Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families.

PURPOSE: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families. METHODS: Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women. RESULTS: We found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward. CONCLUSION: A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance.

Minimal in vitro systems shed light on cell polarity.

Cell polarity - the morphological and functional differentiation of cellular compartments in a directional manner - is required for processes such as orientation of cell division, directed cellular growth and motility. How the interplay of components within the complexity of a cell leads to cell polarity is still heavily debated. In this Review, we focus on one specific aspect of cell polarity: the non-uniform accumulation of proteins on the cell membrane. In cells, this is achieved through reaction-diffusion and/or cytoskeleton-based mechanisms. In reaction-diffusion systems, components are transformed into each other by chemical reactions and are moving through space by diffusion. In cytoskeleton-based processes, cellular components (i.e. proteins) are actively transported by microtubules (MTs) and actin filaments to specific locations in the cell. We examine how minimal systems - in vitro reconstitutions of a particular cellular function with a minimal number of components - are designed, how they contribute to our understanding of cell polarity (i.e. protein accumulation), and how they complement in vivo investigations. We start by discussing the Min protein system from Escherichia coli, which represents a reaction-diffusion system with a well-established minimal system. This is followed by a discussion of MT-based directed transport for cell polarity markers as an example of a cytoskeleton-based mechanism. To conclude, we discuss, as an example, the interplay of reaction-diffusion and cytoskeleton-based mechanisms during polarity establishment in budding yeast.

Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen-activated protein kinase and protein kinase B pathways.

AIM: To identify odontogenesis-promoting compounds and examine the molecular mechanism underlying enhanced odontoblast differentiation and tooth formation. METHODOLOGY: Five different nymphaeols, nymphaeol B (NB), isonymphaeol B (INB), nymphaeol A (NA), 3'-geranyl-naringenin (GN) and nymphaeol C (NC) were isolated from the fruit of Macaranga tanarius. The cytotoxic effect of nymphaeols on human DPSCs was observed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effect of nymphaeols on odontoblast differentiation was analysed with Alizarin Red S staining and odontoblast marker expression was assessed using real-time polymerase chain reaction and Western blot analysis. The molecular mechanism was investigated with Western blot analysis. In order to examine the effect of INB on dentine formation in the developing tooth germ, INB-soaked beads were placed under the tooth bud explants in the collagen gel; thereafter, the tooth bud explant-bead complexes were implanted into the sub-renal capsules for 3 weeks. Tooth root formation was analysed using micro-computed tomography and histological analysis. Data are presented as mean ± standard error (SEM) values of three independent experiments, and results are compared using a two-tailed Student's t-test. The data were considered to have statistical significance when the P-value was less than 0.05. RESULTS: Three of the compounds, NB, INB, and GN, did not exert a cytotoxic effect on human DPSCs. However, INB was most effective in promoting the deposition of calcium minerals in vitro (P < 0.001) and induced the expression of odontogenic marker genes (P < 0.05). Moreover, this compound strongly induced the phosphorylation of mitogen-activated protein (MAP) kinases and protein kinase B (AKT) (P < 0.05). The inhibition of p38 MAP, c-Jun N-terminal kinase (JNK), and AKT substantially suppressed the INB-induced odontoblast differentiation (P < 0.001). In addition, isonymphaeol B significantly induced the formation of dentine and elongation of the tooth root in vivo (P < 0.05). CONCLUSIONS: Prenylflavonoids, including INB, exerted stimulatory effects on odontoblast differentiation and tooth root and dentine formation via the MAP kinase and AKT signalling pathways. These results suggest that nymphaeols could stimulate the repair processes for dentine defects or injuries.

