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Background/purpose Gay and bisexual men are at a higher risk of mental and physical health problems than heterosexual men, reporting higher frequencies of harassment and discrimination in both housing and employment domains. Psychological inflexibility/experiential avoidance (PI/EA) refers to behaviors that are rigidly guided by psychological reactions rather than direct contingencies or personal values; PI/EA referring to a key psychopathology behavior related to greater mental illness. The objective of the study was to examine the association of various types of harassment with PI/EA and the effects of multiple types and site harassment on PI/EA among Taiwanese emergent adult gay and bisexual men. Methods A total of 305 gay and bisexual men aged between 20 and 25 years were recruited into this study. The level of PI/EA and types of harassment were evaluated and further analysis the effect of harassment on PI/EA. Results Findings indicated that various types of harassment exerted significant effects on PI/EA in emergent adult gay and bisexual men; furthermore, the effect was cumulative. The result also revealed that victims of verbal ridicule and relational exclusion, victims of physical aggression and theft of belongings, and victims of cyber harassment had significantly higher PI/EA. Conclusion Harassment experiences appeared to be significantly associated with PI/EA, and the effects could be cumulative. It would be beneficial to construct a friendly world for emergent adult gay and bisexual men. Evaluation and intervention with PI/EA improvement should be considered for emergent adult gay and bisexual men with traditional and cyber harassment experiences.

We conducted a multi-institutional study in Taiwan and a systematic review of the literature for reports of Guillain-​Barré syndrome after coronavirus disease vaccination. This condition, mostly the classic form and the acute inflammatory demyelinating polyneuropathy subtype, has been reported in 39 cases and has occurred within 2 weeks of vaccine administration.

Impaired executive function (EF), verbal comprehension, and theory of mind (ToM) may contribute to social difficulties in children with autism spectrum disorder (ASD). The linkage between cool (cognitive) EF and ToM has been widely investigated, but the relations between hot (affective) EF and ToM remain largely unknown. The roles of cool EF and verbal comprehension have not been previously explored together to address hot EF-ToM relations. This study applied mediation analysis to investigate the mediating effects of cool EF and verbal comprehension to further elaborate the link between hot EF and ToM in children with ASD and average intellectual abilities. A total of 97 children with ASD aged from 6 to 12 years participated in this study. Children's cool EF, hot EF, and verbal comprehension were, respectively, measured with the computerized Dimensional Change Card Sort task, Children's Gambling Task, and the verbal comprehension index of the Wechsler Intelligence Scale for Children-fourth edition. Children's ToM was assessed with the Theory of Mind Task Battery. Partial correlation coefficients indicated that hot EF was significantly related with ToM with age controlled for. The results of the mediation analysis showed that cool EF and verbal comprehension mediated the linkage between hot EF and ToM. These findings highlight not only the connections between hot EF and ToM but also the importance of cool EF and verbal comprehension on hot EF-ToM relations in clinical assessments and interventions for school-aged children with ASD and average intellectual abilities. LAY SUMMARY: Relatively few studies have investigated the hot (affective) executive function (EF)-theory of mind (ToM) relations in children with autism spectrum disorder (ASD). This study discovered that hot EF was significantly related to ToM, while cool (cognitive) EF and verbal comprehension mediated the relationship between hot EF and ToM. Therefore, the influence of cool EF and verbal comprehension on hot EF-ToM relations should be considered in studies involving children with ASD. Autism Res 2021, 14: 921-931. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

In order to improve individual research achievements (IRA), this study investigates which affiliated countries and authors earn the most cited IRAs and whether those types of articles are associated with the number of cited papers on schizophrenia from a leading journal in the field. The Kano model was used for displaying the IRAs. Clusters of medical subject headings (MeSH) were applied to explore the core concepts of a given journal. This study aimed to apply social network analysis (SNA) and an authorship-weighted scheme (AWS) to inspect the association between MeSH terms and IRA. About 2,008 abstracts published between 2012 and 2016 in the journal Schizophrenia Research were downloaded from Pubmed Central using the keyword (Schizophr Res)[Journal] on September 20, 2018. The MeSH terms were clustered by using SNA to separate the core concepts and compare the differences in bibliometric indices (i.e., h, Ag, x and author impact factor or AIF). Visual dashboards were shown on Google Maps. Results indicate that (1) the US, the UK, and Canada earn the highest x-index; (2) the top one author from the US has the highest x-index (= 5.73 with x-core at cited = 16.44 and citable = 2); (3) the article type of schizophrenic psychology shows distinctly higher frequencies than others; and (4) article types are associated with the number of cited papers. Four approaches of the Kano model, SNA, MeSH terms, and AWS can be accommodated to display IRAs, classify article types, and quantify coauthor contributions in the article byline, respectively, and applied to other scientific disciplines in the future, not just in this specific journal.

A major obstacle to nanodrugs-mediated cancer therapy is their rapid uptake by the reticuloendothelial system that decreases the systemic exposure of the nanodrugs to tumors and also increases toxicities. Intralipid has been shown to reduce nano-oxaliplatin-mediated toxicity while improving bioavailability. Here, we have found that Intralipid reduces the cytotoxicity of paclitaxel for human monocytic cells, but not for breast, lung, or pancreatic cancer cells. Intralipid also promotes the polarization of macrophages to the anti-cancer M1-like phenotype. Using a xenograft breast cancer mouse model, we have found that Intralipid pre-treatment significantly increases the amount of paclitaxel reaching the tumor and promotes tumor apoptosis. The combination of Intralipid with half the standard clinical dose of Abraxane reduces the tumor growth rate as effectively as the standard clinical dose. Our findings suggest that pre-treatment of Intralipid has the potential to be a powerful agent to enhance the tumor cytotoxic effects of Abraxane and to reduce its off-target toxicities.

Background: Carbon monoxide (CO) poisoning is the leading cause of poisoning death worldwide, but associations between CO poisoning and weather remain unclear.Objective: To quantify the influence of climate parameters (e.g., temperature, relative humidity, and wind speed) on the incidence risk of acute CO poisoning in Taiwan.Methods: We used negative binomial mixed models (NBMMs) to evaluate the influence of weather parameters on the incidence risk of acute CO poisoning. Subgroup analyses were conducted, based on the seasonality and the intentionality of acute CO poisoning cases.Results: We identified a total of 622 patients (mean age: 32.9 years old; female: 51%) with acute CO poisoning in the study hospital. Carbon monoxide poisoning was associated with temperature (beta: −0.0973, rate ratio (RR): 0.9073, p < 0.0001) but not with relative humidity (beta: 0.1290, RR: 1.1377, p = 0.0513) or wind speed (beta: −0.4195, RR: 0.6574, p = 0.0806). In the subgroup analyses, temperature was associated with the incidence of intentional CO poisoning (beta: 0.1076, RR: 1.1136, p = 0.0333) in spring and unintentional CO poisoning (beta: −0.1865, RR: 0.8299, p = 0.0184) in winter.Conclusion: Changes in temperature affect the incidence risk for acute CO poisoning, but the impact varies with different seasons and intentionality in Taiwan. Our findings quantify the effects of climate factors and provide fundamental evidence for healthcare providers to develop preventative strategies to reduce acute CO poisoning events.

