Dexmedetomidine improves acute lung injury by activating autophagy in a rat hemorrhagic shock and resuscitation model.

Dexmedetomidine (DEX) can reduce lung injury in a hemorrhagic shock (HS) resuscitation (HSR) model in rats by inhibiting inflammation. Here, we aimed to investigate if these effects of DEX are due to autophagy activation. Therefore, we established HSR rat models and divided them into four groups. HS was induced using a blood draw. The rats were then resuscitated by reinjecting the drawn blood and saline. The rats were sacrificed 24 h after resuscitation. Lung tissues were harvested for histopathological examination, determination of wet/dry lung weight ratio, and detection of the levels of autophagy-related marker proteins LC3, P62, Beclin-1, and the ATG12-ATG5 conjugate. The morphological findings of hematoxylin and eosin staining in lung tissues and the pulmonary wet/dry weight ratio showed that lung injury improved in HSR + DEX rats. However, chloroquine (CQ), an autophagy inhibitor, abolished this effect. Detecting the concentration of autophagy-related proteins showed that DEX administration increased LC3, ATG12-ATG5, and Beclin-1 expression and decreased P62 expression. The expression levels of these proteins were similar to those in the HSR group after CQ + DEX administration. In summary, DEX induced autophagic activation in an HSR model. These findings suggest that DEX administration partially ameliorates HSR-induced lung injury via autophagic activation.

Involvement of the mitochondrial retrograde pathway in dihydrosphingosine-induced cytotoxicity in budding yeast.

Sphingoid long-chain bases are essential intermediates of ceramides and complex sphingolipids, and function in the regulation of various signal transduction systems. Previously, we found that, in budding yeast, intracellularly accumulated dihydrosphingosine (DHS) causes mitochondrial reactive-oxygen species (ROS)-mediated cytotoxicity, which is much stronger than phytosphingosine. In this study, we screened for suppressor mutations that confer resistance to DHS, and identified RTG2, which encodes upregulation of the mitochondrial retrograde signaling pathway (RTG pathway). Deletion of RTG3 encoding transcriptional factor for the RTG pathway suppressed the cytotoxicity of DHS, whereas deletion of MKS1 or point mutation of LST8, both of which cause increased activity of the RTG pathway, enhanced the cytotoxicity. Moreover, the deletion of RTG3 also suppressed the DHS-induced increases in ROS levels. Finally, it was found that the RTG pathway is activated on DHS treatment. These results suggested that the cytotoxicity of DHS is partially mediated through activation of the RTG pathway.

Preoperative Prognostic Nutritional Index is a significant predictive factor for posthepatectomy bile leakage.

BACKGROUNDS/AIMS: It is known that preoperative nutritional status can influence patient outcomes after hepatectomy. Prognostic Nutritional Index (PNI) is a useful parameter to reflect patient outcomes undergoing gastro-intestinal surgery. The aim of this study was to retrospectively evaluate relationships of nutritional parameters, demographics, and surgical records with postoperative outcomes in a cohort study. METHODS: Curative hepatectomy was performed for 182 patients at the University of Miyazaki between 2015 and 2018. Each preoperative level of albumin, prealbumin, lymphocyte, total cholesterol, or the comprehensively calculated Onodera's PNI was examined as a nutritional parameter. RESULTS: The mean PNI was 39.6 ± 5.1, with PNI below 40 observed in 91 (50.0%) patients. Nutritional parameters were not different among patients with various liver diseases. Serum albumin or prealbumin level was significantly correlated with each hepatic parameter (p < 0.01). Prealbumin and total cholesterol levels were significantly correlated with postoperative prothrombin activity (p < 0.05). Albumin or prealbumin levels and PNI were significantly lower in patients with posthepatectomy complications, particularly bile leakage in comparison those without such complications (p < 0.05). Multiple logistic analysis showed that albumin level was an independent risk factor for complications after hepatectomy (risk ratio [RR]: 1.33) and that lymphocyte count was an independent risk factor for bile leakage (RR: 1.28) (p < 0.05). The cut-off level of albumin was approximately 3.8 mg/dL and that of lymphocyte count was 1,320/mm3. CONCLUSIONS: Preoperative PNI reflected perioperative liver functional status. It was a predictive parameter for postoperative complications, particularly biliary leakage.

Spontaneous common bile duct perforation due to choledocolithiasis accompanied with pancreaticobiliary maljunction in an adult: a case report.

