the number of preneoplastic liver foci, accompanied by DNA double-strand breaks and late-stage autophagy inhibition, as reflected by increased levels of γ-H2AX, LC3, and p62. Therefore, MNZ could induce steatosis-related hepatocarcinogenesis by inducing DNA double-strand breaks and modulating autophagy in HFD-fed rats.

Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

Hyperperfusion injury is a rare but critical complication associated with revascularization for long-standing severe artery stenosis. Here we report a rare case of a patient with renal hyperperfusion injury after undergoing percutaneous transluminal renal angioplasty for renovascular hypertension as a sequela of neuroblastoma after radiation therapy. (Level of Difficulty: Advanced.), Central Illustration

The impact of pneumonia on prognosis is controversial, and no report has focused on its onset. This study aimed to examine the impact of pneumonia according to its onset on prognosis and its associated risk factors after esophagectomy.In total, 484 patients who underwent curative resection for esophageal squamous cell carcinoma were retrospectively reviewed. Patients with pneumonia were divided into two groups by the date of onset: pneumonia in the acute phase within 7 days after surgery (n = 59) and pneumonia in the subacute phase 8 days after surgery (n = 49).The disease-free survival of patients with acute pneumonia was significantly lower than that of those without pneumonia (P = .0002), whereas the disease-free survival of patients with subacute pneumonia was similar to that of patients without pneumonia (P = .5363). In multivariate analysis for disease-free survival, P-stage III to IV (hazard ratio [HR], 3.344; P.0001), transfusion (HR, 1.4078; P = .0291), and acute pneumonia (HR, 1.8463; P = .0009) were independent prognostic factors. Multivariate analysis revealed that age75 years (odds ratio [OR], 2.1746; P = .0232), respiratory disease comorbidity (OR, 4.3869; P = .0002), cT3-4 (OR, 2.0143; P = .0477), extended surgery duration (OR, 2.3406; P = .0152), and posterior mediastinal reconstruction (OR, 0.1432; P = .0439) were independent risk factors for acute pneumonia.Post-esophagectomy pneumonia in the acute phase was an independent prognostic factor, whereas advanced age, respiratory disease comorbidity, and extended surgery duration were risk factors for acute pneumonia.

BACKGROUND AND PURPOSE: Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH). EXPERIMENTAL APPROACH: Patch-clamp experiments were conducted to examine the activity of voltage-dependent Ca(2+) channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca(2+) concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O(2)) for 4 weeks were used as model of HPH for in vivo experiments. KEY RESULTS: Halofuginone increased voltage-gated K(+) (K(v)) currents in PASMCs and K(+) currents through KCNA5 channels in HEK cells transfected with KCNA5 gene. HF (0.03–1 μM) inhibited receptor-operated Ca(2+) entry in HEK cells transfected with calcium-sensing receptor gene and attenuated store-operated Ca(2+) entry in PASMCs. Acute (3–5 min) intrapulmonary application of halofuginone significantly and reversibly inhibited alveolar hypoxia-induced pulmonary vasoconstriction dose-dependently (0.1–10 μM). Intraperitoneal administration of halofuginone (0.3 mg·kg(−1), for 2 weeks) partly reversed established PH in mice. CONCLUSION AND IMPLICATIONS: Halofuginone is a potent pulmonary vasodilator by activating K(v) channels and blocking VDCC and receptor-operated and store-operated Ca(2+) channels in PASMCs. The therapeutic effect of halofuginone on experimental PH is probably due to combination of its vasodilator effects, via inhibition of excitation–contraction coupling and anti-proliferative effects, via inhibition of the PI3K/Akt/mTOR signalling pathway.

The most recurrent fusion of central nervous system high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) is MN1 rearrangement. Here, we report the case of a 36-year-old man with spinal cord astroblastoma showing Ewing Sarcoma breakpoint region 1/EWS RNA-binding protein 1 (EWSR1)-BEN domain-containing 2 (BEND2) fusion. The patient presented with back pain, gait disturbance and dysesthesia in the lower extremities and trunk. Magnetic resonance imaging showed an intramedullary tumor at the T3-5 level, displaying homogeneous gadolinium enhancement. Partial tumor removal was performed with laminectomy. Histological examinations demonstrated solid growth of epithelioid tumor cells showing high cellularity, a pseudopapillary structure, intervening hyalinized fibrous stroma, and some mitoses. Astroblastoma was diagnosed, classified as HGNET-MN1 by the German Cancer Research Center methylation classifier. MN1 alteration was not detected by fluorescence in situ hybridization (FISH), but EWSR1-BEND2 fusion was detected by FISH and RNA sequencing. Previously, a child with EWSR1-BEND2 fusion-positive spinal astroblastoma classified as HGNET-MN1 was reported. In conjunction with that, the present case provides evidence that EWSR1-BEND2 fusion is identified in the entity of HGNET-MN1. Taken together, the BEND2 alteration rather than MN1 may determine the biology of a subset of the central nervous system HGNET-MN1 subclass.

We report the case of a 2-month-old infant who was found moribund in her crib. Postmortem computed tomography (PMCT) was performed before autopsy. As the baby had a severe subdural hematoma, retinal hemorrhage, and encephalopathy on PMCT, abusive head trauma (AHT) was tentatively diagnosed. At autopsy, no scalp hemorrhages or skull fractures were found; however, the classic triad of AHT was present, mainly on the right side. Additionally, there was dark red discoloration around the heart, and the liver, spleen, and pancreas were enlarged. Peripheral blood was macroscopically cloudy with marked leukocytosis. After careful histological examination, B-cell precursor acute lymphoblastic leukemia (ALL) was diagnosed. All the macroscopic lesions could be attributed to ALL. The manner of death was natural. To the best of our knowledge, this is the first report of infantile ALL mimicking AHT on PMCT images. This case demonstrates the importance of a comprehensive systematic approach to considering differential diagnosis when PMCT shows multiple intracranial hemorrhages suggestive of AHT in an infant.