Children with autistic spectrum disorder (ASD) with mild and moderate symptom levels have significant differences in applied theory of mind (ToM) competence. However, their mediators of applied ToM competence have not been documented.This study aimed to identify the mediators of applied ToM competence in these two clinically distinct groups.A total of 163 children with ASD aged 3-12 years old (88 and 75 children respectively in the mild and moderate groups) and their caregivers participated in this study. Data of children's verbal comprehension, explicit ToM knowledge and applied ToM competence were collected and then analyzed using mediation analysis.The results of mediation analysis showed that verbal comprehension (95% confidence interval [CI] of indirect effect: 0.02 - 0.19) and explicit ToM knowledge (95% CI of indirect effect: 0.01 - 0.07) were the mediators of applied ToM competence in children with mild and those with moderate symptoms, respectively.Our findings demonstrate that the mediators of applied ToM competence differ by symptom level in children with ASD. Applied ToM competence and the mediators should be assessed for designing tailored and effective intervention plans for these children according to their symptom level.

Attention-deficit/hyperactivity disorder (ADHD) is a common neuro developmental disorder that affects children and adolescents. It is estimated that the prevalence of ADHD is 7.2% throughout the world. There have been a number of articles published in the literature related to ADHD. However, it remains unclear which countries, journals, subject categories, and articles have the greatest influence. The purpose of this study was to display influential entities in 100 top-cited ADHD-related articles (T100ADHD) on an alluvial plot and apply alluvial to better understand the network characteristics of T100ADHD across entities.Using the PubMed and Web of Science (WoS) databases, T100ADHD data since 2011 were downloaded. The dominant entities were compared using alluvial plots based on citation analysis. Based on medical subject headings (MeSH terms) and research areas extracted from PubMed and WoS, social network analysis (SNA) was performed to classify subject categories. To examine the difference in article citations among subject categories and the predictive power of MeSH terms on article citations in T100ADHD, one-way analysis of variance and regression analysis were used.The top 3 countries (the United States, the United Kingdom, and the Netherlands) accounted for 75% of T100ADHD. The most citations per article were earned by Brazil (=415.33). The overall impact factor (IF = citations per 100) of the T100ADHD series is 188.24. The most cited article was written by Polanczyk et al from Brazil, with 772 citations since 2014. The majority of the articles were published and cited in Biol Psychiatry (13%; IF = 174.15). The SNA was used to categorize 6 subject areas. On the alluvial plots, T100ADHD's network characteristics were successfully displayed. There was no difference in article citations among subject categories (F = 1.19, P = .320). The most frequently occurring MeSH terms were physiopathology, diagnosis, and epidemiology. A significant correlation was observed between MeSH terms and the number of article citations (F = 25.36; P .001).Drawing the alluvial plot to display network characteristics in T100ADHD was a breakthrough. Article subject categories can be classified using MeSH terms to predict T100ADHD citations. Bibliometric analyses of 100 top-cited articles can be conducted in the future.

Context About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. Objective This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. Methods We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. Results The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. Conclusion Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

To investigate alterations in structural brain networks due to chronic diabetic neuropathic pain.The current study recruited 24 patients with painful diabetic neuropathy (PDN) to investigate the influences of chronic pain on the brain. Thirteen patients with painless diabetic neuropathy (PLDN) and 24 healthy adults were recruited as disease and healthy controls. White matter connectivity of the brain networks constructed by diffusion tractography was compared across groups using the Network-based statistic (NBS) method. Graph theoretical analysis was further applied to assess topological changes of the brain networks.The PDN patients had a significant reduction in white matter connectivity compared with PLDN and controls in the limbic and temporal regions, particularly the insula, hippocampus and parahippocampus, the amygdala, and the middle temporal gyrus. The PDN patients also exhibited an altered topology of the brain networks with reduced global efficiency and betweenness centrality.The current findings indicate that topological alterations of brain networks may serve as a biomarker for pain-induced maladaptive reorganization of the brain in PDN. Given the high prevalence of diabetes worldwide, novel insights from network sciences to investigate the central mechanisms of diabetic neuropathic pain are warranted.

Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.

Atrial fibrillation (AF) is an important complication of acute myocardial infarction (AMI). The association between AF and serum lipid profile is unclear and statin use for lowering the incidence of new-onset AF remains controversial. The objective of this study was to investigate whether statins confer a beneficial effect on AF after AMI. Data available in the Taiwan National Health Insurance Research Database on 32886 AMI patients between 2008 and 2011 were retrospectively analyzed. Total 27553 (83.8%) had complete 1-yr follow-up data. Cardiovascular outcomes were analyzed based on the baseline characteristics and AF type (existing, new-onset, or non-AF). AF groups had significantly higher incidence of heart failure (HF), stroke, all-cause death, and major adverse cardiac and cerebrovascular event (MACCE) after index AMI (all P

Background. The outcomes of patients with concomitant left main coronary artery (LMCA) and right coronary artery (RCA) diseases are reportedly worse than those with only LMCA disease. To date, only few studies have investigated the clinical impact of percutaneous coronary intervention (PCI) on RCA stenosis during the same hospitalization, in which LMCA disease was treated. This study was aimed at comparing the outcomes between patients with and without right coronary artery intervention during the same hospital course for LMCA intervention. Methods and Results. From a total of 776 patients who were undergoing PCI to treat LMCA disease, 235 patients with concomitant RCA significant stenosis (more than 70% stenosis) were enrolled. The patients were divided into two groups: 174 patients received concomitant PCI for RCA stenosis during the same hospitalization, in which LMCA disease was treated, and 61 patients did not receive PCI for RCA stenosis. Patients without intervention to the right coronary artery had higher 30-day cardiovascular mortality rates and 3-year RCA revascularization rates compared to those with right coronary artery intervention. Patients without RCA intervention at the same hospitalization did not increase the 30-day total death, 3-year myocardial infarction rate, 3-year cardiovascular death, and 3-year total death. Conclusions. In patients with LM disease and concomitant above or equal to 70% RCA stenosis, PCI for RCA lesion during the same hospitalization is recommended to reduce the 30-day cardiovascular death and 3-year RCA revascularization rate.

Objective Advanced glycation end products (AGEs) are involved in the pathogenesis of Alzheimer's disease (AD). Specific AGEs and related autoantibodies may be early AD markers. Apolipoprotein A1 (ApoA1) and its post-translational modifications (PTMs) are associated with neurodegeneration and thus selected to test the hypothesis. Methods Serum samples from totally 64 AD or health control (HC) Taiwanese were analyzed. ApoA1 was isolated from the serum and examined through LC-MS/MS and PTM analyses. A specific AGE and its autoantibodies were determined using Western blotting or ELISA. Results Ne-(Carboxyethyl)lysine (CEL) modification, a kind of AGEs, was identified on ApoA1 peptide 141-QKVEPLR-147 (ApoA1141–147) from AD serum. Total CEL adducts and autoantibodies against CEL on ApoA1141–147 were significantly increased in AD samples. The area under the receiver operating characteristic curve was 0.965 for anti-CEL-ApoA1141–147 IgM. Mini Mental State Examination scores of the AD patients were positively correlated with anti-CEL-ApoA1141–147 IgM, suggesting that the IgM level is high in early AD pathology and decreased with disease progression. Conclusion CEL modification was increased on AD serum proteins including ApoA1, leading to an elevated anti-CEL IgM in early disease state. Both CEL and anti-CEL IgM may serve as AD biomarkers.

