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Rupture of a racemose hemangioma causing dilatation and tortuosity of the bronchial artery can result in massive bleeding and respiratory failure. Bronchial artery embolization (BAE) can treat this life-threatening condition, as we show in two cases. The first case was of an 89-year-old female complaining of sudden-onset chest and back pain. Bronchial artery angiography demonstrated a racemose hemangioma with a 2 cm aneurysm. The second case was of a 50-year-old male with hemoptysis and dyspnea, eventually requiring intubation. Bronchial arteriography showed a racemose hemangioma and a bronchial artery-pulmonary arterial fistula. BAE was successfully performed in both cases, with no recurrent hemorrhage. Therapeutic interventions in bronchial artery racemose hemangiomas include lobectomy or segmentectomy, bronchial arterial ligation, and BAE. BAE should be considered as first-line therapy for bleeding racemose hemangiomas of the bronchial artery because of its low risk of adverse effects on respiratory status, minimal invasiveness, and faster patient recovery.

Both low appendicular skeletal muscle index (ASMI) and specific abdominal fat composition [i.e., increased visceral to subcutaneous (V/S) fat ratio] have been associated with cardiovascular events. However, the combined impact of these 2 components on long-term outcomes remains unclear, especially in patients with ST-segment elevation myocardial infarction (STEMI).In 303 patients with STEMI, ASMI and V/S fat ratio were assessed using dual-energy X-ray absorptiometry and abdominal computed tomography. Based on the criteria of the Asian Working Group for Sarcopenia and median of V/S fat ratio, sarcopenic obesity (SO) pattern was defined as low ASMI with high V/S fat ratio. The primary endpoint was composite outcomes of all-cause death, myocardial infarction, ischemic stroke, hospitalization for heart failure and unplanned revascularization.During a median follow-up of 3.9 years, primary endpoint occurred in 67 patients. Patients with an SO pattern showed significantly lower event-free survival rate compared with those without (p=0.006 by log-rank). Notably, when stratified by median age (67 years), this trend was particularly prominent in the younger-age group (p0.001), but not significant in the older-age group (p=0.38). In the younger-age group, the multivariate analysis revealed that patients with SO pattern had a 2.97 (1.10-7.53) fold higher risk for primary endpoints compared with those without.Low ASMI with high V/S fat ratio, or so-called sarcopenic obesity, was associated with poor prognosis after STEMI, particularly in younger-age patients. The combined assessment of skeletal muscle with abdominal fat distribution may help stratify the risk among patients with STEMI, rather than each component alone.

The hemostatic effect of radiation therapy on gastric cancer with bleeding is known. However, blood tests and endoscopes are mainly used to determine the therapeutic effect. Additionally, magnetic resonance imaging has been reported to be useful when needed because endoscopes are invasive. In this study, magnetic resonance diffusion-weighted imaging was used to evaluate the hemostatic effect of gastric cancer. The hemostatic effect and apparent diffusion coefficient value were correlated. The apparent diffusion coefficient value was also effective in salvage irradiation during rebleeding. Although the apparent diffusion coefficient value of gastric cancer did not change during rescue irradiation, the degree of hemostatic effect could be evaluated in more detail by using the ratio of the apparent diffusion coefficient values of diffusion-weighted imaging of gastric cancer and the spleen. In the future, it would be desirable to use diffusion-weighted imaging instead of endoscopy to evaluate the gastric cancer to spleen apparent diffusion coefficient ratio in a large number of cases.

Background Three-dimensional (3D) speckle tracking echocardiography (STE) after ST-elevation acute myocardial infarction (STEMI) is associated with left ventricular (LV) remodeling and 1-year prognosis. This study investigated the clinical significance of 3D-STE in predicting the long-term prognosis of patients with STEMI.Methods and Results:A total of 270 patients (mean age 64.6 years) with first-time STEMI treated with reperfusion therapy were enrolled. At 24 h after admission, standard 2D echocardiography and 3D full-volume imaging were performed, and 2D-STE and 3D-STE were calculated. Patients were followed up for a median of 119 months (interquartile range: 96-129 months). The primary endpoint was occurrence of a major adverse cardiac event (MACE: cardiac death, heart failure with hospitalization), and 64 patients experienced MACEs. Receiver operating characteristic curves and Cox hazard multivariate analysis showed that the 3D-STE indices were stronger predictors of MACE compared with those of 2D-STE. Additionally, 3D-global longitudinal strain (GLS) was the strongest predictor for MACE followed by 3D-global circumferential strain (GCS). The Kaplan-Meier curve demonstrated that 3D-GLS >-11.0 was an independent predictor for MACE (log-rank χ2=132.2, P -18.3, patients with higher values of 3D-GLS and 3D-GCS were found to be at extremely high risk for MACE. Conclusions Global strain measured by 3D-STE immediately after the onset of STEMI is a clinically significant predictor of 10-year prognosis.

The complete blood cell count is one of the most frequently ordered laboratory tests, and many parameters, including red blood cell distribution width (RDW) and mean platelet volume (MPV), are available. The purpose of this study was to investigate the usefulness of the combination of RDW and MPV in patients with ST-segment elevation myocardial infarction (STEMI). Patients with STEMI who underwent primary percutaneous coronary intervention were retrospectively enrolled (n = 229). The association between RDW as well as MPV and cardiovascular events was investigated. The median age was 67 years, and males made up 85% of the sample. Median RDW was 13.6%, and median MPV was 8.2 fL. During a median follow-up period of 528 days (IQR 331.5-920.5), 41 patients died or experienced major adverse cardiac and cerebrovascular events (MACCEs). Patients with RDW ≧ 13.7% had more deaths or MACCEs with marginal significance (p = 0.0799). Patients with MPV ≧ 8.3 fL had significantly more deaths or MACCEs (p = 0.0283). Patients with RDW ≧ 13.7% and MPV ≧ 8.3 fL had significantly more deaths or MACCEs (p = 0.0185). MPV was significantly associated with death or adverse events in patients with STEMI who were treated with primary PCI. RDW had only a weak association with death or adverse events. The results of the combination of MPV and RDW were similar to those of MPV.

