Anterior resection syndrome: a randomized clinical trial of a 5-HT3 receptor antagonist (ramosetron) in male patients with rectal cancer.

BACKGROUND: No effective treatment exists for anterior resection syndrome (ARS) following sphincter-saving surgery for rectal cancer. This RCT assessed the safety and efficacy of a 5-HT3 receptor antagonist, ramosetron, for ARS. METHODS: A single-centre, randomized, controlled, open-label, parallel group trial was conducted. Male patients with ARS 1 month after rectal cancer surgery or ileostomy reversal were enrolled and randomly assigned (1 : 1) to 5 µg of ramosetron (Irribow®) daily or conservative treatment for 4 weeks. Low ARS (LARS) score was calculated after randomization and 4 weeks after treatment. The study was designed as a superiority test with a primary endpoint of the proportion of patients with major LARS between the groups. Primary outcome analysis was based on the modified intention-to-treat population. Safety was assessed by monitoring adverse events during the study. RESULTS: : A total of 100 patients were randomized to the ramosetron (49 patients) or conservative treatment group (51 patients). Two patients were excluded, and 48 and 50 patients were analysed in the ramosetron and control groups, respectively. The proportion of major LARS after 4 weeks was 58 per cent (28 of 48 patients) in the ramosetron group versus 82 per cent (41 of 50 patients) in the control group, with a difference of 23.7 per cent (95 per cent c.i. 5.58 to 39.98, P = 0.011). There were minor adverse events in five patients, which were hard stool, frequent stool or anal pain. These were not different between the two groups. There were no serious adverse events. CONCLUSION: : Ramosetron could be safe and feasible for male patients with ARS. TRIAL REGISTRATION NUMBER: NCT02869984 (http://www.clinicaltrials.gov).

Radiomics-based model for predicting pathological complete response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

AIM: To develop and validate a radiomics-based model for predicting response to neoadjuvant chemotherapy (NAC) using baseline computed tomography (CT) images in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: A radiomics signature for predicting pathological complete response (pCR) was developed using radiomics features selected by a random forest classifier on baseline CT images, and imaging predictors were identified in the training set (87 patients). By incorporating imaging predictors and radiomics signature, an imaging-based model was constructed using multivariate logistic regression analysis and validated in an independent validation set consisting of 48 patients with CT from outside institutions. The performance and clinical usefulness of the imaging-based model for predicting pCR were evaluated using area under the receiver operating characteristic curve (AUC) and decision curve analysis. Using a cut-off determined in the training set, the positive likelihood ratios of the imaging-based model were calculated and compared with imaging and histological predictors. RESULTS: The radiomics signature was developed based on six stable radiomics features. An imaging-based model incorporating radiomics signature, tumour shape, tumour size, and clinical stage showed good performance for predicting pCR in both the training (AUC, 0.85; 95% confidence interval [CI], 0.78-0.93) and validation (AUC, 0.75; 95% CI, 0.60-0.86) sets, providing a larger net benefit in decision curve analysis. The imaging-based model showed a higher positive likelihood ratio (1.91) for pCR than imaging and histological predictors (1.33-1.63). CONCLUSIONS: The radiomics-based model using baseline CT images may predict the response of patients with MIBC to NAC.

Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression.

AIMS: Aggressive meningioma remains incurable with neither chemo- nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression. METHODS: Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression-free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked-down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM-Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)-pretreated or control IOMM-Lee cells were implanted subcutaneously in nude mice. RESULTS: FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of ß-catenin, cyclin D1, p21, interleukin-8, vascular endothelial growth factor-A, PLAU, and epithelial-to-mesenchymal transition-related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model. CONCLUSIONS: Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.

Predictors of permanent stoma creation in patients with mid or low rectal cancer: results of a multicentre cohort study with preoperative evaluation of anal function.