This study aimed to compare symptoms of autism spectrum disorder using the Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRS™-2) and to investigate their influencing factors. The diagnostic agreement was 92.7%, but with a fair Kappa value (0.247). Children’s verbal comprehension was related to the CARS scores, and no variables were related to the SRS™-2 scores. Generally, significant small correlations were found between the two measures in children with normal or borderline to below average verbal comprehension (rs = 0.32 ~ 0.49, p

Background Although we've made big strides in perinatal and neonatal care, auditory handicap remains a serious complication in those who were born very premature. Objectives The aim was to determine the prevalence and analyze possible risk factors of hearing impairment in very-low-birth-weight (VLBW) infants. Materials and methods This was a retrospective study by reviewing medical records of all VLBW infants (BW ≤ 1500 g) admitted to NICU of Chang Gung Children's Hospital over 2 years period from Jan. 2010 to 2011. Brainstem auditory evoked potentials (BAEP) hearing screening was performed at 3 months postnatal corrective age and repeated if failed the 1st time, then refer to ENT doctor if BAEP confirmed abnormal. All VLBW infants examined for hearing impairment were included and data were retrieved retrospectively and analyzed for neonatal risk factors using logistic regression. Results Over the period, 309 VLBW infants were screened. Prevalence of uni- or bilateral hearing impairment was 3.9% (12/309; 95% CI 2.6–4.1). The mean corrective age on diagnosed of hearing impairment was 2.9 ± 1.1 (range 1–5) months. Mean gestational age was 27.9 weeks (SD 1.4) and mean birth weight was 1028 g (SD 180). By univariant analysis for hearing impairment, severe birth asphyxia, craniofacial anomalies, ventilator dependence, patent ductus arteriosus ligation, and use of postnatal ototoxins yielded good prediction of hearing impairment in this population. However, using multivariate analysis revealed that the only independent risk factors for hearing impairment were ototoxins (OR: 3.62; CI: 1.67–7.82), PDA ligation (OR: 4.96; CI: 2.34–10.52), craniofacial anomalies (OR: 3.42; CI: 1.70–6.88)and assisted prolonged use of oxygen at gestational age of >36 weeks (OR: 5.94; CI: 2.61–13.54). Conclusion The incidence of hearing impairment among VLBW infants was 3.9%. Prolonged supplemental oxygen use is a marker for predicting hearing impairment; this requires detailed analysis of the pathophysiologic features, to reduce the prevalence of hearing impairment.

Background. Posttraumatic psychiatric disorders (PTPDs) are common in disaster workers; however, their incidence and resilience in healthcare providers (HCPs) following a disastrous earthquake are still unclear. Therefore, we conducted an interventional study to clarify this issue. Methods. After a medical response to the scene of a collapsed huge building, we conducted an assessment of the HCPs using an immediate self-administered questionnaire and a follow-up questionnaire 1 month later. Psychological support after the operation was implemented. We performed analysis of the risk for PTPDs and comparison between immediate and follow-up questionnaires. Results. The mean age (standard deviation) of the HCPs was 32.7 (5.2) years, with 33.5 (5.8) years for nurses and 32.4 (4.4) years for physicians. The proportion of females among the nurses and physicians was 94.3% and 12.5%, respectively. In total, 16.4% (11/67) of HCPs fit the criteria of PTPDs. Nurses had a trend of higher incidence than physicians. Female HCPs had a trend of higher incidence than male HCPs. After intervention, none of the HCPs reported PTPDs in the follow-up questionnaire (p<0.05). Conclusion. This study delineated that PTPDs were common in HCPs following medical response to an earthquake; however, the resilience was good after the early intervention.

International audience; Hemoglobin (Hb) is an extensively studied paradigm of proteins that alter their function in response to allosteric effectors. Models of its action have been used as prototypes for structure-function relationships in many proteins, and models for the molecular basis of its function have been deeply studied and extensively argued. Recent reports suggest that dynamics may play an important role in its function. Relatively little is known about the slow, correlated motions of hemo-globin subunits in various structural states because experimental and computational strategies for their characterization are challenging. Allosteric effectors such as inositol hexaphosphate (IHP) bind to both deoxy-Hb and HbCO, albeit at different sites, leading to a lowered oxygen affinity. The manner in which these effectors impact oxygen binding is unclear and may involve changes in structure, dynamics or both. Here we use neutron spin echo measurements accompanied by wide-angle X-ray scattering to show that binding of IHP to HbCO results in an increase in the rate of coordinated motions of Hb subunits relative to one another with little if any change in large scale structure. This increase of large-scale dynamics seems to be coupled with a decrease in the average magnitude of higher frequency modes of individual residues. These observations indicate that enhanced dynamic motions contribute to the functional changes induced by IHP and suggest that they may be responsible for the lowered oxygen affinity triggered by these effectors.

It has been proposed that the dopaminergic system and heritability may play roles in attention deficit/hyperactivity disorder (ADHD). We assessed the performance of healthy parents of children with ADHD in the finger tapping test (FTT) in this study, which is a reliable test and sensitive to central dopamine activity. A total of 16 parents of children with ADHD and 32 controls were enrolled. The FTT was conducted. The 16 healthy parents of children with ADHD exhibited a significantly poorer performance in the FTT, using the nondominant hand, than the 32 healthy controls. This finding indicated that poor motor function could be a potential characteristic in parents of offspring with ADHD.

Background and purpose Ischemic stroke is the most common type of cerebrovascular event and is responsible for approximately 85% of all strokes in Taiwan. Neurons contain high concentrations of polyamines, which are prone to various pathological states in the brain and are perturbed after cerebral ischemia. Acrolein, an α,β-unsaturated aldehyde, has been suggested as the primary culprit of neuronal damage in stroke patients. However, the mechanism by which acrolein induces neuronal damage during ischemic stroke is not clear. Methods Urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione (GSH) metabolite, plasma acrolein-protein conjugates (Acr-PC) and plasma GSH levels were analyzed to correlate disease severity and prognosis of stroke patients compared with control subjects. In vivo middle cerebral artery occlusion (MCAO) animal models and an in vitro oxygen glucose deprivation (OGD) stroke model were used to investigate the mechanisms of acrolein-induced neuronal damage. Results A deregulated acrolein metabolism, including significantly increased plasma Acr-PC levels, decreased urinary 3-HPMA levels and decreased plasma GSH levels, was found in stroke patients compared to control subjects. We further observed that acrolein was produced during ischemia resulting in brain damage in in vivo MCAO animal model. The induction of acrolein in neuronal cells during OGD occurred due to the increased expression of spermidine/spermine N1-acetyltransferase (SSAT) by NF-kB pathway activation. In addition, acrolein elicited a vicious cycling of oxidative stress resulting in neurotoxicity. Finally, N-acetylcysteine effectively prevented OGD-induced neurotoxicity by scavenging acrolein. Conclusion Overall, our current results demonstrate that acrolein is a culprit of neuronal damage through GSH depletion in stroke patients. The mechanism underlying the role of acrolein in stroke-related neuronal damage occurs through SSAT-induced polyamine oxidation by NF-kB pathway activation. These results provide a novel mechanism of neurotoxicity in stroke patients, aid in the development of neutralizing or preventive measures, and further our understanding of neural protection.

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.