Background: The significance of late diastolic velocity (a′) obtained by tissue Doppler imaging (TDI), which reveals atrial function, in ST-elevation myocardial infarction (STEMI) remains unclear. This study evaluated the association of TDI parameters determined either immediately or 2 weeks after percutaneous coronary intervention (PCI) with long-term outcomes. Methods and Results: In all, 740 patients with first-time STEMI underwent immediate PCI (i.e., within 12 h of onset). Echocardiography was performed in 307 patients 2 weeks after onset (Group A; mean age 64 years, 249 males), in 277 patients immediately after PCI (Group B; mean age 65 years, 229 males), and in 156 patients twice (i.e., immediately and 2 weeks after PCI; Group C; mean age 65 years, 135 males). Patients were followed-up for up to 10 years (mean 81 months). The primary endpoints were cardiac death or heart failure hospitalization. Major adverse cardiovascular events (MACE) occurred in 143 patients (19%) during the follow-up period. Both univariate and multivariate Cox hazard analyses were used to determine predictors of MACE. At 24 h and 2 weeks after STEMI onset, a′ and E/e′ were the strongest predictors of MACE, respectively. Conclusions: TDI parameters have different implications depending on the timing of echocardiography after a first-time STEMI. Based on the results of this study, atrial dysfunction measured by TDI 24 h after STEMI onset may indicate a poor prognosis.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. Here, we evaluated the performance of two quantitative antigen (Ag) tests, the Roche and Lumipulse Ag tests, using automated platforms. Methods We collected 637 nasopharyngeal swab samples from 274 individuals. Samples were subjected to quantitative reverse transcription PCR (RT-qPCR), the Roche Ag test and Lumipulse Ag test. Results When RT-qPCR was used as a reference, the overall concordance rate of the Roche Ag test was 77.1% (491/637) with 70.0% (341/487) sensitivity and 100% specificity (150/150). When inconclusive results of the Lumipulse Ag test were excluded, the overall concordance rate of the Lumipulse Ag test was 88.3% (467/529) with 84.8% (330/389) sensitivity and 97.9% (137/140) specificity. The overall concordance rate between the Roche and Lumipulse Ag tests was 97.9% (518/529) with 96.7% (322/333) sensitivity and 100% (196/196) specificity. Quantitative Ag levels determined using the Roche and Lumipulse Ag tests were highly correlated (R2 = 0.922). The Roche and Lumipulse Ag tests showed high concordance up to nine days after symptom onset, with progressively lower concordance after that. Conclusions The Roche and Lumipulse Ag tests showed equivalent assay performance and represent promising approaches for diagnosing coronavirus disease 2019.

Isomaltulose is a low glycemic and insulinaemic carbohydrate available as a constituent in sports drink. However, it remains unclear whether postexercise rehydration achieved by isomaltulose drink ingestion alone differs as compared to other carbohydrates. Thirteen young men performed intermittent exercise in the heat (35 °C and relative humidity 40%) to induce a state of hypohydration as defined by a 2% loss in body mass. Thereafter, participants were rehydrated by ingesting drinks equal to the volume of body mass loss with either a mixture of 3.25% glucose and 3.25% fructose, 6.5% sucrose (SUC), or 6.5% isomaltulose (ISO) within the first 30 min of a 3-h recovery. The change in plasma volume (ΔPV) from pre-exercise baseline, blood glucose, and plasma insulin concentration were assessed every 30-min. ΔPV was lower in ISO as compared to SUC until 90 min of the recovery (all P ≤ 0.038) with no difference thereafter (all P ≥ 0.391). The ΔPV were paralleled by concomitant changes in blood glucose levels that were greater in ISO as compared to other drinks after 90 min of the recovery (all P ≤ 0.035). Plasma insulin secretion, which potentially enhances renal sodium reabsorption and fluid retention, did not differ between the trials (interaction, P = 0.653). ISO induced a greater net fluid volume retention as compared to SUC (P = 0.010). We showed that rehydration with an isomaltulose drink following exercise-heat stress induces comparable recovery of PV and a greater net fluid retention as compared to other drinks, albeit this response is delayed. The delayed water transport along with glucose absorption may modulate this response. This trial was registered in 25th Sep 2019 at https://www.umin.ac.jp/ as UMIN000038099. (249/250)

Preconditioning exercise prior to stroke exerts neuroprotection, which is an endogenous strategy that leads the brain cells to express several intrinsic factors and inhibits their apoptosis. However, it is unclear how long these benefits last after exercise cessation. The aim of this study was to investigate the effects of detraining on preconditioning exercise-induced neuroprotective potential after stroke. Rats were trained using a treadmill for aerobic exercise 5 days each week for 3 weeks, and their neuroprotective effects were examined until 3 weeks after exercise cessation. Stroke was induced by 60 min of left middle cerebral artery occlusion at 3 days, 1, 2, and 3 weeks after exercise cessation. Infarct volume, neurological deficits, sensorimotor function, expression levels of brain-derived neurotrophic factor (BDNF), hypoxia-induced factor-1α (HIF-1α), glial fibrillary acidic protein (GFAP), and P2X7 receptors, and apoptosis activity were examined using immunohistochemical and western blot analyses. Preconditioning exercise significantly reduced infarct volume and ameliorated sensorimotor function after stroke, and its beneficial effects were observed until 2 weeks after exercise cessation. The expression level of BDNF in the ischemic brain was significantly upregulated at 3 days after exercise cessation; however, the expression levels of HIF-1α, GFAP, and P2X7 receptor were significantly increased until 2 weeks after exercise cessation; thereby, significant anti-apoptotic effects were lost at 3 weeks of detraining. Our findings suggest that preconditioning exercise-induced neuroprotective potential may be lost shortly after exercise cessation. Neuroprotection through intrinsic protective factors, such as BDNF and HIF-1α, may provide different neuroprotective mechanisms in a time-dependent manner during detraining.

Background Cachexia, characterized by loss of muscle with or without loss of fat mass, is a poor prognostic factor in patients with heart failure (HF). However, there is limited investigation on the prognostic impact of muscle and fat mass separately in HF. We hypothesized that muscle and fat mass have different effects on the prognosis of HF. Methods This was an observational cohort study of 418 patients (59% were men) admitted with a diagnosis of HF (71 ± 13 years [mean ± standard deviation]), with left ventricular ejection fraction (LVEF) of 39 ± 16%, including 31.3%, 14.8%, and 53.8% of patients with preserved LVEF (LVEF ≥ 50%), mid‐range LVEF (40–50%), and reduced (

Introduction Nephrotic syndrome secondary to malignant disease accounts for approximately 10% of cases of nephrotic syndrome in adults. However, urothelial carcinoma of the bladder is a rare cancer, with only four cases reported to date. Case presentation A 76-year-old man presented with chief complaints of edema and anorexia. Laboratory examinations revealed hypoalbuminemia and marked proteinuria, and computed tomography demonstrated multiple bladder tumors. Transurethral resection of the bladder tumors was performed. The pathological diagnosis was urothelial carcinoma with muscular invasion. The patient underwent simple cystectomy and ileal conduit formation, and proteinuria disappeared after 4 weeks. However, urethral recurrence was noted, and he died 35 months after cystectomy. Conclusion Five cases including ours were clinically reviewed. Nephrotic symptoms improved relatively rapidly after surgery in all cases. In contrast to the poor preoperative general condition, postoperative improvement can be expected, and surgical treatment should, therefore, be considered.