AIM: Preoperative factors predictive of permanent stoma creation were investigated in a long-term follow-up of patients with mid or low rectal cancer. METHOD: We included patients who underwent radical resection for mid or low rectal cancer with available data for preoperative anal function measured by manometry and Faecal Incontinence Severity Index questionnaire between January 2005 and December 2015 in three tertiary referral hospitals. A permanent stoma was defined as a stoma present until the patient's last follow-up visit or death. Preoperative factors that predicted permanent stoma creation were analysed. RESULTS: Over a median follow-up of 57.4 months (range 12-143 months), a permanent stoma was created in 144/577 (25.0%) patients, including 89 (15.4%) who underwent abdominoperineal resection, one (0.2%) who underwent Hartmann's operation without reversal, 15 (2.6%) with a diverting ileostomy at the time of initial sphincter-preserving surgery without undergoing stoma reversal, and 39 (6.8%) who underwent permanent ileostomy formation after sphincter-preserving surgery. Patients with permanent stoma creation had a shorter tumour distance from the anal verge (P < 0.001), larger tumour size (P = 0.020) and higher preoperative Faecal Incontinence Severity Index score (P = 0.020). On multivariable analysis, tumour distance from the anal verge predicted permanent stoma formation (relative risk 0.53 per centimetre increase; 95% confidence interval 0.46-0.60; P < 0.001) but preoperative anal function did not. CONCLUSION: Tumour distance from the anal verge was the only preoperative determinant of permanent stoma creation in rectal cancer patients. These data may help mid and low rectal cancer patients understand the need for permanent stoma.

Stromal invasion pattern identifies patients at lowest risk of lymph node metastasis in HPV-associated endocervical adenocarcinomas, but is irrelevant in adenocarcinomas unassociated with HPV.

OBJECTIVE: The Silva invasion pattern-based classification system stratifies endocervical adenocarcinomas (ECAs) into 3 categories corresponding to risk of metastasis and recurrence, but has only been evaluated for HPV-associated ECAs of usual type. We examined whether the Silva system is applicable to all endocervical adenocarcinomas, especially those not associated with HPV. METHODS: Complete slide sets from 341 surgical specimens of ECA were collected from 7 institutions worldwide. All specimens were associated with clinical records covering at least 5 years of follow-up. Tumors were classified as HPV-associated (HPVA) or not (NHPVA) by both morphology and detection of HPV using in situ hybridization. Recurrence and survival were analyzed by multivariate Mantel-Haenszel methods. RESULTS: Most specimens (292; 85.6%) were HPVA, while 49 (14.3%) were NHPVA. All NHPVAs were Silva pattern C, while 76.0% of HPVAs were pattern C, 14.7% pattern A, and 9.3% pattern B. Including both HPVAs and NHPVAs, lymphovascular invasion (LVI) was detected in 0% of pattern A, 18.5% of pattern B and 62.6% of pattern C cases (p < 0.001). None of the pattern A or B cases were associated with lymph node metastases (LNM), in contrast to pattern C cases (21.8%). Among patients with Silva pattern C ECA, those with HPVA tumors had a lower recurrence rate and better survival than those with NHPVA; however, when adjusted for stage at diagnosis, the difference in recurrence and mortality was small and not statistically significant. CONCLUSIONS: Application of the Silva system is only relevant in HPVA cervical adenocarcinoma.

The advantage of digital tomosynthesis for pulmonary nodule detection concerning influence of nodule location and size: a phantom study.