We investigated the accuracy of various bleeding risk scores to estimate the bleeding risk in patients with acute myocardial infarction (AMI) managed with percutaneous coronary intervention (PCI) access via the radial artery.We retrospectively enrolled 1,651 patients who were definitively diagnosed with ST-elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI). We assessed the predictive validities of 30-day bleeding events in various scoring systems using receiver operating characteristic curves.Overall, ACUITY-HORIZONS exhibited the highest area under the curve to predict 30-day bleeding, followed by ACTION and CRUSADE; HAS-BLED displayed the lowest score. With a cut-off of 17, ACUITY-HORIZONS demonstrated the best discrimination for the Thrombolysis in Myocardial Infarction (TIMI) 30-day serious bleeding rate. We observed significant differences among all-cause death, cardiovascular death, and major adverse cardiac events between the ACUITY-HORIZONS groups with a score of ≤ 17 and > 17. ACUITY-HORIZONS score > 17, initial systolic blood pressure (SBP) < 90 mmHg, and Killip III and IV upon admission positively predicted the 30-day bleeding risk, whereas myocardial infarction (MI) and TIMI major bleeding within 30 days, heart failure at admission, and initial SBP < 90 mmHg positively predicted the 30-day mortality.Comparatively, ACUITY-HORIZON is the most reliable system in predicting 30-day bleeding for patients with AMI via transradial PCI. In the transradial scenario, bleeding and MI within 30 days are substantially related to 30-day mortality.

This study investigated the efficacy and safety of ticagrelor compared with clopidogrel in patients with end-stage renal disease (ESRD) and acute myocardial infarction (AMI). We retrospectively enrolled patients who had received regular dialysis and had undergone percutaneous coronary intervention (PCI) for AMI at our hospital between January 2013 and December 2016. Outcomes analyzed included cardiovascular death, death from any cause, MI, stroke, and bleeding events. Patients were allocated to the ticagrelor group (N = 74) or the clopidogrel group (N = 116) according to the treatment they had received. No statistically significant differences were found between the groups in terms of in-hospital primary endpoint (composite of cardiovascular death, MI, and stroke: 12.2% and 15.5% for ticagrelor and clopidogrel, respectively; p = 0.518), secondary endpoint, or any bleeding events (39.2 vs. 34.5%; p = 0.511). No statistically significant differences were found for the 1-year primary endpoint (p = 0.424), secondary endpoint, and any bleeding events (p = 0.663). Risk factors for in-hospital cardiovascular death were shock and cardiopulmonary resuscitation at initial AMI presentation, lack of beta-blocker use, and in-hospital gastrointestinal bleeding. Risk factors for 1-year cardiovascular death were shock at initial AMI presentation and lack of beta-blocker use. Only respiratory failure was a risk factor for in-hospital and 1-year gastrointestinal bleeding. In patients with ESRD and AMI, ticagrelor resulted in numerically fewer but statistically nonsignificant rates of in-hospital and 1-year cardiovascular events with no significant increase in bleeding events compared with clopidogrel.

Hydroxypropyl chitosan (HPCS) has recently attracted increasing attention in biomedical applications because it has enhanced water solubility, excellent biocompatibility, and better antioxidant and antibacterial activities compared with chitosan. However, HPCS doesn't meet the mechanical strength requirement in bone tissue engineering and is not suitable for cell adhesion and growth because of its hydrophilic nature and low crystallinity. In this study, nano-scaled hydroxyapatite (n-HA) and HPCS were synthesized, respectively, and then n-HA/HPCS nanocomposite scaffolds were developed by incorporating n-HA into HPCS matrix accompanied with crosslinking of HPCS by a naturally occurring compound, genipin (GP), which in turn greatly altered the hydrophilicity and mechanical properties. The nanocomposite scaffolds showed an open structure with interconnected pores and a rough morphology with n-HA inserted in the GP-crosslinked HPCS matrix. The porosity, swelling capacity, compressive strength, fluorescence emission and degradation rate can be regulated by varying GP concentrations and n-HA contents. An osteoconductive and osteogenic marine algae polysaccharide, fucoidan, was further adsorbed to the composite scaffolds via electrostatic interactions. Incorporation of n-HA and adsorption of FD into the composite scaffolds increased ALP activity in 7F2 osteoblast cells and promoted their mineralization. The FD-adsorbed n-HA/HPCS composite scaffolds can be a potential biomaterial for BTE applications.

Oral administration is a highly attractive approach for the delivery of protein drugs. However, oral protein therapeutics typically exhibit extremely poor bioavailability due to the harsh gastrointestinal (GI) environments and low permeability of protein across the intestinal barrier. Trimethyl chitosan (TMC) shows excellent mucoadhesive and absorption-enhancing properties while fucoidan (FD) has hypoglycemic effects and can prevent diabetes-related complications. Here we report, for the first time, that TMC combined with FD can be developed to a mutlifunctional nanoplatform for enhancing the transepithelial permeation of insulin through the intestinal epithelial cell barrier and inhibiting the α-glucosidase activity. TMC and FD self-assembled into spherical nanoparticles (NPs) for insulin encapsulation. TMC/FD NPs protected insulin against degradation by releasing insulin in a pH-dependent manner in the gastrointestinal tract fluids. The NPs were able to modulate the barrier function of the Caco-2 intestinal epithelial cell monolayer, and enhance paracellular transport of insulin across the intestinal barrier. TMC/FD NPs also showed α-glucosidase inhibitory activity, with an inhibition ratio of 33.2% at 2 mg/mL. The superior transepithelial absorption enhancing property of the TMC/FD NPs is expected to combine in the future with the functions of fucoidan against diabetes-related complications for development of advanced mutlifunctional therapeutic platforms for diabetes.

Neutrophilic dermatosis on the site of lymphedema is a rare condition and considered as a localized and less severe variant of Sweet syndrome. Only 13 cases of this variant have been reported after mastectomy for breast cancer in the English-language published work. However, this condition has never been described on the lower limbs or from other causes of lymphedema. Herein, we report two cases of localized Sweet syndrome on the lymphedematous lower limbs: one occurred after radical hysterectomy, bilateral pelvic lymph node dissection and radiotherapy for cervical cancer; the other developed after radiotherapy for malignant melanoma on the right groin. Based on clinical and histological features, we suggest the name "lymphedema-associated neutrophilic dermatosis" for this underrecognized disease entity.

Casticin, a polymethoxyflavone occurring in natural plants, has been shown to have anticancer activities. In the present study, we aims to investigate the anti-skin cancer activity of casticin on melanoma cells in vitro and the antitumor effect of casticin on human melanoma xenografts in nu/nu mice in vivo. A flow cytometric assay was performed to detect expression of viable cells, cell cycles, reactive oxygen species production, levels of [Formula: see text] and caspase activity. A Western blotting assay and confocal laser microscope examination were performed to detect expression of protein levels. In the in vitro studies, we found that casticin induced morphological cell changes and DNA condensation and damage, decreased the total viable cells, and induced G2/M phase arrest. Casticin promoted reactive oxygen species (ROS) production, decreased the level of [Formula: see text], and promoted caspase-3 activities in A375.S2 cells. The induced G2/M phase arrest indicated by the Western blotting assay showed that casticin promoted the expression of p53, p21 and CHK-1 proteins and inhibited the protein levels of Cdc25c, CDK-1, Cyclin A and B. The casticin-induced apoptosis indicated that casticin promoted pro-apoptotic proteins but inhibited anti-apoptotic proteins. These findings also were confirmed by the fact that casticin promoted the release of AIF and Endo G from mitochondria to cytosol. An electrophoretic mobility shift assay (EMSA) assay showed that casticin inhibited the NF-[Formula: see text]B binding DNA and that these effects were time-dependent. In the in vivo studies, results from immuno-deficient nu/nu mice bearing the A375.S2 tumor xenograft indicated that casticin significantly suppressed tumor growth based on tumor size and weight decreases. Early G2/M arrest and mitochondria-dependent signaling contributed to the apoptotic A375.S2 cell demise induced by casticin. In in vivo experiments, A375.S2 also efficaciously suppressed tumor volume in a xenotransplantation model. Therefore, casticin might be a potential therapeutic agent for the treatment of skin cancer in the future.