Background Although high-dose glucocorticoids are effective in suppressing active inflammation of Takayasu arteritis (TAK), many patients experience relapse during tapering of glucocorticoids. Recently, the interleukin-6 receptor antibody, tocilizumab (TCZ), was reported to be effective for steroid-resistant TAK. However, there are no objective ways of diagnosing TAK recurrence because TCZ suppresses inflammatory biomarkers. Objectives To investigate the efficacy of TCZ at 1-year follow-up and of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography for detection of recurrence of inflammation during TCZ treatment. Methods and Results We treated 19 patients with refractory TAK with TCZ. TCZ was discontinued in 2 cases because of side effects. Abatement of arteritis symptoms along with reduction of glucocorticoid dosage was achieved in 12 patients, resulting in a remission induction rate of 70.6%. The dosage of glucocorticoid was reduced from 16.1 ± 10.2 mg to 3.8 ± 1.7 mg at 1 year (p Conclusions TCZ injection provides robust steroid-sparing effect and improvement of inflammation without significant adverse effects. Recurrence of inflammation can be detected by FDG-PET even during TCZ treatment.

It is important to determine the functional changes of organs that occur as a result of aging, the understanding of which may lead to the maintenance of a healthy life. Glucose metabolism in healthy bodies is one of the potential markers used to evaluate the changes of organ function. Thus, information about normal organ glucose metabolism may help to understand the functional changes of organs. [18F]-Fluoro-2-deoxy-2-d-glucose (18F-FDG), a glucose analog, has been used to measure glucose metabolism in various fields, such as basic medical research and drug discovery. However, glucose metabolism changes in aged animals have not yet been fully clarified. The aim of this study is to evaluate changes in glucose metabolism in organs and brain regions by measuring 18F-FDG accumulation and 18F-FDG autoradiography with insulin loading in aged and young wild-type mice. In the untreated groups, the levels of 18F-FDG accumulation in the blood, plasma, muscle, lungs, spleen, pancreas, testes, stomach, small intestine, kidneys, liver, brain, and brain regions, namely, the cortex, striatum, thalamus, and hippocampus, were all significantly higher in the aged mice. The treated group showed lower 18F-FDG accumulation levels in the pancreas and kidneys, as well as in the cortex, striatum, thalamus, and hippocampus in the aged mice than the untreated groups, whereas higher 18F-FDG accumulation levels were observed in those in the young mice. These results demonstrate that insulin loading decreases effect on 18F-FDG accumulation levels in some organs of the aged mice. Therefore, aging can increase insulin resistance and lead to systemic glucose metabolism dysfunction.

This study aimed to evaluate the characteristics and prognosis of patients with vasospastic angina (VSA) diagnosed by a provocation test with a secondary prevention implantable cardioverter defibrillator (ICD), compared with patients with organic coronary stenosis. We retrospectively evaluated 309 consecutive patients who received an ICD implantation between January 2010 and March 2018 in our institutions. Of these patients, 206 were implanted with an ICD for secondary prevention. In these 206 patients, 40 with VSA and 72 with organic coronary stenosis were evaluated. Patients with VSA were characterized by younger age (56.1 ± 13.1 versus 69.2 ± 9.5 years, respectively), and a lower prevalence of diabetes (15.0% versus 40.3%, respectively) and heart failure (2.5% versus 26.4%, respectively) than patients with organic coronary stenosis (P < 0.001). Using the Kaplan-Meier analysis, with the VSA group as the reference, the incidence of appropriate ICD shock was similar between the two groups (hazard ratio, 0.85; 95% confidence interval, 0.341-2.109; P = 0.722). The incidence of ventricular fibrillation was significantly higher in the VSA group (hazard ratio, 0.22; 95% confidence interval, 0.057-0.814; P = 0.024), whereas the incidence of major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, and heart failure, was significantly higher in the organic coronary stenosis group (hazard ratio, 13.1; 95% confidence interval, 1.756-98.17; P = 0.012). In conclusion, patients with VSA with an ICD implanted for secondary prevention have a higher risk of ventricular fibrillation and lower risk of major adverse cardiac events than patients with organic coronary stenosis.

Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) channel. In addition to diabetes, DEND patients present muscle weakness as one of the symptoms, and although the muscle weakness is considered to originate in the brain, the pathological effects of mutated KATP channels in skeletal muscle remain elusive. Here, we describe the local effects of the KATP channel on muscle by expressing the mutation present in the KATP channels of the DEND syndrome in the murine skeletal muscle cell line C2C12 in combination with computer simulation. The present study revealed that the DEND mutation can lead to a hyperpolarized state of the muscle cell membrane, and molecular dynamics simulations based on a recently reported high-resolution structure provide an explanation as to why the mutation reduces ATP sensitivity and reveal the changes in the local interactions between ATP molecules and the channel.

Background Selective use of distal filter protection during percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) decreased the incidence of no-reflow phenomena and in-hospital serious adverse cardiac events compared with conventional PCI in patients with attenuated plaque ≥5 mm; however, its long-term clinical outcome remains unknown.Methods and Results:Patients who had ACS with attenuated plaque ≥5 mm were assigned to receive distal protection (DP) (n=98) or conventional treatment (CT) (n=96). The rate of major adverse cardiovascular events (MACE), a composite of death from any cause, non-fatal myocardial infarction, or target vessel revascularization (TVR) at 1 year, was the pre-specified secondary endpoint of the trial. MACE at 1 year occurred in 12 patients (12.2%) in the DP group and 3 patients (3.1%) in the CT group (P=0.029), which was driven by a higher risk of TVR (11 [11.2%] vs. 2 [2.1%], P=0.018). In patients treated with bare-metal stents (n=42), MACE occurred in 25.0% of the patients in the DP group and in none of the patients in the CT group (P=0.029), whereas in patients treated with drug-eluting stents (n=151), rates of MACE were similar in the groups (8.1% vs. 3.9%, P=0.32). Conclusions In ACS patients with attenuated plaque ≥5 mm, the 1-year rates of MACE were higher in the DP group than in the CT group. This effect might be mitigated by the use of drug-eluting stents.