AIM: To investigate the advantage of digital tomosynthesis (DTS) over chest radiography (CXR) and dual-energy subtraction radiography (DES) for pulmonary nodule detection according to the location and size of solid simulated pulmonary nodules (SPNs). MATERIALS AND METHODS: Ninety-six SPNs of variable sizes were inserted into eight different regions of a lung phantom. These regions were further classified into two groups of danger and non-danger zones based on anatomical location influencing the detection of pulmonary nodules. The 96 cases with inserted SPNs and an additional nodule-free 96 control cases all underwent CXR, DES, and DTS examinations. Three observers independently reviewed all the images. The jackknife alternative free-response receiver operating characteristic was used to analyse diagnostic performance for each technique. RESULTS: DTS was superior to CXR and DES for detection of smaller SPNs, except in the retrodiaphragmatic and apical regions. DTS outperformed CXR and DES for detection of larger SPNs in the paramediastinal region. For 5- and 8-mm SPNs, DTS was superior to CXR and DES in the apical, paramediastinal and lateral pulmonary regions. In the retrodiaphragmatic region, the three techniques showed similar diagnostic performance regardless of the SPN size. DES was similar to DTS for detection of 8-mm SPN in the apical region. For 10- and 12-mm SPNs, CXR and DES showed similar diagnostic performance to DTS in the apical and lateral pulmonary regions; however, DTS was superior to CXR and DES in the paramediastinal region. CONCLUSIONS: DTS significantly improved the capability to detect synthetic pulmonary nodules compared with CXR and DES, for detection of smaller nodules in the apical, paramediastinal, and lateral pulmonary regions, and larger nodules located in the paramediastinal region in a thoracic phantom.

Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn's disease: a phase II clinical trial for safety and efficacy.

PURPOSE: Injection of adipose tissue-derived stem cells (ASCs) is a novel method for the treatment of complex perianal fistulas. We aimed to evaluate the safety and efficacy of ASCs in the treatment of complex anal fistulas not associated with Crohn's disease. METHODS: A phase II clinical trial was performed comparing two different doses of ASCs (group 1: 1 × 107 cells/mL and group 2: 2 × 107 cells/mL). Eligible patients were administered an amount of ASCs proportional to the length of the fistula by injection into the submucosal layer surrounding the internal opening and inside of the fistula tract. ASCs at twice the initial concentration were administered if complete closure was not achieved within 8 weeks. The efficacy endpoint was the complete closure of fistulas 8 weeks after injection. Patients demonstrating complete closure at week 8 were subjected to follow-up for 6 months. RESULTS: Fifteen patients were injected with ASCs; thirteen completed the study. Complete closure was observed in 69.2% (9/13) of patients at 8 weeks. Three of five patients in group 1, and six of eight in group 2 displayed complete closure; no significant differences were observed between the groups. Six of nine patients who showed complete closure participated in additional follow-up; five (83.3%) showed persistent response at 6 months. No grade 3 or 4 adverse events (AEs) were observed; observed AEs were not related to ASC treatment. CONCLUSION: ASCs might be a good option for the treatment of complex perianal fistulas are not healed by conventional operative procedures.

Allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn's disease: a pilot clinical trial.

AIM: Many perianal fistulae in Crohn's disease do not respond to conventional surgical and medical management and recurrence rates are high. The study evaluated the safety and feasibility of allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn's disease. METHOD: A multicentre, open-label, dose escalation pilot study was performed. The first three patients (group 1) were administered 1 × 10(7) cells/ml based on the size of the fistula tract. Four weeks later, after which time this dose had been confirmed to be safe, the next three patients (group 2) were administered 3 × 10(7) cells/ml. The end-point was complete closure at 8 weeks after the injection. Patients who attended for the 8 week assessment were followed for an additional 6 months. RESULTS: There were no adverse events of Grade 3 or 4 severity and no adverse events related to the treatment with allogeneic adipose-derived stem cells. Two patients in group 1 achieved complete closure of the fistula at month 4 and month 6, and one patient in group 2 achieved complete closure at 8 weeks. The closure was sustained up to month 8 in all three of those patients. CONCLUSION: These data suggest that allogeneic adipose-derived stem cells may be a feasible treatment option for perianal fistula in Crohn's disease.

Methyl jasmonate inhibits lipopolysaccharide-induced inflammatory cytokine production via mitogen-activated protein kinase and nuclear factor-κB pathways in RAW 264.7 cells.

