Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways. METHODS: To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis. RESULTS: The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy. CONCLUSION: Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.

Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model. METHODS: To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples. RESULTS: Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs. CONCLUSION: The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.

Effects of lysophosphatidic acid (LPA) signaling via LPA receptors on cellular functions associated with ATP reduction in osteosarcoma cells treated with ethidium bromide.

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6) exhibits a variety of malignant properties in cancer cells. Intracellular ATP depletion leads to the development of necrosis and apoptosis. The present study aimed to evaluate the effects of LPA receptor-mediated signaling on the regulation of cancer cell functions associated with ATP reduction. Long-term ethidium bromide (EtBr) treated (MG63-EtBr) cells were established from osteosarcoma MG-63 cells. The intracellular ATP levels of MG63-EtBr cells were significantly lower than that of MG-63 cells. LPAR2, LPAR3, LPAR4 and LPAR6 gene expressions were elevated in MG63-EtBr cells. The cell motile and invasive activities of MG63-EtBr cells were markedly higher than those of MG-63 cells. The cell motile activity of MG-63 cells was increased by LPA4 and LPA6 knockdowns. In cell survival assay, cells were treated with cisplatin (CDDP) every 24 h for 3 days. The cell survival to CDDP of MG63-EtBr cells was lower than that of MG-63 cells. LPA2 knockdown decreased the cell survival to CDDP of MG-63 cells. The cell survival to CDDP of MG-63 cells was inhibited by (2 S)-OMPT (LPA3 agonist). Moreover, the cell survival to CDDP of MG-63 cells was enhanced by LPA4 and LPA6 knockdowns. These results indicate that LPA signaling via LPA receptors is involved in the regulation of cellular functions associated with ATP reduction in MG-63 cells treated with EtBr.

The utility of serum osteopontin levels for predicting postoperative complications after colorectal cancer surgery.

BACKGROUND/AIM: Osteopontin (OPN) is a secretory glycoprotein, which is expressed not only in osteoblasts, but immune cells including macrophages and activated T cells. Its pleiotropic immune functions, such as bone remodeling, cancer progression, immune response, and inflammation have been reported previously. However, the association between OPN and postoperative complications (POC) after colorectal cancer (CRC) surgery has not been studied, so far. METHODS: Peripheral blood samples were collected before (pre) and immediately after surgery (post), and on postoperative days (POD) 1, 3, 5, and 7. Serum OPN levels were measured by ELISA. In total, 78 patients who underwent elective CRC surgery were divided into the No-POC (n = 54) and POC (n = 24) groups. RESULTS: The POC group had significantly higher OPN levels than the No-POC group throughout the postoperative observation period. The maximum OPN levels from pre- to postsurgical samples showed the best predictive potential for POCs (cut off: 20.75 ng/mL, area under the curve: 0.724) and were correlated with length of postoperative stays. OPN values were significantly correlated with C-reactive protein on POD3 and were identified as an independent predictive marker for POCs (odds ratio: 3.88, 95% CI: 1.175-12.798, P = 0.026). The severity of POCs was reflected in increased OPN levels. CONCLUSION: Increased postoperative OPN was associated with increased postoperative inflammatory host responses and POC after CRC surgery. Serum OPN level may be a useful biomarker for early prediction of POC and it may provide additional information for treatment decisions to prevent POC.

Colonic stent-induced mechanical compression may suppress cancer cell proliferation in malignant large bowel obstruction.

