Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis.

Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.

Sex-Specific Left Ventricular and Aorta Size Cut-Off Values for Hemodynamically Significant Chronic Aortic Regurgitation　- Implications for Treatment in Asian Populations.

BACKGROUND: There are no sex-specific guidelines for chronic aortic regurgitation (AR). This retrospective study examined sex-specific differences and propose treatment criteria from an Asian AR cohort.Methods and Results: Consecutive 1,305 patients with moderate-severe AR or greater at 3 tertiary centers in Taiwan and Japan (2008-2022) were identified. Study endpoints were aortic valve surgery (AVS), all-cause death (ACD), and cardiovascular death (CVD). The median follow up was 3.9 years (interquartile range 1.3-7.1 years). Compared with men (n=968), women (n=337) were older, had more advanced symptoms, more comorbidities, larger indexed aorta size (iAortamax) and indexed left ventricular (LV) end-systolic dimension (LVESDi; P<0.001 for all). Symptomatic status was poorly correlated with the degree of LV remodeling in women (P≥0.18). Women received fewer AVS (P≤0.001) and men had better overall 10-year survival (P<0.01). Ten-year post-AVS survival (P=0.9) and the progression of LV remodeling were similar between sexes (P≥0.16). Multivariable determinants of ACD and CVD were age, advanced symptoms, iAortamax, LV ejection fraction (LVEF), LVESDi, LV end-systolic volume index (LVESVi), and Taiwanese ethnicity (all P<0.05), but not female sex (P≥0.05). AVS was associated with better survival (P<0.01). Adjusted LVEF, LVESDi, LVESVi, and iAortamaxcut-off values for ACD were 53%, 24.8 mm/m2, 44 mL/m2, and 25.5 mm/m2, respectively, in women and 52%, 23.4 mm/m2, 52 mL/m2, and 23.2 mm/m2, respectively, in men. CONCLUSIONS: Early detection and intervention using sex-specific cut-off values may improve survival in women with AR.

The Pulse of Singapore: Short-Term HRV Norms.

Short-term heart rate variability (HRV) is increasingly used to assess autonomic nervous system activity and found to be useful for monitoring and providing care due to its quick measurement. With evidence of low HRV associated with chronic diseases, mental disorders, and an increased risk of cardiovascular disease, having normative data of HRV across the age spectrum would be useful for monitoring health and well-being of a population. This study examines HRV of healthy Singapore sample, with ages ranging from 10 to 89 years. Short-term HRV of five minutes was measured from 2,143 participants. 974 males and 1,169 females, and overall HRV was found to be 42.4ms (RMSSD) and 52.0 ms (SDNN) with a further breakdown of HRV by age and gender. Overall HRV declined with age and gender, although gender differences dissipated in the 60s age range onwards, with the 50s age range having the sharpest decline in HRV. Short-term HRV norms were similar to Nunan et al.'s (2010) systematic review in various populations and less similar to Choi et al.'s (2020) study on Koreans.

Comparative Efficacy of Pharmacological Treatments for Acne Vulgaris: A Network Meta-Analysis of 221 Randomized Controlled Trials.

PURPOSE: Acne is an extremely common skin disease with an estimated global prevalence of 9.4%. We aim to provide comprehensive comparisons of the common pharmacological treatments for acne. METHODS: Randomized controlled trials comparing the efficacy of pharmacological therapies for acne vulgaris in patients of any age and sex and with a treatment duration of >2 weeks were included. PubMed and Embase databases were searched from inception until February 2022. Our prespecified primary end points were mean percentage reduction in total, inflammatory, and noninflammatory lesions. Treatment ranking was determined by P values. RESULTS: There were 210 articles describing 221 trials and 37 interventions included in the analysis. Our primary analysis of percentage reduction in total lesion count had 65,601 patients enrolled. Across all trials, the mean age was 20.4 years. The median duration of treatment was 12 weeks. The median total, inflammatory, and noninflammatory lesion counts were 72, 27, and 44, respectively. The most effective treatment was oral isotretinoin (mean difference [MD] = 48.41; P = 1.00), followed by triple therapy containing a topical antibiotic, a topical retinoid, and benzoyl peroxide (BPO) (MD = 38.15; P = .95) and by triple therapy containing an oral antibiotic, a topical retinoid, and BPO (MD = 34.83; P = .90). For monotherapies, oral or topical antibiotics or topical retinoids have comparable efficacy for inflammatory lesions, while oral or topical antibiotics have less effect on noninflammatory lesions. CONCLUSION: The most effective treatment for acne is oral isotretinoin, followed by triple therapies containing a topical retinoid, BPO, and an antibiotic. We present detailed comparisons of each intervention to serve as a practical database.