β3-Adrenergic receptor expression is enhanced in the failing heart, but its functional effects are unclear. We tested the hypothesis that a β3-agonist improves left ventricular (LV) performance in heart failure. We examined the chronic effects of a β3-agonist in the angiotensin II (Ang II)-induced cardiomyopathy mouse model. C57BL/6J mice were treated with Ang II alone or Ang II + BRL 37344 (β3-agonist, BRL) for 4 weeks. Systolic blood pressure in conscious mice was significantly elevated in Ang II and Ang II + BRL mice compared with control mice. Heart rate was not different among the three groups. Systolic performance parameters that were measured by echocardiography and an LV catheter were similar among the groups. LV end-diastolic pressure and end-diastolic pressure-volume relationships were higher in Ang II mice compared with control mice. However, the increase in these parameters was prevented in Ang II + BRL mice, which suggested improvement in myocardial stiffness by BRL. Pathologic analysis showed that LV hypertrophy was induced in Ang II mice and failed to be prevented by BRL. However, increased collagen I/III synthesis, cardiac fibrosis, and lung congestion observed in Ang II mice were inhibited by BRL treatment. The cardioprotective benefits of BRL were associated with downregulation of transforming growth factor-β1 expression and phosphorylated-Smad2/3. Chronic infusion of a β3-agonist has a beneficial effect on LV diastolic function independent of blood pressure in the Ang II-induced cardiomyopathy mouse model. SIGNIFICANCE STATEMENT: Chronic infusion of a β3-adrenergic receptor agonist attenuates cardiac fibrosis and improves diastolic dysfunction independently of blood pressure in an angiotensin II-induced hypertensive mouse model. This drug might be an effective treatment of heart failure with preserved ejection fraction.

Aim: The importance of sarcopenia in cardiovascular diseases has been recently demonstrated. This study aims to examine whether skeletal muscle mass (SMM), an important component of sarcopenia, is associated with an increased risk of poor outcome in patients after ST-segment elevation myocardial infarction (STEMI). Methods: We measured SMM in 387 patients with STEMI using dual-energy X-ray absorptiometry. Patients were divided into low- and high-appendicular skeletal mass index (ASMI: appendicular SMM divided by height squared (kg/m2)) groups using the first quartile of ASMI (≤ 6.64 kg/m2 for men and ≤ 5.06 kg/m2 for women). All patients were followed up for the primary composite outcome of all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for congestive heart failure, and unplanned revascularization. Results: Low-ASMI group was older and had a more complex coronary lesion, a lower left ventricular ejection fraction, and a higher prevalence of Killip classification ≥ 2 than high-ASMI group. During a median follow-up of 33 months, the event rate was significantly higher in low-ASMI group than in high-ASMI group (24.7% vs 13.4%, log-rank p = 0.001). Even after adjustment for patients' background, low ASMI was independently associated with the high risk of primary composite events (adjusted hazard ratio 2.06, 95% confidence interval 1.01–4.19, p = 0.04). In the subgroup analyses of male patients (n = 315), the optimal cutoff point of ASMI for predicting primary composite outcome was 6.75 kg/m2, which was close to its first quartile value. Conclusions: Low ASMI is independently associated with poor outcome in patients with STEMI.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) testing reagents are expected to become scarce worldwide. However, little is known regarding whether pooling of samples accurately detects SARS-CoV-2. To validate the feasibility of pooling samples, serial dilution analysis and spike-in experiments were conducted using synthetic DNA and nucleic acids extracted from SARS-CoV-2-positive and -negative patients. Furthermore, we studied 1000 individuals, 667 of whom were “healthy” individuals (195 healthcare workers and 472 hospitalized patients with disorders other than COVID-19 infection), and 333 infection-suspected patients with cough and fever. Serial dilution analysis showed a limit of detection of around 10–100 viral genome copies according to the protocol of the National Institute of Infectious Diseases, Japan. Spike-in experiments demonstrated that RT-qPCR detected positive signals in pooled samples with SARS-CoV-2-negative and -positive patients at 5-, 10-, 20-fold dilutions. By screening with this pooling strategy, by the end of April 2020 there were 12 SARS-CoV-2-positive patients in 333 infection-suspected patients (3.6%) and zero in 667 “healthy” controls. We obtained these results with a total of 538 runs using the pooling strategy, compared with 1000 standard runs. In a prospective study, we successfully detected SARS-CoV-2 using 10- to 20-fold diluted samples of nasopharyngeal swabs from eighteen COVID-19 patients with wide ranges of viral load. Pooling sample is feasible for conserving test reagents and detecting SARS-CoV-2 in clinical settings. This strategy will help us to research the prevalence infected individuals and provide infected-status information to prevent the spread of the virus and nosocomial transmission.

Arginine vasopressin (AVP) is synthesized in parvocellular- and magnocellular neuroendocrine neurons in the paraventricular nucleus (PVN) of the hypothalamus. Whereas magnocellular AVP neurons project primarily to the posterior pituitary, parvocellular AVP neurons project to the median eminence (ME) and to extrahypothalamic areas. The AVP gene encodes pre-pro-AVP that comprises the signal peptide, AVP, neurophysin (NPII), and a copeptin glycopeptide. In the present study, we used an N-terminal copeptin antiserum to examine copeptin expression in magnocellular and parvocellular neurons in the hypothalamus in the mouse, rat, and macaque monkey. Although magnocellular NPII-expressing neurons exhibited strong N-terminal copeptin immunoreactivity in all three species, a great majority (~90%) of parvocellular neurons that expressed NPII was devoid of copeptin immunoreactivity in the mouse, and in approximately half (~53%) of them in the rat, whereas in monkey hypothalamus, virtually all NPII-immunoreactive parvocellular neurons contained strong copeptin immunoreactivity. Immunoelectron microscopy in the mouse clearly showed copeptin-immunoreactivity co-localized with NPII-immunoreactivity in neurosecretory vesicles in the internal layer of the ME and posterior pituitary, but not in the external layer of the ME. Intracerebroventricular administration of a prohormone convertase inhibitor, hexa-d-arginine amide resulted in a marked reduction of copeptin-immunoreactivity in the NPII-immunoreactive magnocellular PVN neurons in the mouse, suggesting that low protease activity and incomplete processing of pro-AVP could explain the disproportionally low levels of N-terminal copeptin expression in rodent AVP (NPII)-expressing parvocellular neurons. Physiologic and phylogenetic aspects of copeptin expression among neuroendocrine neurons require further exploration.