BACKGROUND: The short-term safety and efficacy of insertion of a self-expandable metallic colonic stent (SEMS) followed by elective surgery, "bridge to surgery (BTS)", for malignant large bowel obstruction (MLBO) have been well described; however, the influence on long-term oncological outcomes is unclear. The aim of this study was to evaluate changes in oncological characteristics in colorectal cancer (CRC) tissues after SEMS insertion, focusing on growth factors, cell cycle and apoptosis. METHODS: From January 2013 to September 2014, a total of 25 patients with MLBO who underwent BTS at our single institution were retrospectively included. Paired CRC tissue samples before (endoscopic biopsy) and after SEMS insertion (surgically resected) were collected from each patient. EGFR, VEGF, Ki-67, p27kip1 and TUNEL expression were determined by immunohistochemistry. RESULTS: No clinical or subclinical perforations evaluated by mechanical ulceration pathologically were observed. Epithelial exfoliation, tumour necrosis, infiltration of inflammatory cells and fibrosis were observed in SEMS-inserted surgically-resected specimens. Overall, 84% (21/25) and 60% (15/25) of patients exhibited no change or a decrease in staining category, respectively, for EGFR and VEGF expression after SEMS insertion. A significant decrease in Ki-67 expression was observed in surgically-resected specimens compared with endoscopic biopsy specimens (P < 0.01). The upstream cell cycle inhibitor, p27kip1, was significantly increased after SEMS insertion (P = 0.049). CONCLUSIONS: Although the long-term safety of BTS should be determined in a future clinical trial, mechanical compression by SEMS may suppress cancer cell proliferation and this result could provide some insights into the issue.

Lysophosphatidylcholine as a predictor of postoperative complications after colorectal cancer surgery.

PURPOSE: Lysophosphatidylcholine (LPC), which is generated from phosphatidylcholine (PC) and metabolized by autotaxin (ATX), modulates immune responses via its anti-inflammatory property. We investigated the association between LPC and postoperative complications (POCs) after colorectal cancer surgery (CRC). METHODS: The subjects of this study were 43 patients who underwent surgery for CRC. Peripheral blood samples were collected preoperatively and immediately after surgery, and on postoperative days (PODs) 1, 3, 5, and 7. Patients were divided into a No-POC group (n = 33) and a POC group (n = 10). Blood LPC, IL-6, PC, and ATX levels were measured by specific enzymatic assays or ELISA. RESULTS: The postoperative to preoperative LPC ratios were lowest on POD 1 in both groups. The POC group had significantly lower LPC ratios throughout the perioperative period than the No-POC group. The LPC ratios were inversely correlated with IL-6. The predictive impact of LPC ratios on POCs was demonstrated by ROC analysis (cut-off 51.2%, AUC 0.798) and multivariate analysis (OR 15.1, P = 0.01). The postoperative PC ratios decreased more after surgery in the POC group. ATX levels did not change significantly in either group. CONCLUSIONS: Decreased postoperative LPC is associated with increased postoperative inflammatory response and POCs. The decreased PC supply to the circulation is a mechanism of the postoperative LPC decrease.

Prognostic Significance of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Oncologic Outcomes of Esophageal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to predict oncologic outcomes in patients with various types of cancer. However, their prognostic value in patients with esophageal cancer is unclear. In this meta-analysis, we evaluated the prognostic significance of NLR and PLR in esophageal cancer patients. METHODS: We performed comprehensive searches of electronic databases to identify studies that evaluated the prognostic impact of pretreatment NLR and PLR in esophageal cancer patients. The end points were overall survival (OS), disease-free survival, and clinicopathologic parameters. A meta-analysis using random-effects models was performed to calculate hazard ratios (HRs) or odds ratios with 95 % confidence intervals (CIs). RESULTS: Seven retrospective, observational, cohort studies involving 1540 patients were included. All seven studies evaluated NLR, and four evaluated PLR. Both high NLR (HR 1.40, 95 % CI 1.08-1.81, P = 0.01) and high PLR (HR 1.59, 95 % CI 1.14-2.21, P = 0.006) were significantly predictive of poorer OS. NLR was not a significant predictor of disease-free survival. High PLR (HR 1.85, 95 % CI 1.50-2.28, P < 0.00001) but not NLR was significantly predictive of poorer OS in a subgroup of patients who underwent curative surgery without neoadjuvant chemoradiation. Both high NLR and high PLR were significantly associated with deeper tumor invasion and lymph node metastasis. CONCLUSIONS: NLR and PLR are associated with tumor progression and are predictive of poorer survival in patients with esophageal cancer. These ratios may thus help to inform treatment decisions and predict treatment outcomes.

