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Objective: Current standard nonsurgical management of endometrial intraepithelial neoplasia (EIN) and grade 1 endometrioid endometrial cancer (g1EEC) is the Mirena levonorgestrel intrauterine device (M−IUD). This retrospective study was designed primarily to determine noninferiority of the Liletta IUD (L-IUD) for pathologic regression of EIN and g1EEC compared to the M−IUD at 6 months of continuous use. Secondary objectives include to determine noninferiority as above at 3, 9, and 12 months of continuous use and to identify factors including DNA mismatch repair (MMR) status associated with pathologic regression after LNG-IUD use. Methods: A retrospective observational study was performed with patients treated for EIN or g1EEC and managed continuously with M- or L-IUD. Patients with recent (within 6 months) or concurrent progesterone use were excluded. For the EIN group, the noninferiority margin of odds ratio was predetermined to be 0.58, and for the g1EEC group it was 0.64. Results: 62 patients from an academic center and a safety-net hospital were identified with continuous M−IUD (n = 44) or L-IUD (n = 18) use for EIN or g1EEC. 85% of patients treated with L-IUD were from a safety-net hospital, which had 63% with public insurance. At 3/6/9 months, 54/71/73% of patients with M−IUD and 80/83/100% with L-IUD had pathologic regression of EIN (95% confidence interval of estimated odds ratio 1.00–2.07/0.84–2.03/0.69–2.10). Lifetime smoking status, not MMR status, was significantly associated with pathologic regression. Conclusions: L-IUD is an effective fertility-sparing treatment for EIN. L-IUD is noninferior to M−IUD for pathologic regression of EIN after 3,6, and 9 months. Further larger studies are warranted to validate findings in EIN and g1EEC.

The 'rule-of-6' prediction tool was shown to be able to identify COVID-19 patients at risk of adverse outcomes. During the pandemic, we frequently observed hyponatremia at presentation. We sought to evaluate if adding hyponatremia at presentation could improve the 'rule-of-6' prediction tool. We retrospectively analysed 1781 consecutive patients admitted to a single tertiary academic institution in Singapore with COVID-19 infection from February 2020 to October 2021. A total of 161 (9.0%) patients had hyponatremia. These patients were significantly older, with more co-morbidities and more likely to be admitted during the Delta wave (2021). They were more likely to have radiographic evidence of pneumonia (46.0% versus 13.0%, p < 0.001) and more adverse outcomes (25.5% vs. 4.1%, p < 0.001). Hyponatremia remained independently associated with adverse outcomes after adjusting for age, lack of medical co-morbidities, vaccination status, year of admission, CRP, LDH, and ferritin. The optimised cut-off for serum sodium in predicting adverse outcomes was approximately <135 mmol/L as determined by the Youden index. Although derived in early 2020, the 'rule-of-6' prediction tool continued to perform well in our later cohort (AUC: 0.72, 95%CI: 0.66-0.78). Adding hyponatremia to the 'rule-of-6' improved its performance (AUC: 0.76, 95%CI: 0.71-0.82). Patients with hyponatremia at presentation for COVID-19 had poorer outcomes even as new variants emerged.

We present the development and validation of an impedance-based urine osmometer for accurate and portable measurement of urine osmolality. The urine osmolality of a urine sample can be estimated by determining the concentrations of the conductive solutes and urea, which make up approximately 94% of the urine composition. Our method utilizes impedance measurements to determine the conductive solutes and urea after hydrolysis with urease enzyme. We built an impedance model using sodium chloride (NaCl) and urea at various known concentrations. In this work, we validated the accuracy of the impedance-based urine osmometer by developing a proof-of-concept first prototype and an integrated urine dipstick second prototype, where both prototypes exhibit an average accuracy of 95.5 ± 2.4% and 89.9 ± 9.1%, respectively in comparison to a clinical freezing point osmometer in the hospital laboratory. While the integrated dipstick design exhibited a slightly lower accuracy than the first prototype, it eliminated the need for pre-mixing or manual pipetting. Impedance calibration curves for conductive and non-conductive solutes consistently yielded results for NaCl but underscored challenges in achieving uniform urease enzyme coating on the dipstick. We also investigated the impact of storing urine at room temperature for 24 hours, demonstrating negligible differences in osmolality values. Overall, our impedance-based urine osmometer presents a promising tool for point-of-care urine osmolality measurements, addressing the demand for a portable, accurate, and user-friendly device with potential applications in clinical and home settings.

