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Claudin-18 splice variant 2 (CLDN18.2), a tight junction protein, is a highly cell type-specific antigen that is expressed by differentiated gastric mucosa cells. The expression of CLDN18.2 in gastric mucosa cells may be retained upon malignant transformation and is displayed on the surface of several tumors, including gastric/gastroesophageal junction adenocarcinoma. Zolbetuximab is a genetically engineered, highly purified chimeric (mouse/human IgG1) antibody directed against CLDN18.2. Nausea and vomiting were observed as adverse events of zolbetuximab. To investigate the mechanism of nausea and vomiting in humans, we evaluated emesis (retching and vomiting) and conducted histopathologic assessment in ferrets after the administration of zolbetuximab. Emesis was frequently observed in all ferrets treated with zolbetuximab in the first hour after administration. Histopathologic assessment revealed the surface of the gastric mucosa was the primary site of emesis-associated tissue damage. The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events., Competing Interests: Declaration of competing interest All authors are employees of Astellas Pharma, Inc. or its affiliates., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Aims: The objective of this analysis was to develop and evaluate a pharmacokinetic/pharmacodynamic (PK/PD) model of the effect of roxadustat on low-density lipoprotein cholesterol (LDL-C) in Japanese patients with anemia of dialysis-dependent chronic kidney disease while considering the impact of covariates on model parameters., Methods: A total of 2330 LDL-C measurements from 275 patients in 3 clinical studies were analyzed using a nonlinear-mixed effects modeling approach in NONMEM software., Results: The PK/PD relationship between roxadustat exposure and LDL-C was well described by a kinetic-pharmacodynamic model with a physiological indirect response model as the PD component. Co-administered statin usage, sevelamer usage, type of dialysis (hemodialysis or peritoneal dialysis), and sex were selected as covariates for LDL baseline . Weight was selected as a covariate for ID 50. I max and ID 50 were estimated as 0.661 and 1.51 mg/h, respectively., Conclusion: Roxadustat can decrease LDL-C independent of statins and sevelamer. Further study of the ability of roxadustat to lower LDL-C and any potential effects on outcomes is needed., Competing Interests: Declaration of competing interest AT is an employee of Astellas Pharma Global Development, Inc., Illinois, United States. TShibata reports personal fees from Astellas. TShiga is an employee of Astellas Pharma, Inc., Tokyo, Japan. TU reports personal fees from Astellas. KK reports personal fees from Astellas. TA reports personal fees from Astellas, Kyowa Kirin, Japan Tabaco, Bayer, GlaxoSmithKline, Ono Pharmaceutical, Torii Pharmaceutical, Fuso Pharmaceutical, Kissei Pharmaceutical, Sanwa Chemical, Otsuka Pharmaceutical, Nipro, and Chugai Pharmaceutical., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

A conventional arteriovenous graft in patients on dialysis often leads to anastomotic stenosis, which decreases the blood flow rate and increases the risk of complications. In this study, based on hydrodynamics, the pulsatile pressure at the blood vessel graft-vein junction was investigated experimentally and numerically for revealing the causes of stenosis formation and inward remodeling. In the experiments, the pulsatile pressure and displacement at the anastomotic connection were measured at a branched collapsible tube. It was revealed that the pressure becomes negative between pressure peaks of the pulsatile flow; furthermore, tube diameter changes in accordance with the pressure pulsation. Subsequently, numerical simulations revealed that a relatively large pressure difference occurs at the anastomotic connection because of flow collision and separation as compared with the other part, and the pulsatile pressure. Therefore, it is possible that vein at an anastomotic connection may change its shape under pulsating flow. Furthermore, it was found that the pressure difference slightly increased with the anastomosis angle, but the anastomosis angle did not affect the flow rate. Clinical trials in the next step are required to reveal the causal relationship between stenosis and the pulsatile pressure, but the pulsatile flow and its pressure are likely to be one factor in stenosis and inward remodeling., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oba, Hosoya, Amamiya, Mitsumura, Kawata, Sasaki, Kamiya, Yamamoto, Ando, Shimada, Shirai, Okamoto, Tateishi, Endo, Aiboshi, Nosaka, Yamanouchi, Ugawa, Nagaoka, Oi, Tao, Maejima, Tanaka, Tanimoto, Takeuchi, Tohda, Hirakawa, Sasano, Arai, Otomo, Miyazaki and Yasuda.)

Veno-venous extracorporeal membrane oxygenation (VV ECMO) is an effective and proven adjunct support for various severe respiratory failures requiring invasive mechanical ventilation and cardiovascular support. In response to the rapidly increasing number of COVID-19 patients in Japan, we launched an ECMO support team comprised of multidisciplinary experts including physicians, nurses, perfusionists, and bioethicists in preparation for the threat of a pandemic. From April 2 to July 15, 2020, Tokyo Medical and Dental University hospital treated 104 PCR confirmed COVID-19 patients. Among those, 34 patients were admitted to intensive care unit (ICU) and 5 patients required VV ECMO. All management related to ECMO was decided by the ECMO support team in addition to participation of the ECMO support team in daily multidisciplinary rounds in the ICU. Median age was 54 years old. Duration from onset to mechanical ventilation (MV) and MV to ECMO were 8 and 7 days, respectively. Four patients (80%) were successfully weaned off from ECMO. One patient died after 81 days of ECMO run. Four patients were discharged and recovered to their prehospital quality of life without major disability. We achieved a high survival rate using ECMO in our low volume ECMO institution during the COVID-19 pandemic. Multidisciplinary decision-making and a team approach for the unclear pathology with an emerging infectious disease was effective and contributed to the survival rate., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Accurate prediction of blood toxin concentration during and after dialysis will greatly contribute to the determination of dialysis treatment conditions. Conventional models, namely single-compartment model and two-compartment model, have advantages and disadvantages in terms of accuracy and practical application. In this study, we attempted to derive the mathematical model that predicts blood toxin concentrations during and after dialysis, which has both accuracy and practicality. To propose the accurate model, a new two-compartment model was mathematically derived by adapting volume-averaging theory to the mass transfer around peripheral tissues. Subsequently, to propose a practical model for predicting the blood toxin concentration during dialysis, an analytical solution expressed as algebraic expression was derived by adopting variable transformation. Furthermore, the other analytical solution that predicts rebound phenomena after dialysis was also derived through similar steps. The comparisons with the clinical data revealed that the proposed analytical solutions can reproduce the behavior of the measured blood urea concentration during and after dialysis. The analytical solutions proposed as algebraic expressions will allow a doctor to estimate the blood toxin concentration of a patient during and after dialysis. The proposed analytical solutions may be useful to consider the treatment conditions for dialysis, including the rebound phenomenon.