Longitudinal mediation effects of activity meaning on the association between activity performance and quality of life among older adults with disabilities.

BACKGROUND: Physical limitations may hinder older adults with physical disabilities' capability to perform various activities, which can affect their quality of life (QOL). Accomplishing meaningful activities may mitigate the impact of limited activity performance on their QOL. This longitudinal study aims to investigate how activity meaning mediates the relationship between activity performance and QOL among older adults with disabilities. METHODS: Data for this longitudinal study was collected from 813 community-dwelling older adults aged 60 and above who had physical disabilities, over a two year interval. Path analysis was used to examine the cross-sectional and longitudinal mediation effects from activity performance, through activity meaning, to QOL. RESULTS: At the same wave, high IADL performance or social activity performance, and high QOL was indirectly associated through high IADL meaning or social meaning. As for longitudinal association, high T1 IADL performance was associated with better T2 QOL through high T1 and T2 IADL meaning. Similarly, high T1 social activity performance also contributed to T2 QOL through high T1 and T2 social activity meaning. Additionally, social activity performance exhibited higher influence on QOL than that of IADL. CONCLUSIONS: Both IADL and social activities have distinct impacts on the QOL of older adults with disabilities. To improve the current and future QOL of older adults with disabilities, professionals must prioritize their involvement in the most meaningful activities while being sensitive to and supportive of their preferences and valued lifestyles.

Correction: Effect of Telehealth Services on Mitral and Tricuspid Regurgitation Progression: Retrospective Study.

[This corrects the article DOI: 10.2196/47947.].

Effect of Telehealth Services on Mitral and Tricuspid Regurgitation Progression: Retrospective Study.

BACKGROUND: Mitral regurgitation (MR) and tricuspid regurgitation (TR) are common cardiac conditions with high mortality risks, which can be improved through early intervention. Telehealth services, which allow for remote monitoring of patient conditions, have been proven to improve the health management of chronic diseases, but the effects on MR and TR progression are unknown. OBJECTIVE: This study aimed to explore whether patients receiving telehealth services have less MR and TR progression compared with a control group. We also aimed to identify the determinants of MR and TR progression. METHODS: This single-center retrospective study conducted at the National Taiwan University Hospital compared MR and TR progression (defined as either progression to moderate or greater MR and TR or MR and TR progression by ≥2 grades during the study period) between the telehealth and control groups. Patients had a minimum of 2 transthoracic echocardiograms at least 6 months apart; baseline mild-moderate MR and TR or lower; and no prior surgeries on the mitral or tricuspid valve. Telehealth patients were defined as those who received telehealth services for at least 28 days within 3 months of baseline. Basic demographics, baseline blood pressure measurements, prescribed medication, and Charlson Comorbidity Index components were obtained for all patients. RESULTS: A total of 1081 patients (n=226 in the telehealth group and n=855 in the control group) were included in the study analyses. The telehealth group showed significantly lower baseline systolic blood pressure (P<.001), higher Charlson Comorbidity Index (P=.02), higher prevalence of prior myocardial infarction (P=.01) and heart failure (P<.001), higher beta-blocker (P=.03) and diuretic (P=.04) use, and lower nitrate use (P=.04). Both groups showed similar cardiac remodeling conditions at baseline. Telehealth was found to be neutral for both MR (hazard ratio 1.10, 95% CI 0.80-1.52; P=.52) and TR (hazard ratio 1.27, 95% CI 0.92-1.74; P=.14) progression. Determinants for moderate or greater MR progression included older age, female sex, diuretic use, larger left atrial dimension, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction. Determinants of moderate or greater TR progression included older age, female sex, diuretic use, presence of atrial fibrillation, LA dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction; statin use was found to be protective. CONCLUSIONS: This is the first study to assess the association between telehealth services and the progression of MR and TR. Telehealth patients, who had more comorbidities, displayed similar MR and TR progression versus control patients, indicating that telehealth may slow MR and TR progression. Determinants of MR and TR progression included easy-to-measure traditional echo parameters of cardiac function, older age, female sex, and atrial fibrillation, which can be incorporated into a telehealth platform and advanced alert system, improving patient outcomes through personalized care.

The Application of Wireless Underground Sensor Networks to Monitor Seepage inside an Earth Dam.