BACKGROUND: Spontaneous common bile duct (CBD) perforation is an extremely rare disease in adults. We report an adult case of CBD perforation due to choledocolithiasis accompanied with pancreaticobiliary maljunction, which is, to our knowledge, the first such case report based on a search using PubMed. CASE PRESENTATION: A 71-year-old woman with consciousness disorder was transported to the emergency department of another hospital. She was diagnosed as having severe peritonitis with septic shock and transferred to our hospital for emergency surgery. Enhanced computed tomography (CT) revealed supraduodenal CBD dilation similar to a diverticulum and a defect of bile duct wall continuity. Furthermore, CT showed a long common channel of the pancreaticobiliary duct, so she was diagnosed as having spontaneous CBD perforation with pancreaticobiliary maljunction. Emergency surgery was performed that revealed a necrotic diverticulum-like change on the supraduodenal part, and a 2.5 × 1 cm perforation was found on the anterolateral wall of the CBD. Peritoneal lavage was performed, and CBD perforation was resolved with a T-tube. The patient suffered refractory intra-abdominal and retroperitoneal abscess formation and bleeding from the abdominal wall, which required a long period of postoperative management. The T-tube was removed on day 136, and the patient was transferred on day 153. CONCLUSION: The cause of CBD perforation is commonly considered to be increased intraductal pressure or weakness of the bile duct wall. In this case, pancreaticobiliary maljunction may have significantly influenced onset and the postoperative course. This case suggests that early surgical intervention and appropriate drainage are important to ensure survival.

Recurrent solitary fibrous tumor of the pleura with malignant transformation: a case report.

We report a rare case of recurrent solitary fibrous tumor (SFT) of the pleura with suspicious malignant transformation. A 78-year-old man had undergone prior surgical resection of the primary and recurrent SFT tumors at 11 and 2 years before the current presentation. Although his primary tumor had a round shape and did not show invasive growth, the current recurrent tumor extended through the neural foramen and had an osteoclastic progression into the thoracic spine. A computed tomography (CT) guided needle biopsy was performed and the pathological diagnosis of the tumor was confirmed as the recurrence of SFT. Immunohistochemically, the MIB-1 proliferation index (Ki-67) of the primary tumor and the current tumor was 1.74 and 30.00%, respectively. These clinical and immunohistochemical findings were strongly suspected the malignant transformation of SFT from benign. He was treated with radiotherapy, and a response was observed.

Mitochondrial reactive oxygen species-mediated cytotoxicity of intracellularly accumulated dihydrosphingosine in the yeast Saccharomyces cerevisiae.

In eukaryotic cells, the content of sphingoid long-chain bases (LCBs) is generally much lower than that of complex sphingolipids and ceramides, and the quantitative balance of these metabolites in cells is tightly regulated. In the budding yeast Saccharomyces cerevisiae, it has been demonstrated that exogenously added phytosphingosine (PHS) causes a strong growth defect in tryptophan auxotrophic cells, due to delayed uptake of tryptophan from the culture medium; however, the growth inhibitory effect of dihydrosphingosine (DHS) is less than that of PHS in tryptophan auxotrophic cells. Here, we found that, in tryptophan-prototrophic yeast cells, exogenously added DHS is much more toxic than PHS. Exogenously added DHS is converted to PHS, Cers, or LCB 1-phosphates through the action of sphingolipid C4-hydroxylase, Cer synthases, or LCB kinases, respectively; however, suppression of further metabolism of DHS in cells resulted in an increase in the growth inhibitory activity of exogenously added DHS, indicating that DHS itself is causative of the cytotoxicity. The cytotoxicity of DHS was not mediated by Pkh1/2, Sch9, and Ypk1/2 kinases, intracellular targets of LCBs. DHS treatment caused an increase in mitochondria-derived reactive oxygen species, and the cytotoxic effect of DHS was suppressed by depletion of mitochondrial DNA or antioxidant N-acetylcysteine, but enhanced by deletion of SOD1 and SOD2 encoding superoxide dismutases. Thus, collectively, these results indicated that intracellularly accumulated DHS has mitochondrial reactive oxygen species-mediated cytotoxic activity, which is much more potent than that of PHS.

[Impact of Physician Order Support Duties on de novo Hepatitis Prevention].

"Immunosuppression and hepatitis B measures and guidelines for chemotherapy" were announced in 2009. However, a fulminant case that appeared when the guidelines were not observed was reported, and de novo hepatitis prevention is an urgent problem. The rate of compliance with these guidelines as of January 2014 was 20.4%, but this rose to 34.3%after the alert indication for de novo hepatitis prevention was set on an electronic chart system from June 2014. The rate of compliance increased to 63.9% at a hospital where de novo hepatitis alerts were put on clinical cards in April 2015, but it gradually decreased thereafter. HBV-DNA measurement was 100% in compliance with the guidelines from August 2016 when HB antigen, HB antibody, and anti-hepatitis B core antigen measurements were all performed in March 2016 because the pharmacists practiced physician order support duties at that time. This helped to reduce the burden on physicians, and the physician order support duties by the pharmacist were educational. Thus, de novo hepatitis prevention may contribute to safe cancer chemotherapy.

[A Case of Rectal Cancer and Multiple Liver Metastases Treated Using mFOLFOX and Bevacizumab under Maintenance Dialysis].