Methyl jasmonate is an important signaling molecule involved in plant defense as well as in the regulation of plant growth and development. Despite its various functions in plants, its effects on animal cells have not been widely studied and no report has been issued on the molecular aspects of its anti-inflammatory effect. In the present study, we investigated the in vitro anti-inflammatory properties of methyl jasmonate in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Methyl jasmonate treatment effectively inhibited LPS-induced production of pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6) in a concentration-dependent manner. Furthermore, it attenuated the LPS-induced activation of nuclear factor-κB (NF-κB) by suppressing the degradation of the inhibitor of κB-α (IκB-α). Additionally, methyl jasmonate dose-dependently blocked the phosphorylation of mitogen-activated protein kinases (MAPKs), i.e., p38 kinase, extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK), in these cells. These results suggest that methyl jasmonate attenuated the LPS-induced release of pro-inflammatory mediators and cytokines by suppressing the activation of MAPK (JNK, ERK and p38) and NF-κB signaling. This study not only demonstrated that methyl jasmonate exerts anti-inflammatory activities in macrophages but also revealed its potential as a candidate for the treatment of various inflammation-associated diseases.

Genetic diversity, population structure, and association mapping of agronomic traits in waxy and normal maize inbred lines.

Understanding genetic diversity, population structure, and linkage disequilibrium is a prerequisite for the association mapping of complex traits in a target population. In this study, the genetic diversity and population structure of 40 waxy and 40 normal inbred maize lines were investigated using 10 morphological traits and 200 simple sequence repeat (SSR) markers. Based on a population structure analysis, the 80 maize inbred lines were divided into three groups: I, II, and admixed. Significant marker-trait associations were identified between the markers and the 10 morphological traits, which were studied according to the model used to confirm the association. Using a general linear model, the lowest R(2) value (9.03) was detected in umc1139, which was associated with ear number, and the highest (43.97) was in umc1858, which was associated with plant height. Using a mixed linear model, the lowest R(2) value (18.74) was in umc1279, which was associated with ear weight; the highest (27.66) was in umc1858, which was associated with 100-kernel weight. The SSR markers identified in the present study may serve as useful molecular markers for selecting important yield and agronomic traits. These results will be useful for marker-assisted selection in maize breeding programs, to help breeders choose parental lines and markers for crosses.

Comparison between a new electronic bidet and conventional sitz baths: a manometric evaluation of the anal resting pressure in normal healthy volunteers.

BACKGROUND: A bidet has been proposed as a replacement for the sitz bath. Like a sitz bath, it brings water into contact with the perineum. However, the high force of water from commercially used electronic bidets may harm the anus. We developed a new electronic bidet and evaluated its effects on anal resting pressure compared with a warm sitz bath. METHODS: Forty volunteers used the electronic bidet and sitz bath on separate days. The electronic bidet was newly designed with warm (38 °C) water and very low force (10 mN) with a fountain type of flow. Anal resting pressure at the high-pressure zone was measured before (control) and after the electronic bidet and sitz bath. Pressure changes after bidet or sitz bath were expressed as percentages compared with control. Water temperatures and rectal temperatures were also recorded. RESULTS: The anal resting pressures before the electronic bidet and sitz bath were 90.2 ± 24.6 and 88.1 ± 16.8 mmHg, respectively. At 3 min after the electronic bidet and sitz bath, the anal resting pressures were 71.3 ± 23.4 and 69.6 ± 19.8 mmHg, respectively. The pressure changes compared with the control were 78.2 ± 12.9 and 78.1 ± 12.5%, respectively, which were not significantly different. The maximal increase and minimal decrease were not significantly different. The rectal temperature was not elevated, and the water temperature decreased significantly with the sitz bath (p < 0.001). CONCLUSIONS: Our new electronic bidet may reduce the anal resting pressure much like a warm sitz bath does.

