Photoinduced Decarboxylative Difluoroalkylation and Perfluoroalkylation of α-Fluoroacrylic Acids.

Herein, a novel and practical methodology for the photoinduced decarboxylative difluoroalkylation and perfluoroalkylation of α-fluoroacrylic acids is reported. A wide range of α-fluoroacrylic acids can be used as applicable feedstocks, allowing for rapid access to structurally important difluoroalkylated and polyfluoroalkylated monofluoroalkenes with high Z-stereoselectivity under mild conditions. The protocol demonstrates excellent functional group compatibility and provides a platform for modifying complex biologically active molecules.

AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood-Brain Barrier.

Aquaporin-4 (AQP4) is characterized by the formation of orthogonal arrays of particles (OAPs) comprising its M1 and M23 isoforms in the plasma membrane. However, the biological importance of OAP formation is obscure. Here, we developed an OAP depolymerization male mouse model by transgenic knock-in of an AQP4-A25Q mutation. Analyses of the mutant brain tissue using blue native polyacrylamide gel electrophoresis, super-resolution imaging, and immunogold electron microscopy revealed remarkably reduced OAP structures and glial endfeet localization of the AQP4-A25Q mutant protein without effects on its overall mRNA and protein expression. AQP4A25Q/A25Q mice showed better survival and neurologic deficit scores when cerebral edema was induced by water intoxication or middle cerebral artery occlusion/reperfusion. The brain water content and swelling of pericapillary astrocytic endfeet processes in AQP4A25Q/A25Q mice were significantly reduced, functionally supporting decreased AQP4 protein expression at the blood-brain barrier. The infarct volume and neuronal damage were also reduced in AQP4A25Q/A25Q mice in the middle cerebral artery occlusion/reperfusion model. Astrocyte activation in the brain was alleviated in AQP4A25Q/A25Q mice, which may be associated with decreased cell swelling. We conclude that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.SIGNIFICANCE STATEMENT Aquaporin-4 (AQP4) is characterized by orthogonal arrays of particles (OAPs) comprising the M1 and M23 isoforms in the membrane. Here, an OAP depolymerization male mouse model induced by AQP4-A25Q mutation was first established, and the functions of OAP depolymerization in cerebral edema have been studied. The results revealed that AQP4 lost its OAP structure without affecting AQP4 mRNA and protein levels in AQP4-A25Q mice. AQP4-A25Q mutation mice has neuroprotective effects on cerebral edema induced by water intoxication and middle cerebral artery occlusion/reperfusion through relieving the activation of astrocytes and suppressed microglia-mediated neuroinflammation. We concluded that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.

Maternal Exposure to Air Pollution Is Associated with Neonatal Jaundice: A Retrospective Cohort Study.

OBJECTIVE: To evaluate the association between maternal ambient pollutant exposure and neonatal jaundice in multiple pollutant species and examine sex differences. STUDY DESIGN: Epidemiologic study: Records of 13 297 newborns (6153 male, 7144 female) born in Taichung, Taiwan were obtained from a national database. Average concentrations of prenatal air pollutants 3 months prior to birth were divided into low, middle, and high levels. Neonatal jaundice phototherapy rates between mothers who suffered varying air pollutant levels were compared. Clinical study: Three hundred seventy-six newborns (189 male, 187 female) born and received jaundice treatment with phototherapy in a hospital in Taichung, Taiwan were recruited. The correlation between prenatal exposure to air pollutants 3 months prior to birth, newborn's serum bilirubin, and serum hemoglobin were calculated. RESULTS: Epidemiologic study: Male newborns born to mothers exposed to high carbon monoxide (CO), nitric oxide (NO), nitrogen dioxide (NO2), and methane (CH4) levels had higher phototherapy rates. In female newborns, the same was noted for CO and CH4. Clinical study: Male newborns had a positive correlation between CO, ≤2.5 µm diameter particles, ≤10 µm diameter particles, NO, NO2, nonmethane hydrocarbon, and CH4 exposure 3 months prior to birth and serum bilirubin levels. Female newborns had a positive correlation for CH4. A positive correlation between CO, ≤2.5 µm diameter particles, ≤10 µm diameter particles, NO2, nonmethane hydrocarbon, CH4 exposure, and serum hemoglobin levels was noted in male newborns. CONCLUSION: Maternal exposure to air pollutants may increase neonatal jaundice treatment rates for phototherapy and higher neonatal serum total bilirubin level. Higher hemoglobin levels because of higher pollutant exposures may explain our findings. The association was more obvious in male newborns.

