An open-label, single-arm study assessing the efficacy and safety of l-menthol sprayed onto the gastric mucosa during upper gastrointestinal endoscopy

Background and aims

The results of a phase III, placebo-controlled study demonstrated that endoscopic direct spraying of l-menthol onto the gastric mucosa effectively suppressed gastric peristalsis in the study patients. The aim of the study reported here was to determine whether the anti-peristaltic effect of an l-menthol preparation facilitates endoscopic examinations in a clinical setting.

Methods

This was a multicenter, open-label, single-arm trial in which the study cohort comprised patients in whom l-menthol was likely to be used to facilitate endoscopic examination in clinical settings. The primary outcome was the proportion of subjects with no peristalsis (Grade 1) after treatment and at the end of endoscopy (defined as the complete suppression of gastric peristalsis). This variable was assessed according to the level of anti-Helicobacter pylori immunoglobulin G (IgG) antibody, pepsinogen test results, whether sedation was performed, and whether subjects were considered unsuitable for the use of conventional antispasmodics.

Results

Of the 119 enrolled subjects, data from 112 were included in the primary efficacy analysis. Gastric peristalsis was completely suppressed in 37.5% of the patients [42/112 patients; 95% confidence interval (CI) 28.5?C47.1]. Subgroup analyses revealed that the rate of peristalsis suppression was significantly higher in patients with elevated levels of anti-H. pylori IgG antibody (26/44, 59.1%; 95% CI 43.2?C73.7); P?P?P?=?0.434) or whether subjects were considered unsuitable for use of conventional antispasmodic agents (14/28, 50.0%; 95% CI 30.6?C69.4; P?=?0.12].

Conclusion

These findings are comparable to those of the phase III placebo-controlled study and provide further evidence that endoscopic direct spraying of l-menthol effectively suppresses gastric peristalsis during upper gastrointestinal endoscopy.     

Preoperative identification of intraoperative blood loss of more than 1,500?mL during elective hepatectomy

Background

Despite recent advances in surgical techniques, hepatectomies remain one of the most hemorrhagic procedures in abdominal surgery. It is important to identify preoperatively patients who are at high risk of suffering massive intraoperative blood loss.

Methods

The clinical records of 251 patients who underwent an elective hepatectomy for liver tumors between September 2007 and December 2009 were reviewed retrospectively. A multivariate logistic regression analysis of preoperative factors potentially influencing intraoperative blood loss was performed. We set the cut-off value of the amount of blood loss for safe hepatectomy as less than 1,500?mL because no patients with blood loss of less than 1,500?mL received blood transfusion in this study. A scoring system to predict blood loss of more than 1,500?mL was constructed and validated in a cohort of 59 subsequent patients.

Results

Intraoperative blood loss of more than 1,500?mL was recognized in 35 of 251 patients (13.9%). Prothrombin activity?<?70%, non-peripheral location of the tumor, involvement of hepatic veins, body mass index????23.0, and major hepatectomy were independently associated with intraoperative blood loss of more than 1,500?mL. The score was calculated by assigning 1 point for each of the 5 risk factors. The area under the receiver operating characteristic curve (AUC) was 0.814 (95% CI 0.731?C0.898). This scoring system was highly predictive in the subsequent validation group of 59 patients (AUC?=?0.839, 95% CI 0.710?C0.969).

Conclusion

This predictive scoring system is considered to be useful for identifying before hepatectomy those patients with a high risk of intraoperative blood loss of more than 1,500?mL.     

A case of hepatitis C-associated osteosclerosis that was improved with the combination therapy of peginterferon alfa-2b and ribavirin

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in skeletal mass in patients who are infected with hepatitis C virus (HCV). The clinical presentation is an acquired deep bone pain with increased serum alkaline phosphatase (ALP) activity. We present a case of a patient with HCAO who was treated with antiviral therapy. A 42-year-old Japanese man presented with severe, stabbing pain in his lower limbs. He was diagnosed with hepatitis C secondary to intravenous drug use 20 years earlier. Serum biochemical studies revealed markedly elevated ALP activity and osteocalcin levels. Skeletal radiographs showed diffuse bony sclerosis with marked cortical thickening in the long bones. The bony findings and clinical symptoms were attributed to HCAO. The HCV RNA viral load was high and the genotype was 2a. The patient was treated with peginterferon alfa-2b and ribavirin for 24 weeks. After 24 weeks of the combination therapy, the patient had a sustained virological response and clinical remission of bone pain and a decrease in the level of serum ALP. In conclusion, HCAO was improved by the combination therapy of peginterferon alfa-2b and ribavirin when the patient achieved sustained virological response. It was confirmed that HCAO was one of the extrahepatic manifestations of HCV.     