Background The efficacy and bleeding complications of direct oral anticoagulant (DOAC) therapy for cancer-associated venous thromboembolism (VTE) in routine clinical practice remain unclear. Moreover, data on long-term outcomes in patients with cancer-associated VTE who received DOAC therapy are limited.Methods and Results:This retrospective study enrolled 1,096 consecutive patients with acute VTE who received warfarin or DOAC therapy between April 2014 and May 2017. The mean follow-up period was 665±490 days. The number of cancer-associated VTE patients who received DOAC therapy was 334. Patients who could not be followed up and those prescribed off-label under-dose DOAC were excluded. Finally, 303 patients with cancer-associated VTE were evaluated. The number of cases of major bleeding and VTE recurrence was 54 (17.8%) and 26 (8.6%), respectively. In the multivariate analysis, the factors correlated with major bleeding were high cancer stage, high performance status, liver dysfunction, diabetes mellitus, and stomach cancer; those correlated with recurrent VTE were initial diagnosis of pulmonary embolism, uterine cancer, and previous cerebral infarction. Major bleeding was an independent risk factor of all-cause death. In the Kaplan-Meier analysis, those who received prolonged DOAC therapy had lower composite major bleeding and recurrent VTE risks than those who did not. Conclusions In DOAC therapy for cancer-associated VTE, major bleeding prevention is important because it is an independent risk factor of death.

The aim of the present study was to determine whether urinary 8-hydroxydeoxyguanosine (8-OHdG), which is a marker of oxidative stress, can predict future cardiovascular death in patients with acute coronary syndrome (ACS). A total of 551 consecutive patients with ACS who underwent admission urinary 8-OHdG measurements were enrolled in this study. The patients were divided into 2 groups according to the optimal cutoff value of admission urinary 8-OHdG determined by a receiver-operating characteristics curve for the prediction of cardiovascular death: a high admission urinary 8-OHdG group, 169 patients with admission urinary 8-OHdG ≥ 17.92 ng/mg creatinine; and a low admission urinary 8-OHdG group, 382 patients with admission urinary 8-OHdG

Aim: The purpose of this study is to investigate the impact of arterial stiffness assessed using Cardio-ankle Vascular Index (CAVI) on long-term outcome after acute coronary syndrome (ACS). Methods: A total of 387 consecutive patients (324 males; age, 64 ± 11 years) with ACS were enrolled. We examined CAVI and brachial-ankle pulse wave velocity (ba PWV) as the parameters of arterial stiffness. The patients were divided into two groups according to the cut-off value of CAVI determined using the receiver operating characteristic curve for the prediction of major adverse cardiovascular events (MACE): low-CAVI group, 177 patients with CAVI < 8.35; high-CAVI group, 210 patients with CAVI ≥ 8.35. The primary endpoint was the incidence of MACE (cardiovascular death, recurrence of ACS, heart failure requiring hospitalization, or stroke). Results: A total of 62 patients had MACE. Kaplan-Meier analysis demonstrated a significantly higher probability of MACE in the high-CAVI group than in the low-CAVI group (median follow-up: 62 months; log-rank, p < 0.001). Multivariate analysis suggested that CAVI was an independent predictor of MACE (hazard ratio [HR], 1.496; p = 0.02) and cardiovascular death (HR, 2.204; p = 0.025), but ba PWV was not. We investigated the incremental predictive value of adding CAVI to the GRACE score (GRS), a validated scoring system for risk assessment in ACS. Stratified by CAVI and GRS, a significantly higher rate of MACE was seen in patients with both higher CAVI and higher GRS than the other groups (p < 0.001). Furthermore, the addition of CAVI to GRS enhanced net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI, 0.337, p = 0.034; and IDI, 0.028, p = 0.004). Conclusion: CAVI was an independent long-term predictor of MACE, especially cardiovascular death, adding incremental clinical significance for risk stratification in patients with ACS.

Background Lipoprotein (a) [Lp(a)] has been reported to be a residual risk factor in patients who have achieved target lipid levels. The aim of the present study was to investigate the associations of Lp(a) with plaque progression and major cardiovascular events in patients with acute coronary syndromes (ACS). Methods The Yokohama-ACS study included 102 patients with ACS who underwent intravascular ultrasound (IVUS) at baseline and at 10-month follow-up after percutaneous coronary intervention (PCI). The patients were randomly assigned to receive either moderate- or low-intensity statin therapy. IVUS was performed to measure the plaque volume at non-culprit lesions. We enrolled 76 patients for whom Lp(a) levels at 10-month follow-up were available. Results The patients were divided into 2 groups according whether their Lp(a) levels were ≤20 mg/dl [low Lp(a) group; n = 49] or >20 mg/dl [high Lp(a) group; n = 27]. Baseline characteristics and low-density lipoprotein cholesterol levels at 10-month follow-up were similar in the low Lp(a) group and high Lp(a) group (87 ± 29 mg/dl vs. 93 ± 27 mg/dl, p = 0.42). The low Lp(a) group had significant plaque regression, whereas the high Lp(a) group showed slight plaque progression (−6.8% vs. 2.5%, p = 0.02). Ninety-five percent of the prognostic data were obtained 5 years after PCI. The cumulative event-free survival rate was significantly lower in the high Lp(a) group (p = 0.02; log-rank test). Conclusions Lp(a) levels may be an alternative predictor of further plaque regression and the likelihood of major adverse cardiovascular events in statin-treated ACS patients.

Background. Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4 + plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG+ cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD. Methods. We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists. Results. Although mean values for IgG+ cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y[IgG] = 0.988 x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent. Conclusion. AC-IgG could replace IgG to count IgG+ cells because of its lower Cv.

Introduction Calciphylaxis is characterized by marked vascular calcification and painful skin ulcers, and it has a poor prognosis. Case presentation The patient was a 72-year-old male. He was referred for penile pain. He had a 4-year history of dialysis therapy under a diagnosis of diabetic nephropathy. Black and yellow necrosis was observed involving the entire glans, accompanying severe pain. Computed tomography revealed marked calcification involving the thoracoabdominal aorta to iliac arteries, the dorsal artery of the penis and the corpus cavernosum, leading to a diagnosis of calciphylaxis. Penile pain gradually exacerbated and partial penectomy was performed. After surgery, penile pain promptly subsided. Pathological examination confirmed marked calcification of the microvascular wall and narrowing of the lumen. Conclusion We reviewed 15 Japanese patients with calciphylaxis who had undergone penile surgery. Surgical treatment was considered to be effective at relieving penile pain, but the prognosis remained poor.

A 60 year-old male was referred to the authors' hospital with a persistent urge to defecate. The patient had undergone stapled hemorrhoidopexy (SH) for the treatment of prolapsed hemorrhoids approximately 10 years earlier. He started to have difficulty with defecation and a false sense of urgency shortly after the surgery. Computed tomography showed a diverticulum-like fistula along the circumference of the rectum. Colonoscopy revealed communication between the diverticular cavity and the rectal lumen. The cavity contained a thumbnail-sized fecalith. When the fecalith was removed, the patient's urge to defecate dissipated. The patient was diagnosed with rectal pocket syndrome secondary to SH. The lower rectum was transected, and the remaining rectum and the anal canal were anastomosed by manual suture. Temporary ileostomy with double orifices was performed. The ileostomy was closed 3 months later. The patient experienced no subsequent difficulty with defecation or urgency.

