Podoplanin is indispensable for cell motility and platelet-induced epithelial-to-mesenchymal transition-related gene expression in esophagus squamous carcinoma TE11A cells.

BACKGROUND: The transmembrane glycoprotein podoplanin (PDPN) is upregulated in some tumors and has gained attention as a malignant tumor biomarker. PDPN molecules have platelet aggregation-stimulating domains and, are therefore, suggested to play a role in tumor-induced platelet activation, which in turn triggers epithelial-to-mesenchymal transition (EMT) and enhances the invasive and metastatic activities of tumor cells. In addition, as forced PDPN expression itself can alter the propensity of certain tumor cells in favor of EMT and enhance their invasive ability, it is also considered to be involved in the cell signaling system. Nevertheless, underlying mechanisms of PDPN in tumor cell invasive ability as well as EMT induction, especially by platelets, are still not fully understood. METHODS: Subclonal TE11A cells were isolated from the human esophageal squamous carcinoma cell line TE11 and the effects of anti-PDPN neutralizing antibody as well as PDPN gene knockout on platelet-induced EMT-related gene expression were measured. Also, the effects of PDPN deficiency on cellular invasive ability and motility were assessed. RESULTS: PDPN-null cells were able to provoke platelet aggregation, suggesting that PDPN contribution to platelet activation in these cells is marginal. Nevertheless, expression of platelet-induced EMT-related genes, including vimentin, was impaired by PDPN-neutralizing antibody as well as PDPN deficiency, while their effects on TGF-ß-induced gene expression were marginal. Unexpectedly, PDPN gene ablation, at least in either allele, engendered spontaneous N-cadherin upregulation and claudin-1 downregulation. Despite these seemingly EMT-like alterations, PDPN deficiency impaired cellular motility and invasive ability even after TGF-ß-induced EMT induction. CONCLUSIONS: These results suggested that, while PDPN seems to function in favor of maintaining the epithelial state of this cell line, it is indispensable for platelet-mediated induction of particular mesenchymal marker genes as well as the potentiation of motility and invasion capacity.

Cha-Koji, comprising green tea leaves fermented with Aspergillus luchuensis var kawachii kitahara, increases regulatory T cell production in mice and humans.

Green tea leaves fermented with Aspergillus luchuensis var kawachii kitahara (Cha-Koji) are a health food containing live A. luchuensis. In this study, we examined the effects of Cha-Koji on the immune system and the enteric environment. First, we designed a clinical trial; after ingesting Cha-Koji daily for 28 days, blood parameters and the fecal composition of the participants were analyzed. Similarly, mice were administered (oral administration) with Cha-Koji suspension or its vehicle for 14 days. Thereafter, both humans and mice were examined by analyzing their immune cell phenotypes and intestinal microbiota. Regulatory T cell (Treg) numbers were significantly increased after administering Cha-Koji. An increase of Clostridium subcluster XIVa, that were known to be rich in butyrate-producing bacterium, was observed in human feces, but not in mice. These results suggest that Cha-Koji has the ability to increase Treg production in both humans and mice, irrespective of the presence of enteric butyrate.

Changes in arrhythmogenic properties and five-year prognosis after carbon-ion radiotherapy in patients with mediastinum cancer.

INTRODUCTION: Carbon-ion irradiation of rabbit hearts has improved left ventricular conduction abnormalities through upregulation of gap junctions. However, to date, there has been no investigation on the effect of carbon-ion irradiation on electrophysiological properties in human. We investigated this effect in patients with mediastinum extra-cardiac cancer treated with carbon-ion radiotherapy that included irradiating the heart. METHODS AND RESULTS: In April-December 2009, eight patients were prospectively enrolled (including two male, aged 72.5 ± 13.0 years). They were treated with 44-72 Gray equivalent (GyE), with their hearts exposed to 1.3-19.1 GyE. High-resolution ambulatory electrocardiography was performed before and after radiotherapy to investigate arrhythmic events, late potentials (LPs), and heart rate variability. Five patients had pre-existing premature ventricular contraction (PVC)/atrial contraction (PAC) or paroxysmal atrial fibrillation (PAF)/AF; after irradiation, this improved in four patients with PVC/PAF/AF and did not deteriorate in one patient with PAC. Ventricular LP findings did not deteriorate and improved in one patient. In eight cases with available atrial LP findings, there was no deterioration, and two patients showed improvements. The low frequency/high frequency ratio of heart rate variability improved or did not deteriorate in the six patients who received radiation exposure to the bilateral stellate ganglions. During the five-year follow-up for the prognosis, six of the eight patients died because of cancer; there was no history of hospitalization for cardiac events. CONCLUSION: Although this preliminary study has several limitations, carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction.

