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Humans have an exceptional ability to extract specific audio streams of interest in a noisy environment; this is known as the cocktail party effect. It is widely accepted that this ability is related to selective attention, a mental process that enables individuals to focus on a particular object. Evidence suggests that sensory neurons can be modulated by top-down signals transmitted from the prefrontal cortex. However, exactly how the projection of attention signals to the cortex and subcortex influences the cocktail effect is unclear. We constructed computational models to study whether attentional modulation is more effective at earlier or later stages for solving the cocktail party problem along the auditory pathway. We modeled the auditory pathway using deep neural networks (DNNs), which can generate representational neural patterns that resemble the human brain. We constructed a series of DNN models in which the main structures were autoencoders. We then trained these DNNs on a speech separation task derived from the dichotic listening paradigm, a common paradigm to investigate the cocktail party effect. We next analyzed the modulation effects of attention signals during all stages. Our results showed that the attentional modulation effect is more effective at the lower stages of the DNNs. This suggests that the projection of attention signals to lower stages within the auditory pathway plays a more significant role than the higher stages in solving the cocktail party problem. This prediction could be tested using neurophysiological experiments.

Background/purpose Sapoviruses (SaVs) become important pathogens causing both sporadic and outbreaks of acute gastroenteritis (AGE) after rotavirus vaccination era worldwide. SaVs were included in AGE screening items when norovirus and rotavirus were negative in Taiwan CDC since 2008. However, no complete SaV genome sequence of any genotype detected in Taiwan was determined. This study aimed to investigate SaVs infection and complete genome sequences detected in Taiwan. Methods This prospective survey, SaVs samples with untyped or weak PCR result were selected for testing the new design qRT-PCR assay from AGE hospitalized children during 2008–2011, 2016–2017 and AGE outbreak in 2012–2014. Those were genetically characterized using long RT-PCR with different primer combinations as well as primer independent deep sequencing and with 5′ RACE and 3′ terminal region targeting RT-PCR. Results Overall, 14 SaV-AGE hospitalized children and 4 SaV-AGE outbreaks were enrolled in this study. In addition to the AGE symptoms, 6 children also showed URI symptoms (cough, pharyngitis, rhinorrhea and nasal congestion). The detected 19 SaVs were classified as eight genotypes (GI.1, GI.2, GI.3, GII.2, GII.3, GII.5, GII.8, and GIV.1) and the complete genome sequence of representative strain for each genotype were determined except GI.3. The GII.3 was the most major genotype following GI.1 and GIV.1. Conclusion Our result confirmed that SaV is one of the pathogens detected from Taiwanese AGE patients. Multiple SaV genotype strains would associate with AGE as similar to those detected in different countries/areas. The whole genome of SaV strains detected including rarely reported GII.8 was firstly determined.

OBJECTIVE Data regarding the prevalence of depression and anxiety among cancer patients, especially before cancer diagnosis, remains scarce. This study investigated the prevalence of these conditions and associated drug use among cancer patients pre- and post-diagnosis. METHODS This population-based cohort study using data from Taiwan's National Health Insurance Research Database recruited patients with a registered cancer diagnosis and matched control between January 1, 2000, and December 31, 2011. We compared the prevalence of anxiety and depressive disorders between cancer patients and non-cancer participants during a 2-year period both pre- and post-diagnosis by Pearson's chi-square test. Psychiatric medication use was also examined for the associated mental condition. RESULTS We examined participants diagnosed with liver (N = 17,154), colorectal (N = 30,391), breast (N = 40,036), gynecological (N = 23,218), and lung (N = 15,671) cancer. Before the cancer diagnosis, the prevalence of depression was higher in non-cancer participants than in gynecological cancer patients (p = 0.018) but anxiety is higher in liver, colorectal, and lung cancer patients when compared to non-cancer participants (p