Roxadustat (Evrenzo ® tablet) is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. Roxadustat has been approved for the treatment of renal anemia in patients on dialysis in September 2019 in Japan. By inhibiting HIF-PH, roxadustat suppresses the degradation of HIF-α, a subunit of the heterodimeric transcription factor HIF, leading to its accumulation and activation of the HIF pathway. Similar to activation of the HIF pathway in response to hypoxia, the production of endogenous erythropoietin is increased and erythropoiesis is stimulated. Moreover, roxadustat stimulates erythropoiesis efficiently by improving iron bioavailability. The efficacy and mechanism of action of roxadustat have been detailed in non-clinical pharmacology studies. Rat models of anemia demonstrated efficacy of roxadustat in correcting anemia and changes in gene expression leading to increased iron bioavailability. Four phase 3 clinical studies in Japan clearly demonstrated the efficacy of roxadustat in patients with renal anemia on dialysis. Roxadustat showed an acceptable safety profile, and the incidences and types of adverse events and serious adverse events reported in the clinical studies were similar with those predicted to occur in these patient population. Since roxadustat is an oral drug, concerns present with erythropoiesis-stimulating agents (ESAs) such as the risk of infection to the medical staff due to accidental needle-stick, pain during ESA injection in patients and burden on patients to visit a hospital, can be avoided or reduced. In November 2020, roxadustat has also been approved for the treatment of renal anemia in patients not on dialysis (data not shown in this article).

Prostaglandins (PGs) are important lipid mediators of numerous physiologic and pathophysiologic processes in the kidney. PGE 2 , the most abundant renal PG, plays a major role in renal physiology, including renin release and glomerular hemodynamics. We investigated the renoprotective properties of the novel PGE 2 EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized rats, a chronic kidney disease (CKD) model. Eight weeks of repeated administration of ASP7657 (0.001-0.1 mg/kg) dose-dependently and significantly reduced urinary protein excretion and attenuated the development of glomerulosclerosis and tubulointerstitial damage, including fibrosis and inflammatory cell infiltration, without affecting blood pressure. Additionally, ASP7657 tended to have beneficial effects on renal function, as indicated by the decrease in plasma creatinine and blood urea nitrogen levels and attenuation of the decline in creatinine clearance (Ccr). The angiotensin II receptor blocker losartan (10 mg/kg) also showed these renoprotective effects while significantly reducing blood pressure. ASP7657 dose-dependently and significantly reduced the EP4 receptor agonist-induced increase in plasma renin activity, as assessed by angiotensin I release in normal rats. Additionally, ASP7657 attenuated hyperfiltration assessed by Ccr without changing the renal blood flow or blood pressure in diabetic rats. These results suggest that ASP7657 suppresses the progression of chronic renal failure by modulating renin release and improving renal hemodynamics, and may therefore be a promising therapeutic option for inhibiting the progression of CKD.

We determined the pharmacologic profile of ASP7657, trans-4-[({[1-(quinolin-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7 yl] carbonyl} amino) methyl] cyclohexanecarboxylic acid methanesulfonate (1:1), a newly synthesized selective E-type prostaglandin (EP)4 receptor antagonist using several in vitro and in vivo experiments. ASP7657 exhibited high affinity for rat and human EP4 receptors, with K i values of 6.02 nM and 2.21 nM, respectively. In addition, ASP7657 potently inhibited the PGE 2 -induced cyclic adenosine monophosphate (cAMP) increase in Chinese hamster ovary (CHO) cells expressing rat EP4 receptors and human lymphoblastoid T (Jurkat) cells, with IC 50 values of 0.86 nM and 0.29 nM, respectively. In contrast, ASP7657 did not inhibit the PGE 2 -induced intracellular calcium increase in HEK293 cells expressing rat EP1 and EP3 receptors, or cAMP increase in CHO cells expressing rat EP2 receptors. ASP7657 showed good pharmacokinetic properties following oral dosing and dose-dependently antagonized the prostaglandin (PG)E 2 -mediated inhibition of lipopolysaccharide-induced tumor necrosis factor-α release from rat whole blood culture. In addition, 4 weeks repeated oral administration of ASP7657 dose-dependently attenuated albuminuria in type 2 diabetic mice; these effects were significant at doses of 0.01 mg/kg or higher. These results demonstrate that ASP7657 is a potent and selective EP4 receptor antagonist that may be useful in future studies to help clarify the physiological and pathophysiological roles of PG.