Introduction: Early in the coronavirus disease 2019 (COVID-19) pandemic, a low incidence of cardiovascular complications was reported in Singapore. Little was known about the trend of cardiovascular complications as the pandemic progressed. In this study, we examined the evolving trends in electrocardiographic and cardiovascular manifestations in patients hospitalised with COVID-19., Methods: We examined the first 1781 consecutive hospitalised patients with polymerase chain reaction-confirmed COVID-19. We divided the population based on whether they had abnormal heart rate (HR) or electrocardiography (ECG) or normal HR and ECG, comparing the baseline characteristics and outcomes. Cardiovascular complications were defined as acute myocardial infarction, stroke, pulmonary embolism, myocarditis and mortality., Results: The 253 (14.2%) patients who had abnormal HR/ECG at presentation were more likely to be symptomatic. Sinus tachycardia was commonly observed. Troponin I levels (97.0 ± 482.9 vs. 19.7 ± 68.4 ng/L, P = 0.047) and C-reactive protein levels (20.1 ± 50.7 vs. 13.9 ± 24.1 μmol/L, P = 0.003) were significantly higher among those with abnormal HR/ECGs, with a higher prevalence of myocarditis (2.0% vs. 0.5%, P = 0.019), pulmonary embolism (2.0% vs. 0.3%, P = 0.008) and acute myocardial infarction (1.2% vs. 0.1%, P = 0.023). After adjusting for age and comorbidities, abnormal HR/ECG (adjusted odds ratio 4.41, 95% confidence interval 2.21-8.77; P < 0.001) remained independently associated with adverse cardiovascular complications. Over time, there was a trend towards a higher proportion of hospitalised patients with cardiovascular complications., Conclusion: Cardiovascular complications appear to be increasing in proportion over time among hospitalised patients with COVID-19. A baseline ECG and HR measurement may be helpful for predicting these complications., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Objective: This in vitro study aimed to quantitatively and qualitatively evaluate and compare the horizontal and vertical accuracies of complete-arch casts produced by six 3D printers with different printing principles and resolutions using a low-viscosity resin material., Methods: A reference cast was designed by CAD software. The 3D printers used were DLPa (Asiga MAX), DLPk (cara Print 4.0), LCD2o (Ondemand 2 K Printer), LCD2p (Photon Mono X), LCD4s (SONIC 4 K), and SLA (ZENITH U). Ten casts were printed for each 3D printer using a low-viscosity resin. The accuracy of each printed cast was evaluated using shell-to-shell deviations, 12 linear, one angular, and five height deviations, with a reference cast as the control. The surface features of the casts were examined using field-emission scanning electron microscopy (FE-SEM) and digital cameras., Results: The evaluation of shell-to-shell deviation revealed that DLPa and SLA printers exhibited low trueness values, whereas LCD printers displayed high trueness values. Among the LCD printers, LCD4s and LCD2o exhibited the lowest and highest trueness values, respectively. DLPa printers showed lower trueness values for intercanine and intermolar distances, whereas LCD printers generally demonstrated high trueness values. However, LCD4s exhibited similar trueness values to those of SLA and DLPk. The height deviation was smallest in the anterior area, whereas the largest height deviation occurred in the canine teeth. The surface characteristics indicated that the SLA casts had greater light reflection and blunt canine tips. The FE-SEM observations highlighted that the LCD and DLP printers exhibited varying layer characteristics, with some presenting rough and uneven borders in the anterior lingual area., Significance: The accuracy of 3D printed casts varied among the 3D printer groups: DLPa and SLA were accurate for shell-to-shell deviation, with DLPa being the most accurate for linear and angular deviations. Regardless of the XY resolution, the DLP printers outperformed the LCD printers. Among the LCD group of 3D printers, higher-resolution LCD4s demonstrated increased accuracy. The SLA exhibited soft layer borders in the FE-SEM owing to its laser spot characteristics and prominent light reflection in the digital camera images., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ji-Man Park reports financial support was provided by Korea Medical Device Development Fund., (© 2024 Published by Elsevier Ltd.)

Objectives: In critically ill patients with COVID-19, distinct hyperinflammatory and hypoinflammatory phenotypes have been described, with different outcomes and responses to therapy. We investigated if similar phenotypes exist in non-severe illness., Methods: Consecutive patients with polymerase chain reaction (PCR) confirmed SARS-CoV-2 were examined. Baseline demographics and laboratory investigations were tabulated, including serum C-reactive protein. Patients were divided into those who were hyperinflammatory (defined as C-reactive protein >17 mg/l) or hypoinflammatory. Adverse outcomes, defined as requiring oxygenation, intensive care, or death, were recorded during the hospital stay. Clinical characteristics and outcomes were compared., Results: Of the 1781 patients examined, 276 (15.5%) had a hyperinflammatory phenotype. They were older (51.8 ± 17.2 vs 40.3 ± 13.8 years, P <0.001), had a lower PCR cycle threshold (PCR cycle threshold value 19.3 ± 6.3 vs 22.7 ± 15.4, P  = 0.025) at presentation, and more medical comorbidities. The hyperinflammatory phenotype was independently associated with adverse clinical outcomes, even after adjusting for age, medical history and viral load on multivariable analyses (adjusted odds ratio 5.78, 95% confidence interval 2.86-11.63)., Conclusion: Even in non-severe COVID-19, there are distinct hyper- and hypoinflammatory phenotypes, with the hyperinflammatory phenotype strongly associated with adverse clinical outcomes, that could be distinguished with a simple biomarker., Competing Interests: The authors have no competing interest to declare., (© 2023 The Author(s).)