A 50s man receiving dialysis for chronic kidney disease due to IgA nephropathy underwent laparoscopic reversal via Hartmann 's procedure for rectal cancer and multiple liver metastases, followed by chemotherapy for the liver metastases. Following a single course of mFOLFOX therapy, bevacizumab was administered for 8 courses, resulting in tumor shrinkage and a decrease in tumor marker levels. The initial doses were 60mg/m2 oxaliplatin and 280(bolus injection)and 1,680mg/m2 (continuous infusion)of 5-FU. Subsequently, these doses were adjusted to be administered every 3 weeks. No serious adverse events other than neutropenia(Grade3 ), anorexia(Grade1 ), and hiccups(Grade1)were noted.

Isolated breast metastasis from gastric cancer in a male patient.

A 72-year-old man underwent total gastrectomy for gastric cancer (por2, T3, N2, Stage IIIA). Eleven courses of postoperative chemotherapy with TS-1 (tegafur/gimeracil/oteracil) were administered. Five months after surgery, the serum carcinoembryonic antigen value was slightly elevated. However, computed tomography did not reveal any metastatic lesions in other organs. Two years after surgery, the patient felt a mass in the left mammary. A 2-cm tumor was palpable in the central portion of the breast. Ultrasonography revealed a hypoechoic tumor, which was Class 3 on aspiration biopsy cytological examination. No mass was detected on positron emission tomography-computed tomography. The mammary gland tumor increased in size to 3 cm, and a core needle biopsy procedure was performed. Histological examination findings revealed breast metastasis of gastric cancer. No other recurrence was found, and radical mastectomy was performed 2 years and 5 months after gastrectomy. Immunohistological analysis of the resected material confirmed breast metastasis of the gastric cancer. Two courses of TS-1 + cisplatin were administered, but this treatment was subsequently terminated because the patient experienced Grade 3 diarrhea and neutropenia. Three years and 1 month after the gastrectomy, the tumor recurred in the pelvic area. Chemotherapy and radiation therapy were performed, but the patient's overall condition became progressively worse, and he died 3 years and 9 months after gastrectomy.

Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction.

BACKGROUND: Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown. OBJECTIVE: The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations. METHODS: We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases. RESULTS: We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001). CONCLUSION: SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC.

[Team Approaches for and Future Challenges to Promoting Perioperative Oral Management].

When the medical fee system was revised in 2012, the category of perioperative oral management was newly organized. However, the calculation of additional fees for such management required referral from medical to dental departments. In addition, requests for such management were limited, possibly owing to an increased burden on doctors engaged in outpatient services. This study examined the usefulness of an approach to promote patients' use of dental services by increasing their awareness of the importance of oral management. In this approach, pharmacists explained doctors' instructions to patients at a chemotherapy center within the study facility. Explanations were provided to 114 patients, 75 (65.8%) of whom subsequently used dental services in the facility. For patients using dental services, oral care was performed most frequently (40; 53.3%), followed by invasive procedures (23; 30.7%). Furthermore, the facility's ethics committee approved a survey to measure the satisfaction of patients undergoing chemotherapy at the center. Of the 110 patients invited to participate in the survey, 77(70.0%) did not respond. Researchers concluded the low response rate was associated with patients' belief that dental services were intended primarily for treating oral cavities and their lack of awareness of the importance of preventive dental care. However, in 2014, the number of calculations of additional fees for perioperative oral management markedly increased each month after the above-mentioned approach, from 62 (January) to 162 (December). Both the hospital-to family and family-to-hospital dentist referral rates significantly increased, from 11.2% and 10.7%, respectively (June 2013), to 21.0% and 41.9%, respectively(June 2014). Future evaluations of the outcomes of perioperative oral management and promoting cooperation between medical and dental communities may be necessary.

[Initial Evaluation of the Efficacy and Safety of Tablets Containing Trifluridine and Tipiracil Hydrochloride--Safety Measures Devised by a Multidisciplinary Team Including a Pharmaceutical Outpatient Clinic].

In May 2014, tablets containing both trifluridine and tipiracil hydrochloride (Lonsurf® tablets) were launched in Japan ahead of other countries, for the treatment of advanced/relapsed unresectable colorectal cancer. The benefits of these tablets in terms of a new therapeutic option have been demonstrated. However, the manufacturer has requested healthcare professionals to help develop safety measures for the appropriate and safe use of the tablets. In this study, we evaluated the efficacy and safety of the tablets in 16 patients who received the tablets at our hospital. Among the 4 evaluable patients, none achieved a complete or partial response. One patient (25.0%) had stable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines outlined in the General Rules of the Study of Colorectal Cancer (The 8th Edition). Lonsurf® is considered to be a third-line (or later) treatment. Among the 16 cases studied, Lonsurf® was used as a third-, fourth-, and fifth-line treatment in 9, 6, and 1 cases, respectively. Therefore, Grade 3 or worse toxicities were a potential concern. Despite a high incidence of Grade 3 or worse neutropenia (7 of the 16 patients [43.8%]), none of the patients were hospitalized due to neutropenia or other treatment-related adverse events. Pharmacists have made 126 proposals to physicians regarding the use of Lonsurf®, 121 (96.0%) of which have been adopted. All of the adverse reactions experienced by our patients were resolved after supportive therapy.