Viral stimulation modulates endotype-related ACE2 expression in eosinophilic chronic rhinosinusitis.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2), a receptor targeted by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the nasal mucosa. Chronic rhinosinusitis (CRS) shows diverse endotypes and is aggravated by viral infection. Whether viral stimulation and CRS endotype influence ACE2 expression remains unclear. We investigated the expression of ACE2 and the transmembrane protease, serine 2 (TMPRSS2), which mediate the entry of SARS-CoV-2 into cells, and assessed polyinosinic:polycytidylic acid (poly[I:C])-induced changes based on CRS endotype. METHODOLOGY: ACE2 and TMPRSS2 expression was evaluated based on CRS phenotype, endotype, and tissue type. Correlations between ACE2/TMPRSS2 expression and inflammatory mediators in nasal polyps (NP) were examined. Air-liquid interface culture experiments were performed to assess the effects of major cytokines or poly(I:C) stimulation on ACE2/TMPRSS2 expression in primary epithelial cells from healthy nasal mucosa, eosinophilic NP (ENP), and non-eosinophilic NP (NENP). RESULTS: In primary nasal epithelial cells, interleukin (IL)-13 decreased ACE2 expression but increased TMPRSS2. Eosinophilic CRS showed lower ACE2 expression than non-eosinophilic CRS, regardless of CRS phenotype. CRS endotype was an independent factor associated with ACE2/TMPRSS2 expression in NP. Serum and tissue eosinophilic marker levels were inversely correlated with ACE2 expression, whereas tissue neutrophilic marker levels and ACE2 expression were positively correlated in NP. ACE2 expression was suppressed in ENP tissues; however, a combination of poly(I:C) and IL-13 induced ACE2/TMPRSS2 upregulation in ENP. CONCLUSIONS: ENP tissues have lower ACE2 expression than NENP; however, viral stimulation promotes ACE2/TMPRSS2 upregulation in ENP.

Desflurane reduces intraoperative remifentanil requirements more than sevoflurane: comparison using surgical pleth index-guided analgesia.

BACKGROUND: Sevoflurane and desflurane are widely used in balanced anaesthesia in combination with opioid analgesics. The opioid remifentanil is frequently chosen because of its extremely rapid pharmacokinetics. However, intraoperative high-dose remifentanil is associated with increased postoperative pain and rescue analgesic use owing to acute tolerance and opioid-induced hyperalgesia. This study aimed to compare intraoperative remifentanil requirements during equi-minimum alveolar concentration (MAC) sevoflurane and desflurane anaesthesia via surgical pleth index-guided remifentanil administration. METHODS: Eighty-two subjects undergoing laparoscopic cholecystectomy were randomly allocated to two groups receiving either sevoflurane (n=40) or desflurane (n=42). Anaesthesia was maintained with the assigned inhaled anaesthetics and remifentanil. End-tidal anaesthetic concentration was maintained at age-corrected 1.0 MAC, and remifentanil infusion was continuously adjusted to achieve a surgical pleth index of 20-50. Mean remifentanil infusion rate, which was the primary outcome of the study, was calculated as the total infused remifentanil dose per kg body weight per minute of total operative time. RESULTS: Mean remifentanil infusion rate [mean (standard deviation)] was significantly higher in the sevoflurane group than in the desflurane group [0.192 (0.064) vs. 0.099 (0.033) µg kg-1 min-1; difference, 0.093 (95% confidence interval, 0.071-0.115); P<0.001]. CONCLUSIONS: During equi-MAC anaesthesia of 1.0 MAC, sevoflurane and desflurane did not show similar intraoperative remifentanil consumption under surgical pleth index-guided opioid administration. Further studies using other monitors with different measuring mechanisms are warranted to determine the cause of this difference. CLINICAL TRIAL REGISTRATION: NCT02830243 (ClinicalTrials.gov).

Pretreatment MRI features associated with diagnostic accuracy of post-treatment MRI after neoadjuvant chemotherapy.

AIM: To investigate whether pretreatment magnetic resonance imaging (MRI) features are associated with diagnostic accuracy of post-treatment MRI for predicting pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with breast cancer. MATERIALS AND METHODS: From January 2005 and December 2016, 221 consecutive patients (mean age, 50 years; range, 20-81 years) who had undergone NAC, breast MRI before and after NAC, and surgery for invasive breast cancer were enrolled. Pretreatment and post-treatment MRI images were reviewed. Radiological complete response (rCR) was defined as the absence of both early and late enhancement on MRI after NAC. The association of pretreatment MRI features and post-treatment MRI diagnostic accuracy was assessed by using logistic regression analysis. RESULTS: Among 221 patients, 60 (27.1%) underwent pCR after NAC. The diagnostic accuracy of post-treatment MRI was 84.2% (186/221). False-positive diagnosis occurred in 21 cases and false-negative diagnosis occurred in 14 cases. Of pretreatment features, the presence of peritumoural oedema (odds ratio, 3; 95% confidence interval [CI]: 1.1, 8.0; p=0.03) and HER2 (human epidermal growth factor receptor 2)-positive status (odds ratio, 3.4; 95% CI: 1.2, 9.9; p=0.02) were significantly associated with false-positive MRI results. Dense fibroglandular tissue (odds ratio, 10.8; 95% CI: 1.1, 105.2; p=0.04), presence of rim enhancement (odds ratio, 7.5; 95% CI: 1.2, 38.3; p=0.02) and oestrogen receptor (ER)-positive status (odds ratio, 6.3; 95% CI: 1.2, 32.5; p=0.03) were significantly associated with false-negative MRI results. CONCLUSION: Pretreatment MRI features and cancer subtypes may be associated with diagnostic accuracy of post-treatment MRI after NAC in patients with breast cancer.