Although established guidelines currently recommend the use of the CHA2DS2-VASc score for evaluating embolic risk in AF patients, few studies have evaluated the use of the CHA2DS2-VASc score for predicting cardiovascular outcomes in patients with acute myocardial infarction (AMI). The aim of this study was to determine whether CHA2DS2-VASc score is a predictor of a major adverse cardiocerebral vascular event (MACCE) in AMI patients. This study analyzed data in the Taiwan National Health Insurance Research Database from January 2008 to December 2012. Cardiovascular outcomes were analyzed according to the baseline characteristics, presence of AF, and CHA2DS2-VASc score. Twenty nine thousand four hundred fifty-two patients with non-fatal AMI, 1171 patients (8.3%) were with AF. The Cox regress model showed with the exception of women sex and peripheral artery disease, all the baseline characteristics considered risks in CHA2DS2-VASc scores were independently associated with the increased incidence of MACCE within 1 year after AMI. A CHA2DS2-VASc score of

Increasing contextual interference (CI) during practice benefits learning, making it a desirable difficulty. For example, interleaved practice (IP) of motor sequences is generally more difficult than repetitive practice (RP) during practice but leads to better learning. Here we investigated whether CI in practice modulated resting-state functional connectivity during consolidation. 26 healthy adults (11 men/15 women, age = 23.3 ± 1.3 years) practiced two sets of three sequences in an IP or RP condition over 2 days, followed by a retention test on Day 5 to evaluate learning. On each practice day, functional magnetic resonance imaging (fMRI) data were acquired during practice and also in a resting state immediately after practice. The resting-state fMRI data were processed using independent component analysis (ICA) followed by functional connectivity analysis, showing that IP on Day 1 led to greater resting connectivity than RP between the left premotor cortex and left dorsolateral prefrontal cortex (DLPFC), bilateral posterior cingulate cortices, and bilateral inferior parietal lobules. Moreover, greater resting connectivity after IP than RP on Day 1, between the left premotor cortex and the hippocampus, amygdala, putamen, and thalamus on the right, and the cerebellum, was associated with better learning following IP. Mediation analysis further showed that the association between enhanced resting premotor-hippocampal connectivity on Day 1 and better retention performance following IP was mediated by greater task-related functional activation during IP on Day 2. Our findings suggest that the benefit of CI to motor learning is likely through enhanced resting premotor connectivity during the early phase of consolidation.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer with poor clinical outcomes and insufficient treatments in Southeast Asian populations. Although concurrent chemoradiotherapy has improved recovery rates of patients, poor overall survival and low efficacy are still critical problems. To improve the therapeutic efficacy, we focused on a tumor-associated protein called Annexin A2 (ANXA2). This review summarizes the mechanisms by which ANXA2 promotes cancer progression (e.g., proliferation, migration, the epithelial-mesenchymal transition, invasion, and cancer stem cell formation) and therapeutic resistance (e.g., radiotherapy, chemotherapy, and immunotherapy). These mechanisms gave us a deeper understanding of the molecular aspects of cancer progression, and further provided us with a great opportunity to overcome therapeutic resistance of NPC and other cancers with high ANXA2 expression by developing this prospective ANXA2-targeted therapy.

Self-assembled nanoparticles (NPs) from arginine-modified chitosan (CS-N-Arg) and thiolated fucoidan (THL-fucoidan) were synthesized to enhance the transport of dextran and curcumin across intestinal epithelial cell layer. CS-N-Arg/THL-fucoidan NPs exhibited a pH-sensitive assembly-disassembly and drug release property. Evaluations of the NPs in enhancing the transport of a hydrophilic macromolecule (FITC-dextran) and a hydrophobic drug (curcumin) were investigated in Caco-2 cell monolayers. The cationic CS-N-Arg in the NPs induced disruption of intestinal epithelial tight junctions as indicated by the decrease of transepithelial electrical resistance (TEER). Permeation studies revealed that the NPs enhanced the paracellular permeation of macromolecular dextran through the monolayer barrier. In addition, the multifunctional NPs increased the permeability of rhodamine 123 because the thiomer THL-fucoidan in the NPs inhibited P-glycoprotein. Cellular uptake and permeability of curcumin encapsulated in the NPs were improved due to increasing their water solubility and stability.

We have developed a new strategy to temporarily blunt the reticuloendothelial system uptake of nanodrugs, a major challenge for nanodrug delivery and causing off-target toxicities, using an FDA approved nutrition supplement, Intralipid. We have tested our methodology in rats using an experimental platinum-containing anti-cancer nanodrug and three FDA approved nanodrugs, Abraxane, Marqibo, and Onivyde, to determine their toxicities in liver, spleen, and kidney, with and without the addition of Intralipid. Our method illustrates its potentials to deliver nanodrugs with an increase in the bioavailability and a decrease in toxicities. Our study shows that Intralipid treatment exhibits no harmful effect on tumor growing and no negative effect on the anti-tumor efficacy of the platinum-containing nanodrug, as well as animal survival rate in a HT-29 xenograft mouse model. Our methodology could also be a valuable complement/supplement to the “stealth” strategies. Our approach is a general one applicable to any approved and in-development nanodrugs without additional modification of the nanodrugs, thus facilitating its translation to clinical settings.

The unliganded tetrameric Hb S has axial and lateral contacts with neighbors and can polymerize in solution. Novel recombinants of Hb S with single amino acid substitutions at the putative axial (recombinant Hb (rHb) (βE6V/αH20R) and rHb (βE6V/αH20Q)) or lateral (rHb (βE6V/αH50Q)) or double amino acid substitutions at both the putative axial and lateral (rHb (βE6V/αH20R/αH50Q) and rHb (βE6V/αH20Q/αH50Q)) contact sites were expressed in Escherichia coli and purified for structural and functional studies. The (1)H NMR spectra of the CO and deoxy forms of these mutants indicate that substitutions at either αHis-20 or αHis-50 do not change the subunit interfaces or the heme pockets of the proteins. The double mutants show only slight structural alteration in the β-heme pockets. All mutants have similar cooperativity (n50), alkaline Bohr effect, and autoxidation rate as Hb S. The oxygen binding affinity (P50) of the single mutants is comparable with that of Hb S. The double mutants bind oxygen with slightly higher affinity than Hb S under the acidic conditions. In high salt, rHb (βE6V/αH20R) is the only mutant that has a shorter delay time of polymerization and forms polymers more readily than Hb S with a dextran-Csat value of 1.86 ± 0.20 g/dl. Hb S, rHb (βE6V/αH20Q), rHb (βE6V/αH50Q), rHb (βE6V/αH20R/αH50Q), and rHb (βE6V/αH20Q/αH50Q) have dextran-Csat values of 2.95 ± 0.10, 3.04 ± 0.17, 11.78 ± 0.59, 7.11 ± 0.66, and 10.89 ± 0.83 g/dl, respectively. rHb (βE6V/αH20Q/αH50Q) is even more stable than Hb S under elevated temperature (60 °C).