Use of permanent marker to deposit a protection layer against FIB damage in TEM specimen preparation.

Permanent marker deposition (PMD), which creates permanent writing on an object with a permanent marker, was investigated as a method to deposit a protection layer against focused ion beam damage. PMD is a simple, fast and cheap process. Further, PMD is excellent in filling in narrow and deep trenches, enabling damage-free observation of high aspect ratio structures with atomic resolution in transmission electron microscopy (TEM). The microstructure, composition, gap filling ability and planarization of the PMD layer were studied using dual beam focused ion beam, transmission electron microscopy, energy dispersive X-ray spectroscopy and electron energy loss spectroscopy. It was found that a PMD layer is basically an amorphous carbon structure, and that such a layer should be at least 65 nm thick to protect a surface against 30 keV focused ion beam damage. We suggest that such a PMD layer can be an excellent protection layer to maintain a pristine sample structure against focused ion beam damage during transmission electron microscopy specimen preparation.

The appearance of dextranomer-hyaluronic acid copolymer implants on ultrasound may predict resolution of vesicoureteral reflux after injection therapy.

AIM: To investigate the correlation between implant appearance on ultrasound (US) and voiding cystourethrography (VCUG) results after dextranomer-hyaluronic acid copolymer (DxHA) injection in children with vesicoureteral reflux (VUR). MATERIALS AND METHODS: Consecutive cases of primary VUR treated by endoscopic subureteral injection of DxHA were retrospectively reviewed. All children had postoperative bladder US and VCUG with a mean interval of 34 days and 47 days after injection, respectively. VUR resolution at postoperative VCUG was considered as treatment success. Implant appearance on US was graded according to the retained volume and its location by visual inspection; it was then correlated with VCUG results using the Spearman correlation coefficient. RESULTS: A total of 36 children (56 ureters) were identified in which 38 ureters (68%) had a clearly visualized implant on postoperative US and 40 ureters (71%) showed VUR resolution. The sensitivity of implant visualization on US for predicting reflux resolution was 73% (29/40), specificity 44% (7/16), positive predictive value 76% (29/38), and negative predictive value 39% (7/18). The grade 1, grade 2, and grade 3 implant appearances showed VUR resolution in 88% (22/25), 54% (7/13), and 61% (11/18), and showed persistent VUR in 8% (2/25), 15% (2/13), and 28% (5/18), respectively (p = 0.032). CONCLUSION: The implant appearance on postoperative US showed good correlation with VCUG results in the early post-injection period. Large retained implants were associated with treatment success, while small or non-visualized implants were related to the persistent reflux.

The beneficial effect of palliative resection in metastatic colorectal cancer.

BACKGROUND: We aimed to determine the role of palliative resection in metastatic colorectal cancer (mCRC) and ascertain which patient populations would benefit most from this treatment. METHODS: A total of 1015 patients diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009 were retrospectively studied. RESULTS: Of the 1015 patients, 168 patients with only liver and/or lung metastasis received curative resection. The remaining 847 patients were treated with palliative chemotherapy and/or palliative resection combined with best supportive care. Palliative resection was performed in 527 (62.2%) cases (complete resection with negative margin (R0) in 93, R1/2 in 434). Resected patients had a more prolonged median overall survival (OS) than unresected patients (21.3 vs 14.1 months; P<0.001). In multivariate analysis, R0 resection was found to be associated with a superior OS compared with R1/2 resection (51.3 vs 19.1 months; P<0.001) and no resection (51.3 vs 14.1 months; P<0.001). When we performed propensity score matching, palliative resection was found to be related to prolonged OS (hazard ratio=0.72, 95% confidence interval=0.59-0.89; P=0.003). CONCLUSION: Palliative resection without residual disease and chemotherapy confers a longer-term survival outcome than palliative chemotherapy alone in mCRC patient subset.

Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.