The value of breast MRI for BI-RADS category 4B mammographic microcalcification: based on the 5th edition of BI-RADS.

AIM: To investigate whether magnetic resonance imaging (MRI) can improve the positive predictive value (PPV) for Breast Imaging-Reporting and Data System (BI-RADS) category 4B mammographic microcalcification. MATERIALS AND METHODS: One hundred and eight consecutive patients with BI-RADS category 4B microcalcification without mass on mammography underwent breast MRI and subsequent histopathological confirmation between January 2009 and December 2015. Mammography and MRI findings were reviewed retrospectively, and imaging features were analysed according to the 5th edition of BI-RADS. The PPV of each descriptor was analysed to identify subgroups in which PPV could be improved by the addition of MRI. RESULTS: When the criteria of presence of enhancement on MRI was applied to category 4B microcalcification, PPV increased from 0.38 (41 of 108) to 0.82 (37 of 45) and reduced benign biopsy results by 88% (59 of 67). Four ductal carcinoma in situ lesions were missed. For amorphous microcalcification with regional or grouped distribution, MRI images increased PPV without missing malignancy. CONCLUSION: Breast MRI has the potential to improve PPV for category 4B mammographic microcalcification by reducing false-positive findings. If amorphous microcalcification with regional or grouped distribution on mammography shows no enhancement on MRI, follow-up could be considered rather than immediate biopsy. In addition, breast MRI might have the potential to guide the best site to biopsy in category 4B microcalcification.

A randomised trial of serratus anterior plane block for analgesia after thoracoscopic surgery.

We evaluated the effect of pre-operative serratus anterior plane block on postoperative pain and opioid consumption after thoracoscopic surgery. We randomly allocated 89 participants to block with 30 ml ropivacaine 0.375% (n = 44), or no block without placebo or sham procedure (n = 45). We analysed results from 42 participants in each group. Serratus anterior plane block reduced mean (SD) remifentanil dose during surgery, 0.12 (0.06) mg.h-1 vs. 0.16 (0.06) mg.h-1 , p = 0.016, and reduced mean (SD) fentanyl consumption in the first 24 postoperative hours, 3.8 (1.9) µg.kg-1 vs. 5.7 (1.6) µg.kg-1 , p = 0.000004. Block also reduced the worst median (IQR [range]) pain scores reported in the first 24 postoperative hours: 6 (5-7 [3-10]) vs. 7 (6-7 [3-10]), p = 0.027. Block decreased dissatisfaction with pain management, categorised as 'highly unsatisfactory', 'unsatisfactory', 'neutral', 'satisfactory' or 'highly satisfactory': 1/2/21/18/0 vs. 1/14/15/11/1, p = 0.0038. There were no differences in the rates of nausea, vomiting, dizziness or length of hospital stay. Serratus anterior plane block may be used to reduce pain and opioid use after thoracoscopic lung surgery.

Wogonin, a flavonoid isolated from Scutellaria baicalensis, has anti-viral activities against influenza infection via modulation of AMPK pathways.

Wogonin, a flavonoid isolated from Scutellaria baicalensis, has attracted increasing scientific attention in recent years because of its potent anti-tumor activity. Its role during viral infection has largely been unexplored. Wogonin treatment effectively suppressed both influenza A and B virus replication in Madin-Darby Canine Kidney (MDCK) cells and human lung epithelial (A549) cells. In contrast, wogonin treatment following influenza A virus infection led to up-regulation of interferon (IFN)-induced antiviral signaling. Additionally, influenza A virus infection in A549 cells induced 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and activation in a time-dependent manner and wogonin treatment led to the suppression of AMPK phosphorylation. Furthermore, the treatment with AMPK-specific inhibitor (compound C; CC) attenuated influenza A virus replication. These data suggest that wogonin possesses a potent anti-influenza activity mediated by regulation of AMPK activation, suggesting that wogonin has the potential to be developed as an anti-influenza drug.

