Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning.

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

Changes in cognitive function and brain glucose metabolism in elderly women with subjective memory impairment: a 24-month prospective pilot study.

OBJECTIVES: Subjective memory impairment (SMI) may precede mild cognitive impairment (MCI) stage and would offer an earlier therapeutic opportunity than MCI would. However, it is not clear whether complaints of forgetfulness are truly reflective of objective memory dysfunction or of impairments in other cognitive domains. The aim of this current longitudinal study was to investigate changes in various cognitive functions and in regional cerebral metabolic rate of glucose (rCMRglc) among elderly women with SMI. MATERIALS AND METHODS: Clinical evaluation, comprehensive neuropsychological test, and 18 F-fluoro-2-deoxyglucose positron emission tomography scans were conducted on 24 women with SMI at the baseline and 24-month follow-up. Changes in the cognitive domain scores and rCMRglc were assessed, and the relationships between them were analyzed. RESULTS: All participants stayed in SMI all the way till the follow-up, not converted to MCI or dementia. A significant reduction in executive function was found (mean difference in z-score: -0.21, P = 0.02) without changes in other cognitive domains. Declines in rCMRglc were detected in the left superior temporal gyrus, right posterior cingulate gyrus, left parahippocampal gyrus, right lingual gyrus, and right angular gyrus. The change in executive function had a positive correlation with the percent change of rCMRglc in the right posterior cingulate gyrus (ß = 0.43, P = 0.02). CONCLUSIONS: Our findings suggest that elderly women with SMI symptoms should be carefully monitored for declines in executive function and related brain glucose metabolism over time.

Predisposition to and effects of methamphetamine use on the adolescent brain.

Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.

First norovirus outbreaks associated with consumption of green seaweed (Enteromorpha spp.) in South Korea.

In February 2012, an outbreak of gastroenteritis was reported in school A; a successive outbreak was reported at school B. A retrospective cohort study conducted in school A showed that seasoned green seaweed with radishes (relative risk 7·9, 95% confidence interval 1·1-56·2) was significantly associated with illness. Similarly, a case-control study of students at school B showed that cases were 5·1 (95% confidence interval 1·1-24·8) times more likely to have eaten seasoned green seaweed with pears. Multiple norovirus genotypes were detected in samples from students in schools A and B. Norovirus GII.6 isolated from schools A and B were phylogenetically indistinguishable. Green seaweed was supplied by company X, and norovirus GII.4 was isolated from samples of green seaweed. Green seaweed was assumed to be linked to these outbreaks. To our knowledge, this is the first reported norovirus outbreak associated with green seaweed.

Optical properties of white organic light-emitting devices fabricated utilizing a mixed CaAl12O19:Mn4+ and Y3Al5O12:Ce3+ color conversion layer.

White organic light-emitting devices (OLEDs) were fabricated by combining a blue OLED with a color conversion layer made of mixed Y3Al5O12:Ce3+ green and Ca2AlO19:Mn4+ red phosphors. The X-ray diffraction patterns showed that Ce3+ ions in the Y3Al5O12:Ce3+ phosphors completely substituted for the Y3+ ions and the Mn4+ ions in the CaAl12O19:Mn4+ phosphors completely substituted for the Ca2+ ions. Electroluminescence spectra at 11 V for the OLEDs fabricated utilizing a color conversion layer showed that the Commission Internationale de l'Eclairage coordinates for the Y3Al5O12:Ce3+ and CaAl12O19:Mn4+ phosphors mixed at the ratio of 1:5 and 1:10 were (0.31, 0.34) and (0.32, 0.37), respectively, indicative of a good white color.

Effects of the mixing ratio of the CaAl12O19:mn and Zn2SiO4:mn color-conversion layer on the color tunable emissions of white organic light-emitting devices.

The optical properties of white organic light-emitting devices (WOLEDs) fabricated utilizing a CaAl12O19:Mn and Zn2SiO4:Mn phosphor layer were investigated. X-ray diffraction patterns for CaAl12O19:Mn and Zn2SiO4:Mn phosphors showed that Mn ions in the CaAl12O19:Mn phosphors were completely substituted into Ca ions and that Mn ions in the Zn2SiO4:Mn phosphors were completely substituted into Zn ions. Field emission scanning electron microscopy images showed that the size of the CaAl12O19:Mn phosphor was approximately between 0.1 and 3 microm, and that the size of the Zn2SiO4:Mn phosphor was smaller than 7 microm. The color coordinates of the electroluminescence spectra for WOLEDs with phosphor thicknesses of 0.25 and 0.35 mm shifted to the white emission side because the generated blue light from the blue OLEDs combined with the red and green lights was converted by the CaAl12O19:Mn and the Zn2SiO4:Mn phosphor down-conversion layers.