Mediastinal Ancient Schwannoma Causing Intrathoracic Bleeding

Spontaneous hemothorax caused by the rupture of a benign schwannoma has rarely been reported. Herein, we present the successful excision of an extremely rare case of mediastinal ancient schwannoma causing intrathoracic bleeding. A 27-year-old man was admitted to our emergency department because of back pain and dyspnea. Computed tomography revealed massive pleural effusion with a posterior mediastinal tumor. We performed a resection of the tumor which had ruptured, and the tumor was diagnosed as an ancient schwannoma.     

Effectiveness of Clipping for Definitive Colonic Diverticular Bleeding in Preventing Early Recurrent Bleeding

Objective Clipping is a common technique for managing colonic diverticular bleeding (CDB), despite the lack of published evidence regarding its effectiveness. We aimed to evaluate the effectiveness of clipping for CDB in preventing early recurrent bleeding. Methods This dual-center retrospective study included 93 patients who underwent emergency hospitalization for bloody stool, diagnosed with definitive CDB, and treated with clipping or conservative treatment. The primary outcome was early recurrent bleeding. A logistic regression analysis was performed to assess the association between the occurrence of early recurrent bleeding and clipping with adjustment for propensity scores. Secondary outcomes included death, transfusion, length of hospitalization, need for transcatheter arterial embolization or surgery, and adverse events. Results The patient characteristics were similar between the clipping (n=85) and conservative treatment (n=8) groups. The rate of early recurrent bleeding was significantly lower in the clipping group than in the conservative treatment group [23.5% (20 cases) vs. 75% (6 cases), p=0.005]. In the propensity score-adjusted logistic regression analysis, the odds ratio for early recurrent bleeding in the clipping group was 0.094 (95% confidence interval, 0.008-0.633, p=0.026). Secondary outcomes were not significantly different between the two groups. Stigmata of recent hemorrhage (SRH) at the time of recurrent bleeding was identified in 79.2% of patients (19/24). In the clipping group, recurrent bleeding was observed in 62.5% of cases (10/16) from the same diverticulum. However, early recurrent bleeding tended to be less likely with direct clipping (p=0.072). Conclusion Clipping for definite CDB was more effective in preventing early recurrent bleeding than conservative treatment.     

microRNA‐99a‐5p induces cellular senescence in gemcitabine‐resistant bladder cancer by targeting SMARCD1

Patients with advanced bladder cancer are generally treated with a combination of chemotherapeutics, including gemcitabine, but the effect is limited due to acquisition of drug resistance. Thus, in this study, we investigated the mechanism of gemcitabine resistance. First, gemcitabine‐resistant cells were established and resistance confirmed in vitro and in vivo. Small RNA sequencing analyses were performed to search for miRNAs involved in gemcitabine resistance. miR‐99a‐5p, selected as a candidate miRNA, was downregulated compared to its parental cells. In gain‐of‐function studies, miR‐99a‐5p inhibited cell viabilities and restored sensitivity to gemcitabine. RNA sequencing analysis was performed to find the target gene of miR‐99a‐5p. SMARCD1 was selected as a candidate gene. Dual‐luciferase reporter assays showed that miR‐99a‐5p directly regulated SMARCD1. Loss‐of‐function studies conducted with si‐RNAs revealed suppression of cell functions and restoration of gemcitabine sensitivity. miR‐99a‐5p overexpression and SMARCD1 knockdown also suppressed gemcitabine‐resistant cells in vivo. Furthermore, β‐galactosidase staining showed that miR‐99a‐5p induction and SMARCD1 suppression contributed to cellular senescence. In summary, tumor‐suppressive miR‐99a‐5p induced cellular senescence in gemcitabine‐resistant bladder cancer cells by targeting SMARCD1.     

Seven‐action approaches for the management of hypertension in Asia – The HOPE Asia network

Asia is a large continent and there is significant diversity between countries and regions. Over the last 30 years, absolute blood pressure (BP) levels in Asia have increased to a greater extent than those in other regions. In diverse Asia‐Pacific populations, for choosing an Asia‐specific approach to hypertension management is important to prevent target organ damage and cardiovascular diseases. In this consensus document of HOPE Asia Network, we introduce seven action approaches for management of hypertension in Asia.     