Single-stage cell-based cartilage repair in a rabbit model: cell tracking and in vivo chondrogenesis of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel composite.

OBJECTIVE: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have gained popularity as a promising cell source for regenerative medicine, but limited in vivo studies have reported cartilage repair. In addition, the roles of MSCs in cartilage repair are not well-understood. The purpose of this study was to investigate the feasibility of transplanting hUCB-MSCs and hyaluronic acid (HA) hydrogel composite to repair articular cartilage defects in a rabbit model and determine whether the transplanted cells persisted or disappeared from the defect site. DESIGN: Osteochondral defects were created in the trochlear grooves of the knees. The hUCB-MSCs and HA composite was transplanted into the defect of experimental knees. Control knees were transplanted by HA or left untreated. Animals were sacrificed at 8 and 16 weeks post-transplantation and additionally at 2 and 4 weeks to evaluate the fate of transplanted cells. The repair tissues were evaluated by gross, histological and immunohistochemical analysis. RESULTS: Transplanting hUCB-MSCs and HA composite resulted in overall superior cartilage repair tissue with better quality than HA alone or no treatment. Cellular architecture and collagen arrangement at 16 weeks were similar to those of surrounding normal articular cartilage tissue. Histological scores also revealed that cartilage repair in experimental knees was better than that in control knees. Immunohistochemical analysis with anti-human nuclear antibody confirmed that the transplanted MSCs disappeared gradually over time. CONCLUSION: Transplanting hUCB-MSCs and HA composite promote cartilage repair and interactions between hUCB-MSCs and host cells initiated by paracrine action may play an important role in cartilage repair.

Potentially modifiable risk factors for atrial fibrillation following lung resection surgery: a retrospective cohort study.

Atrial fibrillation is the most frequent arrhythmia after thoracic surgery and is associated with increased hospital costs, morbidity and mortality. In this study, we aimed to identify potentially modifiable risk factors for postoperative atrial fibrillation following lung resection surgery and to suggest possible measures to reduce risk. We retrospectively reviewed the medical records of 4731 patients who underwent lobectomy or more major lung resection over a 6-year period. Patients who developed atrial fibrillation postoperatively and required treatment were included in the postoperative atrial fibrillation group, while the remaining patients were assigned to the non-postoperative atrial fibrillation group. Risk factors for postoperative atrial fibrillation were analysed by multivariate analysis and propensity score matching. Overall, 12% of patients developed postoperative atrial fibrillation. Potentially modifiable risk factors for postoperative atrial fibrillation were excessive alcohol consumption (odds ratio (OR) = 1.48, 95% CI 1.08-2.02, p = 0.0140), red cell transfusion (2.70(2.13-3.43), p < 0.0001), use of inotropes (1.81(1.42-2.31), p < 0.0001) and open (vs. thoracoscopic) surgery (1.59(1.23-2.05), p < 0.0001). Compared with inotrope use, vasopressor administration was not related to postoperative atrial fibrillation. Use of steroids or thoracic epidural anaesthesia did not reduce the incidence of postoperative atrial fibrillation. We conclude that high alcohol consumption, red cell transfusion, use of inotropes and open surgery are potentially modifiable risk factors for postoperative atrial fibrillation. Pre-operative alcohol consumption needs to be addressed. Avoiding red cell transfusion and performing lung resection via video-assisted thoracoscopic surgery may reduce the incidence of postoperative atrial fibrillation and the administration of vasopressors rather than inotropes is preferred.

Malva verticillata seed extracts upregulate the Wnt pathway in human dermal papilla cells.