Background: In Japan, nafamostat mesylate (NM) is frequently used as an anticoagulant during continuous renal replacement therapy (CRRT). The dialyzer membrane AN69ST has been reported to adsorb NM and affect the management of anticoagulant therapy. However, the adsorbed amount has not yet been quantitatively assessed. Therefore, in this study, we evaluated the pre- and post-hemofilter prolongation of the activated clotting time (ACT) in patients with AN69ST and PS membranes. We also measured the adsorption of NM in three types of CRRT membranes using an experimental model., Methods: In a study of patients who underwent CRRT using AN69ST or PS membranes in 2015 at the Advanced Emergency and Critical Care Center, Okayama University Hospital, pre- and post-hemofilter ACT measurements were extracted retrospectively, and the difference was calculated. In addition, AN69ST (sepXiris100), PS (HEMOFEEL SHG-1.0), and PMMA membranes (HEMOFEEL CH-1.0N) were used in an in vitro model of a dialysis circuit, and the concentrations of NM were measured in pre- and post-hemofilter membranes and filtrates., Results: The ACT difference was significantly lower in the group using AN69ST membranes ( p  < 0.01). In the in vitro model ( n  = 4) with adsorption and filtration, the post-hemofilter and filtrate concentrations of NM in AN69ST membranes were significantly lower than those in the PS and PMMA membranes ( p  < 0.01). The NM adsorption clearance of the AN69ST membrane was significantly higher than that of the PS and PMMA membranes., Conclusions: The AN69ST membrane had higher NM adsorption than the PS and PMMA membranes. This may have resulted in the lower ACT difference in patients undergoing CRRT using the AN69ST membrane than in patients undergoing CRRT using PS or PMMA membranes.

Background: Polyethylene glycol (PEG) is widely used for bowel cleaning in preparation for colonoscopy because of its safety. Septic shock after PEG preparation is an extremely rare complication. Herein, we describe a case of septic shock that occurred immediately after colonoscopy preparation with PEG., Case Presentation: A 75-year-old Japanese male who had previously developed diabetes after total pancreatectomy received PEG in preparation for colonoscopy. He had been admitted to the emergency intensive care unit 4 days earlier due to hematochezia presenting with shock. He ingested PEG to prepare for a colonoscopy examination, which was performed to identify the source of his bleeding over a 5-h period, but suddenly exhibited septic shock and markedly elevated procalcitonin levels. A blood culture subsequently revealed Citrobacter braakii. Immediate resuscitation and intensive care with appropriate antibiotics improved his condition., Conclusions: Clinicians should be aware of the possibility of deteriorating conditions after bowel preparation with PEG among severely ill patients with recent episodes of hemorrhagic shock.

Newly published clinical practice guidelines recommend intracranial pressure (ICP) monitoring in critical care for the management of pediatric acute encephalopathy (pAE), but the utility of ICP monitoring for pAE has been poorly studied. We recently performed direct ICP monitoring for two patients. We observed that although the direct ICP monitoring had clinical benefits with less body weight gain and no vasopressor use in both cases, this monitoring technique is still invasive. Future studies should determine the utility of non-invasive ICP monitoring systems in pAE to further improve the quality of intensive-care management., Competing Interests: No potential conflict of interest relevant to this article was reported.

In recent years, it has become evident that molecular hydrogen is a particularyl effective treatment for various disease models such as ischemia-reperfusion injury; as a result, research on hydrogen has progressed rapidly. Hydrogen has been shown to be effective not only through intake as a gas, but also as a liquid medication taken orally, intravenously, or locally. Hydrogen's effectiveness is thus multifaceted. Herein we review the recent research on hydrogen-rich water, and we examine the possibilities for its clinical application. Now that hydrogen is in the limelight as a gaseous signaling molecule due to its potential ability to inhibit oxidative stress signaling, new research developments are highly anticipated.

Introduction: Massive bleeding from the thyroid gland causing airway compromise secondary to indirect neck trauma is rare., Presentation of Case: An 89-year-old woman was transferred to our emergency department due to anterior neck pain after a traffic accident. She had been propelled forward and struck her head on the front mirror during emergency braking. Airway patency was confirmed at the first contact. Although her vital signs were stable at presentation, she gradually suffered from respiratory distress and severe dyspnea, implying airway compression, therefore requiring endotracheal intubation. Computed tomography (CT) revealed a large, encapsulated hematoma in the left thyroid gland lobe extending to the upper mediastinum. Contrast-enhanced CT demonstrated an extravasation of the contrast agent around the left superior thyroid artery. The left thyroid artery was ligated and the hematoma was removed immediately. She had a favorable course without further complications and was discharged 36days after admission., Discussion: Airway management is the most important consideration in patients with thyroid injury. Treatment should be customized depending on the degree of respiratory distress resulting from of either involvement of the direct airway or secondary compression., Conclusion: Although hemorrhage from the thyroid gland without blunt trauma is rare, emergency physicians should regard possible thyroid gland rupture in patients with swelling of the neck or acute respiratory failure after direct/indirect trauma to the neck. Observation or operative management for limited or expanding hematoma are appropriately based on fundamental neck trauma principles., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cricothyroidotomy is an emergency procedure that can be used to secure the airway in situations in which intubation and ventilation are not possible., Presentation of Case: We describe a case of 79-year-old male presenting with facial trauma combined with massive upper airway bleeding and swelling in which cricothyroidotomy was required to open the airway in an elderly male patient taking antiplatelet agents who suffered a simple ground-level fall., Discussion: Although emergency airway management is often required in patients with Le Fort fractures, mandibular condyle fractures exhibit a significant relationship with ground-level falls, which are not usually associated with emergency airway management. Prophylactic intubation should be considered prior to transfer or deterioration in a trauma patient with dual antiplatelet drugs and fractures of bilateral mandibular condyle., Conclusion: Clinicians should be aware of the life-threatening injuries that can be caused by simple ground-level falls in patients taking antiplatelet agents., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Superior ophthalmic vein thrombosis is a rare entity, but is associated with significant morbidities. We describe a case in which superior ophthalmic vein thrombosis occurred shortly after severe facial trauma., Case Presentation: A 77-year-old Japanese man was transferred to our tertiary hospital after a motor vehicle accident. Le Fort III facial bone fractures and a minor cerebral contusion were detected. Follow-up computed tomography scans detected dilatation of his left superior ophthalmic vein on day 3 and thrombosis on day 12; however, no causative carotid cavernous fistula was observed. As he did not present with any symptoms other than slight conjunctival congestion, a conservative management strategy was adopted along with anticoagulant therapy against deep venous thrombosis. The superior ophthalmic vein thrombosis resolved spontaneously and the conjunctival congestion also improved., Conclusions: Superior ophthalmic vein thrombosis should be taken into consideration and managed properly after severe facial injuries, and further investigation of its cause is necessary to prevent morbidities.