Objectives: In the early months of the COVID-19 pandemic in Singapore, the vast majority of infected persons were migrant workers living in dormitories who had few medical comorbidities. In 2021, with the Delta and Omicron waves, this shifted to the more vulnerable, elderly population within the local community. We examined evolving trends among the hospitalised cases of COVID-19., Methods: All patients with polymerase chain reaction-positive SARS-CoV-2 admitted from February 2020 to October 2021 were included and subsequently stratified by their year of admission (2020 or 2021). We compared the baseline clinical characteristics, clinical course, and outcomes., Results: A majority of cases were seen in 2020 (n = 1359), compared with 2021 (n = 422), due to the large outbreaks in migrant worker dormitories. Nevertheless, the greater proportion of locally transmitted cases outside of dormitories in 2021 (78.7% vs 12.3%) meant a significantly older population with more medical comorbidities had COVID-19. This led to an observably higher proportion of patients with severe disease presenting with raised inflammatory markers, need for therapeutics, supplemental oxygenation, and higher mortality., Conclusion: Changing demographics and the characteristics of the exposed populations are associated with distinct differences in clinical presentation and outcomes. Older age remained consistently associated with adverse outcomes., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dentistry requires high manual dexterity, and few studies have investigated the challenges and impact on dental students of attaining manual dexterity skills. This study aimed to investigate dental students' perceptions of manual dexterity, including their awareness of manual dexterity requirements in dentistry, self-perceptions of manual dexterity competency, and whether manual dexterity should be part of admission to dentistry training. A link to a 12-item online Qualtrics survey was sent out to students in either their 2nd or 5th year of the Bachelor of Dental Surgery (BDS) degree at the University of Otago, New Zealand. The anonymous survey collected basic demographic data and included closed and open-ended questions about manual dexterity. Descriptive statistics were calculated for quantitative variables and a general inductive approach was used to analyze free-text responses. Those were later grouped into a theoretical domain framework. The overall response rate was 53%. All participants acknowledged the importance of manual dexterity in dentistry. Most participants thought that manual dexterity can be improved with practice and that including a manual dexterity test in the admission criteria may cause unnecessary stress for students. Striving to achieve manual dexterity impacted participants' performance in the BDS course. However, most participants viewed it as a challenge that can be overcome with practice and improvement, and that current BDS admission requirements are sufficient., (© 2022 The Authors. Journal of Dental Education published by Wiley Periodicals LLC on behalf of American Dental Education Association.)

Background: Infections following cardiac implantable electronic device (CIED) implantation can require surgical device removal and often results in significant cost, morbidity, and potentially mortality. We aimed to systemically review the literature and identify risk factors associated with mortality following CIED infection., Methods: Electronic searches (up to June 2021) were performed on PubMed and Scopus. Twelve studies (10 retrospective, 2 prospective cohort studies) were included for analysis. Meta-analysis was conducted with the restricted maximum likelihood method, with mortality as the outcome. The overall mortality was 13.7% (438/1398) following CIED infection., Results: On meta-analysis, the male sex (OR 0.77, 95%CI 0.57-1.01, I 2 = 2.2%) appeared to have lower odds for mortality, while diabetes mellitus appeared to be associated with higher mortality (OR 1.47, 95%CI 0.67-3.26, I 2 = 81.4%), although these trends did not reach statistical significance. Staphylococcus aureus as the causative organism (OR 2.71, 95%CI 1.76-4.19, I 2 = 0.0%), presence of heart failure (OR 1.92, 95%CI 1.42-4.19, I 2 = 0.0%) and embolic phenomena (OR 4.00, 95%CI 1.67-9.56, I 2 = 69.8%) were associated with higher mortality. Surgical removal of CIED was associated with lower mortality compared with conservative management with antibiotics alone (OR 0.22, 95%CI 0.09-0.50, I 2 = 62.8%)., Conclusion: We identified important risk factors associated with mortality in CIED infections, including Staphyloccocus aureus as the causative organism, and the presence of complications, such as heart failure and embolic phenomena. Surgery, where possible, was associated with better outcomes.

Background: Infective endocarditis (IE) confers significant mortality and morbidity in patients with underlying mitral stenosis (MS), with both diseased native valves and after valvular procedures., Purpose: We examined the clinical and echocardiographic parameters in association with the development of IE on patients with significant MS., Methods: A total of 478 consecutive patients with index echocardiographic diagnosis of significant mitral stenosis (mitral valve area <1.5 cm 2 ) were included. Patients were grouped into those with or without IE on at least 5 years of follow-up. Baseline clinical, echocardiographic profile and clinical outcomes were compared., Results: IE was observed in 4.4% (n = 21) of the cohort. These patients were younger (45.3 ± 14.6 vs. 53.2 ± 15.5 years, p = 0.022) at the time of MS diagnosis. NT-proBNP was higher in patients who developed IE (13529 ± 12230 vs. 4381 ± 5875 pg/ml, p < 0.001), with larger left atrial diameter (54.4 ± 10.1 vs. 49.9 ± 9.5 mm, p = 0.040) and elevated pulmonary artery systolic pressure (PASP, 62.3 ± 17.2 vs. 47.2 ± 16.5 mmHg, p = 0.026). There was no significant difference in terms of MS severity, other concomitant valvulopathies, or etiology (rheumatic or degenerative) of MS. Patients who smoked had higher incidence of IE (33.3% vs. 14.2%, log-rank 7.27, p = 0.007). After adjusting for age, valve procedure and PASP, patients who smoked remained at elevated risk of IE (adjusted hazards ratio 2.99, 95% confidence interval 1.18-7.56, p = 0.021)., Conclusion: IE occurs in a proportion of patients with MS. Smoking, younger age of diagnosis of MS as well as dilated left atria with elevated PASP may be associated with an elevated risk of this complication., (© 2021 Wiley Periodicals LLC.)