BACKGROUND: Pacing-induced cardiomyopathy is an undesired outcome in patients with atrioventricular block (AVB), and our animal model showed lipotoxic cardiomyopathy after pacing.OBJECTIVES: The purpose of this study was to explore the mechanisms and clinical outcomes of statins in AVB patients receiving pacing.METHODS: Rat ventricular cardiomyocytes were treated with atorvastatin, liver X receptor (LXR) agonist, and LXR antagonist during pacing. Pigs were divided into 3 groups: right ventricular pacing, pacing with concomitant atorvastatin treatment, and sham control. Clinically, we enrolled 1717 AVB patients who had received a permanent pacemaker from Chang Gung Memorial Hospital Medical database. The primary outcome (cardiovascular death or heart failure [HF] hospitalization) and individual outcome were compared between statin and nonstatin groups after inverse probability of treatment weighting.RESULTS: Lipid accumulation in rat cardiomyocytes by pacing was significantly reduced by treatment with LXR agonist and atorvastatin, whereas LXR antagonist counteracted the atorvastatin effect on lipid expression. Left ventricular ejection fraction (LVEF) was significantly lower in the AVB pig pacing group compared to the group concomitantly treated with atorvastatin. Moreover, lipid accumulation and fibronectin expression were significantly ameliorated by concomitant treatment with atorvastatin. In the clinical study, the statin group had a significantly lower risk of the primary outcome event (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56-0.84), less HF hospitalization (HR 0.45; 95% CI 0.30-0.67), and higher LVEF than the nonstatin group.CONCLUSION: In experimental models, atorvastatin ameliorated lipid accumulation in cardiomyocytes and fibrosis in left ventricular myocardium induced by pacing. Clinically, treatment with statins was associated with less HF hospitalization and cardiovascular death in AVB patients receiving pacemaker therapy.

Rotavirus A (RVA) are a group of diverse viruses causing acute gastroenteritis (AGE) in humans and animals. Zoonotic transmission is an important mechanism for rotavirus evolution and strain diversity in humans, but the extent of pigs as a major reservoir for human infection is not clear.We have surveyed 153 pig farms across Taiwan with a total of 4588 porcine stool samples from three age groups from 2014 to 2017. Nursing piglets (less than one month of age) had higher detection rate for rotavirus than older age groups. Five VP7 (G) genotypes and 5 VP4 (P) genotypes were found in a total of 14 different G/P genotype combinations. In addition, porcine RVA strains had 2 NSP4 (E) genotypes and 3 VP6 (I) genotypes. A P[3]-like genotype was also discovered among strains collected in 2016 and 2017.Most of the genes from Taiwanese porcine strains clustered with each other and the lineages formed by these strains were distinct from the sequences of numerous regional variants or globally circulating porcine strains, suggesting an independent evolutionary history for Taiwanese rotavirus genotypes. The close relationship among porcine RVA strains and some unique porcine-like genotypes detected sporadically among human children in swine farms illustrates that pigs might serve as a reservoir for potential zoonotic transmission and novel genotype evolution in Taiwan's insular environment.

Background Studies have reported an association between allergy and panic disorder. However, few studies have explored the relationship between allergic rhinitis and panic disorder. Previous studies were limited by cross-sectional study designs, self-reported symptoms, absence of matched controls, and lack of consideration of the influence of steroid and comorbidities. This study aimed to explore the longitudinal association between allergic rhinitis and panic disorder in a large population-based cohort of young people. Methods In this study, 79,917 new cases of allergic rhinitis between 1998 and 2012 in individuals younger than 20 years were identified from Taiwan's National Health Insurance Research Database. One control (nonallergic rhinitis) per case (allergic rhinitis) was randomly selected from the remaining sample, matching for age, sex, residence, and insurance premium. Both groups were followed until the end of 2013 for incidence of panic disorder. Cox regression analysis was performed, adjusting for sex, age, residence, insurance premium, systemic steroids, asthma, atopic dermatitis, allergic conjunctivitis, attention deficit hyperactivity disorder, depression, and Charlson index. Results Allergic rhinitis was associated with a 2-fold increase in risk for panic disorder after adjustment for other variables. Additional independent risk factor of panic disorders were female sex, older age group, and depression. Limitations Lifestyle, substance use, smoking by the patient or family members, and psychosocial stressors were not evaluated. Conclusions Allergic rhinitis was associated with increased risk of panic disorder. Assessment and intervention of allergy rhinitis among young people with panic disorder are critical.

Background: Obesity has been regarded as a risk factor for epiblepharon. This study aims to investigate the age- and sex-specific relationship between epiblepharon and obesity in children.Methods: A retrospective case-control study was conducted using Chang Gung Research Database. Children ≤ 18 years of age with epiblepharon were identified from 1 January 2009 to 31 December 2019. Children were classified into four groups: underweight, normal, overweight and obese groups.Results: A total of 513 patients and 1026 controls (57.7% of males) aged 1 to 18 matched by sex and age were included in the analysis. The median body mass index (BMI) of children with epiblepharon was significantly higher than that of children without epiblepharon (p < 0.001). In the subgroup analysis, among boys aged 4 to 9 years, the BMI in boys with epiblepharon was significantly higher than that in boys without epiblepharon (p < 0.05) and the risk of epiblepahron in overweight and obese boys was significantly higher than in non-overweight boys (OR = 1.74, 95% CI = 1.07-2.82; OR = 3.06, 95% CI = 1.56-6.03). On the other hand, among girls aged 13 to 18 years, the BMI in adolescent girls with epiblepharon was significantly higher than that in the control group (p < 0.05) and overweight and obese girls had statistically higher risk of persistent epiblepharon than non-overweight girls (OR =3.70, 95% CI = 1.38-9.97).Conclusions: The association between obesity and epiblepharon varies in strength according to age in a sex-specific manner.