An 83-year-old woman with no significant medical history was transferred to our tertiary hospital after being hit by a car and presenting with haemorrhagic shock. Immediate fluid resuscitation was performed; physical, chest/pelvic X-ray and echographic examinations did not detect any major sources of bleeding. However, a contrast-enhanced CT scan revealed multiple regions of significant contrast extravasation in an extensive part of the subcutaneous tissue of the patient's lower back, which is an unusual source of bleeding. Transcatheter arterial embolisation of the lumbar and internal iliac arteries and their branches was carried out. In addition, haemostatic resuscitation was performed for damage control resuscitation, which successfully resolved the patient's haemorrhagic shock., (2015 BMJ Publishing Group Ltd.)

The management of severely burned patients remains a major issue worldwide as indicated by the high incidence of permanent debilitating complications and poor survival rates. In April 2012, the Advanced Emergency & Critical Care Medical Center of the Okayama University Hospital began implementing guidelines for severely burned patients, distributed as a standard burn treatment manual. The protocol, developed in-house, was validated by comparing the outcomes of patients with severe extensive burns (SEB) treated before and after implementation of these new guidelines at this institution. The patients included in this study had a burn index (BI) ≥30 or a prognostic burn index (PBI = BI + patient's age) ≥100. The survival rate of the patients with BI ≥30 was 65.2% with the traditional treatment and 100% with the new guidelines. Likewise, the survival rate of the patients with PBI ≥100 was 61.1% with the traditional treatment compared to 100% with the new guidelines. Together, these data demonstrate that the new treatment guidelines dramatically improved the treatment outcome and survival of SEB patients.

We sought to identify the incidence, injury patterns, and financial burden of ladder fall injuries to provide a reference for reinforcing guidelines on the prevention of such injuries. We enrolled the patients who were injured in a ladder-related fall and required intensive care between April 2012 and March 2014 at Okayama University Hospital, a tertiary care hospital in Okayama City:9 patients injured in 7 stepladder falls and 2 straight ladder falls. The median patient age was 69 years, and 8 were males. Six falls occurred in non-occupational settings. Head injuries predominated, and the injury severity score ranged from 2 to 35 (mean＝21±12). At the time of discharge from the intensive care unit, one patient had died and 5 patients had some neurological disabilities. The case fatality rate was 11%. The total cost of care during the review period was ￥16,705,794, with a mean cost of ￥1,856,199 per patient. Ladder fall injuries are associated with a high rate of neurological sequelae and pose a financial burden on the health insurance system. A prevention education campaign targeting at older-aged males in non-occupational settings may be a worthwhile health service investment in this community.

Hyponatremia, a common electrolyte disorder associated with traumatic brain injuries (TBIs), has high mortality and morbidity rates. The aim of this study was to identify the risk factors for hyponatremia associated with TBI. We retrospectively analyzed the cases of TBI patients who were admitted to the emergency intensive care unit at Okayama University Hospital between October 2011 and September 2014. A total of 82 TBI patients were enrolled. The incidences of hyponatremia (serum sodium level of＜135mEq/L) and severe hyponatremia (serum sodium level of＜130mEq/L) within the first 14 days after admission were 51% (n＝42) and 20% (n＝16), respectively. After admission, hyponatremia took a median period of 7 days to develop and lasted for a median of 3 days. Multivariate analysis demonstrated that higher fluid intake from days 1 to 3 and the presence of cranial fractures were risk factors for hyponatremia. The 58 patients with hyponatremia experienced fewer ventilator-free days, longer intensive care unit stays, and less favorable outcomes compared to the 24 patients without hyponatremia;however, these differences were not significant. Further studies are needed to determine the optimal management strategy for TBI-associated hyponatremia in the intensive care unit setting.

Introduction: Aeromonas hydrophila sometimes causes bacteremia, which can be fatal in compromised patients, such as those with liver cirrhosis. We present a case of septic shock due to Aeromonas hydrophila bacteremia in a patient with liver cirrhosis, which was successfully treated with rapid resuscitation and critical care., Case Presentation: A 71-year-old Japanese man with liver cirrhosis was transported to our emergency center by ambulance after presenting with gait difficulties and fever. On arrival, he exhibited shock and severe lactic acidosis, which was suggestive of sepsis, and was immediately resuscitated and administered empiric antibiotic therapy. He also displayed catecholamine-resistant hypotension, which was successfully treated with critical care including supportive therapies, such as polymyxin B hemoperfusion and cytokine-absorbing hemofiltration. Aeromonas hydrophila was detected in his initial blood cultures., Conclusions: Aeromonas septicemia should be considered in patients with alcoholic liver cirrhosis who have profound shock. In addition to goal-directed therapy and the prompt administration of empiric antibiotic therapy, aggressive critical care involving multiple supportive therapies can save such patients.