Earth dams or embankments are susceptible to instability due to internal seepage, piping, and erosion, which can lead to catastrophic failure. Therefore, monitoring the seepage water level before the dam collapses is an important task for early warning of dam failure. Currently, there are hardly any monitoring methods that use wireless underground transmission to monitor the water content inside earth dams. Real-time monitoring of changes in the soil moisture content can more directly determine the water level of seepage. Wireless transmission of sensors buried underground requires signal transmission through the soil medium, which is more complex than traditional air transmission. Henceforth, this study establishes a wireless underground transmission sensor that overcomes the distance limitation of underground transmission through a hop network. A series of feasibility tests were conducted on the wireless underground transmission sensor, including peer-to-peer transmission tests, multi-hop underground transmission tests, power management tests, and soil moisture measurement tests. Finally, field seepage tests were conducted to apply wireless underground transmission sensors to monitor the internal seepage water level before an earth dam failure. The findings show that wireless underground transmission sensors can achieve the monitoring of seepage water levels inside earth dams. In addition, the results supersede those of a conventional water level gauge. This could be crucial in early warning systems during the era of climate change, which has caused unprecedented flooding events.

Micropulse transscleral cyclophotocoagulation in a Taiwanese population: 2-year clinical outcomes and prognostic factors.

PURPOSE: To evaluate the 2-year efficacy and safety of micropulse transscleral cyclophotocoagulation (MP-TSCPC) in Taiwanese patients with glaucoma. METHODS: We included the patients who received standardized MP-TSCPC with follow-up examinations on a regular basis for 24 months. Treatment success was defined as the attainment of a postoperative intraocular pressure (IOP) between 6 and 21 mmHg or a ≥ 20% reduction in IOP from baseline without an increase in glaucoma medications. RESULTS: A total of 60 eyes from 56 patients who underwent MP-TSCPC for refractory glaucoma were included. The median age at MP-TSCPC intervention was 58.9 ± 12.4 years. The percentage of treatment success was 88.3% at 3 months, 83.3% at 6 months, 78.3% at 12 months, and 75.0% at 24 months. The mean baseline IOP prior to MP-TSCPC was 34 ± 11.9 mmHg (range 14-56 mmHg). The mean postoperative IOP decreased to 20.9 ± 10.0 mmHg, 18.0 ± 7.8 mmHg, 17.5 ± 6.4 mmHg, and 18.2 ± 7.1 mmHg after 3 months, 6 months, 12 months, and 24 months, respectively, in successful cases. The mean number of glaucoma medications at baseline was 3.8 ± 0.2, and the mean numbers of glaucoma medications at postoperative months 3, 6, 12, and 24 were 2.6 ± 0.7, 2.8 ± 0.6, 2.5 ± 1.4 and 2.6 ± 1.4, respectively, in successful cases. Younger age and prior CW-TSCPC significantly contributed to surgical failure in the multivariate model. Complications after MP-TSCPC included mild anterior chamber inflammation, conjunctival hemorrhage, hypotony, and mydriasis, and all subsided after treatment. None of the eyes developed vitreous hemorrhage, cystoid macular edema, or phthisis bulbi in the late postoperative period. CONCLUSIONS: This study demonstrated that younger age and prior CW-TSCPC were risk factors for MP-TSCPC failure within 2 years. MP-TSCPC might be safe and effective for refractory glaucoma patients with maximal antiglaucoma medications.

Involvement of AMPKα and MAPK-ERK/-JNK Signals in Docetaxel-Induced Human Tongue Squamous Cell Carcinoma Cell Apoptosis.