BACKGROUND: There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear. METHODS: Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared. RESULTS: Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76-16.8). CONCLUSION: Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.

The relationship between implant stability quotient values and implant insertion variables: a clinical study.

The aim of this study was to determine whether resonance frequency analysis can be integrated into the routine clinical evaluation of the initial healing of dental implants. In addition, this study was designed to verify whether there was a correlation between implant stability quotient (ISQ) values, maximum insertion torque values, angular momentum and energy, and to evaluate the importance of different clinical factors in the determination of ISQ values and maximum insertion torque values at implant insertion. Two different implant designs of 81 dental implants in 41 patients were evaluated using ISQ values. Maximum insertion torque values were obtained during the placement procedure. Two new methods were used to calculate the angular momentum developed due to implant installation as well as the energy absorbed by the bone. A linear correlation between ISQ values and maximum insertion torque values at the initial implant surgery was found (P < 0·01). There was a correlation between ISQ values and angular momentum (P < 0·05), although ISQ values and energy did not show a significant linear correlation at the initial surgery (P > 0·05). There was a correlation between maximum insertion torque values, each part's angular momentum, and their energies during installation (P < 0·01). The sequence of the variables that influenced ISQ values was implant location, design, diameter, and gender of the patient. The results of this experiment suggest that both ISQ values and new methods to calculate angular momentum and energy can help to predict implant stability.

Putative down-stream signaling molecule of GTPase in Porphyromonas gingivalis.

Porphyromonas gingivalis is a strict anaerobic bacterium mainly responsible for periodontal disease in oral cavity. Putative GTPase gene (pgp) of this bacterium was cloned and its recombinant protein (rPGP) was produced in Escherichia coli. Based on the amino acid sequence of SGP that is a GTP-binding protein of Streptococcus mutans, putative GTPase amino acid sequence was deduced in the data base of genome sequences of Porphyromonas gingivalis. A 900-bp PCR fragment was amplified with P. gingivalis genomic DNA as a template and cloned into E. coli JM 109. Then pgp was transferred into pQE-30 expression vector to make pQE-PGP for production of rPGR. This protein was produced and purified by Ni-NTA affinity column chromatography. Anti-PGP antibody was also produced in Sprague Dawley rats. Using Westernblot analysis with this antibody, it was confirmed that the rPGP produced in E. coli was identical to that of donor strain. Furthermore, by Southernblot analysis it was revealed that the pgp was originated from P. gingivalis. By immunoprecipitation with anti-PGP antibody and N-terminal amino acid sequence analysis it was found that PGP was able to bind to acetate kinase, which was reported to be a secondary signaling-molecule in anaerobic microorganisms. Therefore, these results imply that P. gingivalis produces putative GTPase and this protein might play a potential role in signaling pathway in oral biofilm formation.

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control.

OBJECTIVE: To investigate whether drugs targeting peripheral cannabinoid-1 (CB1) receptor ameliorate adiposity comparable to central CB1-receptor antagonist or not. MEASUREMENTS: Receptor binding assay and functional assay in vitro. Pharmacokinetic parameters in mice, brain uptake clearance of compounds in rats and antagonism on the CB1-agonist-induced hypothermia in mice. Diet consumption, body weight changes, hepatic gene expression of sterol-regulatory element-binding protein-1 (SREBP-1) and plasma/tissue concentrations of compounds in HF diet-induced obese (HF-DIO) mice after acute and chronic treatment. RESULTS: Compound-1, an SR141716A derivative, is a peripheral CB1-receptor-selective antagonist that is 10 times less potent than SR141716A in in vitro evaluations. Although the plasma concentrations of Compound-1 are five times higher than those of SR141716A, its potency is still 10 times lower than that of SR141716A in reducing the consumption of normal or HF diet by mice. Through evaluations of brain uptake and the effect on CB1-agonist-induced hypothermia, it was verified that the blood-brain barrier (BBB) penetration of Compound-1 is much lower than that of SR141716A. In HF-DIO mice, chronic treatment by Compound-1 showed dose-dependent antiobesity activities, while its brain distribution was very low as compared with that of SR141716A. Compound-1's effective doses for antiobesity activity were just over 30 mg kg(-1). However, Compound-1 completely suppressed the elevated hepatic SREBP-1 expression even at 10 mg kg(-1). CONCLUSION: These results suggest that (1) central CB1 receptors mediate anorectic response of CB1-receptor antagonists and (2) peripheral modulations, including SREBP-1 expression, are not major mechanisms in the antiobesity effects of CB1-receptor antagonists.