In adult high-frequency oscillatory ventilation (HFOV), stroke volume (SV) and mean lung pressure (PLung) are important for lung protection. We measured the airway pressure at the Y-piece and the lung pressure during HFOV using a lung model and HFOV ventilators for adults (R100 and 3100B). The lung model was made of a 20-liter, airtight rigid plastic container (adiabatic compliance: 19.3 ml/cmH2O) with or without a resistor (20 cmH2O/l/sec). The ventilator settings were as follows: mean airway pressure (MAP), 30 cmH2O; frequency, 5-15 Hz (every 1 Hz); airway pressure amplitude (AMP), maximum;and % of inspiratory time (IT), 50% for R100, 33% or 50% for 3100B. The measurements were also performed with an AMP of 2/3 or 1/3 maximum at 5, 10 and 15 Hz. The PLung and the measured MAP were not consistently identical to the setting MAP in either ventilator, and decreasing IT decreased the PLung in 3100B. In conclusion, we must pay attention to the possible discrepancy between the PLung and the setting MAP during adult HFOV.

Background: Hemostatic resuscitation might improve the survival of severely injured trauma patients. Our objective was to establish a simplified screening system for determining the necessity of massive transfusions (MT) at an early stage in trauma cases., Methods: We retrospectively analyzed the cases of trauma patients who had been transported to our institution between November 2011 and October 2013. Patients who were younger than 18 years of age or who were confirmed to have suffered a cardiac arrest at the scene or on arrival were excluded. MT were defined as transfusions involving the delivery of ≥10 units of red blood cell concentrate within the first 24 h after arrival., Results: A total of 259 trauma patients were included in this study (males: 178, 69%). Their mean age was 49 ± 20, and their median injury severity score was 14.4. Thirty-three (13%) of the patients required MT. The presence of a shock index of ≥1, a base excess of ≤ -3 mmol/L, or a positive focused assessment of sonography for trauma (FAST) result was found to exhibit sensitivity and specificity values of 0.97 and 0.81, respectively, for predicting the necessity of MT. Furthermore, this method displayed an area under the receiver operating characteristic curve of 0.934 (95% confidence interval, 0.891-0.978), which indicated that it was highly accurate., Conclusions: Our screening method based on the shock index, base excess, and FAST result is a simple and useful way of predicting the necessity of MT early after trauma.

Aim: This study was designed to identify the incidence, injury patterns, and financial burden of ditch-related injuries to provide a reference for establishing guidelines on the prevention of such injuries., Methods: A retrospective chart review in a tertiary care hospital in Okayama city, Japan, focused on patients injured following a ditch-related fall and requiring intensive care between April 2012 and August 2013. Analysis was carried out to describe the epidemiology of ditch-related injuries., Results: Thirteen patients (median age, 60 years) met the inclusion criteria. The median time lag between the fall and rescue was approximately 1.5 h. Ten patients were injured in residential areas, and three were injured in rural areas. Eight patients were riding a bicycle at the time of the accident. Head and spine injuries predominated, although there were two cases of drowning, of which one died. The injury severity score ranged from 1 to 50 (mean, 17.8 ± 13). At the time of discharge from the intensive care unit, 6, 4, and 1 patients were classified into cerebral performance categories 1, 3, and 4, respectively. There were two in-hospital deaths, resulting in a case fatality rate of 15.3%. The total cost during the review period was ¥27,572,630, with a mean cost of ¥2,120,971 per patient., Conclusion: Ditch-related injuries are associated with a high rate of poor neurological outcome and pose a financial burden on the health insurance system. Injury prevention efforts directed at decreasing the risk of ditch-related falls are required to minimize these outcomes.

Current systems for the evaluation of trauma severity are tedious and difficult to apply in an actual emergency setting. We aimed to develop and assess the accuracy of a more efficient severity evaluation system, termed the Ugawa classification, using brain-type natriuretic peptide (BNP) measurement and the estimated glomerular filtration rate (eGFR). Two-hundred trauma patients were divided into 2 groups using an eGFR cut-off value of 90ml/min/1.73m2 as an indicator of normal renal function and 2 additional groups according to whether the BNP values were greater or less than the age in years. This resulted in 4 subject groups with different combinations of eGFR and BNP. The mean SOFA score, injury severity scores (ISS), trauma and injury severity scores (TRISS), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of the groups were compared by Kruskal-Wallis test, and the mortality rate after 90 days was calculated. Significant intergroup differences were found in SOFA scores, ISS scores, and APACHE II-predicted mortality rates. Although no significant differences were found in the mortality rate after 90 days or TRISS-predicted mortality rate among the 4 groups, there was a trend toward increasing trauma severity from group 1 to 4. Thus, the Ugawa classification is as accurate as existing systems, has greater efficiency, and is user-friendly.

The functioning of an arteriovenous fistula (AVF) used for vascular access during hemodialysis has been assessed mainly by dilution methods. Although these techniques indicate the immediate recirculation rate, the results obtained may not correlate with Kt/V. In contrast, the clearance gap (CL-Gap) method provides the total recirculation rate per dialysis session and correlates well with Kt/V. We assessed the correlation between Kt/V and CL-Gap as well as the change in radial artery (RA) blood flow speed in the fistula before percutaneous transluminal angioplasty (PTA) in 45 patients undergoing continuous hemodialysis. The dialysis dose during the determination of CL-Gap was 1.2 to 1.4 Kt/V. Patients with a 10% elevation or more than a 10% relative increase in CL-Gap underwent PTA (n = 45), and the values obtained for Kt/V and CL-Gap before PTA were compared with those obtained immediately afterward. The mean RA blood flow speed improved significantly (from 52.9 to 97.5cm/sec) after PTA, as did Kt/V (1.07 to 1.30) and CL-Gap (14.1% to -0.2%). A significant correlation between these differences was apparent (r = -0.436 and p = 0.003). These findings suggest that calculating CL-Gap may be useful for determining when PTA is required and for assessing the effectiveness of PTA, toward obtaining better dialysis.

Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using (3)H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 micromol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 micromol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 micromol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 micromol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 micromol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.

The Shumiya cataract rat (SCR) is a hereditary cataractous strain. It is thought that the continuous occurrence of poorly differentiated epithelial cells at the bow area of the lens forms the pathophysiological basis for cataract formation in SCRs. In this study, we attempted to identify the genes associated with cataract formation in SCRs by positional cloning. Genetic linkage analysis revealed the presence of a major cataract locus on chromosome 20 as well as a locus on chromosome 15 that partially suppressed cataract onset. Hypomorphic mutations were identified in genes for lanosterol synthase (Lss) on chromosome 20 and farnesyl diphosphate farnesyl transferase 1 (Fdft1) on chromosome 15, both of which function in the cholesterol biosynthesis pathway. A null mutation for Lss was also identified. Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal. Thus, cholesterol insufficiency may underlie the deficient proliferation of lens epithelial cells in SCRs, which results in the loss of homeostatic epithelial cell control of the underlying fiber cells and eventually leads to cataractogenesis. These findings may have some relevance to other types of cataracts, inborn defects of cholesterol synthesis, and the effects of cholesterol-lowering medication.

Activation of the volume-regulated anion channels (VRAC) is considered to be involved in arrhythmia, but it has not yet been fully elucidated because of the lack of its high affinitive and selective compounds. A newly synthesized compound, YM-198313 (sodium 4-({[2-(methylthio)benzyl]amino}-5-[(1-phenylethyl)thio]isothiazol-3-olate), strongly inhibited VRAC in HeLa cells with an IC50 of 3.03+/-0.05 microM. However, YM-198313 weakly affected both the Ca2+-activated Cl- channels in HTC cells and the cAMP-activated Cl- channels in T84 cells, demonstrating that this compound is selective for VRAC among Cl- channels. At 10 microM, YM-198313 almost completely (100+/-7.8%) inhibited the VRAC current in guinea pig atrial myocytes. However, at the same concentration, YM-198313 showed little inhibitory effect on the cardiac cation currents in ventricular myocytes. We believe that YM-198313 is a potent and selective VRAC inhibitor, therefore, it should be use to clarify the role VRAC plays in arrhythmia.

Squalene synthase inhibitors are potentially superior hypolipidemic agents. We synthesized novel propylamine derivatives, as well as evaluated their ability to inhibit squalene synthase and their lipid-lowering effects in rats. 1-Allyl-2-[3-(benzylamino)propoxy]-9H-carbazole (YM-75440) demonstrated potent inhibition of the enzyme derived from HepG2 cells with an IC(50) value of 63 nM. It significantly reduced both plasma total cholesterol and plasma triglyceride levels following oral dosing to rats with a reduced tendency to elevate plasma transaminase levels.

Squalene synthase inhibitors have the potential to be superior hypocholesterolemic agents. A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (+/-)-3-(10-Methyl-10H-phenothiazin-3-ylmethoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC(50) value of 0.12 microM. Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels. Compound 19 showed a reduced tendency to elevate plasma transaminase levels, an indicator of hepatotoxicity. Enantiomerically pure (-)-19, YM-53546, was found to be more potent than the corresponding (+)-enantiomer.

Squalene synthase (E.C. 2.5.1.21) is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene, and is involved in the first committed step in cholesterol biosynthesis. It is an attractive target for hypocholesterolemic and hypotriglyceridemic strategies. We synthesized a series of 3-ethylidenequinuclidine derivatives, and evaluated their ability to inhibit squalene synthase in vitro and to lower non-HDL cholesterol levels in hamsters. 3-Ethylidenequinuclidine derivatives incorporating an unsubstituted 9H-carbazole moiety reduced plasma non-HDL cholesterol levels and did not affect plasma transaminase levels, indicating a lack of hepatotoxicity. Among the novel compounds, (Z)-2-[2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 8 (YM-53579) and (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 28 (YM-53601) were potent inhibitors of squalene synthase derived from human hepatoma cells, with IC(50) values of 160 and 79 nM, respectively. They also reduced plasma non-HDL cholesterol levels in hamsters by approximately 50 and 70%, respectively, at an oral dose of 50 mg/kg/day for 5 days.

Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerization of two molecules of farnesyl diphosphate to form squalene and is involved in the first committed step in cholesterol biosynthesis. Inhibition of this enzyme is therefore an attractive target for hypocholesterolemic strategies. A series of quinuclidine derivatives incorporating a tricyclic system was synthesized and evaluated for their ability to inhibit squalene synthase in vitro. A 9H-fluorene moiety was found to be optimal as the tricyclic system for potent inhibitory activity. Improved activity can be achieved with a conformationally constrained three-atom linkage connecting the tricyclic system with the quinuclidine nucleus. Among these compounds, (Z)-3-[2-(9H-fluoren-2-yloxy)ethylidene]-quinuclidine hydrochloride 31 was found to be a potent inhibitor of squalene synthase derived from hamster liver and human hepatoma cells with IC(50) values of 76 and 48 nM, respectively. Oral dosing of compound 31 demonstrated effective reduction of plasma non-HDL cholesterol levels in hamsters.