Optimal management strategy for spontaneous isolated dissection of a visceral artery.

Objectives To describe our clinical experiences and recommend a management strategy for spontaneous isolated dissection of a visceral artery. Methods A retrospective study of patients from December 2005 to December 2015 was performed. Thirty-two patients had spontaneous isolated dissection of a visceral artery. Clinical features, computed tomography findings, the treatment method, and follow-up results were evaluated. Results There were 28 men and 4 women (mean age, 54 years). Dissection locations were the celiac artery in 10, superior mesenteric artery in 17, and celiac artery and superior mesenteric artery in 5 patients. Celiac artery stenosis existed with spontaneous isolated dissection of a visceral artery at a high rate. After diagnosis, the blood pressure of all patients was immediately controlled to a lower level. Three patients with arterial rupture and one patient with bowel infarction underwent operations for complications. Overall, the treatment of dissection involved drug therapy alone. The last follow-up computed tomography results of the true lumen residual ratio and the length of the dissected artery improved compared to the values on admission; the maximum diameter of the dissected artery did not enlarge. Eleven patients almost completely improved. No patients had any adverse event. Conclusions Most patients with spontaneous isolated dissection of a visceral artery can be first treated conservatively for dissection with strict blood pressure control and surveillance.

Multiple Patients With Heatstroke Air Evacuated by Agreement Concerning Collaboration.

On August 30, 2017, the wet-bulb globe temperature was 30°C. Three female military personnel fell unconscious almost simultaneously around noon after a long-distance march that had started at 6 am. The fire department in Gotenba received a 119 call [at 1:16 PM] and requested dispatch of the eastern Shizuoka doctor helicopter (DH) because it would take about 1 hour from the scene to arrive at our hospital by ground ambulance. At that time, the DH of eastern Shizuoka was transporting an injured patient to Kanagawa Prefecture, so the flight dispatcher of the DH of eastern Shizuoka decided to request support DHs from Kanagawa Prefectures based on an agreement concerning collaboration using the DH. The DH of Kanagawa Prefecture met 1 of the patients and transported her to its base hospital. The remaining 2 patients were then transported by the DH of eastern Shizuoka to its base hospital after completing the previous mission. All patients obtained a survival discharge without major complications after receiving proper treatment and rehabilitation. The agreement concerning collaboration using multiple DHs was important in this case, and dispersion transportation was successfully achieved.

Detection of synthetic cannabinoids using GC-EI-MS, positive GC-CI-MS, and negative GC-CI-MS.

Recently, various synthetic cannabinoid (SC) compounds that have been slightly modified at the functional groups have been identified in Japan. However, the structural elucidation of these new compounds using conventional approaches such as gas chromatography-electron impact-mass spectrometry (GC-EI-MS) is difficult. As such, indole and indazole SCs were scanned using GC-MS-EI, positive GC-chemical ionization (CI)-MS, and negative GC-chemical ionization-MS, allowing for efficient structural elucidation of unknown SC compounds. Pure substances have been employed for the study.

Inducibility of Ventricular Arrhythmia 1 Year Following Treatment with Heavy Ion Irradiation in Dogs with Myocardial Infarction.

BACKGROUND: Targeted external heavy ion irradiation (THIR) of rabbit hearts 2 weeks after myocardial infarction (MI) reduced the vulnerability of fatal ventricular tachyarrhythmias (VT/VF) in association with the increased connexin43 (Cx43). Increased Cx43 was maintained for at least 1 year in normal rabbits, but the long-term antiarrhythmic effects in the MI model are unknown. We investigated the propensity for late potentials and VT/VF inducibility. METHODS: Intracoronary injection of microspheres was performed to induce nontransmural MI in anesthetized eight beagles. Four beagles were treated with THIR (12 C6+ , 15 Gy) 2 weeks later (MI + THIR group), and four without THIR served as controls (MI group). Signal-averaged electrocardiography, programmed electrical stimulation, immunohistochemical analysis, and echocardiograms were performed at 1 year. RESULTS: Filtered QRS duration was exacerbated after MI and remained unchanged for 1 year in the MI group (118 ± 1.4 ms), but significantly returned toward baseline in the MI + THIR group (109 ± 6.9 ms). Similarly, root mean square voltage of the last 40 ms was exacerbated after MI, but recovered after THIR. VT/VF inducibility decreased to 25% in the MI + THIR group compared with 100% in the MI group. Immunostaining Cx43 expression in cardiac tissues significantly increased by 24-45% in the MI + THIR group. Left ventricular ejection fractions remained within the normal range in both groups. CONCLUSION: A single exposure of the dog heart to 12 C irradiation attenuated vulnerability to ventricular arrhythmia after the induction of MI for at least 1 year through the modulation of Cx43 expression.