Impact of Neoadjuvant Chemoradiation on Short-Term Outcomes for Esophageal Squamous Cell Carcinoma Patients: A Meta-analysis.

BACKGROUND: Neoadjuvant chemoradiation (NCRT) has emerged as a component of the standard treatment for esophageal squamous cell carcinoma (SCC). The primary benefit of NCRT is an improvement in long-term survival; however, the impact of NCRT on short-term outcomes is unclear. METHODS: A comprehensive electronic literature search was performed via the MEDLINE (PubMed), Cochrane Library, and Google Scholar databases through November 2015 for the inclusion of randomized controlled trials (RCTs) that evaluated short-term outcomes of patients administered NCRT followed by surgery compared with surgery alone for resectable esophageal SCC. The main outcome measures were postoperative mortality and morbidity. A meta-analysis was performed using random-effects models to calculate odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: Eight RCTs were included, for a total of 1058 patients. Meta-analysis of the overall postoperative mortality and cardiopulmonary complication rates showed that there was a significant increase for patients administered NCRT followed by surgery compared with surgery alone (OR 1.87, 95 % CI 1.07-3.28, p = 0.03, number of patients needed to harm = 33.3; and OR 2.12, 95 % CI 1.03-4.35, p = 0.04, respectively). Dropout before surgery was higher for patients in the NCRT followed by surgery group compared with patients in the surgery-alone group. NCRT has no statistically impact on anastomosis and other complications compared with surgery alone. CONCLUSIONS: NCRT for esophageal SCC significantly increases postoperative mortality and cardiopulmonary complications.

Comparison between metallic stent and transanal decompression tube for malignant large-bowel obstruction.

BACKGROUND: The short-term safety and efficacy of a self-expandable metallic colonic stent (SEMS) insertion followed by elective surgery, "bridge to surgery (BTS)", for malignant large-bowel obstruction (MLBO) have been well described comparing with emergency surgery. The aim of this study was to compare short-term outcomes of endoscopic decompression using a SEMS versus a transanal decompression tube (TDT). MATERIALS AND METHODS: From January 2005 to November 2014, a total of 101 patients with MLBO underwent surgery at our single institution were retrospectively identified. Among them, 73 patients who underwent preoperative complete insertion of a decompression device (TDT, n = 45; SEMS, n = 28) were finally included in this study. Six patients with incomplete insertion of a decompression device (TDT, n = 5; SEMS, n = 1) were also excluded. The primary endpoints of this study were the postoperative morbidity and mortality rates. The secondary endpoints were decompression-related outcomes. Additionally, propensity score matched (PSM) analysis was conducted in short-term outcomes between the groups. RESULTS: The SEMS group had significantly higher proportion of right-sided tumor and bigger tumor size compared with those of the TDT group. The SEMS group had a significantly higher proportion of patients who underwent laparoscopic surgery, and consequently, a longer surgical duration than did the TDT group. Higher rates of insertion failure and perforation were recognized in the TDT group than in the SEMS group (10.0% versus 3.6% and 8.9% versus 0.0%, respectively), although these differences were not statistically significant (P = 0.406 and 0.291, respectively). The two groups showed similar occurrences of anastomotic leakage, bowel obstruction, overall complications, and mortality. Compared with the TDT group, the SEMS group had a significantly lower rate of surgical site infection (24.4% versus 3.6%, respectively; P = 0.023 and P = 0.025 after PSM) and a shorter length of hospital stay (median, 21 d [interquartile range, 18-29 d] versus 38 d [interquartile range, 28-45 d], respectively; P = 0.015 and P = 0.003 after PSM). Solid food intake after decompression and preoperative temporary discharge occurred only in the SEMS group. CONCLUSIONS: Preoperative SEMS insertion for MLBO is effective with at least equivalent short-term outcomes and superior preoperative quality of life compared with decompression using TDT.

