Dog sperm cryopreservation using cryovials and different dilution steps.

BACKGROUND: The conventional sperm freezing method for dog sperm is with straws and includes two-step dilution and a long equilibration time. OBJECTIVE: To develop a more efficient freezing method using cryovials. MATERIALS AND METHODS: Three freezing protocols using cryovials (0.5 mL) were conducted with dog spermatozoa at 1 x 108 sperm/mL: Group 1 spermatozoa were cooled in cryovials and extender 1 (E1) and extender 2 (E1 +1 M glycerol) at 4 degree C for 50 min and then frozen over LN2 for 20 min; Group 2 sperm was cooled and frozen in cryovials with a mixture of E1 and E2 (1:1) in a deep freezer (-80 degree C) for 30 min; Group 3 sperm in cryovials and E1 were cooled at 4 degree C for 20 min, cooled for an additional 20 min after addition of E2 (E1:E2, 1:1), and then frozen using LN2/ vapour for 20 min. The control (Group 4) consisted of spermatozoa in straws being frozen using the conventional freezing method using two-step dilution. All groups were plunged and stored in LN2 after freezing and their functional performance and gene expression determined. RESULTS: Progressive motility and acrosome integrity were highest (P < 0.05) in Groups 2, 3 and 4 (only acrosome integrity). Viability in Group 3 was significantly better that in the other Groups, and the reactive oxygen species (ROS) level and phosphatidylserine (PS) translocation index were significantly lower in Group 2 than the other Groups. The expression of sperm mitochondria-associated cysteine-rich protein (SMCP) and anti-apoptotic B-cell lymphoma 2 (BCL2) genes was highest (P < 0.05) in Group 2 and the expression of pro-apoptotic Bcl2-associated X protein (BAX) was lowest (P < 0.05) in Group 4. CONCLUSION: The sperm frozen using cryovials, one step dilution and the deep freezer (Group 2) proved to be a simple and suitable cryopreservation method for dog sperm. https://doi.org/10.54680/fr24110110312.

Chronic rhinitis and stress: the possible culprits of midfacial segment pain.

BACKGROUND: Bilateral symmetrical pain in the midfacial region without evidence of sinonasal disease is termed midfacial segment pain (MSP), about which little is known. The present study explored the prevalence of facial pain and the risk factors for MSP. METHODS: We analysed cross-sectional data from the Korea National Health and Nutrition Examination Survey (KNHANES). Those who reported facial pain or pressure lasting at least three months with no evidence of a sinonasal disease on nasal endoscopy were considered to have MSP. The participants were categorised according to the presence of facial pain and chronic rhinosinusitis. Basic demographic data and medical conditions, including hypertension, diabetes mellitus, and dyslipidemia, were compared between subject groups. We also evaluated psychological stress, depressive episodes, and suicidal thoughts, as well as physician-diagnosed nasal diseases, including chronic rhinitis and symptomatic nasal septal deviation. Univariate and multivariate logistic regression analyses were performed to determine risk factors for MSP. RESULTS: Of 31,999 participants, the prevalence of facial pain was 0.59%. A total of 58 (0.18%) respondents had MSP, of whom 40 (73.5%) were female. On univariate analysis, female sex, chronic rhinitis, and psychological stress were more prevalent in the subjects with MSP than the control subjects. However, in the multivariate analysis, only chronic rhinitis and psychological stress remained significant, while the female sex exhibited only marginal significance. CONCLUSION: Chronic rhinitis and psychological stress may be significant risk factors for MSP.

Increased risk of cardiovascular diseases in patients with chronic rhinosinusitis: a longitudinal follow-up study using a national health screening cohort.

BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases and is characterized by sinonasal inflammation that lasts longer than 12 weeks. Whether the effect of chronic inflammation caused by CRS on cardiovascular diseases (CVDs) is similar to its effect on other inflammatory disorders has not been thoroughly evaluated. We aimed to demonstrate whether CRS patients have a higher prevalence of CVDs, including stroke and ischemic heart disease (IHD). METHODOLOGY: We compared the prevalence of various comorbidities between CRS and control participants through a case-control cohort study from 2002 to 2015 that included 514,866 participants. CRS (n=6,552) and control (n=26,208) participants who were over 40 years old were selected by matching age, sex, income, and area of residence at a 1:4 ratio. RESULTS: A stratified Cox proportional hazards model was utilized to assess the hazard ratio (HR) of CRS for stroke and IHD. The HRs for stroke and IHD were significantly increased in CRS patients compared to controls after adjusting for obesity, alcohol consumption, smoking, systolic and diastolic blood pressure, fasting blood glucose, total cholesterol, hemoglobin, and Charlson Comorbidity Index (CCI) scores. The HR of stroke was significantly higher in the absence of nasal polyps than in the presence of nasal polyps. The HR of IHD was significantly increased in the CRS group regardless of the presence of nasal polyps. CONCLUSIONS: This study showed that CRS participants had a significantly higher prevalence of stroke and IHD.