1. To better understand how it decreases plasma cholesterol and triglyceride levels, we evaluated the effect of (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole monohydrochloride(YM-53601) on lipogenic biosynthesis in the liver and lipid secretion from the liver in rats and hamsters. 2. Single administration of YM-53601 in cholestyramine-treated rats inhibited triglyceride and free fatty acid (FFA) biosynthesis at a similar dose range to that at which it inhibited cholesterol biosynthesis. YM-53601 inhibited both triglyceride and FFA biosynthesis in hamsters treated with cholestyramine. 3. YM-53601 by single oral administration decreased the enhanced plasma triglyceride levels in hamsters induced by an injection of protamine sulfate, which inhibits lipoprotein lipase (LPL) and consequently increases plasma very low-density lipoprotein (VLDL) triglyceride levels. YM-53601 also decreased the enhanced plasma triglyceride and cholesterol levels in hamsters treated with Triton WR1339, which also inhibits the degradation of VLDL. Plasma cholesterol was significantly decreased as soon as 1 h after single administration of YM-53601 in hamsters fed a normal diet. 4. This is the first report that a squalene synthase inhibitor suppresses lipogenic biosynthesis in the liver and cholesterol and triglyceride secretion from the liver in vivo. We therefore suggest that the mechanism by which YM-53601 decreases plasma triglyceride might include these effects. The finding that YM-53601 rapidly decreased plasma cholesterol suggests that this compound may be effective in decreasing plasma cholesterol levels early in the course of treatment of hypercholesterolemia in humans.

1. To better understand how it decreases plasma cholesterol and triglyceride, we evaluated the effect of YM-53601 ((E-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbozole monohydrochloride) on the clearance rate of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) in hamsters. 2. Treatment with YM-53601 at 50 mg kg(-1) for 5 days in hamsters fed a normal diet enhanced the disappearance of 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-VLDL and DiI-LDL. This effect on DiI-LDL was lost in the early phase after DiI-methyl(met)-LDL, chemically modified to block LDL receptor binding, was injected in hamsters, but was retained in the late phase. Pre-treatment with protamine sulphate, which inhibits the activity of LPL, also failed to enhance DiI-VLDL clearance rate by YM-53601. 3. Even on single oral administration at 30 mg kg(-1), YM-53601 enhanced the disappearance of the high concentration of plasma triglyceride after injection of intrafat, an emulsion of fat. Plasma triglyceride was significantly decreased as soon as 1 h after single administration of YM-53601 in hamsters fed a normal diet. 4. These results indicate that the decrease in plasma total cholesterol and triglyceride after the treatment with YM-53601 is due to its enhancement of the clearance rate of LDL and VLDL, respectively. Moreover, YM-53601 may be effective in decreasing plasma triglyceride levels early in the course of treatment of hypertriglyceridaemia in humans.

1. The aim of this study was to establish an experimental model of the escape phenomenon, in which plasma cholesterol, initially reduced by a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor such as pravastatin, increases again on long-term administration. We also evaluated the efficacy of YM-53601 ((E)-2-[2-fluoro-2- (quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a squalene synthase inhibitor, in this model. 2. Pravastatin inhibited cholesterol biosynthesis in hamster primary hepatocytes (IC(50), 14 nM). After pre-treatment with pravastatin, in contrast, almost no effect on cholesterol biosynthesis was seen. 3. In hamsters fed a high fat diet, 3 mg kg(-1) pravastatin for 9 days decreased plasma non-HDL cholesterol (total cholesterol - high density lipoprotein cholesterol) (P<0.01), but this effect was lost between 17 and 27 days of treatment, accompanied by an increase in HMG-CoA reductase activity. No such increase in plasma non-HDL cholesterol was seen with YM-53601 at 30 mg kg(-1) after 9 (P<0.001), 17 (P<0.01) or 27 (P<0.001) days of treatment. Replacement of pravastatin with YM-53601 caused a decrease in plasma non-HDL cholesterol by 53% (P<0.001) and in HMG-CoA reductase activity. 4. This animal model thus satisfactorily replicates the escape phenomenon observed in humans and may therefore be useful in evaluation of lipid-lowering agents, specifically comparison of HMG-CoA reductase inhibitors. Further, YM-53601 may be useful in the treatment of hypercholesterolemia without induction of the escape phenomenon.

The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and fibrates, respectively. YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED(50), 32 mg kg(-1)). In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol - high density lipoprotein cholesterol) by 47% (P<0.001) and 33% (P<0.001), respectively (100 mg kg(-1), daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg(-1), twice daily for 21 days, P<0.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg(-1), twice daily for 28 days). YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg(-1), daily for 5 days, P<0.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P<0.001) was superior to that of fenofibrate (by 53%, P<0.001), the most potent fibrate (dosage of each drug: 100 mg kg(-1), daily for 7 days). This is the first report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a fibrate in significantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.

From 1995 to 1996, we performed aortic arch replacement using antegrade cerebral perfusion under deep hypothermia in 7 patients, in whom 4 cases accompanied with cardiac lesion which treated simultaneously and 3 cases had abdominal aortic aneurysm. We compared the surgical results between cases with (group II, n = 4) and without (group I, n = 3) combined cardiovascular lesion. There is no difference between two groups in the cerebral perfusion time and the amount of bleeding and blood transfusion. The cardiac ischemic time and bypass time were insignificantly longer in group II than in group I. We experienced no early death and no cardiac and brain complication in both groups. Three cases with abdominal aortic aneurysm had two-staged operation successfully after arch surgery within a half year. In conclusion, we successfully treated aortic arch aneurysm even in patients combined with other cardiovascular lesion as well as in patients without that.