Easy access to screening for timely identification and isolation of infectious COVID-19 patients remains crucial in sustaining the international efforts to control COVID-19 spread. A major barrier limiting broad-based screening is the lack of a simple, rapid, and cost-effective COVID-19 testing method. We evaluated the feasibility and utility of facemask sampling in a cohort of 42 COVID-19-positive and 36 COVID-19-negative patients. We used a prototype of Steri-Strips™ (3 M) applied to the inner surface of looped surgical facemasks (Assure), which was worn by patients for a minimum wear time of 3 h, then removed and sent for SARS-CoV-2 PCR testing. Baseline demographics and symptomatology were also collected. Facemask sampling positivity was highest within the first 5 days of symptomatic presentation. Patients with nasopharyngeal and/or oropharyngeal swab SARS-CoV-2 PCR Ct values < 25.09 had SARS-CoV-2 detected on facemask sampling, while patients with Ct values ≥ 25.2 had no SARS-CoV-2 detected on facemask sampling. Facemask sampling can identify patients with COVID-19 during the early symptomatic phase or those with high viral loads, hence allowing timely identification and isolation of those with the highest transmission risk. Given the widespread use of facemasks, this method can potentially be easily applied to achieve broad-based, or even continuous, population screening., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Mental illness among survivors of coronavirus disease 2019 (COVID-2019) during the post-illness period is an emerging and important health issue., Aims: We aimed to investigate the prevalence of mental illness and the associated factors for its development among COVID-2019 survivors., Method: From 1 January to 4 June 2020, data were extracted from the National Health Insurance Service COVID-19 database in South Korea. Patients with COVID-19 were defined as those whose test results indicated that they had contracted the infection, regardless of disease severity. COVID-19 survivors were defined as those who recovered from the infection. The primary end-point was the development of mental illness, which was evaluated between 1 January and 1 December 2020., Results: A total 260 883 individuals were included in this study, and 2.36% (6148) were COVID-19 survivors. The COVID-19 survivors showed higher prevalence of mental illness than the control group (12.0% in the COVID-19 survivors v. 7.7% in the control group; odds ratio (OR) = 2.40, 95% CI 2.21-2.61, P < 0.001). Additionally, compared with the control group, the no specific treatment for COVID-19 group (OR = 2.23, 95% CI 2.03-2.45, P < 0.001) and specific treatment for COVID-19 group (OR = 3.27, 95% CI 2.77-3.87, P < 0.001) showed higher prevalence of mental illness among survivors., Conclusions: In South Korea, COVID-19 survivors had a higher risk of developing mental illness compared with the rest of the populations. Moreover, this trend was more evident in COVID-19 survivors who experienced specific treatment in the hospital., Competing Interests: None, (© The Author(s) 2021.)

Background and Rationale: Uncertainty persists over the optimal management of blood pressure (BP) in the early phase of acute ischemic stroke (AIS). This study aims to determine the safety and effects of intensive BP lowering on cerebral blood flow (CBF) and functional in AIS patients treated with intravenous thrombolysis., Methods: In a randomized controlled trial, 54 thrombolysed AIS patients with a systolic BP of 160 to 180 mm Hg will be randomized to early intensive BP lowering (systolic target range 140-160 mm Hg) or guideline-based BP management (systolic range 160-180 mm Hg) during first 72-hours using primarily intravenous labetalol. We hypothesize that early intensive BP lowering will not reduce CBF by 20% and/or increase the volume of hypoperfused tissue by >20% on computed tomographic perfusion. Clinical outcome will be assessed using a dichotomized modified Rankin scale (scores 0-1 as excellent outcome vs scores 2-6 as dead or dependent) at 90 days. Other outcome would be symptomatic intracerebral hemorrhage. The trial is registered at ClinicalTrials.gov, NCT03443596., Conclusion: This randomized study will provide important information about the physiological effects of BP reduction on cerebral perfusion after intravenous thrombolysis in AIS.

Constitutive activation of the NF-κB signaling cascade is associated with tumourigenesis and poor prognosis in many human cancers including RCC. YM155, a small molecule inhibitor of survivin, was previously shown to potently inhibit the viability of immortalized and patient derived renal cell carcinoma (RCC) cell lines. Here we investigated the role of NF-κB signaling to the anti-cancer properties of YM155 in RCC786.0 cells. YM155 diminished nuclear levels of p65 and phosphorylated p65 and attenuated the transcriptional competencies of the p65/p50 heterodimers. Accordingly, we found that YM155 diminished the transcription of NF-κB target gene survivin. Events that led to the interception of the nuclear translocation of p65/p50 were the activation of the deubiquinating enzyme CYLD by YM155, which led to the inhibition of IKKβ, stabilization of IκBα and retention of NF-κB heterodimers in the cytosol. Importantly, the suppressive effects of YM155 were time-dependent and observed at the 24 h time point, and not earlier. TNF-α, a stimulator of NF-κB signaling did not affect its inhibitory properties. The ability of YM155 to intercept a major transcriptional pathway like NF-κB, would have important ramifications on the pharmacodynamics effects elicited by this unusual molecule.