The expression of annexin A2 (ANXA2) in nasopharyngeal carcinoma (NPC) cells induces the immunosuppressive response in dendritic cells; however, the oncogenic effect and clinical significance of ANXA2 have not been fully investigated in NPC cells. Immunohistochemical staining for ANXA2 was performed in 61 patients and the association with clinicopathological status was determined. Short hairpin (sh)RNA knockdown of ANXA2 was used to examine cellular effects of ANXA2, by investigating alterations in cell proliferation, migration, invasion, adhesion, tube-formation assay, and chemo- and radiosensitivity assays were performed. RT-qPCR, Western blotting, and immunofluorescence were applied to determine molecular expression levels. Clinical association studies showed that the expression of ANXA2 was significantly correlated with metastasis (p = 0.0326) and poor survival (p = 0.0256). Silencing of ANXA2 suppressed the abilities of cell proliferation, adhesion, migration, invasion, and vascular formation in NPC cell. ANXA2 up-regulated epithelial-mesenchymal transition associated signal proteins. Moreover, ANXA2 reduced sensitivities to irradiation and chemotherapeutic drugs. These results define ANXA2 as a novel prognostic factor for malignant processes, and it can serve as a molecular target of therapeutic interventions for NPC.

Using 10-year population data from 2000 through 2009 in Taiwan, this is the first paper to analyze the relationship between margin trading in stock markets and stroke hospitalizations. The results show that 3 and 6 days after an increase of margin trading in the Taiwan stock markets are associated with greater stoke hospitalizations. In general, a 1 % increase in total margin trading positions is associated with an increment of 2.5 in the total number of stroke hospitalizations, where the mean number of hospital admissions is 233 cases a day. We further examine the effects of margin trading by gender and age groups and find that the effects of margin trading are significant for males and those who are 45-74 years old only. In summary, buying stocks with money you do not have is quite risky, especially if the prices of those stocks fall past a certain level or if there is a sudden and severe drop in the stock market. There is also a hidden danger to one's health from margin trading. A person should be cautious before conducting margin trading, because while it can be quite profitable, danger always lurks just around the corner.

// Yu-Tang Tung 1, * , Pin-Wu Huang 1, * , Yu-Ching Chou 1 , Cheng-Wei Lai 1 , Hsiu-Po Wang 1 , Heng-Chien Ho 2 , Chih-Ching Yen 1, 3 , Chih-Yen Tu 1, 3 , Tung-Chou Tsai 1 , Dah-Cherng Yeh 4 , Jiun-Long Wang 1, 5 , Kowit-Yu Chong 6, 7 , Chuan-Mu Chen 1, 8 1 Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan 2 Department of Medicine, China Medical University Hospital, Taichung 404, Taiwan 3 Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan 4 Department of General Surgery and Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan 5 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan 6 Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan 7 Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan 8 Rong-Hsing Translational Medicine Center and iEGG Center, National Chung Hsing University, Taichung 402, Taiwan * These authors have contributed equally to this work Correspondence to: Chuan-Mu Chen, e-mail: chchen1@dragon.nchu.edu.tw Keywords: VEGF, transgenic mice, pulmonary tumorigenesis, magnetic resonance imaging (MRI), miRNA therapy Received: November 03, 2014 Accepted: April 10, 2015 Published: April 22, 2015 ABSTRACT Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A 165 (hVEGF-A 165 ) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A 165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A 165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A 165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT-PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes ( hvegf-A 165 , cyclin b1 , cdc2 , egfr , mmp9 , nrp-1 , and kdr ) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A 165 in Clara cells increases CD105, fibrogenic genes ( collagen α1 , α-SMA , TGF-β1 , and TIMP1 ), and inflammatory cytokines (IL-1, IL-6, and TNF- α ) in the lungs of hVEGF-A 165 -overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A 165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF-targeted therapies in lung adenocarcinoma.

Mumps is caused by a paramyxovirus. It is an acute, but mild infectious disease. However, approximately 10% of patients with mumps can develop severe meningoencephalitis, disability, and death. Seasonal patterns in mumps vary across countries, but the reasons for this phenomenon remain unclear. The aim of this study was to assess the role of meteorological factors on mumps infection. We investigated the relationships between weather variability and the incidence of mumps in Taiwan using a Poisson regression analysis and case-crossover methodology. Between 2006 and 2011, 6,612 cases of mumps were reported to the Centers for Disease Control, Taiwan (Taiwan CDC). The incidence of mumps showed a significant seasonality in summertime (for oscillation, P < 0.001). The number of mumps started to increase at temperatures of 20°C (r(2) = 0.73, P < 0.001), and the case count of mumps began to decline when the temperatures were higher than approximately 25°C (r(2) = 0.24, p = 0.04), producing an inverted V-shaped relationship. Similarly, the number of mumps began to increase at a vapor pressure of 5-9 hPa (r(2) = 0.87, P < 0.005) and decreased at a vapor pressure higher than 25-29 hPa (r(2) = 0.21, p = 0.05). The number of mumps cases was positively associated with temperature and vapor pressure in the preceding period of the infection. In conclusion, this study showed that the occurrence of mumps is significantly associated with increasing temperature and vapor pressure in Taiwan. Therefore, these factors could be regarded as warning signals indicating the need to implement preventive measures.

Invasive pneumococcal disease (IPD) and pneumonia are the major causes of morbidity and deaths in children in the world. The management of IPD and pneumonia is an important economic burden on healthcare systems and families. The aim of this study was to assess the economic burden of IPD and pneumonia among younger children in Taiwan. We used a cost-illness approach to identify the cost categories for analysis in this study according to various perspectives. We obtained data of admission, outpatient, and emergency department visit data from the National Health Insurance Research (NHIR) database for children