Cancers of the oral cavity can develop in the anatomic area extending from the lip, gum, tongue, mouth, and to the palate. Histologically, about 85-90% of oral cavity cancers are of the type squamous cells carcinomas (SCCs). The incidence of oral tongue SCC is higher in the tongue than any other anatomic area of the oral cavity. Here, we investigated the therapeutic effects and molecular mechanisms of docetaxel, which is a paclitaxel antitumor agent, on the cell growth of a human tongue SCC-derived SAS cell line. The results showed that docetaxel (10-300 nM) induced cytotoxicity and caspase-3 activity in SAS cells. Moreover, docetaxel (100 nM) promoted the expression of apoptosis-related signaling molecules, including the cleavages of caspase-3, caspase-7, and poly (ADP-ribose) polymerase (PARP). In mitochondria, docetaxel (100 nM) decreased the mitochondrial membrane potential (MMP) and Bcl-2 mRNA and protein expression and increased cytosolic cytochrome c protein expression and Bax mRNA and protein expression. In terms of mitogen-activated protein kinase (MAPK) and adenosine monophosphate-activated protein kinase (AMPK) signaling, docetaxel increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK), and p-AMPKα protein expression but not p-p38 protein expression. Moreover, the increase in caspase-3/-7 activity and Bax protein expression and decreased Bcl-2 protein expression and MMP depolarization observed in docetaxel-treated SAS cells could be reversed by treatment with either SP600125 (a JNK inhibitor), PD98059 (an MEK1/2 (mitogen-activated protein kinase kinase 1/2) inhibitor), or compound c (an AMPK inhibitor). The docetaxel-induced increases in p-JNK, p-ERK, and p-AMPKα protein expression could also be reversed by treatment with either SP600125, PD98059, or compound c. These results indicate that docetaxel induces human tongue SCC cell apoptosis via interdependent MAPK-JNK, MAPK-ERK1/2, and AMPKα signaling pathways. Our results show that docetaxel could possibly exert a potent pharmacological effect on human oral tongue SCC cell growth.

Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells via a Ca2+-Regulated ERK1/2-Activating Pathway.

Ketamine-associated cystitis is characterized by suburothelial inflammation and urothelial cell death. Norketamine (NK), the main metabolite of ketamine, is abundant in urine following ketamine exposure. NK has been speculated to exert toxic effects in urothelial cells, similarly to ketamine. However, the molecular mechanisms contributing to NK-induced urothelial cytotoxicity are almost unclear. Here, we aimed to investigate the toxic effects of NK and the potential mechanisms underlying NK-induced urothelial cell injury. In this study, NK exposure significantly reduced cell viability and induced apoptosis in human urinary bladder epithelial-derived RT4 cells that NK (0.01-0.5 mM) exhibited greater cytotoxicity than ketamine (0.1-3 mM). Signals of mitochondrial dysfunction, including mitochondrial membrane potential (MMP) loss and cytosolic cytochrome c release, were found to be involved in NK-induced cell apoptosis and death. NK exposure of cells also triggered the expression of endoplasmic reticulum (ER) stress-related proteins including GRP78, CHOP, XBP-1, ATF-4 and -6, caspase-12, PERK, eIF-2α, and IRE-1. Pretreatment with 4-phenylbutyric acid (an ER stress inhibitor) markedly prevented the expression of ER stress-related proteins and apoptotic events in NK-exposed cells. Additionally, NK exposure significantly activated JNK, ERK1/2, and p38 signaling and increased intracellular calcium concentrations ([Ca2+]i). Pretreatment of cells with both PD98059 (an ERK1/2 inhibitor) and BAPTA/AM (a cell-permeable Ca2+ chelator), but not SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), effectively suppressed NK-induced mitochondrial dysfunction, ER stress-related signals, and apoptotic events. The elevation of [Ca2+]i in NK-exposed cells could be obviously inhibited by BAPTA/AM, but not PD98059. Taken together, these findings suggest that NK exposure exerts urothelial cytotoxicity via a [Ca2+]i-regulated ERK1/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in urothelial cell death. Our findings suggest that regulating [Ca2+]i/ERK signaling pathways may be a promising strategy for treatment of NK-induced urothelial cystitis.

Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic ß-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway.

Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic ß-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 µM) significantly decreased insulin secretion and cell viability in pancreatic ß-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (Bax, Bak, p53)/antiapoptotic (Bcl-2) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 µM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 µM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 µM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to ß-cell death.

Otorhinolaryngological Management in Taiwanese Patients with Mucopolysaccharidoses.

Background: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders wherein glycosaminoglycans accumulate because the enzymes that degrade them are insufficient. The earliest symptoms, which are the main reasons for seeking consultation, are otorhinolaryngological and commonly occur in MPS I, II, IV, and VI. This retrospective study aimed to determine the occurrence of otorhinolaryngological manifestations in MPS patients in Taiwan and to analyze the prognosis of surgical intervention, including its effect on symptoms. Methods: We reviewed 42 patients (30 males and 12 females), with a median age of 20.5 years, who had MPS (16.7% type I, 35.7% type II, 19.0% type IIIB, 21.4% type IVA, and 7.2% type VI). The following otorhinolaryngological manifestations were collected: annual number of upper respiratory tract infections (URTIs) and otitis media with effusion (OME) episodes, adenoid size, tonsillar size, and apnea-hypopnea index (AHI). Results: Among 42 patients, we found recurrent otitis media in 42.9% of the patients, hearing loss in 83.3% (mixed: 52.4%, conductive: 21.4%, and sensorineural: 9.5%), frequent URTIs in 47.6%, and obstructive sleep apnea syndrome in 35.7%. Moreover, 76% of the patients underwent ear, nose, and throat (ENT) surgery, including adenoidectomy, tonsillectomy, tympanostomy with ventilation tube insertion, tracheotomy, and supraglottoplasty. Conclusions: MPS patients had a high incidence of ENT problems. ENT surgery reduced the severity of hearing loss, degree of symptoms related to upper airway obstruction, and severity of respiratory tract and otological infections of patients with MPS.