Introduction: Psychotic spectrum disorder (PSD) links the syndromes of bipolar disorder, psychotic depression, and schizophrenia, often viewed as unique disorders., Aims: Application of the PSD concept to a single patient rather than across groups of patients and demonstration of a remarkable remission of schizophrenia phenotype with recovery of gray matter in specific brain regions., Results: We report a woman who experienced discrete, nonoverlapping periods of each of the above syndromes, in the order noted, over a 30-year period, followed by abrupt ending of psychosis and full remission lasting at least 7 years. This patient had 2 episodes of Bipolar 1 mania, followed by a 20-year period of psychotic depression. From ages 35-48, she manifested severe, paranoid schizophrenia with marked functional decline. She became refractory to antipsychotic drugs, including oral risperidone and clozapine. At age 48, while participating in a double-blind, 6-month clinical trial of long-acting injectable risperidone (Consta®, 100 mg IM biweekly) for treatment-resistant schizophrenia, at week 23, upon awakening, complete disappearance of psychosis and marked improvement in function was noted, which persisted until the present (approximately 7 years). Remarkably, cognitive test performance in most domains improved beginning at 6 weeks and reached normal levels in executive function, despite minimal improvement in psychosis until week 23. MRI studies before and after remission revealed unique and substantial increases in gray matter of the cingulate and parietal cortex, and subthalamic nucleus, not seen in other patients in this study., Conclusions: The 3 discrete periods of psychopathology support the diagnosis of PSD. The unusual course and outcome, including remarkable improvement, in executive function and enhanced cortical gray matter in selective brain regions may have been the result of unique endogenous genetic and epigenetic factors and effect of medication., (© 2018 John Wiley & Sons Ltd.)

Aim: To investigate the effect of dioxonaphthoimidazolium analog YM155 on cell cycle progression of the clear-cell variant of renal cell carcinoma (ccRCC)., Main Methods: Cell cycle analysis was performed using bromodeoxyuridine (BrdU) and PI, apoptosis initiation was monitored using Annexin V and proteins expression was determined using western immunoblotting., Key Findings: Here, we showed that YM155 activated stress-related molecules (histone H2AX, checkpoint kinases Chk1 and Chk2, p53) that mediate DNA damage checkpoint responses. The coordinated activation of these effector molecules disrupts progression of the cell cycle at the S phase as deduced from BrdU pulsing experiments and the ensuing changes in the levels of proteins (cyclins, CDKs, CDK inhibitors, phosphatases) that control cell cycle progression. Notably, we found increases in cyclin E and Cdc2 which regulate transition of cells from G1 to S, even as losses were observed for other CDKs and their cyclin partners. Furthermore, by inducing a loss in total pRb possibly by promoting its degradation, YM155 promoted the E2F transcription of genes that regulate entry into the S phase. After 24 h, cell cycle arrest to repair YM155-inflicted DNA damage was overtaken by p53-mediated apoptosis. YM155 induced increases in pro-apoptotic proteins (Bax and Bad), diminished anti-apoptotic proteins (Mcl-1, Bcl-xl, XIAP, survivin) and initiated cleavage of apoptotic marker proteins caspase 3 and PARP., Significance: Taken together, the added insight provided on the cell cycle perturbative effects of YM155 may assist clinicians in framing rational choices for combining YM155 with other anti-cancer drugs or treatment modalities in ccRCC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Some studies have provided evidence for a possible association between vitamin D and testosterone levels; however, the evidence from studies in Koreans is inconsistent. In addition, insufficient evidence is available to support an association between seasonal variations in vitamin D and testosterone levels in Koreans. Therefore, we aimed to investigate the association between vitamin D and testosterone levels, and between seasonal variations in these levels in Korean men., Methods: This cross-sectional study included 1,559 men, aged 25-86 years, who underwent a medical examination. We measured serum 25-hydroxyvitamin D (25[OH]D) and total testosterone levels, and compared other laboratory test results and patient lifestyle characteristics. On the basis of sample collection time, we categorized patients into four seasons, and analyzed seasonal variability in 25(OH)D and total testosterone levels., Results: The average participant age (±standard deviation) was 53.3±8.8 years, and the average serum 25(OH)D and total testosterone levels were 15.9±7.0 ng/mL and 5.1±1.6 ng/mL, respectively. In the analysis of variance (ANOVA) model, no significant association was found between 25(OH)D and testosterone levels (P=0.51). ANOVA of the average 25(OH)D levels in season-based groups revealed significant seasonal variations in 25(OH)D levels (P-value for trend <0.001). No significant association was found between seasonal variations in total testosterone levels (P=0.06). However, after adjustment for confounding variables, total testosterone and 25(OH)D showed significant seasonal variability (P=0.007 and P<0.001, respectively)., Conclusion: We found no significant correlation between serum 25(OH)D and total testosterone levels in Korean men. Moreover, serum 25(OH)D and total testosterone levels showed significant seasonal variations., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

The dioxonapthoimidazolium YM155 is a survivin suppressant which has been investigated as an anticancer agent in clinical trials. Here, we investigated its growth inhibitory properties on a panel of immortalized and patient derived renal cell carcinoma (RCC) cell lines which were either deficient in the tumour suppressor von Hippel-Lindau (VHL) protein or possessed a functional copy. Neither the VHL status nor the survivin expression levels of these cell lines influenced their susceptibility to growth inhibition by YM155. Of the various RCC lines, the papillary subtype was more resistant to YM155, suggesting that the therapeutic efficacy of YM155 may be restricted to clear cell subtypes. YM155 was equally potent in cells (RCC786.0) in which survivin expression had been stably silenced or overexpressed, implicating a limited reliance on survivin in the mode of action of YM155. A follow-up in-vitro high throughput RNA microarray identified possible targets of YM155 apart from survivin. Selected genes (ID1, FOXO1, CYLD) that were differentially expressed in YM155-sensitive RCC cells and relevant to RCC pathology were validated with real-time PCR and western immunoblotting analyses. Thus, there is corroboratory evidence that the growth inhibitory activity of YM155 in RCC cell lines is not exclusively mediated by its suppression of survivin. In view of the growing importance of combination therapy in oncology, we showed that a combination of YM155 and sorafenib at ½ x IC50 concentrations was synergistic on RCC786.0 cells. However, when tested intraperitoneally on a murine xenograft model derived from a nephrectomised patient with clear cell RCC, a combination of suboptimal doses of both drugs failed to arrest tumour progression. The absence of synergy in vivo highlighted the need to further optimize the dosing schedules of YM155 and sorafenib, as well as their routes of administration. It also implied that the expression of other oncogenic proteins which YM155 may target is either low or absent in this clear cell RCC.