OBJECTIVE: Mesenchymal-epithelial interactions are important in controlling hair growth and the hair cycle. The ß-catenin pathway of dermal papilla cells (DPCs) plays a pivotal role in morphogenesis and normal regeneration of hair follicles. Deletion of ß-catenin in the dermal papilla reduces proliferation of the hair follicle progenitor cells that generate the hair shaft and induces an early onset of the catagen phase. In this study, a modulator of the Wnt/ß-catenin activity was studied in oriental herb extracts on cultured human DPCs. METHODS: The effect of Malva verticillata (M. verticillata) seeds on human DPCs was investigated by a Wnt/ß-catenin reporter activity assay system (ß-catenin-TCF/LEF reporter gene) and cell proliferation analysis. The synthesis of the factors related to hair growth and cycling was measured at both the mRNA and the protein level by semi-quantitative PCR and Western blot analysis, respectively. RESULTS: An extract from M. verticillata seeds increased Wnt reporter activity in a concentration-dependent manner and also led to increased ß-catenin levels in cultured human DPCs. Myristoleic acid, identified as an effective compound of M. verticillata seeds, stimulated the proliferation of DPCs in a dose-dependent manner and increased transcription levels of the downstream targets: IGF-1, KGF, VEGF and HGF. Myristoleic acid also enhanced the phosphorylation of MAPKs (Akt and p38). CONCLUSION: Overall, the data suggest that this extract of M. verticillata seeds could be a good candidate for treating hair loss by modulating the Wnt/ß-catenin pathway in DPCs.

Synergistic effects of A1896, T1653 and T1762/A1764 mutations in genotype c2 hepatitis B virus on development of hepatocellular carcinoma.

The effects of genomic changes in hepatitis B virus (HBV) on the occurrence of hepatocellular carcinoma (HCC) are still unclear, especially in relation to the genotype of HBV. In this study, we examined the effects of genomic changes in HBV of genotype C2 on the development of HCC. A total of 318 patients with HBV-associated HCC and 234 patients with chronic hepatitis B (CHB) were studied. All of HCC cases were diagnosed histologically and treated with surgical resection. The whole of the X, S, basal core promoter (BCP) and precore regions of the viral genome from sera or liver tissues were sequenced. All subjects had HBV of genotype C2. The prevalence of the T1653 mutation in the X region and the A1896 mutation in the precore region of HBV was significantly higher in the HCC group than in the control CHB group (22% vs 11%, P = 0.003; 50% vs 23%, P < 0.001, respectively). Moreover, the T1762/A1764 mutations in the BCP region in combination with either T1653 or A1896 were more common in the HCC compared with the CHB group (BCP+X1653: 18% vs 11%, P = 0.05; BCP+PC, 40% vs 15%, P < 0.001, respectively). In multivariate analysis, T1653 and A1896 were revealed to be independent risk factors for HCC development. G1896A in the precore region and C1653T mutation in the X region of genotype C2 HBV are important risk factors for HCC development. Also, the A1762T/G1764A double mutation may act in synergy with C1653T to increase the risk of HCC in patients chronically infected with HBV genotype C2.

The chromene sargachromanol E inhibits ultraviolet A-induced ageing of skin in human dermal fibroblasts.

BACKGROUND: Skin ageing is influenced by environmental factors such as ultraviolet (UV) radiation. The effects of UV radiation on skin functions should be investigated using human in vitro models to understand the mechanisms of skin ageing. Additionally, marine algae provide a valuable source for identifying and extracting biologically active substances. OBJECTIVES: In this study, sargachromanol E was isolated from a marine brown alga, Sargassum horneri, and its inhibitory effect on skin ageing was investigated using UVA-irradiated dermal fibroblasts. METHODS: Formation of intracellular reactive oxygen species (ROS), lipid peroxidation and protein oxidation induced by UVA irradiation were investigated in UVA-irradiated human dermal fibroblasts. The levels of matrix metalloproteinases (MMPs) were determined by reverse-transcriptase polymerase chain reaction and Western blot analysis. RESULTS: Sargachromanol E did not exhibit any significant cytotoxicity or phototoxicity in UVA-exposed dermal fibroblasts. Additionally, sargachromanol E suppressed intracellular formation of ROS, membrane protein oxidation, lipid peroxidation and expression of collagenases such as MMP-1, MMP-2 and MMP-9, all of which are caused by UVA exposure. It was further found that these inhibitions were related to an increase in the expression of the tissue inhibitor of metalloproteinase (TIMP) genes, TIMP1 and TIMP2. Moreover, we have shown that the transcriptional activation of activator protein 1 (AP-1) signalling caused by UVA irradiation was inhibited by treatment with sargachromanol E. CONCLUSIONS: This study suggests that UVA irradiation modulates MMP expression via the transcriptional activation of AP-1 signalling, whereas treatment with sargachromanol E protected cell damage caused by UVA irradiation.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