Office-based salivary gland ductal irrigation in patients with chronic sialoadenitis: A preliminary study.

BACKGROUND/PURPOSE: To evaluate the therapeutic responsiveness of office-based salivary gland ductal irrigation in patients with chronic sialoadenitis. METHODS: Between August 2017 and April 2019, 55 patients comprising the following three disease groups were enrolled: Sjogren's syndrome: 39 patients; postradiotherapy sialoadenitis: ten patients; and post-RAI sialoadenitis: six patients. Quantitative salivary scintigraphy was recorded, and a formulated questionnaire including the Summated Xerostomia Inventory was utilized to assess acute/chronic symptoms. All patients received at least three serial salivary gland ductal irrigations with a one-month interval in our outpatient department. RESULTS: The general response rates for each disease groups are as follows: Sjogren's syndrome: 61.5% (24/39); postradiotherapy: 60% (6/10); and post-RAI: 83.3% (5/6). Among the patients with Sjogren's syndrome, the parotid scintigraphic Tmin showed a significant positive correlation with the responsiveness of salivary irrigation (P = 0.046), whereas the treatment tended to be irresponsive in patients who previously took medicine for their related discomfort (P = 0.009). In the postradiotherapy and post-RAI groups, no significant factors were found to be associated with the responsiveness of irrigation. CONCLUSION: Simple salivary ductal irrigation without complex equipment can be performed as an outpatient procedure to alleviate glandular swelling or xerostomia in patients with Sjogren's syndrome, postradiotherapy sialoadenitis or post-RAI sialoadenitis, and it can be considered an alternative management approach for patients refractory to conventional strategies.

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic ß-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway.

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic ß-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic ß-cells and elucidated the cellular mechanism involved in MBP-induced ß-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of ß-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on ß-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.

The impact of obesity in cognitive and memory dysfunction in obstructive sleep apnea syndrome.

OBJECTIVE: Obstructive sleep apnea (OSA), a sleep disorder, results in decreased daytime alertness and neurocognitive dysfunction. Obesity is considered a major risk factor for the development and progression of OSA and the resulting cognitive dysfunction. However, the effect of obesity on neurocognitive dysfunction in OSA has been rarely investigated. METHODS: Eighty-three patients with moderate to severe OSA syndrome were recruited in our study. After matching for education, age, and body mass index (BMI), 40 patients were enrolled into our study with matched obese (BMI ≧ 30) and non-obese (BMI < 30) groups. All enrolled patients completed a polysomnographic study, sleepiness questionnaires, and attention, cognitive, and memory function tests. RESULTS: Compared to obese OSA patients, non-obese OSA patients had shorter reaction times in the psychomotor vigilance task but not the Flanker or Stroop cognitive tasks. Additionally, obese OSA patients had a reduced capacity for working memory relative to non-obese OSA patients. CONCLUSIONS: Obesity had a significant effect on OSA patients in our study, including delayed reaction times in the psychomotor vigilance task and a decrease in working memory.