Mechanical thrombectomy has been widely used for the treatment of acute ischemic stroke. During this procedure, operators must navigate the microcatheter with a microguidewire (MGW) into vessels that cannot be visualized on fluoroscopy as rapidly as possible. In this study, we developed a modified pigtail-shaped MGW (MPMGW) for security and controllability. Moreover, the efficacy of the MPMGW for the treatment of acute ischemic stroke was assessed. The MPMGW was designed using 0.014 MGW. Because we created four MPMGWs during a clinical evaluation before the launch in the market, these wires were used in four consecutive patients with acute ischemic stroke in the single institution. The occluded arteries were the basilar artery (n = 1), middle cerebral arteries (M1 and M2, n = 2), and internal carotid artery (n = 1). All four procedures were conducted without any complications. The procedures included navigating the MGW and passing it through the clot. Complete recanalization was achieved in all cases. The average time between femoral artery puncture and recanalization was 15 min. The use of the preshaped MPMGW in acute thrombectomy was effective in terms of both security of procedure and reduction in recanalization time.

Background Balloon angioplasty, including drug-coated balloon (DCB), is an important option of percutaneous coronary interventions (PCI), even in the drug-eluting stent era. Although quantitative coronary angiography (QCA) has been frequently used to determine the optimal endpoint of balloon angioplasty, physiological assessment may add incremental prognostic values. Quantitative flow ratio (QFR) has evolved as a novel 3D QCA-based physiological index to estimate fractional flow reserve without hyperemia nor pressure guidewire, offering both anatomical and functional lesion assessments. This study aimed to characterize post-procedural anatomical and physiological indexes by QFR and to compare their prognostic impacts on long-term clinical outcomes. Methods This retrospective study included 98 patients with de novo (n=39) or in-stent restenosis (n=59) lesions who underwent PCI with DCB (n=69) or plain-old balloon angioplasty (POBA, n=29). All lesions were analyzed by QCA and QFR. QCA analysis measured lesion length, reference lumen diameter (RLD), minimum lumen diameter (MLD) and percent diameter stenosis (%DS) at pre- and post-procedures as anatomical indexes. QFR analysis measured post-procedural QFR of target vessel (QFR-vessel) and QFR-gradient (ΔQFR between proximal and distal segments of the lesion) as physiological indexes. Primary endpoint was target lesion revascularization (TLR) within 1-year post-procedure. Results Target lesion profiles were as follows: lesion length 26.3±16.6 mm, RLD 2.90±0.70 mm, MLD 0.94±0.32 mm and %DS 79.3±18.6%. At post-procedure, MLD, residual %DS, QFR-vessel and QFR-gradient of target lesions were 1.88±0.49 mm, 34.7±10.6%, 0.84±0.13 and 0.06±0.04, respectively. During 1 year post-procedure, TLR occurred in 19 (19%) patients. Patients with TLR showed smaller MLD (1.66±0.45 mm vs. 1.93±0.49 mm, p=0.028) and QFR-vessel (0.79±0.03 vs. 0.85±0.01, p=0.06), and greater residual %DS (42.7±11.3% vs. 32.8±9.5%, p=0.0002) and QFR-gradient (0.12±0.06 vs. 0.04±0.02, p Conclusions Post-procedural QFR-gradient within the lesion was an independent and stronger predictor of subsequent TLR, compared with anatomical indexes. Further studies are warranted to investigate whether QFR guidance to optimize PCI procedure could improve clinical outcomes in patients with balloon angioplasty. Figure 1 Funding Acknowledgement Type of funding source: None

BackgroundThe epidemiology and treatment of isolated pelvic fracture is not well understood in Japan. This study aimed to evaluate epidemiological trends in isolated pelvic trauma and in-hospital survival rates over 15 years.MethodsThis retrospective cohort study analyzed data from the Japan Trauma Data Bank for 2004-2018. Patients of any age with isolated pelvic fracture were grouped according to time period: 2004-2008 (Phase 1), 2009-2013 (Phase 2), and 2014-2018 (Phase 3). The main outcome was 30-day in-hospital survival rate. The data were analyzed using chi-squared, Kruskal-Wallis, and Mantel-Haenszel trend tests. We analyzed changes in the main outcome over time in a multiple logistic regression analysis fitted with a generalized estimating equation, accounting for the within-cluster association.ResultsIn total, 5348 isolated pelvic fractures occurred during the study period. There was no significant between-phase difference in proportions of patients who underwent resuscitative balloon occlusion of the aorta or external fixation. The proportion of patients who underwent transcatheter arterial embolization increased year by year (p=0.003). There was a significant increase in the survival rate over time (Phase 1, 77%; Phase 2, 86%; and Phase 3, 91%; p

Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients.Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests.Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08–42.3, and 1.06–9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics.Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.

Background This study aimed to investigate the effect of periodontal disease (PD) on the outcomes of patients with coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI).Methods and Results:The study included 77 consecutive non-smoking patients with de novo coronary lesions treated with a drug-eluting stent (DES). Periodontal measurements, including the community periodontal index (CPI), were performed by independent periodontists. A CPI score of ≥3 was used to define PD. The occurrence of major adverse cardiac events (MACEs), which were defined as a composite of cardiovascular death, non-fatal myocardial infarction, target lesion revascularization, or non-target lesion revascularization, was compared between patients with and without PD. Of the 77 patients, 49 (63.6%) exhibited a CPI score of 3 or 4 and were assigned to the PD group. The remaining 28 patients (36.4%) were assigned to the non-PD group. Baseline clinical characteristics and angiographic findings were comparable between the 2 groups. MACEs occurred in 13 (26.5%) of the PD patients and 2 (7.1%) of the non-PD patients. Kaplan-Meier analysis showed a significantly lower MACE-free survival rate in the PD group than for the non-PD group (P=0.034). Conclusions PD at baseline was associated with an increased risk of MACEs in CAD patients who were treated with a DES for de novocoronary lesions.