AIMS: This study was designed to assess the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, gemigliptin versus sitagliptin added to metformin in patients with type 2 diabetes. METHODS: We conducted a double-blind, randomized, active-controlled trial in 425 Asian patients with inadequately controlled type 2 diabetes being treated with metformin alone. Eligible patients were randomized into three groups: 50 mg gemigliptin qd, 25 mg gemigliptin bid or sitagliptin 100 mg qd added to ongoing metformin treatment for 24 weeks. Haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) were measured periodically, and oral glucose tolerance tests were performed at baseline and 24 weeks after starting the treatment regimen. RESULTS: Twenty-four weeks later, adding gemigliptin (50 mg/day) to ongoing metformin therapy significantly improved glycaemic control. Reduction in HbA1c caused by 50 mg gemigliptin qd (-0.77% ± 0.8) was non-inferior to that caused by 100 mg sitagliptin qd (-0.8% ± 0.85). Proportion of patients achieving HbA1c <7% while taking 25 mg gemigliptin bid (50%) or 50 mg gemigliptin qd (54.07%) was comparable to the results with 100 mg sitagliptin qd (48.87%). There were significant decreases in FPG, postprandial glucose and AUC0-2 h glucose, as well as increases in GLP-1 and ß cell sensitivity to glucose (supported by homeostasis model assessment of ß-cell function, postprandial 2-h c-peptide and insulinogenic index) in patients receiving gemigliptin treatment with their metformin therapy. There was no increased risk of adverse effects with this dose of gemigliptin compared with sitagliptin 100 mg qd. CONCLUSIONS: Addition of gemigliptin 50 mg daily to metformin was shown to be efficacious, well tolerated and non-inferior to sitagliptin in patients with type 2 diabetes mellitus.

A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes.

AIM: This study was designed to assess the efficacy and safety of the dipeptidyl peptidase IV inhibitor gemigliptin (LC15-0444) 50 mg versus placebo in patients with type 2 diabetes. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled phase III trial in 182 patients (74 from Korea and 108 from India) with type 2 diabetes. After an initial 2 weeks of a diet and exercise programme followed by 2 weeks of a single-blind placebo run-in period, eligible patients were randomized to gemigliptin 50 mg or placebo, receiving the assigned treatment for 24 weeks. HbA1c and fasting plasma glucose (FPG) were measured periodically, and oral glucose tolerance test was performed at baseline and weeks 12 and 24. RESULTS: At week 24, gemigliptin treatment led to significant reductions in HbA1c measurements compared to placebo (adjust mean after subtracting the placebo effect size: -0.71%, 95% confidence interval: -1.04 to -0.37%). A significantly greater proportion of patients achieved an HbA1c <7% with gemigliptin than with placebo. The placebo-subtracted FPG change from baseline at week 24 was -19.80 mg/dl. The overall incidence rates for adverse events were similar in the gemigliptin and placebo groups. CONCLUSIONS: This study showed the efficacy and safety of gemigliptin 50 mg administered once daily as a monotherapy for type 2 diabetes patients.

Double-lumen tube tracheal intubation using a rigid video-stylet: a randomized controlled comparison with the Macintosh laryngoscope.

BACKGROUND: Despite an increasing need, there is limited experience of double-lumen endobronchial tube (DLT) placement using video laryngoscope. We evaluated DLT intubation using an OptiScope, a rigid video-stylet with a malleable tip derived from the Clarus Video System, in comparison with a Macintosh laryngoscope. METHODS: After airway evaluation and anaesthetic induction, Cormack and Lehane (C and L) grade was initially assessed in all patients using a Macintosh laryngoscope before tracheal intubation. The trachea was then intubated using either a Macintosh laryngoscope (n=200) or an OptiScope® (n=200). Success rate, intubation time, number of attempts at intubation, vocal cord view during intubation, need for external manipulation, and the incidences of oral mucosal or dental injury were compared between the two devices. RESULTS: Data were analysed for 397 patients. Intubation time with the OptiScope® was faster [median (inter-quartile range): 15 (12-19) s] than with the Macintosh [18(12-28) s] {mean difference [95% confidence interval (CI)}: 5.5 (3.8-13.2) s, P=0.010]. The success rate of the first intubation was higher with the OptiScope® than with the Macintosh [80.4% vs 89.9%, odds ratio (95% CI): 2.2 (1.22-3.87), P=0.036]. Initial view of the vocal cords was also better, although the final success rate was not different between devices. The need for external laryngeal manipulation, oral mucosal, or dental injury was lower with the OptiScope® compared with the Macintosh laryngoscope (all P<0.01). CONCLUSIONS: The OptiScope® provides faster tracheal intubation and a higher success rate for the first intubation with less trauma and a better vocal cord view than the Macintosh laryngoscope.