Failure to recognize a carotid-cavernous fistula (CCF) promptly may lead to worse prognosis due to a setback in providing proper treatment. To promote early diagnosis of non-traumatic CCF, we report a case with classic clinical symptoms and signs that was diagnosed and followed up with carotid Doppler sonography (CDS) and transcranial color-coded duplex (TCD).A 45-year-old woman developed an intermittent headache, pulsatile tinnitus, and double vision sequentially within ten days. Progressive left retro-orbital pain, continuous ringing in the left ear, sensory impairment of trigeminal nerve and abducens nerve palsy were also noted on examination. Despite insignificant findings on computed tomography (CT) of the brain, TCD revealed an aberrant flow pattern with high velocity and low resistance at the left carotid siphon. Digital subtraction angiography (DSA) later confirmed a left direct type CCF by illustrating a quick opacification of left cavernous sinus via the internal carotid artery.In addition to invasive DSA, non-invasive CDS and TCD may serve as useful apparatus during the initial evaluation and subsequent follow-ups. The positive sonographic clues, including abnormal turbulent and hemodynamic parameters, are quite exhibitive in the existence of CCFs.

Background: The aim of this study was to compare the risk of developing sudden sensorineural hearing loss (SSHL) in patients with hypopharyngeal cancer with that in patients with nasopharyngeal carcinoma (NPC). Methods: A population-based, retrospective cohort study was performed using the Taiwan National Health Research Database databank. Patients selected for this study were diagnosed with hypopharyngeal cancer or NPC and treated with radiotherapy in the period from 2001 to 2004. Routine follow-up was conducted for 8 years (2004–2012), and the incidence of SSHL was calculated at the final follow-up. Results: There was no significant difference in the risk of developing SSHL between the hypopharyngeal cancer group and its control group (p = 1.000). In hypopharyngeal cancer and NPC groups, the rates of SSHL were 0.12% and 1.00%, respectively (p < 0.001). The cumulative hazard of SSHL during the follow-up period was significantly higher in the NPC group than in the control group (p < 0.001). Conclusion: Radiotherapy in patients with hypopharyngeal cancer did not increase the risk of developing SSHL, but postirradiation NPC was significantly associated with an increased incidence of SSHL.

Objective To investigate the safety of adenoidectomy and risk factors of re-adenoidectomy, and intend to provide evidence-based information to clinicians for further consideration. Methods and materials This study was based on data obtained from Taiwan’s National Health Insurance Research Database from the period 2002–2011. We utilized that data from the hospitalization group and collected information regarding those individuals who accepted adenoidectomy with or without tonsillectomy and post-adenoidectomy bleeding. Thereafter, we performed univariate and multi-variate analysis to explore the possible risk factors of re-adenoidectomy. Results A total of 5435 individuals who accepted a first adenoidectomy with or without tonsillectomy were collected. After further tracing treatment of these individuals, 107 (1.97%) accepted the revision adenoidectomy until 2011. Post-op bleeding was approximately 0.28%. The revision rate associated with patient age showed the following: 0–4 years (0.61%), 4–12 years (2.06%) and 12–18 years (2.56%). The revision rate associated with surgeon age showed: 28–41 years (1.42%), 41–50 years (2.96%), 50–65 years (2.74%); the surgeons’ surgery volume showed low (4.34%), medium (0.71%), and higher (1.02%). There are 4 diseases (otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder) that showed a significant relationship with the revision rate when subject to univariate and multivariate analysis. The revision rate incorporating hospital locations, volumes and levels revealed no significant difference with each other. Conclusions Adenoidectomy is a generally safe surgical procedure, with low complication and low revision rate. Our study indicated that the revision rate of adenoidectomy might be lower when performed by young visiting staff with medium to higher surgical volume in the medium to higher volume hospital. If patients had diseases such as otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder, they would be subject to higher rate of re-adenoidectomy. Surgeons should be aware and sufficiently explain this information to the parents before surgery.