Effect of synthetic cholesterol (Synthechol) supplementation in an egg yolk-free extender on dog sperm cryopreservation.

BACKGROUND: SyntheChol is a new synthetic, non-animal-derived cholesterol that is easily dissolved in ethanol, ready to use, and behaves in a similar way as natural cholesterol. Therefore, it could be used as a substitute of natural cholesterol in dog sperm freezing extender. OBJECTIVE: To evaluate the effect of supplementing an egg yolk-free (EY-free) extender with synthetic cholesterol (SyntheChol) on cryopreserved dog sperm. MATERIALS AND METHODS: Spermatozoa (1 × 108 sperm/mL) were suspended in EY-free extender supplemented with 0 % (control), 0.25, 0.5, 1, 2, 4, or 6 % SyntheChol (Extender 1), cooled at 4 degree C for 1 h, and diluted (1:1, v/v) with Extender 1 containing 1 M glycerol. The spermatozoa were then cooled to 4 degree C for 30 min. Sperm-containing straws were frozen using LN2 vapor. Sperm motility (computer-assisted sperm analysis, CASA), sperm membrane integrity (SYBR-14 and PI staining), and acrosome integrity (FITC-PSA) were evaluated after thawing. Thereafter, optimal concentrations were determined (0.25, 0.5, 1, or 2 %) and used to evaluate reactive oxygen species (ROS) generation, apoptosis, and the gene expression of motility-related sperm mitochondria-associated cysteine-rich protein, apoptosis-related B-cell lymphoma 2 (BCL2), and BCL2-associated X protein (BAX) in cryopreserved sperm. RESULTS: Sperm progressive motility, membrane integrity, and acrosome integrity were markedly greater in the SyntheChol-supplemented groups (0.25, 0.5, 1, or 2 %) than in the control group. Only BAX expression was significantly reduced in the SyntheChol groups (0.25, 1, or 2 %) compared with the control group. However, there were no significant effects on the ROS generation or apoptosis index. CONCLUSION: SyntheChol (0.25, 1, or 2 %) proved to be effective in reducing the BAX gene expression level and improving sperm progressive motility, and membrane and acrosome integrity. doi.org/10.54680/fr22210110212.

Is dual-energy absorptiometry accurate in the assessment of bone status of patients with chronic kidney disease?

Several patients with chronic kidney disease (CKD) have deteriorated bone status. Estimation of bone status using DXA has limitations especially in patients with CKD accompanying aortic calcifications. Quantitative CT and the trabecular bone score could be more accurate methods to estimate bone status for patients with CKD and vascular calcifications. INTRODUCTION: It remains unclear whether dual-energy absorptiometry (DXA) is appropriate for the assessment of bone status in patients with chronic kidney disease (CKD), a disease that impacts bone health. The aims of this study were to compare DXA and central quantitative computed tomography (cQCT) and to evaluate bone status in patients with pre-dialysis CKD. METHODS: This retrospective study included 363 healthy control subjects whose bone mineral density (BMD) was evaluated with DXA and 117 CKD patients whose BMD was evaluated using both cQCT and DXA. Diagnostic discordance was assessed between the lumbar spine (LS) and femur neck (FN) from DXA or between two modalities. The trabecular bone score (TBS) was extracted from DXA images. The volume of abdominal aortic calcification (AAC) was calculated using CT images from cQCT. RESULTS: Using LS DXA T-score, osteoporosis was less common in the CKD group than in controls. Patients with normal LS BMD using DXA were reclassified into osteopenia or osteoporosis using cQCT in CKD patients. Among discordant subjects between FN and LS in DXA, a higher BMD of LS was more common in CKD patients than in controls. CKD patients had lower TBS than controls despite having the same diagnosis using DXA. AAC volume negatively correlated with BMD from cQCT and with TBS but not with BMD from DXA. CONCLUSIONS: TBS and cQCT could accurately assess bone status in CKD patients since DXA may overestimate LS BMD, likely due to an increased AAC volume.