Isoperistaltic versus antiperistaltic stapled side-to-side anastomosis for colon cancer surgery: a randomized controlled trial.

BACKGROUND: Isoperistaltic stapled side-to-side anastomosis (SSSA), which is a modified technique from conventional antiperistaltic SSSA, has the benefits of antiperistaltic SSSA but requires less intestinal mobility. The aim of this randomized controlled trial was to evaluate short-term outcomes of isoperistaltic SSSA comparing them with antiperistaltic SSSA during colon cancer surgery. MATERIALS AND METHODS: We conducted a randomized controlled trial of patients with colon cancer who underwent elective curative resection and had enough intestinal mobility at anastomosis. The primary outcome was the presence of anastomotic failure, including leakage, hemorrhage, and stenosis. RESULTS: Between July 2012 and January 2014, forty patients were enrolled (20 patients in each group). The study was suspended on detecting excess morbidity in the isoperistaltic SSSA group. No significant differences were observed in all preoperative backgrounds between the two groups. Anastomotic leakage was seen in two patients in the isoperistaltic SSSA group, compared with none in the antiperistaltic SSSA group, although the difference was not statistically significant (P = 0.487). One patient in the antiperistaltic SSSA group had anastomotic stenosis, which improved conservatively, compared with none in the isoperistaltic SSSA group (P = 1.000). No anastomotic hemorrhage was seen in either group. There was no significant difference in the median postoperative hospital stay (P = 0.313). CONCLUSIONS: This study did not show any short-term advantage or disadvantage of isoperistaltic SSSA compared with that of antiperistaltic SSSA. However, considering that anastomotic leakage occurred only in the isoperistaltic SSSA group, additional modifications are recommended to perform safe isoperistaltic SSSA for colon surgery.

Protective effects of a nicotinamide derivative, isonicotinamide, against streptozotocin-induced ß-cell damage and diabetes in mice.

OBJECTIVE: Nicotinamide rescues ß-cell damage and diabetes in rodents, but a large-scale clinical trial failed to show the benefit of nicotinamide in the prevention of type 1 diabetes. Recent studies have shown that Sirt1 deacetylase, a putative protector of ß-cells, is inhibited by nicotinamide. We investigated the effects of isonicotinamide, which is a derivative of nicotinamide and does not inhibit Sirt1, on streptozotocin (STZ)-induced diabetes in mice. RESEARCH DESIGN AND METHODS: Male C57BL/6 mice were administered with three different doses of STZ (65, 75, and 100 mg/kg BW) alone or in combination with subsequent high-fat feeding. The mice were treated with isonicotinamide (250 mg/kg BW/day) or phosphate-buffered saline for 10 days. The effects of isonicotinamide on STZ-induced diabetes were assessed by blood glucose levels, glucose tolerance test, and immunohistochemistry. RESULTS: Isonicotinamide effectively prevented hyperglycemia induced by higher doses of STZ (75 and 100mg/kg BW) alone and low-dose STZ (65 mg/kg BW) followed by 6-week high-fat diet in mice. The protective effects of isonicotinamide were associated with decreased apoptosis of ß-cells and reductions in both insulin content and insulin-positive area in the pancreas of STZ-administered mice. In addition, isonicotinamide inhibited STZ-induced apoptosis in cultured isolated islets. CONCLUSIONS: These data clearly demonstrate that isonicotinamide exerts anti-diabetogenic effects by preventing ß-cell damage after STZ administration. These findings warrant further investigations on the protective effects of isonicotinamide and related compounds against ß-cell damage in diabetes.

A Study on Points of Respiratory Assist Devices Using in Pre-Hospital Care Respiratory Assist Devices in Pre-Hospital Care.