We report the first nationwide population-based cohort study using Taiwan's National Health Insurance Research Database on the association between enterovirus (EV) infection and the incidence of sleep disorders in a pediatric population.Two matched groups of children under 18 years of age were included in the analyses for nonapneic sleep disorder and obstructive sleep apnea (OSA). Among them, 316 subjects were diagnosed with OSA during the surveillance period, including 182 in the EV infection group and 134 in the non-EV infection group.Hospitalization because of EV infection was associated with OSA after adjusting for age, sex, urbanization atopic disease and perinatal complications (adjusted hazard ratio: 1.62, 95% confidence interval: 1.18-2.21; P = 0.003). An additional factor significantly associated with sleep apnea was allergic rhinitis (hazard ratio: 4.82, 95% confidence interval: 3.45-6.72).Children with severe EV infection (ie, requiring hospitalization) carry a significantly higher risk of developing OSA, particularly in those with allergic rhinitis. As pediatric obstructive sleep apnea is a treatable sleep disorder, we emphasize regular follow-up and early detection in children with EV infection.

Summary: The Muscleblind-like protein family (MBNL) plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder. How different MBNL isoforms contribute to the differentiation and are affected in DM1 has not been investigated. Here, we show that the MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA. Cytoplasmic MBNL1 is polyubiquitinated by lysine 63 (K63). Reduced cytoplasmic MBNL1 in the DM1 mouse brain is consistent with the reduced extent of K63 ubiquitination. Expanded CUG RNA induced the deubiqutination of cytoplasmic MBNL1, which resulted in nuclear translocation and morphological impairment that could be ameliorated by inhibiting K63-linked polyubiquitin chain degradation. Our results suggest that K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and that deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain. : Wang et al. find that MBNL1 ubiquitination is required for cytoplasmic localization and promotion of neurite outgrowth. In myotonic dystrophy, expanded CUG repeat RNA leads to MBNL1 deubiquitination, resulting in nuclear-translocation-associated morphological defects that can be rescued by preventing degradation of lysine 63-linked polyubiquitin chains or enhancing MBNL1 ubiquitination. Keywords: MBNL1, polyubiquitination, myotonic dystrophy, nucleocytoplasmic localization, neurite outgrowth

Preventive effect of stimulants on the risk of brain injuries had been reported. The aim of this study is to determine the extent to which methylphenidate (MPH) prescription moderates the risk of traumatic brain injuries (TBI) in individuals with attention-deficit/hyperactivity disorder (ADHD). Individuals with a recent diagnosis of ADHD between January 1997 and December 2013 (n = 163,618) were identified from Taiwan's National Health Insurance Research Database. A total of 124,438 adolescents and children with ADHD and without prior TBI diagnoses were included and evaluated for subsequent TBI. Methylphenidate prescription duration was subgrouped by the annual average cumulative defined daily dose (DDD): 0, >0 to ≤28, > 28 to ≤84, and >84. We identified 11,463 diagnoses of TBI among 124,438 adolescents and children with ADHD. A Cox regression model was used to investigate whether MPH prescription influenced the risk for TBI after adjusting for sex, age, level of urbanization, seizure, autism and sedative-anxiolytics use. A reduced TBI incidence was observed with MPH prescription DDDs > 84. The protective effect of MPH against TBI persisted after adjusting for confounding factors [hazard ratio (HR) = 0.49; 95% confidence interval (CI): 0.47-0.51]. There was also statistically significant difference in risk for TBI in subjects receiving > 0 to ≤28 or >28 to ≤84 DDDs of MPH treatment (HR = 0.88, 95% CI = 0.83-0.92; HR = 0.76, 95% CI = 0.72-0.80, respectively) when compared with subjects not receiving treatment with MPH. Treatment with MPH for greater than 84 DDDs reduced the risk for TBI among children with ADHD.

In Taiwan, acute gastroenteritis outbreaks caused by a new norovirus genotype GII.2 increased sharply toward the end of 2016. Unlike previous outbreaks, which often involved restaurants, GII.2 outbreaks mainly occurred in schools. Phylogenetic analysis indicates that these noroviruses are recombinant GII.P16-GII.2 strains.