Quasisymmetric Optimization of Nonaxisymmetry in Tokamaks.

Predictive 3D optimization reveals a novel approach to modify a nonaxisymmetric magnetic perturbation to be entirely harmless for tokamaks, by essentially restoring quasisymmetry in perturbed particle orbits as much as possible. Such a quasisymmetric magnetic perturbation (QSMP) has been designed and successfully tested in the KSTAR and DIII-D tokamaks, demonstrating no performance degradation despite the large overall amplitudes of nonaxisymmetric fields and strong response otherwise expected in the tested plasmas. The results indicate that a quasisymmetric optimization is a robust path of error field correction across the resonant and nonresonant field spectrum in a tokamak, leveraging the prevailing concept of quasisymmetry for general 3D plasma confinement systems such as stellarators. The optimization becomes, in fact, a simple eigenvalue problem to the so-called torque response matrices if a perturbed equilibrium is calculated consistent with nonaxisymmetric neoclassical transport.

Does serum vitamin D level affect the association between cardiovascular health and cognition? Results of the Cardiovascular and Metabolic Diseases Etiology Research Center (CMERC) study.

BACKGROUND AND PURPOSE: Few studies have assessed the role of vitamin D in the association between cardiovascular risk factors and cognitive function. Here, the aim was to investigate the association between cardiovascular health (CVH) and cognitive function according to vitamin D level in a middle-aged Korean population. METHODS: This cross-sectional study included 840 men and 1811 women (mean age 57.2 years) from the Cardiovascular and Metabolic Diseases Etiology Research Center study baseline enrolment (2013-2018). Life's Simple 7 tools from the American Heart Association were used to assess CVH. Cognitive function was evaluated using the Mini-Mental State Estimation for Dementia Screening (MMSE-DS), and the serum 25-hydroxyvitamin D level was measured. RESULTS: In the adjusted generalized linear regression models, no significant association between a high Life's Simple 7 score (4-7 metric at optimal level) and MMSE-DS score (ß = 0.01, P = 0.93) was found. Amongst men with a high vitamin D level, the high Life's Simple 7 score group showed a significantly higher MMSE-DS score (ß = 0.48, P = 0.03). However, amongst men in the low vitamin D group, the association was opposite with no statistical significance (ß = -0.23, P = 0.08). In women, the results were similar, but both strata according to vitamin D level showed no statistical significance. CONCLUSIONS: Our findings suggest that vitamin D is an effect modifier in the association between CVH and cognition, especially in men.

Cryopreservation of Dog Spermatozoa Using Essential and Non-Essential Amino Acids Solutions in An Egg Yolk-Free Polyvinyl Alcohol Extender.

BACKGROUND: Amino acids (AAs) have been indicated to have cryoprotective and antioxidative effects on sperm freezing using egg yolk (EY)-based extender. However, EY-based extender is difficult to be standardized for the effect of amino acids because the EY composition varies with the animal's diet. OBJECTIVE: To test the effect of AAs in EY-free polyvinyl alcohol (EY-free PVA) extender and develop a chemically defined extender for dog sperm cryopreservation. MATERIALS AND METHODS: In the first experiment (E1), dog spermatozoa (1ｘ108 sperms/mL) were frozen with EY-free PVA extender without AAs or supplemented with essential (EAAs, 50 x: 1, 2, 4 %) or non-essential amino acids (NEAAs, 100 x: 1, 2, 4 %). In the second experiment (E2), spermatozoa were frozen with EY-free PVA extender supplemented with 0, 0.5, 1 or 2 % of an EAA-NEAA mixture. Motility, viability and acrosome integrity were evaluated after thawing in E1 and E2. In the third experiment (E3), spermatozoa were frozen using an extender supplemented with 2 % EAAs, 2 % NEAAs or a 0.5 % EAA-NEAA mixture. Reactive oxygen species (ROS) and phosphatidylserine (PS) translocation were assessed. Expression of genes for motility-related sperm mitochondrial-associated cysteine-rich protein (SMCP), apoptosis-related B-cell lymphoma 2 (BCL2) and BCL2 associated X protein (BAX) was measured. RESULTS: Addition of EAAs, NEAAs or an EAA-NEAA mixture to EY-free PVA extender significantly increased sperm motility without affecting viability. Only 1 % NEAAs significantly increased the acrosome membrane. EAA-NEAA mixture (0.5 %) significantly increased SMCP, BCL2 and BAX expression compared to the control group without significant effect on PS translocation or ROS. CONCLUSION: EAAs and NEAAs addition in EY-free PVA extender improved sperm motility, with limited effect on acrosome integrity and gene expression of SMCP, BCL2 and BAX during dog sperm cryopreservation.