Prolonged inspiratory time produces better gas exchange in patients undergoing laparoscopic surgery: A randomised trial.

BACKGROUND: Laparoscopic surgery performed with a patient in the Trendelenburg position is known to have adverse effects on pulmonary gas exchange and respiratory mechanics. We supposed that prolonged inspiratory time can improve gas exchange at lower airway pressure. METHODS: One hundred patients undergoing gynaecologic laparoscopic surgery were randomly assigned to one of four groups: conventional inspiratory-to-expiratory (I : E) ratio (Group 1 : 2), I : E ratio of 1 : 1 (Group 1 : 1), 2 : 1 (Group 2 : 1), or 1 : 2 with external positive end-expiratory pressure (PEEP) of 5 cmH2 O (Group 1 : 2 PEEP). Tidal volume was set to 6 ml/kg, and I : E ratio was adjusted at the onset of pneumoperitoneum. Arterial blood gas analysis with measurements of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2 /FiO2 ), and physiologic dead space-to-tidal volume ratio (VD /VT ) was performed 15 min after anaesthetic induction (T1), and 30 (T2) and 60 min (T3) after onset of CO2 insufflation. RESULTS: PaO2 /FiO2 at T3 in Groups 1 : 1, 2 : 1, and 1 : 2 PEEP were higher than Group 1 : 2. The partial pressure of arterial carbon dioxide at T3 in Group 2 : 1 was lower than the other groups. The VD /VT at T2 and T3 were lower in Groups 1 : 1 and 2 : 1 than Groups 1 : 2 and 1 : 2 PEEP. Peak or plateau airway pressure was higher in Group 1 : 2 PEEP than the other groups. CONCLUSIONS: A prolonged inspiratory time demonstrated a beneficial effect on oxygenation. Furthermore, it showed better CO2 elimination without elevating the peak or plateau airway pressure compared with applying external PEEP. In terms of gas exchange and respiratory mechanics, a prolonged inspiratory time appears to be superior to applying external PEEP in patients undergoing laparoscopic surgery in the Trendelenburg position.

Ecklonia cava promotes hair growth.

BACKGROUND: Previous studies have reported the protective effects on skin elasticity of the edible marine seaweed Ecklonia cava, which acts through regulation of both antioxidative and anti-inflammatory responses. AIM: We evaluated the effect of E. cava and one of its components, dioxinodehydroeckol, on hair-shaft growth in cultured human hair follicles and on hair growth in mice. METHODS: The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to check cell viability of human dermal papilla cells (DPCs) and outer root sheath (ORS) cells after treatment with E. cava and its metabolite, dioxinodehydroeckol. Hair-shaft growth was measured using the in vitro hair-follicle organ-culture system, in the presence or absence of E. cava and dioxinodehydroeckol. Anagen induction activity was examined by topical application of E. cava to the dorsal skin of C57BL/6 mice. Insulin-like growth factor (IGF)-1 expression was measured by reverse transcriptase PCR and ELISA. RESULTS: The proliferation activity was found to be highest for the ethyl acetate-soluble fraction of E. cava (EAFE) in DPCs and in ORS cells. Treatment with EAFE resulted in elongation of the hair shaft in cultured human hair follicles, and promoted transition of the hair cycle from the telogen to the anagen phase in the dorsal skin of C57BL/6 mice. In addition, EAFE induced an increase in IGF-1 expression in DPCs. Dioxinodehydroeckol, a component of E. cava, induced elongation of the hair shaft, an increase in proliferation of DPCs and ORS cells, and an increase in expression of IGF-1 in DPCs. CONCLUSIONS: These results suggest that E. cava containing dioxinodehydroeckol promotes hair growth through stimulation of DPCs and ORS cells.