Ketogenic Effects of Multiple Doses of a Medium Chain Triglycerides Enriched Ketogenic Formula in Healthy Men under the Ketogenic Diet: A Randomized,Double-Blinded,Placebo-Controlled Study

Ketogenic diets, which are carbohydrate-restricted high-fat diets, may have therapeutic effects on various diseases, including cancer. However, ketogenic diets are often not standardized and, therefore, results are difficult to interpret. We previously investigated the usefulness of ketogenic diets in cancer therapy, where ketogenic formulas (KF) were used as supplements to enhance blood ketone bodies; however, the amount of KF was determined empirically with reference to blood ketone bodies levels. Here, to determine a standardized optimal amount of KF, we investigated temporal changes in blood ketone bodies (acetoacetic acid (AcAc), β-hydroxybutyrate (BHB)) and safety in 20 healthy individuals when KF was taken repeatedly under the conditions of a ketogenic diet (UMIN000034216). The diurnal variation in total ketone bodies, and AcAc and BHB levels significantly increased after lunch and after dinner, on the 4th day of KF administration. There were no significant safety issues related to KF in the context of anthropometric, metabolic, nutritional, urological and gastrointestinal parameters. In addition, ketogenic diets lead to changes in gut microbiota. KF showed a decrease in phylum Firmicutes. Our study provides baseline data of the usefulness of KF in a ketogenic diet.     

Lack of cooperation between physicians and dentists during osteoporosis treatment may increase fractures and osteonecrosis of the jaw

Objective: Our previous questionnaire-based survey suggested that discontinuation of antiresorptive agents before tooth extraction may increase adverse events and disturb osteoporosis treatment without completely preventing osteonecrosis of the jaw (O.N.J.). We also found little cooperation between physicians and dentists in Japan. However, limitations of our previous study included a survey of doctors belonging to small clinics and a small sample size. Our current study aimed to confirm the results of our previous survey in doctors mainly belonging to academia.

Methods: A structured questionnaire including 14?key clinical queries was sent to 1812 physicians of the Japan Osteoporosis Society, and 629 responses were received.

Results: Dentists requested discontinuation of many medications that were not associated with the incidence of O.N.J. A total of 523 respondents had received discontinuation requests from dentists. Of these, 97 respondents experienced 119 adverse events including 25 fractures and seven incidences of O.N.J. The ratios of valid responses for fractures were 3.6% and 5.3% in patients with a discontinuation of <3 and ≥3 months, respectively. Those for O.N.J. were 0.7% and 1.6%, respectively. Respondents who refused discontinuation requests reported no cases of O.N.J. Approximately 17% of respondents had patients who discontinued osteoporosis treatment following a requested drug discontinuation after tooth extraction. Approximately 62% of respondents did not request oral health care by a dentist before antiresorptive therapy, and 72% reported no cooperation between physicians and dentists in their region.

Conclusions: This study reconfirms the results of our previous survey. Discontinuation of antiresorptive treatment may increase both fractures and O.N.J. Immediate development of a strategy for sharing information about O.N.J. among physicians, dentists, and patients is required to reduce the incidence of both O.N.J. and skeletal events in osteoporosis treatment. Study limitations were selection bias due to low response rate and possible inaccurate responses to the questionnaire.     

去甲斑蝥素诱导人黑色素瘤A375-S2细胞凋亡

目的:研究去甲斑蝥素(NCTD)诱导人黑色素瘤A375-S2细胞凋亡的机制.方法:采用MTT法、形态学观察、DNA凝胶电泳及Western blot检测法.结果:去甲斑蝥素可诱导A375-S2细胞发生凋亡.半胱氨酸天冬氨酸酶(caspase)-3,-9抑制剂可以部分的抑制NCTD诱导的细胞死亡.细胞凋亡时caspase-3,8,-9酶活力升高,caspase-3底物-caspase-3激活的DNA酶抑制物(ICAD)蛋白表达下降,同时Bcl-2/Bax、Bcl-xL/Bax蛋白表达比率明显降低.结论:去甲斑蝥素通过激活caspase和Bcl-2家族诱导A375-S2细胞凋亡.