Context: The benefit of estrogen therapy in postmenopausal women is still uncertain. Based upon extensive observational data, it was believed that estrogen was cardioprotective. The relationship between the period of exposure to endogenous estrogens and the risk of cardiovascular disease (CVD) has not been studied in Korean women., Objective: To assess associations between reproductive lifespan and CVD by using the Framingham risk score (FRS) in postmenopausal Korean women., Design and Setting: This cross-sectional, population-based study used data from the Korea National Health and Nutrition Examination Survey (KNHANES) for the five years 2008-2012,after adjustment for relevant variables using complex sample analysis and data weighting., Participants: Among 25,534 women, 1973 women were enrolled, after excluding those <20 or >80 years of age (n=6194), those with diabetes, CVD or cancer (n=491), those with unrecorded physical measurements (n=7335), those with menarche age ≤8 years or ≥20 years (n=6194), and premenopausal women (n=3347)., Results: The FRS tended to show a significant negative correlation with the reproductive lifespan (p<0.001). In multiple linear regression analysis, a negative correlation was observed between the reproductive lifespan and FRS (adjusted relative risk [RR] for <28 reproductive years [shortest lifespan group] compared with 28-33 reproductive years [moderate lifespan group], 1.2, p<0.001 and adjusted RR for >33 reproductive years [longest lifespan group] compared with 28-33 reproductive years [moderate lifespan group], -0.42, p=0.011)., Conclusion: A longer reproductive lifespan is associated with a lower estimated risk of CVD in the next 10 years in postmenopausal women. This result suggests that estrogen has a long-term protective effect against CVD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The anticancer agent YM155 is widely investigated as a specific survivin suppressant. More recently, YM155 was found to induce DNA damage and this has raised doubts as to whether survivin is its primary target. In an effort to assess the contribution of DNA damage to the anticancer activity of YM155, several analogs were prepared and evaluated for antiproliferative activity on malignant cells, participation in DNA intercalation and free radical generation by redox cycling. The intact positively charged scaffold was found to be essential for antiproliferative activity and intercalation but was less critical for redox cycling where the minimal requirement was a pared down bicyclic quinone. Side chain requirements at the N(1) and N(3) positions of the scaffold were more alike for redox cycling and intercalation than antiproliferative activity, underscoring yet again, the limited structural overlaps for these activities. Furthermore, antiproliferative activities were poorly correlated to DNA intercalation and redox cycling. Potent antiproliferative activity (IC50 9-23 nM), exceeding that of YM155, was found for a minimally substituted methyl analog AB7. Like YM155 and other dioxonaphthoimidazoliums, AB7 was a modest DNA intercalator but with weak redox cycling activity. Thus, the capacity of this scaffold to inflict direct DNA damage leading to cell death may not be significant and YM155 should not be routinely classified as a DNA damaging agent., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Serotonin (5-HT)2C receptors in brain affect psychosis, reward, substance abuse, anxiety, other behaviors, appetite, body temperature, and other physiological measures. They also have been implicated in antipsychotic drug efficacy and side effects. We previously reported that the hyperthermia following administration of MK-212, a predominantly 5-HT(2C) receptor agonist, was diminished in a small sample of patients with schizophrenia (SCH), suggesting decreased 5-HT(2C) receptor responsiveness. We have now studied the responses to oral MK-212 and placebo in a larger sample of unmedicated male SCH (n = 69) and normal controls (CON) (n = 33), and assessed the influence of comorbid substance abuse (SA) on oral body temperature, behavioral responses, etc. The placebo-adjusted oral body temperature response to MK-212 was significantly lower in SCH compared to CON and not significantly different between the SCH with or without SA. Some behavioral responses to MK-212, e.g. self-rated feelings of increased anxiety, depression and decreased calmness, or good overall feeling, were significantly lower in the SCH patients compared to CON. These results add to the evidence for diminished 5-HT(2C) receptor responsiveness in SCH patients compared to CON and are consistent with reported association of HTR(2C) polymorphisms, leading to decreased expression or function of the HTR(2C) in patients with SCH., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: We hypothesised that CD1d expression in renal cell carcinoma (RCC) may play a role in modifying the host immune response. Our aims were to investigate the expression of CD1d and to correlate this with histopathology and clinical outcomes in a cohort study of patients with RCC., Methods: Gene expression and tissue microarray studies on a panel of RCC tissue were performed. Clinicopathological correlation was analysed using χ(2)/Fisher's exact test. Relapse-free survival, cancer-specific survival and overall survival were calculated for both CD1d high and low expressors. Survival outcomes were estimated with the Kaplan-Meier method and compared using Cox regression analysis., Results: Gene expression microarray showed significant expression of CD1d in RCC versus normal renal tissue. By immunohistochemistry, we found that CD1d expression significantly associated with tumour stage/grade, higher relapse rates, poorer cancer-specific and overall survival., Conclusions: CD1d expression on RCC correlated with aggressive disease and poorer clinical outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Sorafenib, a multikinase inhibitor, is currently used as monotherapy for advanced renal cell carcinoma (RCC). However, adverse effects associated with its use have been experienced by some patients. In this study, we examined the antitumor and antiangiogenic activities of low-dose sorafenib in combination with the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244 induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation of VEGFR-2, PDGFR-β and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244 also caused upregulation of p27, Bad and Bim but downregulation of survivin and cyclin B1. These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth. This study provides sound evidence for the clinical investigation of low-dose sorafenib in combination with AZD6244 in patients with advanced RCC.