Hemoglobin (Hb) is a truly remarkable molecule. Human adult hemoglobin (Hb A) has a tetrameric structure consisting of two α-chains with 141 amino acids each and two β-chains with 146 amino acids each. Figure 1 illustrates features of the molecule that will be discussed. The tertiary structure is the three dimensional structure of the individual protein chains. The quaternary structure is the arrangement of the multiple protein chains into a multi-subunit complex stabilized through non-covalent interactions. Each of the four chains in Hb possesses a heme group, the binding site for ligands, such as oxygen (O2), carbon monoxide (CO), or nitric oxide (NO). It is an essential protein for all vertebrates, designed to facilitate the loading of oxygen molecules in the lungs (or gills) and unloading of oxygen molecules in the tissues efficiently. Hb is one of the first proteins whose structure was determined by X-ray crystallography in the 1960s and has also been used as a paradigm for understanding the structure-function relationship in allosteric proteins. An allosteric protein is one in which binding of a substrate, product, or other effector to a subunit of a multi-subunit protein at a site (allosteric site) other than the functional site alters its conformation and functional properties and can therefore contribute to regulating its physiological properties. For a review of the structure-function relationship of Hb, see ref.1 Most of the published results and conclusions regarding the molecular basis for Hb function, until recently, were based on the information derived from X-ray crystallographic data of Hb, e.g., the classical Monod-Wyman-Changeux (MWC) and Perutz's two-structure stereochemical model for hemoglobin allostery.2-3 Figure 1 Structures of Hb A: (a) Crystal structure of deoxy-Hb A (2DN2); (b) Crystal structure of HbCO A (2DN3); (c) The 10 lowest-energy solution structures of HbCO A obtained by NMR spectroscopy (2M6Z); (d) Superimposition of the R (2DN3, colored in red), R2 ... The classical MWC/Perutz model postulates that all four subunits in Hb have to assume simultaneously either the tense (T)- or relaxed (R)-structure.2-3 Both structures can bind ligands while the affinity towards the ligand changes in transiting from the T- to the R-structure. Noticing the marked differences in the crystal structures of oxy- and deoxy-Hb, Perutz3 put forward his stereochemical mechanism that correlated the T- and R- states of the MWC model to the deoxy- and oxy-structures of Hb. A key feature of the MWC model is that all four subunits must make the switch from T to R or R to T at the same time. In other words, the ligation of one subunit would not affect the ligand affinity of the neighboring subunits within the same quaternary structure. It is a concerted quaternary structural transition model. Perutz's model further postulates that inter- and intra-subunit salt bridges stabilize the Hb molecule in the T-structure. The deoxy- or T-structure has a lower ligand affinity compared to the oxy- or R-structure and the binding of oxygen is cooperative, i.e., binding of the first oxygen molecule increases the affinity of the Hb molecule for additional oxygen molecules. The induced-fit or sequential model [also known as the Koshland-Nemethy-Filmer (KNF) model] is another classical model for Hb allostery.4-5 It postulates that the binding of a ligand to one subunit can induce the conformational changes in the tertiary structure of its neighboring subunits without their having a bound ligand. Thus, the ligand binding in a multi-subunit protein is a sequential process; there are not just two final states, T and R, but a series of intermediate states. A conformational change in a neighboring subunit can take place in the absence of ligand binding. Both the MWC and the KNF models can account for the cooperative oxygen binding to Hb, thus the ligand-binding data alone cannot distinguish the KNF model from the MWC/Perutz model. Much work has been done in the last sixty years in order to determine whether the transition from the T to the R state is concerted or sequential and to gain an understanding of the atomic and molecular details of the cooperative oxygenation of Hb A and the mechanism of allostery. The stereochemical mechanism of Perutz was extended by Szabo and Karplus6 and later refined by Lee and Karplus.7 This statistical-mechanical model derives a partition function that describes the influence of homotropic (oxygen) and heterotropic [e.g., hydrogen ions and 2,3-bisphosphoglycerate (2,3-BPG)] effectors on the Hb structural changes. Two different tertiary structures for each of the two quaternary structures have been included in their formulation. Contrary to Perutz's model, the Szabo-Karplus model takes into account the differences in strength of the salt bridges that stabilize the T-structure and the contributions of the pH-independent steric constraints in reducing the ligand affinity of Hb in the deoxy state. Yonetani and co-workers proposed a global allostery model.8 This model stipulates that in the absence of heterotropic effectors, the allostery of Hb follows the MWC/Perutz model. Heterotropic effectors, when present, interact with both T and R states of Hb to induce tertiary rather than quaternary structural changes. The changes in oxygen affinity, Bohr effect, and cooperativity of Hb are primarily the consequence of heterotropic effector-induced tertiary structural changes. The tertiary two-state model of Eaton and co-workers9 can be considered as a variation of the MWC/Perutz model. Within each quaternary structure, the subunits exist in equilibrium of high (r) and low (t) affinity conformers. The R- and T-structures as defined in the MWC/Perutz model favor the r and t formation, respectively. As in the MWC/Perutz model, ligand binding without a quaternary conformation change is non-cooperative. However, the tertiary conformations of individual subunits play the primary role instead of the quaternary conformations. The molecular code for cooperativity of Ackers and coworkers10-11 points out that there are eight ligation intermediates between the completely unliganded and the fully liganded tetrameric Hb. The tetrameric Hb switches from T- to R-form when at least one subunit of each dimer is liganded. Hence, five ligation intermediates plus the fully liganded tetrameric Hb exist in the R-structure. Within each quaternary state, oxygen binding or releasing “sequentially” modulates the tertiary constraints, which ultimately leads to the quaternary structural switch. Cooperativity is the result of both “concerted” quaternary switching and “sequential” modulation of ligand binding within each quaternary form. There are many crystal structures determined over the years and several well-characterized T- and R-types of crystal structures of Hb A reported in the literature are summarized in Table 1. This multitude of structures and recent results obtained by other methods clearly show that the classical two-structure MWC/Perutz description for hemoglobin allostery as presented in biochemistry, biophysics, and molecular biology textbooks cannot account for Hb function in details and needs revision. In our last review12 ten years ago, we gave a summary of our experimental results on the molecular basis of the Bohr effect of Hb A and the solution conformation, dynamics, and subunit communication of Hb A as derived from our nuclear magnetic resonance (NMR) studies. Here, we present new results of NMR and wide-angle X-ray scattering (WAXS) studies that are relevant to the structure-function relationship in hemoglobin. Table 1 Crystallization conditions and resolutions of various crystal structures. During the past 10 years, hemoglobin has remained an active research area for biochemical, biophysical, and computational studies with over 6,500 papers published in the literature. It is interesting to note that a search of PubMed indicates that there were 489 papers with hemoglobin titles published in 2004, 632 papers in 2009, and 813 papers in 2013. This increase in the number of Hb publications indicates that there are new results as well as new thinking in the field of hemoglobin research. This article is not intended to cover all areas of Hb research, but focuses on new findings on the nature of Hb as a dynamic ensemble as related to its properties in solution. For additional readings on Hb and Hb allostery, one could consider a number of relevant articles.13-31

Background Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinuses and mucosa with unclear pathogenesis. Interleukin (IL)-21 is mainly expressed in activated cluster of differentiation (CD)4+ T cells and has potent regulatory effects on the immune system. Objective This study is to determine whether IL-21 in the blood is correlated with CRS. Methods The blood samples from CRS patients and normal controls were analyzed in correlation with clinical features. The eosinophil percentage was counted, and serum levels of total immunoglobulin E (IgE) and IL-21 were analyzed by enzyme-linked immunosorbent assay (ELISA). In addition, IL-21 and interferon (IFN)-γ secreted from stimulated peripheral blood mononuclear cells (PBMCs) were measured by ELISA, and their mRNA expression levels were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Disease severity was scored based on computed tomography (CT) scan, nasal endoscopy, and global osteitis scoring scale (GOSS). Results A total of 55 CRS and 37 healthy subjects were recruited. The average levels of serum total IgE were 20 kU/L in normal group, 290 kU/L in CRS with nasal polys (CRSwNP), and 187 kU/L in CRS without nasal polys (CRSsNP). IL-21 levels were 28 pg/mL in normal group, 54 pg/mL in CRSwNP, and 71 pg/mL in CRSsNP. Both IgE and IL-21 were significantly elevated in both CRS patient subgroups. However, no significant difference was found between these two patient subgroups. The serum IL-21 levels correlated well with the disease severity in the patients. In addition, the secreted IL-21 was enhanced significantly in the patient's PBMCs stimulated by phytohemagglutin (PHA). Conclusion IL-21 could be a target for diagnosis and treatment of CRS.

Dendritic cells (DCs) play an essential role in immunity and are used in cancer immunotherapy. However, these cells can be tuned by tumors with immunosuppressive responses. DC-specific intercellular adhesion molecule 3-Grabbing Nonintegrin (DC-SIGN), a C-type lectin expressed on DCs, recognizes certain carbohydrate structures which can be found on cancer cells. Nasopharyngeal carcinoma (NPC) is an epithelial cell-derived malignant tumor, in which immune response remains unclear. This research is to reveal the molecular link on NPC cells that induces the immunosuppressive responses in DCs. In this article, we report identification of annexin A2 (ANXA2) on NPC cells as a ligand for DC-SIGN on DCs. N-linked mannose-rich glycan on ANXA2 may mediate the interaction. ANXA2 was abundantly expressed in NPC, and knockdown of ANXA2 suppressed NPC xenograft in mice, suggesting a crucial role of ANXA2 in NPC growth. Interaction with NPC cells caused DC-SIGN activation in DCs. Consequently DC maturation and the proinflammatory interleukin (IL)-12 production were inhibited, and the immunosuppressive IL-10 production was promoted. Blockage of either DC-SIGN or ANXA2 eliminated the production of IL-10 from DCs. This report suggests that suppression of ANXA2 at its expression or glycosylation on NPC may improve DC-mediated immunotherapy for the tumor.