The organ-specific differential roles of rice DXS and DXR, the first two enzymes of the MEP pathway, in carotenoid metabolism in Oryza sativa leaves and seeds.

BACKGROUND: Deoxyxylulose 5-phosphate synthase (DXS) and deoxyxylulose 5-phosphate reductoisomerase (DXR) are the enzymes that catalyze the first two enzyme steps of the methylerythritol 4-phosphate (MEP) pathway to supply the isoprene building-blocks of carotenoids. Plant DXR and DXS enzymes have been reported to function differently depending on the plant species. In this study, the differential roles of rice DXS and DXR genes in carotenoid metabolism were investigated. RESULTS: The accumulation of carotenoids in rice seeds co-expressing OsDXS2 and stPAC was largely enhanced by 3.4-fold relative to the stPAC seeds and 315.3-fold relative to non-transgenic (NT) seeds, while the overexpression of each OsDXS2 or OsDXR caused no positive effect on the accumulation of either carotenoids or chlorophylls in leaves and seeds, suggesting that OsDXS2 functions as a rate-limiting enzyme supplying IPP/DMAPPs to seed carotenoid metabolism, but OsDXR doesn't in either leaves or seeds. The expressions of OsDXS1, OsPSY1, OsPSY2, and OsBCH2 genes were upregulated regardless of the reductions of chlorophylls and carotenoids in leaves; however, there was no significant change in the expression of most carotenogenic genes, even though there was a 315.3-fold increase in the amount of carotenoid in rice seeds. These non-proportional expression patterns in leaves and seeds suggest that those metabolic changes of carotenoids were associated with overexpression of the OsDXS2, OsDXR and stPAC transgenes, and the capacities of the intermediate biosynthetic enzymes might be much more important for those metabolic alterations than the transcript levels of intermediate biosynthetic genes are. Taken together, we propose a 'Three Faucets and Cisterns Model' about the relationship among the rate-limiting enzymes OsDXSs, OsPSYs, and OsBCHs as a "Faucet", the biosynthetic capacity of intermediate metabolites as a "Cistern", and the carotenoid accumulations as the content of "Cistern". CONCLUSION: Our study suggests that OsDXS2 plays an important role as a rate-limiting enzyme supplying IPP/DMAPPs to the seed-carotenoid accumulation, and rice seed carotenoid metabolism could be largely enhanced without any significant transcriptional alteration of carotenogenic genes. Finally, the "Three Faucets and Cisterns model" presents the extenuating circumstance to elucidate rice seed carotenoid metabolism.

Mental health states and influencing factors of risky and problem drinking in South Korean female adolescents.

OBJECTIVES: Alcohol is one of the most used and abused psychoactive substances by adolescents. We investigated influencing factors of risky and problem drinking in Korean female adolescents. STUDY DESIGN: The study design used is a cross-sectional modeling. METHODS: We used data from the 13th Korean Youth Risk Behavior Web-based Survey (KYRBS) conducted in 2017. KYRBS data were obtained from a stratified, multistage, clustered sample. Risky drinking was binge drinking and problem drinking was drinking with several conflicts association with alcohol consumption. RESULTS: Among 62,276 participants, the rates of current, risky, and problem drinking among all participants were 16.1%, 8.3%, and 6.1%, respectively. Although all of these rates were higher in males, risky and problem drinking rates among current female drinkers were higher than those of males (55.4 vs 48.5%, 38.9 vs 37.2%, respectively). Problem drinking was most strongly associated with risky drinking (adjusted odds ratio: 17.53 [95% confidence interval: 14.63-21.00]), similarly, risky drinking was most strongly associated with problem drinking in female current drinkers (17.76 [14.84-21.27]). Current smoking was the second strongest risk factor for risky and problem drinking in females (5.22 [3.92-6.95] and 2.93 [2.21-3.89], respectively). CONCLUSION: Many female adolescents in Korea drink alcohol in an unhealthy manner. The female risky and problem drinking rates among current drinkers were higher than those of males. Risky drinking and problem drinking was most significant influencing factor among females, reciprocally. Public education on abstinence in female adolescents is warranted.

Comparison between the effects of deep and moderate neuromuscular blockade during transurethral resection of bladder tumor on endoscopic surgical condition and recovery profile: a prospective, randomized, and controlled trial.