BACKGROUND: In Japan, increasing the number of ambulance requests, the case with the use of respiratory assistance devices in prehospital care by paramedics is also increasing1. When patient experiences respiratory failure, the first responders frequently select a respiratory assist device (RAD) such as Bag Valve Mask (BVM), Jackson Rees (JR), or BVM with Gas Supply Valve® (BVM+GSV). This is based on both evaluation and experience as there is no study indicating which RAD is the best choice at the pre-hospital emergency site. This study clarified the precautions when using BVM, JR, and BVM+GSV in pre-hospital emergency medical care with healthy volunteers. METHODS: Twenty healthy adults were fitted with a RAD while breathing spontaneously, and changes in vital signs and ETCO2 were observed. RESULTS: The level of ETCO2 became elevated after each RAD was attached. The value was significantly higher in the JR group than in the others. CONCLUSIONS: The study showed that even in the presence of spontaneous breathing, ETCO2 increased markedly with the application of respiratory assist devices that are used in pre-hospital care for conditions such as hypoxemia and ventilatory disturbance. The increase in ETCO2 was particularly significant in the JR group, suggesting the need for caution when selecting JRs for pre-hospital care. As the number of subjects was only 20 for each RAD, studies with a larger sample size are needed.

Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice.

Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, plays an important role in obesity-induced insulin resistance. Inhibition of iNOS by gene disruption or pharmacological inhibitors reverses or ameliorates obesity-induced insulin resistance in skeletal muscle and liver in mice. It is unknown, however, whether increased expression of iNOS is sufficient to cause insulin resistance in vivo. To address this issue, we generated liver-specific iNOS transgenic (L-iNOS-Tg) mice, where expression of the transgene, iNOS, is regulated under mouse albumin promoter. L-iNOS-Tg mice exhibited mild hyperglycemia, hyperinsulinemia, insulin resistance, and impaired insulin-induced suppression of hepatic glucose output, as compared with wild type (WT) littermates. Insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) and -2, and Akt was significantly attenuated in liver, but not in skeletal muscle, of L-iNOS-Tg mice relative to WT mice without changes in insulin receptor phosphorylation. Moreover, liver-specific iNOS expression abrogated insulin-stimulated phosphorylation of glycogen synthase kinase-3ß, forkhead box O1, and mTOR (mammalian target of rapamycin), endogenous substrates of Akt, along with increased S-nitrosylation of Akt relative to WT mice. However, the expression of insulin receptor, IRS-1, IRS-2, Akt, glycogen synthase kinase-3ß, forkhead box O1, protein-tyrosine phosphatase-1B, PTEN (phosphatase and tensin homolog), and p85 phosphatidylinositol 3-kinase was not altered by iNOS transgene. Hyperglycemia was associated with elevated glycogen phosphorylase activity and decreased glycogen synthase activity in the liver of L-iNOS-Tg mice, whereas phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and proliferator-activated receptor γ coactivator-1α expression were not altered. These results clearly indicate that selective expression of iNOS in liver causes hepatic insulin resistance along with deranged insulin signaling, leading to hyperglycemia and hyperinsulinemia. Our data highlight a critical role for iNOS in the development of hepatic insulin resistance and hyperglycemia.

Evaluation of outcomes after EMS-witnessed traumatic out-of-hospital cardiac arrest caused by traffic collisions.

AIM: The survival rate of patients with traumatic cardiac arrest is 3% or lower. Cardiac arrest witnessed by emergency medical services (EMS) accounts for approximately 16% of prehospital traumatic cardiac arrests, but the prognosis is unknown. We aimed to compare the 1-month survival rate of cardiac arrest witnessed by EMS with that of cardiac arrest witnessed by bystanders and unwitnessed cardiac arrest in traffic trauma victims; further, the time from injury to cardiac arrest was assessed. METHODS: This analysis used the Utstein Registry in Japan and included data of 3883 patients with traumatic cardiac arrest caused by traffic collisions registered between 2014 and 2019 in Japan. RESULTS: The 1-month survival rate was 10.9% in the EMS-witnessed cardiac arrest group; this was significantly higher than that in the bystander-witnessed (7.2%) and unwitnessed (5.6%) cardiac arrest groups (P < 0.01). The median time from injury to cardiac arrest was 18 min (25% quartile: 12, 75% quartile: 26). CONCLUSION: The 1-month survival rate was significantly higher in the EMS-witnessed cardiac arrest group than in the bystander-witnessed and unwitnessed cardiac arrest groups. It is important to prevent progression to cardiac arrest in trauma patients with intact respiratory function and pulse rate at the time of contact with EMS. A system for early recognition of severe trauma is needed, and a doctor's car or helicopter can be requested as needed. We believe that early recognition and prompt intervention will improve the prognosis of prehospital traumatic cardiac arrest.

Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance.

Treatment with statins, inhibitors of HMG-CoA reductase, extends the survival of septic mice. However, the molecular mechanisms underlying the cholesterol-lowering, independent beneficial effects of statins in sepsis are poorly understood. The inhibition of protein isoprenylation, namely farnesylation and geranylgeranylation, has been proposed as a mediator of the pleiotropic protective effects of statins, although direct evidence is lacking. Major features of sepsis-induced immune suppression include T-cell dysfunction, which is characterized by apoptosis of splenic T cells, increased CD4(+)Foxp3(+) regulatory T cells (Tregs), and suppression of type 1 helper T-cell response [e.g., interferon-γ (IFN-γ) secretion] in mice. Here, we show that the induction of sepsis by cecal ligation and puncture (CLP) resulted in increases in farnesyltransferase activity and farnesylated proteins in the spleen relative to sham operation. Treatment with farnesyltransferase inhibitor N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) (25 mg/kg b.wt. i.p.) at 2 h after CLP blocked the increase in farnesylated proteins and improved survival and bacterial clearance of septic mice. FTI-277 reverted to or mitigated sepsis-induced apoptosis in spleen and thymus, increased splenic CD4(+)Foxp3(+) Tregs, and suppressed IFN-γ secretion and proliferation of splenocytes in response to anti-CD3+CD28 antibodies in mice. Moreover, FTI-277 promoted macrophage phagocytotic activity in septic mice. These results indicate that elevation in protein farnesylation plays a role in derangements in immune function and mortality of septic mice. These findings suggest that prevention of immune dysfunction might contribute to FTI-277-induced improvement in survival of septic mice. These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis.

Functional Capacity Index: cultural adaptation and measurement of validity and reliability.

OBJECTIVE: To carry out a cultural adaptation of the Functional Capacity Index (FCI) into Portuguese and to verify its reliability and validity in traffic accident victims. METHOD: Methodological study for cultural adaptation of the FCI. Reliability and validity were verified in a convenience sample of traffic accident victims, in São Paulo city. Data from the patient's medical record were collected retrospectively in 2015. Reliability verified by Cronbach's alpha coefficient and validity by Spearman's correlation and Mann-Whitney test. RESULTS: The FCI in Portuguese was applied to 50 traffic accident victims. The internal consistency reached Cronbach's alpha values >0.70. The FCI correlated with the Katz index, did not correlate with the severity of trauma and the FCI of trauma patients was higher compared to those without trauma. CONCLUSION: The FCI in Portuguese showed satisfactory internal consistency, allowing the measurement of functional capacity, discriminating against people with and without traumatic injuries.

Breast Cancer Detection from a Urine Sample by Dog Sniffing: A Preliminary Study for the Development of a New Screening Device, and a Literature Review.

BACKGROUND: Breast cancer is a leading cause of cancer death worldwide. Several studies have demonstrated that dogs can sniff and detect cancer in the breath or urine sample of a patient. This study aims to assess whether the urine sample can be used for breast cancer screening by its fingerprints of volatile organic compounds using a single trained sniffer dog. This is a preliminary study for developing the "electronic nose" for cancer screening. METHODS: A nine-year-old female Labrador Retriever was trained to identify cancer from urine samples of breast cancer patients. Urine samples from patients histologically diagnosed with primary breast cancer, those with non-breast malignant diseases, and healthy volunteers were obtained, and a double-blind test was performed. Total of 40 patients with breast cancer, 142 patients with non-breast malignant diseases, and 18 healthy volunteers were enrolled, and their urine samples were collected. RESULTS: In 40 times out of 40 runs of a double-blind test, the trained dog could correctly identify urine samples of breast cancer patients. Sensitivity and specificity of this breast cancer detection method using dog sniffing were both 100%. CONCLUSIONS: The trained dog in this study could accurately detect breast cancer from urine samples of breast cancer patients. These results indicate the feasibility of a method to detect breast cancer from urine samples using dog sniffing in the diagnosis of breast cancer. Although the methodological standardization is still an issue to be discussed, the current result warrants further study for developing a new breast cancer screening method based on volatile organic compounds in urine samples.