Prognosis of surgical hernia repair in cirrhotic patients with refractory ascites.

BACKGROUND: Abdominal wall hernias are common in patients with ascites. Elective surgical repair is recommended for the treatment of abdominal wall hernias. However, surgical hernia repair in cirrhotic patients with refractory ascites is controversial. In this study, we aimed to evaluate the outcomes of elective surgical hernia repair in patients with liver cirrhosis with and without refractory ascites. METHOD: From January 2005 to June 2018, we retrospectively reviewed the records of consecutive patients with liver cirrhosis who underwent a surgical hernia repair. RESULTS: This study included 107 patients; 31 patients (29.0%) had refractory ascites. Preoperatively, cirrhotic patients with refractory ascites had a higher median model for end-stage liver disease (MELD) score (13.0 vs 11.0, P = 0.001) than those without refractory ascites. The 30-day mortality rate (3.2% vs 0%, P = 0.64) and the risk of recurrence (hazard ratio 0.410; 95% CI 0.050-3.220; P = 0.39) did not differ significantly between cirrhotic patients with refractory ascites and cirrhotic patients without refractory ascites. Among cirrhotic patients with refractory ascites, albumin (P = 0.23), bilirubin (P = 0.37), creatinine (P = 0.97), and sodium levels (P = 0.35) did not change significantly after surgery. CONCLUSION: In advanced liver cirrhosis patients with refractory ascites, hernias can be safely treated with elective surgical repair. Mortality rate within 30 days did not differ by the presence or absence of refractory ascites. Elective hernia repair might be beneficial for treatment of abdominal wall hernia in cirrhotic patients with refractory ascites.

Airflow limitation as a risk factor for vascular stiffness.

BACKGROUND: Cardiovascular disease is one of the main causes of mortality in patients with chronic obstructive pulmonary disease (COPD), and atherosclerosis is a cause of cardiac comorbidities in COPD. However, it is not clear whether airflow limitation is associated with atherosclerosis irrespective of smoking.OBJECTIVE: To investigate whether airflow limitation is independently associated with vascular stiffness.METHODS: We enrolled 18 893 participants (male 70.5%; mean age 47.5 ± 9.8 years; never smokers 44.2%) who underwent spirometry and brachial-ankle pulse wave velocity (baPWV) as part of a standard health examination at Ajou University Hospital, Suwon, South Korea, from January 2010 to December 2015.We defined vascular peripheral atherosclerosis as baPWV ≥ 1400 cm/s and airflow limitation as pre-bronchodilator ratio of forced expiratory volume in 1 sec (FEV1) to forced vital capacity (FVC) <70%.RESULTS: Mean baPWV was higher in subjects with airflow limitation (1477.6 ± 331.7 cm/sec, n = 638) than in those without airflow limitation (1344.1 ± 231.8 cm/sec, n = 18255, P < 0.001). In multivariate logistic regression analysis, the following were independent predictors associated with peripheral atherosclerosis (P < 0.05): age, male sex, fasting serum glucose, mean blood pressure, serum leukocyte count, serum low density lipoprotein level and FEV1.CONCLUSION: Airflow limitation was an independent predictor of vascular stiffness irrespective of smoking history, which suggests that airflow limitation is linked with atherosclerosis.