Background: The efficacy, safety and tolerability of adjunctive armodafinil for cognitive performance, and negative and affective symptoms, were examined in 60 patients with schizophrenia or schizoaffective disorder., Method: This was a 6-week, double-blind, placebo-controlled, fixed dose trial of armodafinil (150 mg/d) augmentation in patients with clinically stable schizophrenia or schizoaffective disorder. Cognition, psychopathology, alertness/wakefulness and adverse effects were assessed with standardized rating instruments. The primary endpoint was performance on measures of attention/vigilance., Results: Patients were randomly allocated to adjunctive armodafinil or placebo. There was a significant Drug×Time interaction effect for attention/vigilance, due to modest non-significant worsening in the armodafinil group and improvement in the armodafinil group [CPT-Pairs d', F(1,40)=6.2, p=0.017]. However, it became non-significant after correction for multiple comparisons. There were no differences between armodafinil and placebo in other cognitive domains or psychopathology measures. However, armodafinil was associated with significant improvement in the Scale for the Assessment of Negative Symptoms (SANS) anhedonia-asociality [F(1,41)=4.1, p=0.05]., Conclusions: There were no significant differences in neurocognitive measures between adjunctive armodafinil and placebo in this 6-week study. Armodafinil improved anhedonia-asociality, but not other negative symptom domains., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient-derived RCC xenografts to delineate the angiogenic and non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC)., Methods: We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides., Results: All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-β, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells., Conclusion: This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects.

The main objective of this study was to determine whether active NH(4) (+) excretion occurred in the giant mudskipper, Periophthalmodon schlosseri, during emersion. Our results demonstrated that continual ammonia excretion in P. schlosseri during 24 hr of emersion resulted in high concentrations ( approximately 30 mmol l(-1)) of ammonia in fluid collected from the branchial surface. For fish injected intraperitoneally with 8 mumol g(-1) ammonium acetate (CH3COONH4) followed by 24 hr of emersion, the cumulative ammonia excreted was significantly greater than that of the control injected with sodium acetate. More importantly, the ammonia excretion rate at hour 2 in fish injected with CH3COONH4 followed by emersion was greater than that in fish immersed in water as reported elsewhere, with the greatest change in the ammonia excretion rate occurring at hour 2. Assuming that the rate of endogenous ammonia production remained unchanged, 33% of the exogenous ammonia was excreted through the head region, presumably through the gills, during the first 6 hr of emersion. Indeed, at hour 6, the ammonia concentration in the branchial fluid increased to an extraordinarily high concentration of >90 mmol l(-1). Therefore, our results confirm for the first time that P. schlosseri can effectively excrete a high load of ammonia on land, and corroborate the proposition that active NH(4) (+) excretion through its gills contributes in part to its high tolerance of aerial exposure. Only 4.6% of the exogenous ammonia was detoxified to urea. The glutamate contents in the muscle and liver also increased significantly, but the glutamine contents remained unchanged., ((c) 2007 Wiley-Liss, Inc.)

This study was conducted to investigate the different effects of ectomycorrhizal fungal (ECMF) species on the growth of seedlings of Pinus densiflora, and the effects of ECMF diversity on plant productivity. A total of five species of ECMF were isolated from root tips of pine seedlings collected from Mt. Songni and used as inocula. Pots containing pine seedlings were inoculated with either a single ECMF species or a mixture of five ECMF species. All of the seedlings formed ECM on their roots except for the control plants. The pine seedlings' growth responses varied by the different ECMF species. Also, pine seedlings inoculated with a mixture of five ECMF species showed the highest growth response. The results of the study suggest that the colonization of diverse species of ECMF will increase plant productivity, and the selection of suitable ECMF species could be an important factor for plant growth.

A combined transcriptome and proteome analysis was carried out to identify key genes and proteins differentially expressed in Chinese hamster ovary (CHO) cells producing high and low levels of dhfr-GFP fusion protein. Comparison of transcript levels was performed using a proprietary 15K CHO cDNA microarray chip, whereas proteomic analysis was performed using iTRAQ quantitative protein profiling technique. Microarray analysis revealed 77 differentially expressed genes, with 53 genes upregulated and 24 genes downregulated. Proteomic analysis gave 75 and 80 proteins for the midexponential and stationary phase, respectively. Although there was a general lack of correlation between mRNA levels and quantitated protein abundance, results from both datasets concurred on groups of proteins/genes based on functional categorization. A number of genes (20%) and proteins (45 and 23%) were involved in processes related to protein biosynthesis. We also identified three genes/proteins involved in chromatin modification. Enzymes responsible for opening up chromatin, Hmgn3 and Hmgb1, were upregulated whereas enzymes that condense chromatin, histone H1.2, were downregulated. Genes and proteins that promote cell growth (Igfbp4, Ptma, S100a6, and Lgals3) were downregulated, whereas those that deter cell growth (Ccng2, Gsg2, and S100a11) were upregulated. Other main groups of genes and proteins include carbohydrate metabolism, signal transduction, and transport. Our findings show that an integrated genomic and proteomics approach can be effectively utilized to monitor transcriptional and posttranscriptional events of mammalian cells in culture.