Monocyte Chemoattractant Protein-1, a Possible Biomarker of Multiorgan Failure and Mortality in Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) leads to increased patients' mortality and medical expenditure. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the pathogenesis of lung inflammation and infection. Therefore, the plasma concentration of MCP-1 was assessed and correlated with the clinical course in VAP patients. This retrospective observational study recruited 45 healthy volunteers, 12 non-VAP subjects, and 30 VAP patients. The diagnostic criteria for VAP were based on the American Thoracic Society guidelines, and the level of plasma MCP-1 was determined by ELISA. Plasma MCP-1 concentration was significantly elevated in the acute stage in VAP patients when compared with the control (p < 0.0001) and non-VAP patient groups (p = 0.0006). Subsequently, it was remarkably decreased following antibiotic treatment. Moreover, plasma MCP-1 concentration was positively correlated with indices of pulmonary dysfunction, including the lung injury score (p = 0.02) and the oxygenation index (p = 0.02). When patients with VAP developed adult respiratory distress syndrome (ARDS), their plasma MCP-1 concentrations were significantly higher than those of patients who did not develop ARDS (p = 0.04). Moreover, plasma MCP-1 concentration was highly correlated with organ failure scores, including simplified acute physiology score II (SAPS II, p < 0.0001), sequential organ failure assessment score (SOFA, p < 0.0001), organ dysfunctions and/or infection (ODIN, p < 0.0001), predisposition, insult response and organ dysfunction (PIRO, p = 0.005), and immunodeficiency, blood pressure, multilobular infiltrates on chest radiograph, platelets and hospitalization 10 days before onset of VAP (IBMP-10, p = 0.004). Our results demonstrate that plasma MCP-1 is an excellent marker for recognizing VAP when the cut-off level is set to 347.18 ng/mL (area under the curve (AUC) = 0.936, 95% CI = 0.863-0.977). In conclusion, MCP-1 not only could be a biological marker related to pulmonary dysfunction, organ failure, and mortality in patients with VAP, but also could be used for early recognition of VAP.

How Plastic Surgeons Value Professionalism: Using Q Methodology to Explore the Prioritization of Professionalism.

BACKGROUND: Medicine is no longer limited to the treatment of diseases-the use of plastic surgical techniques as a commodity to improve the appearance of healthy people has become a trend, and plastic surgeons who invest in the market of cosmetic medicine have quickly gained considerable benefits. Will the transformation of the role of plastic surgeons from aesthetic restoration to commercial embellishment damage the creation and maintenance of their sense of professionalism? OBJECTIVES: The purpose of this study was to determine, by utilizing Q methodology, which aspects of professionalism plastic surgeons value. METHODS: Q methodology is a mixed research method employed to study subjectivity through factor analysis. This study analyzes a rank-ordering of participants' level of agreement with a set of subjective statements related to a given topic. Q statements were developed on the basis of a literature review, expert panels, and medical organizations' codes of conduct. After face and construct validity checks, as well as a pilot test, we interviewed 31 attending plastic surgeons. Data were collected from April to May 2017. RESULTS: This study concluded that the main types of medical professionalism held by the respondents can be represented in 4 factors: (1) mastery of clinical skills, (2) leadership and management, (3) knowledge sharing, and (4) multifaceted. CONCLUSIONS: Respondents in this study highly emphasized surgical skill and sought to maintain good relationships with their patients based on their settings. Although they were reluctant to place community service as a top priority, our respondents tended to emphasize the healer aspect over commercialization.

S- Cis Diene Conformation: A New Bathochromic Shift Strategy for Near-Infrared Fluorescence Switchable Dye and the Imaging Applications.

In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S- cis diene conformer. This is the first example where a fluorescent dye adopts the stable S- cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S- cis diene conformation can lead to new strategies for the design of near-IR dyes.

Treatment outcome of non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae infections: a multicenter study in Taiwan.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with high mortality, and experiences with its treatment are usually based on carbapenemase-producing strains. Non-carbapenemase-producing CRKP is of clinical significance, but relevant studies are lacking. This nationwide study aimed to evaluate the outcome of antimicrobial therapy in patients with non-carbapenemase-producing CRKP infections. Patients with non-carbapenemase-producing CRKP infections were enrolled from 16 hospitals during January 2013 to December 2014 in Taiwan. Carbapenem resistance was defined as reduced susceptibility with a minimum inhibitory concentration of ≥2 mg/L for imipenem or meropenem. The resistance mechanisms of CRKP isolates were analyzed, and the clinical data of these patients were collected retrospectively. Independent risk factors of 14-day morality were determined by Cox regression analysis. A total of 99 patients with non-carbapenemase-producing CRKP infections were enrolled, and 14-day mortality was 27.3%. Among 67 patients treated with appropriate antimicrobial therapy, most (n = 61) patients received monotherapy. The 14-day mortality was lower in patients treated with appropriate monotherapy (21.3%) than in those with inappropriate therapy (37.5%). The multivariate regression model identified monotherapy (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.13-0.71; P = 0.005) as protective factor, and APACHE II scores (HR, 1.09; 95% CI, 1.01-1.18; P = 0.022) as risk factor associated with 14-day mortality. Tigecycline, colistin, and carbapenem were the most commonly used drugs in monotherapy. This study provides evidence supporting the efficacy of monotherapy in the treatment of non-carbapenemase-producing CRKP infections, and provides a future target for antibiotics stewardship for CRKP infection.