Aims Attention-deficit/hyperactivity disorder (ADHD) is associated with a higher risk of burn injury than in the normal population. Nevertheless, the influence of methylphenidate (MPH) on the risk of burn injury remains unclear. This retrospective cohort study analysed the effect of MPH on the risk of burn injury in children with ADHD. Method Data were from Taiwan's National Health Insurance Research Database (NHIRD). The sample comprised individuals younger than 18 years with a diagnosis of ADHD (n = 90 634) in Taiwan's NHIRD between January 1996 and December 2013. We examined the cumulative effect of MPH on burn injury risk using Cox proportional hazards models. We conducted a sensitivity analysis for immortal time bias using a time-dependent Cox model and within-patient comparisons using the self-controlled case series model. Results Children with ADHD taking MPH had a reduced risk of burn injury, with a cumulative duration of treatment dose-related effect, compared with those not taking MPH. Compared with children with ADHD not taking MPH, the adjusted hazard ratio for burn injury was 0.70 in children taking MPH for Conclusion This study showed that MPH treatment was associated with a lower risk of burn injury in a cumulative duration of treatment dose-related effect manner.

Anxiety and depression are common emotional problems in children and adolescents. This study used a long-term tracking large database to investigate whether the proportion of children who were diagnosed with speech and language impairments were later diagnosed with anxiety or depression were significantly greater than that of matched group of the same age and gender without speech and language impairments. More than 4300 eligible children with speech and language impairments and matched controls were identified and assessed for anxiety and depression. The risk of anxiety and depressive disorders in children with speech and language impairments were examined with Cox regression analyses and adjusting for covariables (gender, age, and comorbidities). The results showed that speech and language impairments were positively associated with anxiety disorders (adjusted hazard ratio [AHR] 2.87, 95% confidence interval [CI] 2.20–3.76) and depressive disorders (AHR 2.51, 95% CI 1.52–4.13). The number of boys with speech and language impairments was more than twofold that of girls, but boys did not different from girls in the risk of anxiety disorders (AHR 0.95, 95% CI 0.75–1.20) and depressive disorders (AHR 0.72, 95% CI 0.47–1.11). Infantile autism and intellectual disabilities were positively associated with anxiety (AHR 1.54, 95% CI 1.07–2.21; AHR 1.47, 95% CI 1.09–1.98), and the latter was positively associated with depression (AHR 1.83, 95% CI 1.06–3.17). In addition to speech and language impairments interventions, our findings supported the necessity of identification and interventions in anxiety and depressive disorders among children with speech and language impairments from elementary school until youth.

// Erh-Hsuan Lin 1, 2, 3, 4 , Yu-Rung Kao 1 , Chih-An Lin 5 , Ting-Yu Kuo 4 , Sheng-Ping Yang 2 , Chiung-Fang Hsu 1 , Teh-Ying Chou 3, 6 , Chao-Chi Ho 7 , Cheng-Wen Wu 1, 2, 3, 4 1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 2 Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 4 Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan 6 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 7 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan Correspondence to: Cheng-Wen Wu, e-mail: cwwu@ym.edu.tw Keywords: lung adenocarcinoma, Hedgehog pathway, HHIP, drug resistance, HGF/MET Received: July 30, 2015 Accepted: March 02, 2016 Published: March 22, 2016 ABSTRACT Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic.

Objective Psoriasis is a chronic inflammatory disease putatively associated with dementia. However, the epidemiologic evidence of the relationship between psoriasis and dementia has been limited. We used a large national sample to investigate this relationship as well as the association between systemic therapy for psoriasis and incident dementia. Methods The cases were identified as a first recorded diagnosis of psoriasis (ICD-9-CM codes: 696.0, 696.1, or 696.8) between 1996 and 2013 from Taiwan's National Health Insurance Research Database (NHIRD). Each selected case of psoriasis was compared with 4 sex-, age-, and urbanization-matched comparison subjects. The first diagnosis of dementia (ICD-9-CM codes: 290.0-290.4, 294.1-294.2, 331.0-331.2, or 331.82) that covered vascular and nonvascular subtypes until the end of 2013 was tracked in both groups. Cox regression analyses and a competing risk model were applied to evaluate the risk, adjusting for sex, urbanization, age, hypertension, diabetes, heart disease, hyperlipidemia, stroke, and depression. The association between systemic therapy and incidence of dementia in the psoriasis group was examined in further stratified analyses. Results Overall, 3,820 patients with psoriasis and 15,280 comparisons were identified. After adjustment, a significantly higher risk of dementia was identified in the psoriasis group than in the comparison group (adjusted hazard ratio [aHR] = 1.23; 95% CI, 1.06-1.42). A significant association between psoriasis and dementia was identified for nonvascular dementia (aHR = 1.25, 95% CI, 1.07-1.45) but not for vascular dementia (aHR = 1.27, 95% CI, 0.83-1.93). Receiving systemic therapy for psoriasis for more than 90 days significantly reduced the risk of developing dementia compared with no systemic therapy (aHR = 0.66; 95% CI, 0.45-0.97). Compared with those who received no systemic therapy, the patients who received disease-modifying antirheumatic drugs and/or biologics had a significantly lower risk of dementia incidence (aHR = 0.69; 95% CI, 0.50-0.97), which was not the case in patients who received only phototherapy. Conclusions Individuals with psoriasis have a significantly higher incidence of dementia, particularly the nonvascular type. Systemic therapy might be protective in preventing dementia in patients with psoriasis.