Normal 123 I-MIBG uptake areas may be associated with hyperinnervation and arrhythmia risk in phenol model rabbit hearts.

BACKGROUND: Iodine-123 metaiodobenzylguanidine (123 I-MIBG) is useful for detecting sympathetic innervation in the heart, and has been closely associated with fatal arrhythmias. However, such imaging is typically calibrated to the area of highest uptake and thus is unable to identify areas of hyperinnervation. We hypothesized that normal 123 I-MIBG uptake regions in the denervated heart would demonstrate nerve sprouting and correlate with the potential for arrhythmogenesis. METHODS: Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4 weeks after phenol application, and electrophysiological study was performed. RESULTS: 123 I-MIBG revealed maximal local differences in isotope uptake in the border zone between areas with attenuated and abundant MIBG compared with that seen between adjacent regions within the lowest uptake areas. On immunostaining, heterogeneous and decreased expressions of growth-associated protein 43 signal were observed in the MIBG-attenuated areas; however, abundant signals were recognized in the MIBG-abundant areas. Upregulation of the tyrosine hydroxylase signal was observed at the part of the MIBG-abundant area. In electrophysiological study, the dispersion of activation recovery interval (ARI) was increased in the phenol-applied areas by norepinephrine infusion. Stellate stimulation exacerbated the ARI dispersion in both the phenol-applied and nonapplied areas, and was associated with increased inducibility of ventricular tachycardia and ventricular fibrillation. CONCLUSIONS: The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal 123 I-MIBG uptake and contributes to electrical instability.

Does Antiarrhythmic Drug During Cardiopulmonary Resuscitation Improve the One-month Survival: The SOS-KANTO 2012 Study.

BACKGROUND: Antiarrhythmic drugs (AAD) are often used for fatal ventricular arrhythmias during cardiopulmonary resuscitation (CPR). However, the efficacy of initial AAD administration during CPR in improving long-term prognosis remains unknown. This study retrospectively evaluated the effect of AAD administration during CPR on 1-month prognosis in the SOS-KANTO 2012 study population. METHODS AND RESULTS: Of the 16,164 out-of-hospital cardiac arrest cases, 1350 shock-refractory patients were included: 747 patients not administered AAD and 603 patients administered AAD. Statistical adjustment for potential selection bias was performed using propensity score matching, yielding 1162 patients of whom 792 patients were matched (396 pairs). The primary outcome was 1-month survival. The secondary outcome was the proportion of patients with favorable neurological outcome at 1 month. Logistic regression with propensity scoring demonstrated an odds ratio (OR) for 1-month survival in the AAD group of 1.92 (P < 0.01), whereas the OR for favorable neurological outcome at 1 month was 1.44 (P = 0.26). CONCLUSIONS: Significantly greater 1-month survival was observed in the AAD group compared with the non-AAD group. However, the effect of ADD on the likelihood of a favorable neurological outcome remains unclear. The findings of the present study may indicate a requirement for future randomized controlled trials evaluating the effect of ADD administration during CPR on long-term prognosis.

Arrhythmogenic Substrates in Sleep-Disordered Breathing with Arterial Hypertension.

BACKGROUND: Sleep-disordered breathing (SDB) is highly associated with arterial hypertension (HT). Sympathetic hypertonia increases the risk of sudden cardiac death in patients with sleep apnea. This study aims to noninvasively investigate the electrophysiological features in SDB patients with and without arterial HT. METHODS: Fifty-three patients with SDB were classified into two groups: SDB group and SDB + HT group. Twenty subjects with arterial HT were enrolled as controls (HT group). To assess arrhythmogenic vulnerability, high-resolution 24-hour ambulatory electrocardiograms were obtained for analyzing continuous late potential (LP), T-wave amplitude variability (TAV), and heart rate variability (HRV). RESULTS: A higher incidence of positive LP was observed in the SDB + HT (85%) group than that observed in the SDB (50%) and HT (20%) groups (P < 0.01). TAV was highest in the SDB + HT group (78 µV) compared with the SDB (61 µV) and HT groups (42 µV; P < 0.01). Positive LP and TAV values were observed at night in the SDB + HT and SDB groups. The low-frequency/high-frequency of the HRV analysis was highest in the SDB + HT (4.7) group compared with that in the SDB (2.9) and HT (2.9) groups (P = 0.01). CONCLUSION: Nocturnal LP, TAV, and HRV examinations were useful to investigate arrhythmogenesis. SDB patients with arterial HT showed a high prevalence of depolarization and repolarization abnormalities and relative sympathetic hyperactivity. This suggests that an electrophysiological instability is more prevalent in SDB patients with arterial HT.