Effect of the Fungal Immunomodulatory Protein FIP-fve in the Neutrophilic Asthma Animal Model.

BACKGROUND: Asthma animal models provide valuable information about the pathogenesis and the treatment of asthma. An ovalbumin (OVA)/complete Freund's adjuvant (CFA)-sensitized model was developed to induce neutrophil-dominant asthma and to investigate whether fungal immunomodulatory peptide-fve (FIP-fve) could improve asthma features in the OVA/CFA-sensitized model. METHODS: We used female BALB/c mice and sensitized them intraperitoneally with OVA/CFA on days 1, 2, and 3. On days 14, 17, 21, 24, and 27, they were challenged with intranasal OVA. The airway hyper-responsiveness (AHR) was detected by BUXCO, inflammatory cells were stained with Liu's stain, the cytokines were detected using ELISA, and the airway inflammation was analyzed with hematoxylin and eosin stain. RESULTS: According to the results, OVA/CFA sensitization could induce AHR, high levels of IgE, and inflammatory cells especially neutrophils infiltration in the lung and airway inflammation. IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17, IL-25, IL-33, and transforming growth factor-ß (TGF-ß) increased in the OVA/CFA-sensitized mice. OVA/CFA-sensitized mice treated with FIP-fve not only increased IL-12 and IFN-γ but also decreased IL-4, IL-5, IL-6, IL-8, IL-13, IL-17, IL-25, IL-33, and TGF-ß in the bronchoalveolar lavage fluid. Moreover, FIP-fve significantly decreased neutrophil infiltration in the lung. CONCLUSION: The OVA/CFA model induced neutrophilic asthma successfully, and FIP-fve improved neutrophil-dominant asthma.

TRIM32 Deficiency Impairs Synaptic Plasticity by Excitatory-Inhibitory Imbalance via Notch Pathway.

Synaptic plasticity is the neural basis of physiological processes involved in learning and memory. Tripartite motif-containing 32 (TRIM32) has been found to play many important roles in the brain such as neural stem cell proliferation, neurogenesis, inhibition of nerve proliferation, and apoptosis. TRIM32 has been linked to several nervous system diseases including autism spectrum disorder, depression, anxiety, and Alzheimer's disease. However, the role of TRIM32 in regulating the mechanism of synaptic plasticity is still unknown. Our electrophysiological studies using hippocampal slices revealed that long-term potentiation of CA1 synapses was impaired in TRIM32 deficient (KO) mice. Further research found that dendritic spines density, AMPA receptors, and synaptic plasticity-related proteins were also reduced. NMDA receptors were upregulated whereas GABA receptors were downregulated in TRIM32 deficient mice, explaining the imbalance in excitatory and inhibitory neurotransmission. This caused overexcitation leading to decreased neuronal numbers in the hippocampus and cortex. In summary, this study provides this maiden evidence on the synaptic plasticity changes of TRIM32 deficiency in the brain and proposes that TRIM32 relates the notch signaling pathway and its related mechanisms contribute to this deficit.

Electroconvulsive therapy treatment responsive multimodal brain networks.

Electroconvulsive therapy is regarded as the most effective antidepressant treatment for severe and treatment-resistant depressive episodes. Despite the efficacy of electroconvulsive therapy, the neurobiological underpinnings and mechanisms underlying electroconvulsive therapy induced antidepressant effects remain unclear. The objective of this investigation was to identify electroconvulsive therapy treatment responsive multimodal biomarkers with the 17-item Hamilton Depression Rating Scale guided brain structure-function fusion in 118 patients with depressive episodes and 60 healthy controls. Results show that reduced fractional amplitude of low frequency fluctuations in the prefrontal cortex, insula and hippocampus, linked with increased gray matter volume in anterior cingulate, medial temporal cortex, insula, thalamus, caudate and hippocampus represent electroconvulsive therapy responsive covarying functional and structural brain networks. In addition, relative to nonresponders, responder-specific electroconvulsive therapy related brain networks occur in frontal-limbic network and are associated with successful therapeutic outcomes. Finally, electroconvulsive therapy responsive brain networks were unrelated to verbal declarative memory. Using a data-driven, supervised-learning method, we demonstrated that electroconvulsive therapy produces a remodeling of brain functional and structural covariance that was unique to antidepressant symptom response, but not linked to memory impairment.

A Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Oral Administration of a Heat-Treated Lactobacillus paracasei  Supplement in Infants with Atopic Dermatitis Receiving Topical Corticosteroid Therapy.

BACKGROUND/AIMS: Atopic dermatitis (AD) is a common disease in infancy, for which topical steroids are the first-line therapy but have side effects. Innovative approaches are needed to reduce the burden of AD and corticosteroid usage in infants. METHODS: The once-daily consumption of heat-treated probiotic Lactobacillus paracasei GM-080 or placebo for 16 weeks as supplementary approach to topical treatment with fluticasone propionate cream was compared in AD infants aged 4-30 months. Outcomes were SCORAD and its subscores, TEWL, Infants' Dermatitis Quality of Life Index (IDQOL), corticoid "sparing effect," CCL17/TARC, and IgE status. RESULTS: SCORAD, objective SCORAD, itching, and IDQOL decreased significantly (p < 0.001) over the treatment period in both treatment groups. Slight decreases (ns) were noted in TEWL in lesional and unaffected skin and CCL17 levels. There were no differences between the treatment groups. Total IgE increased over the treatment period in both groups, with significantly higher increase in the heat-treated probiotic group (p = 0.038). There was no evidence of a corticoid "sparing effect" by the probiotic. CONCLUSIONS: In this design, the probiotic L. paracasei was not beneficial as a complementary approach to topical corticosteroids in infants with AD. However, slight beneficial effects may have been masked by the moderate potency corticoid.

Connectome-based individualized prediction of temperament trait scores.

Temperament consists of multi-dimensional traits that affect various domains of human life. Evidence has shown functional connectome-based predictive models are powerful predictors of cognitive abilities. Putatively, individuals' innate temperament traits may be predictable by unique patterns of brain functional connectivity (FC) as well. However, quantitative prediction for multiple temperament traits at the individual level has not yet been studied. Therefore, we were motivated to realize the individualized prediction of four temperament traits (novelty seeking [NS], harm avoidance [HA], reward dependence [RD] and persistence [PS]) using whole-brain FC. Specifically, a multivariate prediction framework integrating feature selection and sparse regression was applied to resting-state fMRI data from 360 college students, resulting in 4 connectome-based predictive models that enabled prediction of temperament scores for unseen subjects in cross-validation. More importantly, predictive models for HA and NS could be successfully generalized to two relevant personality traits for unseen individuals, i.e., neuroticism and extraversion, in an independent dataset. In four temperament trait predictions, brain connectivities that show top contributing power commonly concentrated on the hippocampus, prefrontal cortex, basal ganglia, amygdala, and cingulate gyrus. Finally, across independent datasets and multiple traits, we show person's temperament traits can be reliably predicted using functional connectivity strength within frontal-subcortical circuits, indicating that human social and behavioral performance can be characterized by specific brain connectivity profile.

Protective effect of wogonin on endotoxin-induced acute lung injury via reduction of p38 MAPK and JNK phosphorylation.

Acute lung injury (ALI) is a serious inflammatory disorder which remains the primary cause of incidence and mortality in patients with acute pulmonary inflammation. However, there is still no effective medical strategy available clinically for the improvement of ALI. Wogonin, isolated from roots of Scutellaria baicalensis Georgi, is a common medicinal herb which presents biological and pharmacological effects, including antioxidation, anti-inflammation, and anticancer. Preadministration of wogonin inhibited not only lung edema but also protein leakage into the alveolar space in murine model of lipopolysaccharide (LPS)-induced ALI. Moreover, wogonin not only reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 but also inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) induced by LPS. We further found wogonin inhibited the phosphorylation of p38 MAPK and JNK at a concentration lower than ERK. In addition, inhibition of lung edema, protein leakage, expression of iNOS and COX-2, and phosphorylation of p38 MAPK and JNK were all observed in a parallel concentration-dependent manner. These results suggest that wogonin possesses potential protective effect against LPS-induced ALI via downregulation of iNOS and COX-2 expression by blocking phosphorylation of p38 MAPK and JNK. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 397-403, 2017.