Patients with risk factors including younger age, mastoiditis, external ear disease, treatment by older surgeons, and concomitant mastoidectomy should receive detailed management to minimize the probability of re-operation for chronic otitis media (COM).Although COM remains a common ear disease requiring surgical intervention, its re-operation risks are less well-documented. This study aimed to compare patients with COM who underwent re-operation and those patients with no re-operation, and identify the risks of re-operation.This retrospective cohort study analyzed the trend of COM surgery from 1999-2009, and identified the re-operation risks of 18 895 patients with COM who underwent surgery from 2002-2006 using the National Health Insurance Research Database in Taiwan.Among the study population, 129 patients underwent revision surgery during a 5.5 ± 1.5 year follow-up period. A univariate logistic regression analysis showed that the re-operation rate was significantly higher in patients under 18 years of age, those with mastoiditis, disorders of external ear, treatment by surgeons of 50-64 years of age, use of a very high volume surgeon, and combined surgery with mastoidectomy. A multivariate analysis further limited the re-operation risk factors to younger patients, those with mastoiditis, external ear disorders, treatment by older surgeons, and concomitant mastoidectomy.

Helicobacter pylori neutrophil-activating protein (HP-NAP) activates several innate leukocytes including neutrophils, monocytes, and mast cells. It has been reported that HP-NAP induces degranulation and interleukin-6 (IL-6) secretion of rat peritoneal mast cells. However, the molecular mechanism is not very clear. Here, we show that HP-NAP activates human mast cell line-1 (HMC-1) cells to secrete histamine and IL-6. The secretion depends on pertussis toxin (PTX)-sensitive heterotrimeric G proteins but not on Toll-like receptor 2. Moreover, HP-NAP induces PTX-sensitive G protein-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38 MAPK), and Akt in HMC-1 cells. Inhibition of ERK1/2, p38 MAPK, or phosphatidylinositol 3-kinase (PI3K) suppresses HP-NAP-induced release of histamine and IL-6 from HMC-1 cells. Thus, the activation of HMC-1 cells by HP-NAP is through Gi-linked G protein-coupled receptor-mediated MAPKs and PI3K/Akt pathways.

Both virus-induced asthma and enterovirus (EV) infection are common in children; however, the relationship between EV infection and virus-induced asthma has not been systematically investigated in a cohort study. This nationwide population-based cohort study investigated the association between EV infection and asthma.We used data from the Taiwan National Health Insurance Research Database. The study sample consisted of insured children who were younger than 18 years and had EV infection between 1997 and 2013 and were followed until December 2013. We identified 36,935 children with EV infection and compared them based on 36,935 age-, sex-, urbanization- and income-matched controls to analyze the risk of subsequent asthma. Cox regression analyses were performed and adjusted for sex, age, urbanization, income, preterm labor and small for gestational age, perinatal complications, allergic rhinitis, allergic conjunctivitis, atopic dermatitis and bronchiolitis.The mean follow-up interval for all patients was 8.59 years (standard deviation = 4.35 years). The mean latency period between initial EV infection and onset of asthma was 2.77 years (standard deviation = 2.43 years). EV infection was significantly associated with a higher incidence of asthma (hazard ratio = 1.65; 95% confidence interval: 1.60-1.71).A significant association was observed between EV infection and asthma in children. Health providers should be aware of the higher potential for children with EV to develop asthma in the future.