1. The compound YM-16638, [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid was developed in a series of in vitro and in vivo studies as a leukotriene D4 receptor antagonist. 2. In a clinical trial as a leukotriene antagonist drug, this compound was found to have a potent serum cholesterol lowering effect in normolipidaemic healthy male volunteers. 3. In the present study, we investigated the serum cholesterol lower effect of this compound in various species of experimental animals. 4. Administration of YM-16638 did not cause a significant decrease in serum total cholesterol (TC) in mice (up to 200 mg kg-1, body weight per day for 28 days), rats (200 mg kg-1 for 15 days) or rabbits (90 mg kg-1 for 18 days). In hamsters, administration of YM-16638 orally or by peritoneal injection at 50 mg kg-1 or more daily for 7 days caused a significant decrease in serum TC and the rate of body weight gain. In monkeys, serum TC did not change in YM-16638-administered squirrel monkeys (50 mg kg-1 daily for 3 weeks), but a significant decrease in serum TC was observed in cynomolgus monkeys (33% decrease at 30 mg kg-1 for 4 weeks) and rhesus monkeys (27% decrease at 30 mg kg-1 for 3 weeks) without any serious decrease in body weight. These results were consistent with those in a phase I study with human subjects. In contrast, serum alanine aminotransferase (ALT) level decreased in all animals after YM-16638 treatment. 5. From these results, we conclude that YM-16638 has a potent hypocholesterolaemic effect, but that this effect if species-specific and is only recognized clearly in human subjects and old-world monkeys.

The hemodynamic effects of a left intraatrial infusion of prostaglandin E1 (PGE1) given to ten patients after open-heart surgery (LA group), were compared with those following no treatment in a control group of ten patients, and to those following a right intraatrial infusion given to another ten patients (RA group). PGE1 was infused at a rate of 0.03 microgram/kg/min in the RA group and at 0.003 microgram/kg/min in the LA group, and hemodynamics were measured immediately after surgery, then 3, 6, and 12 h after the PGE1 infusion was commenced. The heart rate, right atrial pressure, left atrial pressure, and mean pulmonary arterial pressure remained almost unchanged in all three groups; however, the mean radial arterial pressure and systemic vascular resistance index decreased, and the cardiac index increased in the RA and LA groups. The pulmonary vascular resistance index decreased only in the LA group. Thus, a much smaller dose of PGE1, being one-tenth of that used for the right atrial infusion, administered directly into the left atrium yielded almost the same hemodynamic effects as the larger dose infused into the right atrium. Furthermore, this method of infusing PGE1 is safe, efficacious, and cost-efficient.

The effects of salts on canine taste responses to umami substances were examined by recording the activity of the chorda tympani nerve. 1) The responses to monosodium glutamate (MSG), disodium 5'-guanylate (GMP), and that induced by the synergism between MSG and GMP were enhanced by the presence of various salts. 2) The effective salts were those carrying inorganic cations such as Na, K, and Mg, while CaCl2 had no enhancing effect. Salts carrying organic cations such as tris(hydroxymethyl)aminomethane (Tris), choline, N-methyl-D-glucamine, and 1,3-bis[tris(hydroxymethyl)-methylamino]propane also produced positive results. 3) The dependence of the umami responses on NaCl and MgCl2 concentrations showed a bell-shaped response curve with the maximal enhancing effect being seen at 100 mM NaCl and 3-10 mM MgCl2. 4) The degree of the enhancement depended not only on the species of the cation, but also on that of anion. For example, 100 mM NaCl showed a much larger enhancing effect than Na phosphate, Na2SO4, and Na4Fe(CN)6 at equimolar Na+. 5) The enhancing effects of salts on the responses to the umami substances could not be simply explained in terms of the permeability of cation and anion of salts. It was speculated that the binding of both cations and anions to the receptor membranes leads to changes in the interaction of the umami substances with the receptor proteins.

Autotransfusion of the shed mediastinal blood after cardiac operations was performed in 20 cases (ATS group). Safety and efficacy of the autotransfusion were studied comparing with the 10 cases without autotransfusion (control group). A 65.1 +/- 17.1% of bleeding volume within 24 hours after surgery was autotransfused in the ATS group. The ATS group received 1,396 +/- 1,674 ml of the banked blood compared with 780 +/- 1,194 ml for the control group. There was no significant difference between two groups in regard to saving the banked blood. Hematological and biochemical studies after surgery in the ATS and control groups revealed that CPK, BUN and creatinine of the ATS group were significantly higher than those of the control group, although these changes were transitory and trivial. However, prothrombin time of the ATS group was lower than that of control group, so there may be the possibility that this technique itself increases the hemorrhage. Since the cardiotomy filter was obstructed with clots in cases of massive bleeding, shed mediastinal blood may not be fully defibrinogenated in the cases with massive bleeding. These results lead to the following conclusions: autotransfusion of the shed mediastinal blood after cardiac operations is a safe method, but the efficacy of it is doubtful.

The effects of salts on the canine taste responses to amino acids were examined by recording the activity of the chorda tympani nerve. 1) The tonic responses to most amino acids examined were significantly enhanced by the presence of various salts. 2) The degree of the enhancement varied with the species of amino acid and salt. The responses to most amino acids were enhanced by sodium, potassium, and calcium salts, but not enhanced by magnesium salts. The response to methionine, for example, was enhanced by NaCl, but not by Na phosphate of equimolar Na+. 3) The responses to glycine and alanine were suppressed by high concentrations of NaCl. 4) The presence of salts (NaCl and CaCl2) enhanced the responses to amino acids without affecting the thresholds for the amino acids, suggesting that the presence of the salts did not change the affinity of amino acids to the receptor sites. 5) The enhancing effects of salts on the responses to amino acids could not be explained in terms of permeability of cation and anion of salts. It was speculated that the binding of cation and anion of salts on the receptor membranes induces exposure of the receptor sites for amino acids available for binding of amino acids.