A prediction model using 2-propanol and 2-butanone in urine distinguishes breast cancer.

Safe and noninvasive methods for breast cancer screening with improved accuracy are urgently needed. Volatile organic compounds (VOCs) in biological samples such as breath and blood have been investigated as noninvasive novel markers of cancer. We investigated volatile organic compounds in urine to assess their potential for the detection of breast cancer. One hundred and ten women with biopsy-proven breast cancer and 177 healthy volunteers were enrolled. The subjects were divided into two groups: a training set and an external validation set. Urine samples were collected and analyzed by gas chromatography and mass spectrometry. A predictive model was constructed by multivariate analysis, and the sensitivity and specificity of the model were confirmed using both a training set and an external set with reproducibility tests. The training set included 60 breast cancer patients (age 34-88 years, mean 60.3) and 60 healthy controls (age 34-81 years, mean 58.7). The external validation set included 50 breast cancer patients (age 35-85 years, mean 58.8) and 117 healthy controls (age 18-84 years, mean 51.2). One hundred and ninety-one compounds detected in at least 80% of the samples from the training set were used for further analysis. The predictive model that best-detected breast cancer at various clinical stages was constructed using a combination of two of the compounds, 2-propanol and 2-butanone. The sensitivity and specificity in the training set were 93.3% and 83.3%, respectively. Triplicated reproducibility tests were performed by randomly choosing ten samples from each group, and the results showed a matching rate of 100% for the breast cancer patient group and 90% for the healthy control group. Our prediction model using two VOCs is a useful complement to the current diagnostic tools. Further studies inclusive of benign tumors and non-breast malignancies are warranted.

Rare complication of hepatocellular carcinoma in Wilson's disease.

The complication of hepatocellular carcinoma (HCC) in Wilson's disease is rare. Wilson's disease treatment using D-penicillamine (DPA) is useful to prevent HCC occurrence; however, it also causes iron accumulation and synergistic radical formation in the liver, which may enhance carcinogenesis. Reported herein is a case of HCC in Wilson's disease treated with DPA for 36 years. The tumor was surgically resected and histologically diagnosed with moderately differentiated HCC surrounded by cirrhotic tissue with fatty infiltration. Rhodanine staining revealed a slight positively stained area in both tumor and surrounding tissues. Information obtained from this case and literature review highlight the feature of HCC in Wilson's disease.

Wearing a face mask during controlled-intensity exercise is not a risk factor for exertional heatstroke: A pilot study.

AIM: This study aimed to measure the influence of wearing face masks on individuals' physical status in a hot and humid environment. METHODS: Each participant experienced different physical situations: (i) not wearing a mask (control), (ii) wearing a surgical mask, (iii) wearing a sport mask. An ingestible capsule thermometer was used to measure internal core body temperature during different exercises (standing, walking, and running, each for 20 min) in an artificial weather room with the internal wet-bulb globe temperature set at 28°C. The change in the participants' physical status and urinary liver fatty acid-binding protein (L-FABP) were measured. RESULTS: Six healthy male volunteers were enrolled in the study. In each participant, significant changes were observed in the heart rate and internal core temperatures after increased exercise intensity; however, no significant differences were observed between these parameters and urinary L-FABP among the three intervention groups. CONCLUSION: Mask wearing is not a risk factor for heatstroke during increased exercise intensity.