Endotoxin-induced acute lung injury in mice is protected by 5,7-dihydroxy-8-methoxyflavone via inhibition of oxidative stress and HIF-1α.

Up to date, the morbidity and mortality rates of acute lung injury (ALI) still rank high among clinical illnesses. Endotoxin, also called lipopolysaccharide (LPS), induced sepsis is the major cause for ALI. Beneficial biological effects, such as antioxidation, anti-inflammation, and neuroprotection was found to express by 5,7-dihydroxy-8-methoxyflavone (DHMF). The purpose of present study was to investigate the potential protective effects of DHMF and the possibile mechanisms involved in LPS-induced ALI. In our experimental model, ALI was induced in mice by intratracheal injection of LPS, and DHMF at various concentrations was injected intraperitoneally for 30 min prior to LPS administration. Pretreatment with DHMF inhibited not only the histolopatholgical changes occurred in lungs but also leukocytes infiltration in LPS-induced ALI. Decreased activity of antioxidative enzymes (AOE) such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) caused by LPS was reversed by DHMF. LPS-induced lipid peroxidation HIF-1α accumulation, NF-κB phosphorylation, and IκBα degradation were all inhibited by DHMF. In addition, LPS-induced expression of proinflammatory mediators such as TNF-α and IL-1ß were also inhibited by 5,7-dihydroxy-8-methoxyflavone. These results suggested that the protective mechanisms of DHMF on endotoxin-induced ALI might be via up-regulation of antioxidative enzymes, inhibition of NFκB phosphorylation, and HIF-1α accumulation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1700-1709, 2016.

Photoinduced decarboxylative germylation of α-fluoroacrylic acids: access to germylated monofluoroalkenes.

Herein, a novel strategy is presented for the photoinduced decarboxylative and dehydrogenative cross-coupling of a wide range of α-fluoroacrylic acids with hydrogermanes. This methodology provides an efficient and robust approach for producing various germylated monofluoroalkenes with excellent stereoselectivity within a brief photoirradiation period. The feasibility of this reaction has been demonstrated through gram-scale reaction, conversion of germylated monofluoroalkenes, and modification of complex organic molecules.

Effect of the fungal immunomodulatory protein FIP-fve on airway inflammation and cytokine production in mouse asthma model.

The allergy is dependent on the balance between Th1 and Th2. The fungal immunodulatory protein (FIP-fve) was isolated from Flammulina velutipes. FIP-fve has been demonstrated to skew the response to Th1 cytokine production. We investigated whether oral administrations of FIP-fve inhibited allergen (OVA)-induced chronic airway inflammation in the mouse asthma model. After intranasal challenge with OVA, the airway inflammation and hyperresponsiveness were determined by bronchoalveolar lavage fluid (BALF) analysis and ELISA assay. Both pre-treated and post-treated with FIP-fve suppressed the airway hyperresponsiveness by methacholine challenge and significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid (BALF) and serum compared with the OVA sensitized mice. In addition, FIP-fve reduced OVA-specific IgE levels in serum. FIP-fve markedly alleviated the OVA-induced airway hyperresponsiveness (AHR) to inhaled methacholine. Based on lung histopathological studies using hematoxylin and Liu's staining, FIP-fve inhibited inflammatory cell infiltration compared with the OVA-sensitized mice. Oral FIP-fve had an anti-inflammatory effect on OVA-induced airway inflammations and might posses the potential for alternative therapy for allergic airway diseases.

Neonatal jaundice is a risk factor for childhood asthma: a retrospective cohort study.

BACKGROUND: The association between neonatal jaundice and childhood asthma is a new finding of two reports. The purpose of the study was to verify their results. METHODS: Data from 11,321 children were collected from the National Health Insurance Research Database. Their claims data were evaluated from birth to 10 yr old. Children were analyzed as case (those with neonatal jaundice) and controls (those without neonatal jaundice). The diagnostic criteria for asthma were as follows: at least four asthma diagnoses at outpatient services and emergency department (ED), or one asthma diagnosis during an admission. In children fitting the asthma criteria, those with no asthma diagnosis after 1 yr of age were excluded. Mantel-Haenszel's odds ratios were calculated after adjustment for the following confounders: preterm/low birth weight, neonatal infection, other respiratory conditions, other birth conditions, and gender. Asthma rate, onset time, the use of drugs, upper respiratory infection and lower respiratory infection (LRI) rates, hospital admission/ED visit rates, and the effect of phototherapy were evaluated. RESULTS: After adjustment for the confounding factors, the rate of asthma was higher in icteric children (OR: 1.64, 95% CI 1.36-1.98, p < 0.001), and the influence in females was stronger. There still was an association between neonatal jaundice and late onset asthma (asthma onset after 3 yr of age). In asthmatic children, those with neonatal jaundice have increased asthma onset rate before age 6, increased use of inhalant steroids, LRI rates, and ED visits for respiratory disease. CONCLUSIONS: Neonatal jaundice increased the rate and severity of childhood asthma in subjects aged up to 10 yr and may be a risk factor for childhood asthma.