ObjectiveTo evaluate whether the distribution of large-vessel lesions (LVLs) in giant cell arteritis (GCA) is associated with poor treatment outcomes.MethodsIn a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014, 68 newly-diagnosed patients with LVLs were identified by imaging. Non-achievement of clinical remission by week 24 and/or relapse within 104 weeks were primarily evaluated. Factors influencing the poor treatment outcome were analyzed using Cox proportional hazard modeling. Cumulative rates and median time to the first event were analyzed by the Kaplan-Meier method and log-rank testing.ResultsAortic lesions were detected in 72.1% of the 68 GCA patients with LVLs (defined as group 2). Patients without aortic lesions were classified as having large-vessel GCA with subclavian lesions (group 1) or atypical large-vessel GCA without subclavian lesions (group 3). The mean age and proportions of PMR in group 3 were higher than those in the other two groups. Cranial lesions were observed in 66.7%, 55.1%, and 80.0% of patients in groups 1, 2 and 3, respectively. In group 2, 73.5% had lesions in both the aorta and aortic branches. Group 1 had axillary lesions in 33.3%, and carotid lesions in 44.4%. Atypical LVLs in group 3 included pulmonary, hepatic or mesenteric lesions in addition to carotid lesions. Baseline doses of GCs were not different across the groups. Mean time to achievement of low-dose GC treatment (prednisolone ≤5 mg/day) was also not significantly different between the groups. The cumulative rate of poor treatment outcome over the two years was 11.1%, 55.3% and 88.0% in the groups 1, 2 and 3, respectively; mean time to the events was significantly different among the groups. Multivariable analysis showed that the risk of poor treatment outcome was significantly higher in the group 3.ConclusionsThe distribution of LVLs was associated with treatment outcomes in large-vessel GCA. In addition to subclavian arteries, lesions in aorta and aortic branches other than subclavian arteries should be evaluated by imaging for large-vessel GCA. The pattern of LVLs determined by imaging should be considered when determining treatment strategies for GCA.

Introduction Chronic inflammation has been receiving considerable attention as an emerging risk factor for cardiovascular disease. In contrast, with the aging of the population, frailty has been also attracting a great deal of attention as the residual risk for cardiovascular disease. Although inflammation and frailty exacerbate each other and have an adverse effect on many diseases, the relationship between chronic inflammation and frailty and the impact of these combination on long-term prognosis in patients with acute coronary syndrome (ACS) are not elucidated. Purpose The aims of this study were to determine the association between chronic inflammation and frailty and its impact on long-term cardiovascular outcomes in patients with ACS. Methods A total of 482 consecutive ACS patients with obstructive coronary artery disease (age 66±12 years, male 81%) were enrolled in this observational study. We evaluated patients' gait speed as a measure of frailty before discharge. C-reactive protein (CRP) levels at 1 month after discharge were also evaluated as inflammation in the chronic phase. According to commonly used criteria of the residual inflammation (CRP>0.2 mg/dL) and the definition of the European Working Group for Sarcopenia (gait speed ≤0.8 m/sec), patients were stratified by 4 subgroups: low/high CRP with slow/normal gait speed. The primary endpoint was composite outcomes of cardiovascular death, myocardial infarction and ischemic stroke. Results While there was no significant association between CRP levels and gait speed in all patients, a significant negative association between two variables was observed in the high CRP group (Spearman's ρ = −0.31, p=0.001). During the median follow-up of 6 years, primary endpoints have occurred in 82 patients. Overall, event-free rates differed significantly among the 4 groups, demonstrating the lowest event-free rate in the patients with high CRP and slow gait speed (p Conclusion In the patients with ACS, CRP levels and gait speed were negatively associated in the high CRP group. Chronic inflammation and frailty were both associated with poor prognosis in ACS and in particular, the combination of these factors was strongly associated with poor prognosis. Funding Acknowledgement Type of funding sources: None. Figure 1

A recent increase in the number of surgeries performed on obese patents has raised several issues. In this study, we examined the effects of obesity on laparoscopic and open distal gastrectomy.A total of 262 patients with gastric cancer (cStage I) who underwent distal gastrectomy were classified into open distal gastrectomy (ODG) (145 patients) and laparoscopic distal gastrectomy (LDG) (117 patients) groups. According to their body mass index (BMI), they were subdivided into obese (BMI ≥ 25) and non-obese patients (BMI25) to examine the duration of surgery, blood loss, the number of lymph node dissections, postoperative hospital stay, and incidence of postoperative complications.The duration of surgery was longer and blood loss was higher for obese patients than for non-obese patients in both groups. The results for these two endpoints were significantly reduced in the LDG group than in the ODG group both in obese and non-obese patients. Furthermore, the number of lymph nodes dissected tended to be higher in the LDG group than in the ODG group in obese patients. Postoperative hospital stay was not significantly different between obese and non-obese patients in both groups, but was significantly shorter in the LDG group than in the ODG group regardless of the body weight. The incidence of postoperative complications was significantly higher in obese patients than in non-obese patients, although the difference between the groups was not significant.These findings indicate that LDG may be useful for obese patients with cStage I gastric cancer.

The effectiveness of mechanical thrombectomy for acute ischemic stroke of extracranial vascular embolism remains controversial. Cerebral infarction with brachiocephalic artery occlusion is rare, and treatment strategy have not been adequately discussed. We describe a rare case of cerebral infarction due to brachiocephalic artery occlusion treated by mechanical thrombectomy. Although the time delay to treatment caused poor outcome, mechanical thrombectomy could be expected to be effective in cerebral infarction due to brachiocephalic artery occlusion, since partial reperfusion was achieved in the present case. When a patient is diagnosed with brachiocephalic artery occlusion, it is important that the possibility of cerebral infarction should be recognized at the primary contact to ensure prompt diagnosis and treatment.

Background The present article describes two cases of patients with coronary arteritis (CA) whose identification of CA diagnosis (late vs. early) resulted in different clinical courses and outcomes. Case summary Case 1 is a 53-year-old woman with multiple coronary risk factors who was admitted with acute coronary syndrome (ACS) and significant stenosis in the left main trunk (LMT). Although clues suggested arteritis (LMT lesion without any other stenosis, occlusion of left internal thoracic artery, etc.), the diagnosis of CA (coronary involvement of unclassified arteritis) was delayed and revascularization, including coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), was performed under uncontrolled inflammatory status. As a result, Case 1 experienced repeated ACS episodes due to graft failure and in-stent restenosis, and repeatedly underwent PCI. Case 2 is a 76-year-old woman with no significant coronary risk factors who was admitted with ACS. This patient was successfully diagnosed with coronary involvement of Takayasu arteritis before revascularization. Coronary artery bypass grafting was performed after stabilizing inflammation with prednisolone, and the patient remains angina-free beyond 1-year post-CABG. In both cases, intravascular imaging clearly identified the localization and degree of inflammation related to CA by demonstrating specific findings (ambiguous typical three-layer structure of arterial wall and extended low-echoic areas within adventitia). Discussion Accurate and early diagnosis with meticulous diagnostic and therapeutic strategies appear to be important for favourable clinical outcomes in the medical treatment of patients with coronary involvement of arteritis. Intravascular imaging has the potential to contribute to optimizing clinical management of CA.