The objective of this study was to elucidate if chronic and acute ammonia intoxication in mudskippers, Periophthalmodon schlosseri and Boleophthalmus boddaerti, were associated with high levels of ammonia and/or glutamine in their brains, and if acute ammonia intoxication could be prevented by the administration of methionine sulfoximine [MSO; an inhibitor of glutamine synthetase (GS)] or MK801 [an antagonist of N-methyl D-aspartate type glutamate (NMDA) receptors]. For P. schlosseri and B. boddaerti exposed to sublethal concentrations (100 and 8 mmol l(-1) NH4Cl, respectively, at pH 7.0) of environmental ammonia for 4 days, brain ammonia contents increased drastically during the first 24 h, and they reached 18 and 14.5 micromol g(-1), respectively, at hour 96. Simultaneously, there were increases in brain glutamine contents, but brain glutamate contents were unchanged. Because glutamine accumulated to exceptionally high levels in brains of P. schlosseri (29.8 micromol g(-1)) and B. boddaerti (12.1 micromol g(-1)) without causing death, it can be concluded that these two mudskippers could ameliorate those problems associated with glutamine synthesis and accumulation as observed in patients suffering from hyperammonemia. P. schlosseri and B. boddaerti could tolerate high doses of ammonium acetate (CH3COONH4) injected into their peritoneal cavities, with 24 h LC50 of 15.6 and 12.3 micromol g(-1) fish, respectively. After the injection with a sublethal dose of CH3COONH4 (8 micromol g(-1) fish), there were significant increases in ammonia (5.11 and 8.36 micromol g(-1), respectively) and glutamine (4.22 and 3.54 micromol g(-1), respectively) levels in their brains at hour 0.5, but these levels returned to normal at hour 24. By contrast, for P. schlosseri and B. boddaerti that succumbed within 15-50 min to a dose of CH3COONH4 (15 and 12 micromol g(-1) fish, respectively) close to the LC50 values, the ammonia contents in the brains reached much higher levels (12.8 and 14.9 micromol g(-1), respectively), while the glutamine level remained relatively low (3.93 and 2.67 micromol g(-1), respectively). Thus, glutamine synthesis and accumulation in the brain was not the major cause of death in these two mudskippers confronted with acute ammonia toxicity. Indeed, MSO, at a dosage (100 microg g(-1) fish) protective for rats, did not protect B. boddaerti against acute ammonia toxicity, although it was an inhibitor of GS activities from the brains of both mudskippers. In the case of P. schlosseri, MSO only prolonged the time to death but did not reduce the mortality rate (100%). In addition, MK801 (2 microg g(-1) fish) had no protective effect on P. schlosseri and B. boddaerti injected with a lethal dose of CH3COONH4, indicating that activation of NMDA receptors was not the major cause of death during acute ammonia intoxication. Thus, it can be concluded that there are major differences in mechanisms of chronic and acute ammonia toxicity between brains of these two mudskippers and mammalian brains.

Nociceptin is a non-opioid peptide that modulates pain response. One of mechanism underlying its analgesic action is the inhibition of voltage-dependent calcium current (ICa), similar to that of opioids. We investigated the molecular mechanism by which nociceptin inhibits ICa using sensory neurons and a heterologous expression system. ICa inhibition by nociceptin was voltage-dependent, exhibited the slowing of activation kinetics and prepulse facilitation, and was blocked by N-ethylmaleimide, indicating the involvement of Gi/Go protein. ICa inhibition by nociceptin was primarily mediated through binding to its own receptor, ORL-1, but not through affecting other mu-opioid receptors. Thus, our results strongly demonstrate that heterologous cross-talk between ORL1 and muOR is not involved in the ICa inhibition by nociceptin.

Biological rhythmic movements can be viewed as instances of self-sustained oscillators. Auto-oscillatory phenomena must involve a nonlinear friction function, and usually involve a nonlinear elastic function. With respect to rhythmic movements, the question is: What kinds of nonlinear friction and elastic functions are involved? The nonlinear friction functions of the kind identified by Rayleigh (involving terms such as theta3) and van der Pol (involving terms such as theta2theta), and the nonlinear elastic functions identified by Duffing (involving terms such as theta3), constitute elementary nonlinear components for the assembling of self-sustained oscillators, Recently, additional elementary nonlinear friction and stiffness functions expressed, respectively, through terms such as theta2theta3 and thetatheta2, and a methodology for evaluating the contribution of the elementary components to any given cyclic activity have been identified. The methodology uses a quantification of the continuous deviation of oscillatory motion from ideal (harmonic) motion. Multiple regression of this quantity on the elementary linear and nonlinear terms reveals the individual contribution of each term to the oscillator's non-harmonic behavior. In the present article the methodology was applied to the data from three experiments in which human subjects produced pendular rhythmic movements under manipulations of rotational inertia (experiment 1), rotational inertia and frequency (experiment 2), and rotational inertia and amplitude (experiment 3). The analysis revealed that the pendular oscillators assembled in the three experiments were compositionally rich, braiding linear and nonlinear friction and elastic functions in a manner that depended on the nature of the task.