Coexistence of allergic diseases: patterns and frequencies.

The atopic march hypothesis suggests that allergy diseases often progress from atopic dermatitis to allergic asthma, and allergic rhinitis. How often can the classic progression of allergic diseases be observed in the pediatric patient population? This study aimed to observe the pattern of allergic diseases progression, onset age, disease intervals, and frequency of the allergic march. Data from the National Health Insurance Research Database in the period 1996-2008 were used to obtain a cohort of children with allergic disease. Physician's diagnosis was used to confirm the allergic disease based on the international disease coding. The age of disease onset was compared. There were 10,729 children aged <5 years enrolled from the 200,000 individuals randomly sampled in 2000. Of these, 5866 (54.7%) had been diagnosed with at least one allergic disease. The rate of only one of three diseases diagnosed was 29.8% (3195 patients), whereas 18.8% had two allergic diseases and 6.1% had all three allergic diseases. Only 4.2% of cases matched the allergic march. Patients with more than one disease had earlier onset age than those who had only one disease (4.17 versus 2.79 and 2.32 years old; p < 0.05). The allergic march accounts for only 4.2% in this study. A patient with only one allergic disease after the age of 4.17 years will not have another allergic disease until the age of 12 years. However, a patient with an allergic disease before 2.79 years old will probably have another allergic disease in 1.96-2.5 years.

Major health-care providers and the 10 leading reasons for adolescent ambulatory visits.

BACKGROUND: Epidemiological research underpins the importance of effective health-care strategies for adolescents. This descriptive study compares the 10 most common diseases among Taiwanese adolescents for 2000 and 2009. METHODS: Data for a total of 69,594 visits in 2000 and 65,802 visits in 2009 by adolescents aged between 10 and 20 years were collected from the National Health Insurance Research Database. A maximum of three outpatient diagnostic codes (International Classification of Disease, ninth revision) could be listed for every visit. The data categories were: principal diagnosis, patient age, and physician specialty. RESULTS: The middle adolescent age group utilized the least amount of medical services. Respiratory (46.2% in 2000, 40.5% in 2009) and digestive (16.5% in 2000 and 16.9% in 2009) tracts were the leading two diagnostic categories for adolescent ambulatory visits. Teeth (6.8%, 6.1%) and eye (4.0%, 3.1%) problems were also among the top 10 diseases. Family practitioners, ear-nose-throat specialists, and traditional Chinese medicine physicians were the major health-care providers for Taiwanese adolescents, especially in the middle and late groups. Although noted as the first option for consultation in the early group, the role of pediatricians with regard to adolescent health care declined in importance with age. CONCLUSIONS: Nearly 99% of the population in Taiwan is covered under the national health insurance system. The different disease patterns and major health-care providers between Taiwan and other countries are compared.

Effect of combination treatment with Lactobacillus rhamnosus and corticosteroid in reducing airway inflammation in a mouse asthma model.