This is the fourth and final study designed to develop International Classification of Functioning, Disability and Health (ICF, and children and youth version, ICF-CY) core sets for attention-deficit hyperactivity disorder (ADHD). To investigate aspects of functioning and environment of individuals with ADHD as documented by the ICF-CY in clinical practice settings. An international cross-sectional multi-centre study was applied, involving nine units from eight countries: Denmark, Germany, India, Italy, Portugal, Saudi Arabia, Sweden and Taiwan. Clinicians and clinical researchers rated the functioning level of 112 children, adolescents and adults with ADHD using the extended ICF-CY checklist version 2.1a. The ratings were based on a variety of information sources, such as medical records, medical history, clinical observations, clinical questionnaires, psychometric tests and structured interviews with participants and family members. In total, 113 ICF-CY categories were identified, of which 50 were related to the activities and participation, 33 to environmental factors and 30 to body functions. The clinical study also yielded strengths related to ADHD, which included temperament and personality functions and recreation and leisure. The study findings endorse the complex nature of ADHD, as evidenced by the many functional and contextual domains impacted in ADHD. ICF-CY based tools can serve as foundation for capturing various functional profiles and environmental facilitators and barriers. The international nature of the ICF-CY makes it possible to develop user-friendly tools that can be applied globally and in multiple settings, ranging from clinical services and policy-making to education and research.

Rationale: Numerous types of flap coverage have been reported to prevent or to repair bronchopleural fistulas. Most of the flaps were harvested from chest area. However, these pedicled flaps might not be optimal for the patient who has undergone previous radiotherapy on pulmonary parenchyma because the pedicle artery of the flap might have been injured by irradiation. Therefore, an alternative flap outside of the chest area is necessary. Patient concerns: A 61-year-old male was diagnosed of squamous cell carcinoma in right upper lobe lung (cT3N2M0, stage IIIa). After completing the neoadjuvant chemoradiotherapy, he underwent video-assisted thoracoscopic surgery with right side intrapericardial pneumonectomy. Diagnosis: Persistent air leak due to postpneumonectomy bronchopleural fistula. Interventions: Pedicled transverse rectus abdominis myocutaneous (TRAM) flap was used to repair the bronchial stump. Outcomes: The bronchial stump was repaired successfully, the bronchopleural fistula was obliterated, and the patient was free from air leak after following for 12 months. Lessons: This case demonstrated that pedicled TRAM flap is a feasible alternative to repair bronchopleural fistula.

Background. This study evaluated the impact on clinical outcomes using a cloud computing system to reduce percutaneous coronary intervention hospital door-to-balloon (DTB) time for ST segment elevation myocardial infarction (STEMI). Methods. A total of 369 patients before and after implementation of the transfer protocol were enrolled. Of these patients, 262 were transferred through protocol while the other 107 patients were transferred through the traditional referral process. Results. There were no significant differences in DTB time, pain to door of STEMI receiving center arrival time, and pain to balloon time between the two groups. Pain to electrocardiography time in patients with Killip I/II and catheterization laboratory to balloon time in patients with Killip III/IV were significantly reduced in transferred through protocol group compared to in traditional referral process group (both p<0.05). There were also no remarkable differences in the complication rate and 30-day mortality between two groups. The multivariate analysis revealed that the independent predictors of 30-day mortality were elderly patients, advanced Killip score, and higher level of troponin-I. Conclusions. This study showed that patients transferred through our present protocol could reduce pain to electrocardiography and catheterization laboratory to balloon time in Killip I/II and III/IV patients separately. However, this study showed that using a cloud computing system in our present protocol did not reduce DTB time.

Sparse sampling methods have emerged as effective tools to accelerate cardiac magnetic resonance imaging (MRI). Low-rank model-based cardiac imaging uses a pre-determined temporal subspace for image reconstruction from highly under-sampled (k, t)-space data and has been demonstrated effective for high-speed cardiac MRI. The accuracy of the temporal subspace is a key factor in these methods, yet little work has been published on data acquisition strategies to improve subspace estimation. This paper investigates the use of non-Cartesian k-space trajectories to replace the Cartesian trajectories which are omnipresent but are highly sensitive to readout direction. We also propose “self-navigated” pulse sequences which collect both navigator data (for determining the temporal subspace) and imaging data after every RF pulse, allowing for even greater acceleration. We investigate subspace estimation strategies through analysis of phantom images and demonstrate in vivo cardiac imaging in rats and mice without the use of ECG or respiratory gating. The proposed methods achieved 3-D imaging of wall motion, first-pass myocardial perfusion, and late gadolinium enhancement in rats at 74 frames per second (fps), as well as 2-D imaging of wall motion in mice at 97 fps.

Magnetic resonance imaging (MRI) has long been recognized as a powerful tool for cardiovascular imaging because of its unique potential to measure blood flow, cardiac wall motion, and tissue properties jointly. However, many clinical applications of cardiac MRI have been limited by low imaging speed. In this paper, we present a novel method to accelerate cardiovascular MRI through the integration of parallel imaging, low-rank modeling, and sparse modeling. This method consists of a novel image model and specialized data acquisition. Of particular novelty is the proposed low-rank model component, which is specially adapted to the particular low-rank structure of cardiovascular signals. Simulations and in vivo experiments were performed to evaluate the method, as well as an analysis of the low-rank structure of a numerical cardiovascular phantom. Cardiac imaging experiments were carried out on both human and rat subjects without the use of ECG or respiratory gating and without breath holds. The proposed method reconstructed 2-D human cardiac images up to 22 fps and 1.0 mm × 1.0 mm spatial resolution and 3-D rat cardiac images at 67 fps and 0.65 mm × 0.65 mm × 0.31 mm spatial resolution. These capabilities will enhance the practical utility of cardiovascular MRI.

The solution structure of human adult carbonmonoxy hemoglobin (HbCO A) was refined using stereospecifically assigned methyl groups and residual dipolar couplings based on our previous nuclear magnetic resonance structure. The tertiary structures of individual chains were found to be very similar to the X-ray structures, while the quaternary structures in solution at low salt concentrations resembled the X-ray R structure more than the R2 structure. On the basis of chemical shift perturbation by inositol hexaphosphate (IHP) titration and docking, we identified five possible IHP binding sites in HbCO A. Amide-water proton exchange experiments demonstrated that αThr38 located in the α1β2 interface and several loop regions in both α- and β-chains were dynamic on the subsecond time scale. Side chain methyl dynamics revealed that methyl groups in the α1β2 interface were dynamic, but those in the α1β1 interface were quite rigid on the nanosecond to picosecond and millisecond to microsecond time scales. All the data strongly suggest a dynamic α1β2 interface that allows conformational changes among different forms (like T, R, and R2) easily in solution. Binding of IHP to HbCO A induced small structural and dynamic changes in the α1β2 interface and the regions around the hemes but did not increase the conformational entropy of HbCO A. The binding also caused conformational changes on the millisecond time scale, very likely arising from the relative motion of the α1β1 dimer with respect to the α2β2 dimer. Heterotropic effectors like IHP may change the oxygen affinity of Hb through modulating the relative motion of the two dimers and then further altering the structure of heme binding regions.