Objective To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). Methods Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators’ discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. Results All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to Conclusion These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. Trial registration JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Background Spinal epidural hematoma associated with epidural metastasis is very rare. Epidural hematoma is unusual in itself, and metastatic epidural tumors do not commonly occur. Case Description A 76-year-old man with a medical history of untreated stage III rectal cancer and chronic obstructive pulmonary disease underwent emergency spine surgery for acute development of severe quadriplegia due to cervical epidural hematoma after minor indirect trauma. Hemorrhagic lesions, such as yellow ligaments, were accompanied by hematomas that adhered to the dura mater and were confirmed on pathology to be small cell carcinoma. Some nodules were detected in the right pulmonary hilar lesion and pleural lesion on computed tomography, and stage IV small cell carcinoma was diagnosed. Conclusions To our knowledge, spinal epidural hematoma accompanied by epidural metastasis has not previously been reported. We hypothesized that tissue invasion of malignant neoplasms may cause hemorrhagic conditions. The presence of a tumor should therefore be considered in the differential diagnosis of cases of epidural hematoma.

A 40-week-old male spontaneous diabetic Torii rat, an animal model of type 2 diabetes mellitus, was found to have marked urinary calculi with hematuria in the urinary bladder on necropsy. Histological findings in the urinary bladder included a papillary growth pattern with a fibrovascular stroma without atypia. Fine granular materials in the bladder lumen were positive for Von Kossa staining but negative for periodic acid-Schiff or Gram staining, indicating no apparent bacterial infection in the urinary bladder. Scanning electron microscopy revealed that the urinary calculi were magnesium ammonium phosphate crystals (struvite). On the basis of the results, the lesion was diagnosed as urothelial hyperplasia with calculi (papillomatosis). Chronic inciting stimuli by struvite crystals were considered the primary cause of the bladder findings.

Objectives: To clarify (1) the prevalence and associating factors of work-life conflict (WLC); (2) the details of gender-based discrimination; and (3) the association between WLC and gender-based discrimination among various professionals in a medical university organization. Methods: This cross-sectional study, conducted in 2017, included all employees working at a public medical university and two affiliated hospitals that lie in provincial cities in Japan. The outcome of interest was time-based WLC in the work-to-family or family-to-work direction, measured with a shortened version of an existing scale. Gender-based discrimination was measured according to a three-point scale. Results: Among the 3,347 employees, complete data sets were available for 2,285 (complete response rate, 68.3%). Of these, approximately 30% of respondents had perceived WLC. Multivariable logistic regression analysis showed that faculty members, nurses, and employees between 30 and 39 years old had a greater risk of WLC regardless of gender. Men were more likely to perceive gender-based discrimination in the contents of their work and the number of incidental tasks, while women were more likely to perceive discrimination with promotions and evaluation of academic achievements. Both men and women respondents who perceived gender-based discrimination had an increased risk of WLC. Conclusions: When promoting organizational well-being in a medical university, increased attention should be paid to faculty members, nurses and employees between 30 and 39 years old, as they have a greater risk of WLC. Our results also suggest that promoting gender equality is important to help achieve appropriate work-life balance.

Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin–proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.

Body weight (BW) is regulated in age-dependent manner; it continues to increase during growth period, and reaches a plateau once reaching adulthood. However, its underlying mechanism remains unknown. Regarding such mechanisms in the brain, we here report that neural circuits from the hypothalamus (paraventricular nucleus: PVN) to the brainstem (dorsal vagal complex: DVC) suppress late-onset BW gain without affecting food intake. The genetic suppression of the PVN-DVC circuit induced BW increase only in aged rats, indicating that this circuit contributes to suppress the BW at a fixed level after reaching adulthood. PVN neurons in the hypothalamus were inactive in younger rats but active in aged rats. The density of neuropeptide Y (NPY) terminal/fiber is reduced in the aged rat PVN area. The differences in neuronal activity, including oxytocin neurons in the PVN, were affected by the application of NPY or its receptor inhibitor, indicating that NPY is a possible regulator of this pathway. Our data provide new insights into understanding age-dependent BW regulation.

Background: When inserting coils under stent deployment, a jailed microcatheter technique is typically applied as a first line approach. However, the trans cell approach might be required to achieve satisfactory complete occlusion. The trans cell approach occasionally ends in failure because the catheter cannot safely follow a proceeding guidewire into the aneurysm. Here, we report the new wireless trans cell approach (WTA), which allows feasible and safe catheter navigation through the stent strut into the aneurysm, without a proceeding guidewire. Methods: A straight tip microcatheter was used, and the tip was shaped as a very small bend of approximately 45°. The side aspect of the catheter tip exhibited a right angled edge, while the front aspect showed a round curve in the advancing direction. We compared the 45° microcatheter with a straight tip microcatheter using a silicon vascular model and then applied the WTA in a case of an unruptured basilar apex aneurysm. Results: Catheter navigation through the stent strut was smoother with the WTA than the conventional wire assisted approach. Our case of a basilar apex aneurysm was successfully treated with the dual catheter technique, which involved a jailed catheter and navigation using the WTA. After stent deployment from the right posterior cerebral artery to the basilar artery through the 45° microcatheter, the WTA was applied using the same catheter. No stress was detected during catheter navigation through the stent strut into the aneurysm. Conclusions: The WTA is associated with smoother catheter navigation compared with the conventional wire assisted approach in cases of a terminal type aneurysm.

Genome-wide association studies (GWAS) have identified ~170 genetic loci associated with prostate cancer (PCa) risk, but most of them were identified in European populations. We here performed a GWAS and replication study using a large Japanese cohort (9, 906 cases and 83, 943 male controls) to identify novel susceptibility loci associated with PCa risk. We found 12 novel loci for PCa including rs1125927 (TMEM17, P = 3.95 × 10−16), rs73862213 (GATA2, P = 5.87 × 10−23), rs77911174 (ZMIZ1, P = 5.28 × 10−20), and rs138708 (SUN2, P = 1.13 × 10−15), seven of which had crucially low minor allele frequency in European population. Furthermore, we stratified the polygenic risk for Japanese PCa patients by using 82 SNPs, which were significantly associated with Japanese PCa risk in our study, and found that early onset cases and cases with family history of PCa were enriched in the genetically high-risk population. Our study provides important insight into genetic mechanisms of PCa and facilitates PCa risk stratification in Japanese population., 前立腺がんの若年発症を予測するゲノム診断手法を開発 --前立腺がんのゲノムワイド関連解析からゲノム医療へ--. 京都大学プレスリリース. 2019-10-08.