BACKGROUND: Asthma is a complex multifactorial chronic airway inflammatory disease with diverse phenotypes and levels of severity and is associated with significant health and economic burden. In a certain population of asthma patients, the symptoms cannot be well controlled with steroid. There has been long standing interest in the use of probiotics for treating allergic diseases. The purpose of this study is to investigate whether the combination of Lactobacillus rhamnosus GG (LGG) with prednisolone could reduce the dosage of glucocorticoid in controlling airway inflammation in a murine model for allergic asthma. MATERIAL AND METHODS: We used Der p 2-sensitized asthma model in female BALB/c mice. The animals were treated with 75 µl or 50 µl oral prednisolone or combination treatment of these two doses of oral prednisolone with LGG. Airway hyperresponsiveness, serum specific IgE/IgG1/IgG2a, infiltrating inflammatory cells in lung and cytokines were assessed. RESULTS: Compared to 75 µl prednisolone, a lower dose of prednisolone with 50 µl was less satisfactory in suppressing airway hyperresponsives, serum IgE and IgG1, Th2 cytokines and inflammatory cytokines such as IL-6, IL-8 and IL-17 as well as infiltrating inflammatory cells. However, combination of 50 µl prednisolone and LGG decreased airway resistance and serum IgE and IgG1, inhibited the production of IL-4, IL-5, IL-6, IL-8, IL-13 and IL-17, upregulated serum IgG2a and enhanced Th1 immune response. CONCLUSIONS: LGG may reduce the dosage of prednisolone and thus may be beneficial in the treatment of asthma.

Taiwan guidelines for the diagnosis and management of pediatric atopic dermatitis: Consensus statement of the Taiwan Academy of Pediatric Allergy, Asthma and Immunology.

Atopic dermatitis (also known as atopic eczema) is a chronic relapsing inflammatory skin disease commonly seen in children, with increasing prevalence over the past few decades in many countries including Taiwan. The management of pediatric atopic dermatitis can be challenging, particularly as treatment options are expanding with the emergence of novel systemic and topical anti-inflammatory medications in recent years. The Taiwan Academy of Pediatric Allergy, Asthma and Immunology (TAPAAI) has developed the Taiwan guidelines for the diagnosis and management of pediatric atopic dermatitis, which provides a concise overview of its epidemiology, clinical characteristics and diagnosis, mechanisms, treatments, and education. The contents of this guideline integrate the principles of recent national and international guidelines for the diagnosis and management of atopic dermatitis, latest research findings, and expert opinions of experienced pediatric allergy specialists in Taiwan. For practical purposes, this guideline presents simplified and easy-to-use diagnostic criteria and severity grading for pediatric atopic dermatitis. A stepwise treatment algorithm is also proposed to expedite rational, cost-effective, and evidence-based management strategy. This guideline, developed based on current best evidence and real-world experience of pediatric allergy experts in Taiwan, is intended to facilitate practical, up-to-date management of pediatric atopic dermatitis among physicians.

Coenzyme Q10 Supplementation Increases Removal of the ATXN3 Polyglutamine Repeat, Reducing Cerebellar Degeneration and Improving Motor Dysfunction in Murine Spinocerebellar Ataxia Type 3.

Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.

Maternal and childhood exposure to inorganic arsenic and airway allergy - A 15-Year birth cohort follow-up study.

BACKGROUND: The prevalence of allergic diseases in children has increased globally. Early-life exposure to inorganic arsenic has been found to be associated with impaired immune function and decreased lung function in children; however, the results are inconsistent. We aimed to evaluate the effect of prenatal and childhood exposure to inorganic arsenic on allergic diseases in children, through a 15-year follow-up birth cohort study, conducted in central Taiwan. METHODS: Children born to women enrolled in the Taiwan Maternal and Infant Cohort Study (TMICS-pilot) from December 2000 to November 2001 were recruited and followed every 2-3 years until the age of 14 years. Urinary specimens were collected in the pregnant women during the 3rd trimester and the followed children. Diagnoses of allergic diseases were based on physician diagnoses using the International Study of Asthma and Allergies in Childhood questionnaire. Urinary arsenic speciation was performed using high-performance liquid chromatography and inductively coupled plasma dynamic reaction cell mass spectrophotometry. RESULTS: Of the 261 children from 358 mother-infant pairs for this study, those with asthma and allergic rhinitis reported a higher prevalence of maternal allergy (49.47%) than did non-allergic children (29.81%). In the fully adjusted model, levels of maternal urine (iAs + MMA + DMA) greater than the median were found to be significantly associated with an increased risk of asthma (OR = 4.28; 95% CI 1.32, 13.85). Levels of urinary (iAs + MMA + DMA) in children higher than the median were associated with an increased risk of allergic rhinitis (OR = 2.26; 95% CI 1.20, 4.26). CONCLUSION: Prenatal and childhood exposure to inorganic arsenic were found to be significantly associated with the occurrence of asthma and allergic rhinitis in children, respectively. Further large cohort follow-up studies are important to validate the association between inorganic arsenic exposure and allergic diseases in children.