PURPOSE: To compare between deep neuromuscular blockade (NMB) and moderate NMB with respect to endoscopic surgical conditions and recovery profiles in patients with general anesthesia for transurethral resection of bladder (TURB). METHODS: 108 patients undergoing elective TURB were randomized into two groups: the moderate NMB (n = 54) or deep NMB (n = 54) group. After the operation, NMB was reversed with 2 mg/kg sugammadex at a train-of-four (TOF) count of 1 or 2 (moderate NMB group) or with 4 mg/kg sugammadex at post-tetanic count (PTC) of 2 (deep NMB group). Surgeons, who were blinded to the study design, rated the endoscopic surgical condition on a 5-point scale (1 = extremely poor, 2 = poor, 3 = acceptable, 4 = good, 5 = optimal) immediately following the operation. Recovery profiles, including postoperative residual curarization (PORC), respiratory complication, and recovery time, were recorded. RESULTS: No difference was observed between the two groups regarding patients and anesthesia characteristics. There were statistically significant differences in endoscopic surgical conditions between the two groups (P < 0.001). Thirty-eight patients in the deep NMB group (74%) showed optimal surgical conditions, whereas 16 patients in the moderate NMB group (30%) showed optimal endoscopic surgical conditions. No PORC and respiratory complications occurred in both groups, and no difference was found between the two groups in terms of recovery profiles, including recovery time and other adverse events. CONCLUSIONS: Deep NMB and reversal with sugammadex improved the endoscopic surgical condition without complications compared with moderate NMB and reversal with sugammadex in patients undergoing TURB.

Type III interferons are critical host factors that determine susceptibility to Influenza A viral infection in allergic nasal mucosa.

BACKGROUND: Allergic respiratory conditions have been associated with increased susceptibility to viral infection due to impaired interferon (IFN)-related immune responses, but the mechanisms for reinforcement of mucosal immunity against viral infection in allergic diseases are largely unknown. OBJECTIVES: To determine whether IFN induction would be impaired in allergic nasal mucosa and to identify whether higher loads of influenza A virus (IAV) in allergic nasal mucosa could be controlled with IFN treatment. METHODS: Influenza A virus mRNA, viral titres and IFN expression were compared in IAV-infected normal human nasal epithelial (NHNE, N = 10) and allergic rhinitis nasal epithelial (ARNE, N = 10) cells. We used in vivo model of allergic rhinitis (BALB/c mice, N = 10) and human nasal mucosa from healthy volunteers (N = 72) and allergic rhinitis patients (N = 29) to assess the induction of IFNs after IAV infection. RESULTS: Influenza A virus mRNA levels and viral titres were significantly higher in ARNE compared with NHNE cells. IFN-ß and IFN-λs were induced in NHNE and ARNE cells up to 3 days after IAV infection. Interestingly, induction of IFN-λs mRNA levels and the amount of secreted proteins were considerably lower in ARNE cells. The mean IFN-λs mRNA level was also significantly lower in the nasal mucosa of AR patients, and we found that recombinant IFN-λ treatment attenuated viral mRNA levels and viral titres in IAV-infected ARNE cells. In vivoAR mouse exhibited higher viral load after IAV infection, but intranasal inoculation of IFN-λ completely decreased IAV protein expression and viral titre in nasal mucosa of IAV-infected AR mouse. CONCLUSION: Higher susceptibility of the allergic nasal mucosa to IAV may depend on impairment of type III IFN induction, and type III IFN is a key mechanistic link between higher viral loads and control of IAV infection in allergic nasal mucosa.

The Effect of Intraoperative Nefopam Administration on Acute Postoperative Pain and Chronic Discomfort After Robotic or Endoscopic Assisted Thyroidectomy: A Randomized Clinical Trial.

BACKGROUND: Acute postoperative pain and chronic discomfort are reported after robotic or endoscopic thyroidectomy. The purpose of this prospective, randomized, and double-blinded clinical trial was to investigate whether intraoperative infusion of nefopam decreases acute postoperative pain and chronic discomfort following either a robotic or endoscopic thyroidectomy via the bilateral axillo-breast approach (BABA). METHODS: Patients were randomized into two groups: The control group (n = 29) or the nefopam group (n = 29). Patients in each group were infused with the same volume of saline or nefopam (0.2 mg/kg bolus, 120 µg/kg/h continuous infusion) during surgery. Acute postoperative pain, the need for rescue analgesics, and other postoperative adverse effects were assessed at 1, 6, 24, and 48 h postoperatively. Chronic pain and discomfort was recorded at 3 months after surgery. RESULTS: Patients in the nefopam group reported lower pain scores in the neck, as well as the axilla and anterior chest areas at 1, 6, 24, and 48 h postoperatively, when compared with the control group (P < 0.05 at each time points). Rescue analgesics were required less in the nefopam group than in the control group (1.4 [1] vs. 2.3 [1.5]; P = 0.001). The degree of chronic pain and discomfort were relatively lower in the nefopam group (P < 0.05). CONCLUSION: We report that intravenous nefopam infusion during surgery decreased acute postoperative pain and the need for rescue analgesics, as well as chronic discomfort, following BABA robotic or endoscopic thyroidectomy without adverse events.

Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma.

Background: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored. Patients and methods: We investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes. Results: Here, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells. Conclusion: Taken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.

Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.

Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. Patients and methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate. Results: A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity. Conclusion: Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.

Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance.

BACKGROUND: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. METHODS: To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. RESULTS: Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression. CONCLUSIONS: Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.

Propagation Dynamics Associated with Resonant Magnetic Perturbation Fields in High-Confinement Mode Plasmas inside the KSTAR Tokamak.

The propagation dynamics of resonant magnetic perturbation fields in KSTAR H-mode plasmas with injection of small edge perturbations produced by a supersonic molecular beam injection is reported for the first time. The results show that the perturbation field first excites a plasma response on the q=3 magnetic surface and then propagates inward to the q=2 surface with a radially averaged propagation velocity of resonant magnetic perturbations field equal to 32.5 m/ s. As a result, the perturbation field brakes the toroidal rotation on the q=3 surface first causing a momentum transport perturbation that propagates both inward and outward. A higher density fluctuation level is observed. The propagation velocity of the resonant magnetic perturbations field is larger than the radial propagation velocity of the perturbation in the toroidal rotation.

A multicenter study on anaphylaxis caused by peanut, tree nuts, and seeds in children and adolescents.

Peanut (PN) and tree nuts (TNs) are common causes of anaphylaxis in Western countries, but no information is available in Korea. To feature clinical characteristics of anaphylaxis caused by PN, TNs, and seeds, a retrospective medical record review was performed in 14 university hospitals in Korea (2009-2013). One hundred and twenty-six cases were identified, with the mean age of 4.9 years. PN, walnut (WN), and pine nut accounted for 32.5%, 41.3%, and 7.1%, respectively. The median values of specific IgE (sIgE) to PN, WN, and pine nut were 10.50, 8.74, and 4.61 kUA /l, respectively. Among 50 cases managed in the emergency department, 52.0% were treated with epinephrine, 66.0% with steroid, 94.0% with antihistamines, 36.0% with oxygen, and 48.0% with bronchodilator. In conclusion, WN, PN, and pine nut were the three most common triggers of anaphylaxis in Korean children, and anaphylaxis could occur at remarkably low levels of sIgE.

Biological characteristics of Bacillus amyloliquefaciens AK-0 and suppression of ginseng root rot caused by Cylindrocarpon destructans.

AIMS: The effect of Bacillus amyloliquefaciens AK-0 (AK-0) on ginseng root rot disease caused by Cylindrocarpon destructans was investigated. METHODS AND RESULTS: From 190 ginseng rhizosphere bacteria, AK-0 was selected for further analysis; its morphological characteristics were investigated by microscopy. AK-0 was identified as B. amyloliquefaciens using the Biolog system, 16S rRNA gene sequence analysis and examination of morphological and biochemical characteristics. Bacterial population and media optimization were estimated by the bacterial growth curve. The number of AK-0 cells was relatively higher in brain-heart infusion (BHI) medium than in other media. The potential antifungal effect of AK-0 culture filtrate on the in vitro conidial germination of C. destructans and root rot development on root discs and 4-year-old ginseng roots were assessed. Polymerase chain reaction (PCR) analysis of antibiotic biosynthesis gene expression suggested that the release of antibiotic compounds is involved in the antifungal effect of AK-0 and the suppression of ginseng root rot. CONCLUSION: These results indicate that the CF of AK-0 has antifungal effects on fungal pathogens of ginseng, resulting in the suppression of root rot disease caused by C. destructans. SIGNIFICANCE AND IMPACT OF THE STUDY: AK-0 is a potential source of novel bioactive metabolites. AK-0 CF exhibited antifungal effects against C. destructans on ginseng roots. PCR analysis indicated that the AK-0 harbours genes involved in the biosynthesis of antimicrobial compounds.