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the 3' untranslated region (UTR) of the dystrophia myotonia protein kinase (DMPK) gene. Cognitive impairment associated with structural change in the brain is prevalent in DM1. How this histopathological abnormality during disease progression develops remains elusive. Nuclear accumulation of mutant DMPK mRNA containing expanded CUG RNA disrupting the cytoplasmic and nuclear activities of muscleblind-like (MBNL) protein has been implicated in DM1 neural pathogenesis. The association between MBNL dysfunction and morphological changes has not been investigated. We generated a mouse model for postnatal expression of expanded CUG RNA in the brain that recapitulates the features of the DM1 brain, including the formation of nuclear RNA and MBNL foci, learning disability, brain atrophy and misregulated alternative splicing. Characterization of the pathological abnormalities by a time-course study revealed that hippocampus-related learning and synaptic potentiation were impaired before structural changes in the brain, followed by brain atrophy associated with progressive reduction of axon and dendrite integrity. Moreover, cytoplasmic MBNL1 distribution on dendrites decreased before dendrite degeneration, whereas reduced MBNL2 expression and altered MBNL-regulated alternative splicing was evident after degeneration. These results suggest that the expression of expanded CUG RNA in the DM1 brain results in neurodegenerative processes, with reduced cytoplasmic MBNL1 as an early event response to expanded CUG RNA.

Attention-deficit hyperactivity disorder (ADHD) is associated with higher risk for fracture. Whether the medical treatment for ADHD would mitigate the risk remains unclear. In this study, we sought to investigate the effect of methylphenidate treatment on risk for fracture, as well the moderational role of treatment duration on the risk of fracture, in a large national sample. Cases less than 18 years old were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of ADHD (ICD-9:314) between 1996 and 2013. A total of 6201 cases with ADHD were included as the study cohort. The cases were divided into 3 groups according to the duration of methylphenidate treatment (0, 1-180, and more than 180 days). All groups were followed until the end of 2013 for first diagnoses of fracture (ICD-9 codes 800 to 829). Cox proportional hazards models were applied. Compared to the group without methylphenidate treatment, the risk for fracture was lower among the group treated for more than 180 days. The adjusted hazard ratio was 0.77 (95% Confidence interval: 0.63-0.94). The groups treated for 180 days or fewer had no significant difference in the risk for fracture. In conclusion, methylphenidate treatment was associated with lower risk for fracture among ADHD patients. The association was evident only in the cohort treated for more than 180 days.

Post-traumatic endocrine dysfunction is a complication of traumatic brain injury (TBI). However, there is lack of long-term follow-up and large sample size studies. This study included patients suffering from TBI registered in the Health Insurance Database. Endocrine disorders were identified using the ICD codes: 244 (acquired hypothyroidism), 253 (pituitary dysfunction), 255 (disorders of the adrenal glands), 258 (polyglandular dysfunction), and 259 (other endocrine disorders) with at least three outpatient visits within 1 year or one admission diagnosis. Overall, 156,945 insured subjects were included in the final analysis. The 1- and 5-year incidence rates of post-traumatic endocrinopathies were 0.4% and 2%, respectively. The risks of developing a common endocrinopathy (p

Palatoplasty can significantly decrease their middle ear re-intubation rate with a relatively lower hazard ratio compared to children who underwent VTI only.In children with cleft palate, questions remain about the overall effect of ventilation tube insertion (VTI) and palatoplasty for their OME. A large-scale study might offer more evidence for the roles of palatal surgery.This was a retrospective birth cohort study based upon a national database. We analyzed children born between 1999-2004 and diagnosed as cleft palate and/or lips. These children, according to their surgeries, were separated into two groups: (1) VTI only, and (2) VTI and palatoplasty. Kaplan-Meier analysis and log-rank test were used to calculate their cumulative tube re-insertion rates. Their hazard ratios of tube re-insertion were also analyzed.In total, 1205 cleft children were collected, with 151 in the VTI only group and 1054 in the VTI + palatoplasty group. Ventilation tube re-insertion rates were significantly lower in the VTI + palatoplasty group (p = 0.002). The cumulative re-insertion rates also showed a significant difference (p = 0.001). When compared to the VTI only group, the adjusted hazard ratio was 0.528 in the VTI + palatoplasty group (p = 0.001).

The extension of axon branches is important for target innervation but how axon branching is regulated is currently not well understood. Here, we report that Bcl11A/CTIP1/Evi9, a zinc finger transcription factor, downregulates axon branching. Knockdown of Bcl11A induced axon branching and multi-axon formation, as well as dendrite outgrowth. Due to alternative splicing, a single Bcl11A gene encodes two protein products, Bcl11A-L and -S. Bcl11A-L was found to be the main Bcl11A player in regulation of neurite arborization; Bcl11A-S is an antagonist of Bcl11A-L. Time-lapse study further suggests that Bcl11A-L knockdown enhances axon dynamics and increases the duration of axon outgrowth. Finally, the expression of DCC and MAP1b, two molecules involved in direction and branching of axon outgrowth, is controlled by Bcl11A-L. DCC overexpression rescues the phenotype induced by Bcl11A-L knockdown. In conclusion, this report provides the first evidence that Bcl11A is important for neurite arborization.

Calcium/calmodulin-dependent serine kinase (CASK), a causative gene in X-linked mental retardation, carries out multiple functions in neurons, including vesicle trafficking of ion channels, synapse formation, and gene transcription. From a yeast two-hybrid screen, Kruppel-like zinc finger protein B cell lymphoma/COUP-TF-interacting protein 1 (Bcl11A/CTIP1) was identified as a CASK binding protein. Through alternative splicing, a single Bcl11A gene encodes two major protein products in neurons, Bcl11A-S and Bcl11A-L. CASK interacted with both Bcl11A-S and Bcl11A-L in transfected COS cells and brain. Immunofluorescence staining further indicated the colocalization of CASK and Bcl11A in the nuclei of neurons. These studies supported an interaction between CASK and Bcl11A in vivo. Bcl11A-L has previously been shown to play a role in gene transcription as well as axon outgrowth and branching. Here, we further show that Bcl11A-L rearranges the distribution of nuclear actin, which may be related to the function of Bcl11A-L in gene expression. More importantly, using cultured hippocampal neurons as a model system, we show that CASK enhances the ability of Bcl11A-L to restrict axon outgrowth and branching. Interruption of the interaction between CASK and Bcl11A increased the outgrowth and branching of axons, suggesting that the interaction between CASK and Bcl11A controls axon arborization. In conclusion, our results suggest that, through the interaction with Bcl11A, CASK plays a role in axonogenesis, which may be related to brain anatomical characteristics in humans.

Bcl11A/Evi9/CTIP1, a Kruppel-like zinc finger gene, plays an important role in B-cell development. In addition to expression in B lymphocytes, Bcl11A/Evi9/CTIP1 is also highly expressed in the brain, although its function there is still unclear. In the present study, regional and subcellular distributions of Bcl11A/Evi9/CTIP1 in rat brain were investigated by immunostaining and biochemical fractionation. Using antibodies recognizing the first 18 amino acid residues of Bcl11A/Evi9/CTIP1, the distribution of 2 isoforms of Bcl11A/Evi9/CTIP1 gene products, Bcl11A-L/Evi9a and Bcl11A-S/Evi9c, was examined. In rat brain, both Bcl11A-L/Evi9a and Bcl11A-S/Evi9c were expressed, although the amount of Bcl11A-S/Evi9c protein was higher. Bcl11A-S/Evi9c was widely expressed in different regions of the rat brain. In contrast, Bcl11A-L/Evi9a was more restricted, being expressed in the cerebral cortex, hippocampus, and olfactory bulb. At the subcellular level, biochemical fractionation and confocal analysis of adult rat brain revealed that, in addition to being in the nuclei of neurons, fractions of Bcl11A-L/Evi9a and Bcl11A-S/Evi9c could be found in extranuclear locations. Double staining with the synaptic marker synaptophysin indicated a synaptic distribution of Bcl11A/Evi9/CTIP1. Postsynaptic density was also biochemically purified and subjected to immunoblotting using Bcl11A/Evi9/CTIP1 antibodies. The results showed that Bcl11A-L/Evi9a was enriched in the PSD I and PSD II fractions. In contrast, only a trace amount of Bcl11A-S was detected in PSD fractions. Our study also indicated that a fraction of Bcl11A/Evi9/CTIP1 was present in the cytoplasm, even at synapses. To regulate gene expression in the nuclei, nuclear translocation of Bcl11A/Evi9/CTIP1 may be one of the mechanisms controlling neuronal Bcl11A/Evi9/CTIP1 function. © 2007 Wiley-Liss, Inc.

CASK acts as a coactivator for Tbr-1, an essential transcription factor in cerebral cortex development. Presently, the molecular mechanism of the CASK coactivation effect is unclear. Here, we report that CASK binds to another nuclear protein, CINAP, which binds histones and facilitates nucleosome assembly. CINAP, via its interaction with CASK, forms a complex with Tbr-1, regulating expression of the genes controlled by Tbr-1 and CASK, such as NR2b and reelin. A knockdown of endogenous CINAP in hippocampal neurons reduces the promoter activity of NR2b. Moreover, NMDA stimulation results in a reduction in the level of CINAP protein, via a proteasomal degradation pathway, correlating with a decrease in NR2b expression in neurons. This study suggests that reduction of the CINAP protein level by synaptic stimulation contributes to regulation of the transcriptional activity of the Tbr-1/CASK/CINAP protein complex and thus modifies expression of the NR2b gene.