Efficacy and tolerability of mirtazapine in treating major depressive disorder with anxiety symptoms: an 8-week open-label randomised paroxetine-controlled trial.

AIMS: Prominent anxiety symptoms are related to poor clinical course and outcome in major depressive disorder (MDD). The aim of this randomised, open-label, controlled study is to compare the efficacy and tolerability of mirtazapine in the form of orally disintegrating tablets against paroxetine in treating MDD patients with anxiety symptoms. METHODS: A total of 60 MDD patients with a score above 18 on the Hamilton Anxiety Rating Scale (HARS) were randomly assigned to 8 weeks of fixed dosing treatment with mirtazapine (15-30 mg/day) and paroxetine (10-20 mg/day). Efficacy was primarily assessed with the HARS and with the 17-item Hamilton Depression Rating Scale (HDRS) at weeks 1, 2, 4 and 8 after treatment. Tolerability was assessed from adverse events. RESULTS: The generalised estimating equations (GEE) models showed that the rates of improvement in HDRS scores from baseline to week 8 were similar between mirtazapine and paroxetine groups. However, patients with mirtazapine exhibited earlier improvement in HARS scores at weeks 1 and 2. Week-by-week GEE models showed that these significant differences in improvement of HARS scores between the two treatment groups were detectable from the first evaluation after the treatment (week 1) and maintained through week 2. There was no difference in the overall frequency of adverse events experienced between the two treatment groups. The most common adverse event in the mirtazapine group was somnolence (n = 8), whereas that in the paroxetine group was gastrointestinal discomfort (n = 9). CONCLUSIONS: Mirtazapine and paroxetine were equally effective and well tolerated for the depressive symptoms in MDD patients with the high level of anxiety symptoms. Mirtazapine was, however, more effective in reducing the anxiety symptoms than paroxetine in the early weeks of treatment, suggesting that mirtazapine may have an earlier-onset action for the anxiety symptoms in MDD patients.

Analysis of local invasion and regional spread in malignant sublingual gland tumour: Implications for surgical planning.

Malignant tumours arising from the sublingual glands are very rare, and the extent and frequency of local invasion or regional spread in malignant sublingual gland tumour (MSLT) has not been fully studied due to the disease rarity. To provide comprehensive features of local and regional spread of MSLT, we reviewed 20 surgical cases for detailed pathological analyses among 26 cases diagnosed as having primary MSLT. Adenoid cystic carcinoma (ACC) was the most common pathological subtype, followed by mucoepidermoid carcinoma. Disease-free and overall survivals at 5 years were 76.1 % and 77.7 %, respectively. High-grade malignant tumours and grade 2-3 ACC accounted for 41.7 % and 85.7 %. Clinical and pathological extraparenchymal extensions were found in 34.6 % and 80.0 %, respectively. Tumour invasion to the lingual nerve and submandibular gland/ductal system were also detected in 40.0 % and 28.6 %. The incidences of lingual nerve invasion in ACC and ACC ≥4 cm were 30.8 % and 42.9 %. Regional nodal involvement occurred in seven of 26 cases, and all metastatic lymph nodes were found in neck levels Ib and IIa. In summary, a significant portion of MSLT cases consisted of high-grade tumours and grade 2-3 ACC; therefore local invasion into adjacent structures should be cautiously evaluated in cases of MSLT.

Genetic analysis of norovirus GII.4 variants circulating in Korea in 2008.

Noroviruses are the enteric pathogens most commonly responsible for infectious gastroenteritis and outbreaks of foodborne illness. The GII.4 norovirus, in particular, is responsible for the majority of epidemics. Here, we present data on the distribution of norovirus genotypes in Chungnam, Korea, in 2008, measure genetic variation among GII.4 strains, and compare Korean GII.4 variants with reference strains based on the 237-bp junction of ORF1 and ORF2. We detected 139 different strains, which formed two distinct genetic clusters with significant sequence diversity. One Korean cluster (2008-Korea_a) showed high similarity to the Sakai cluster that appeared in Japan and Europe in 2006. The other cluster (2008-Korea_b) was unique and unrelated to previously reported clusters. Genotype GII.4 was confirmed as the predominant cause of norovirus epidemics in Korea. Foodborne norovirus infections, on the other hand, were generally caused by emerging GII.4 genetic variants similar to those responsible for global epidemics.

Assessment of cell surface properties and adhesion potential of selected probiotic strains.

AIM: To evaluate the physicochemical cell surface and adhesive properties of selected probiotic strains for human use. METHODS AND RESULTS: Probiotic strains, Bifidobacterium longum B6, Lactobacillus acidophilus ADH, Lactobacillus paracasei, Lactobacillus rhamnosus GG, Lactobacillus brevis, Lactobacillus casei, Leuconostoc mesenteroides and Pediococcus acidilactici were tested for the physicochemical properties of cell surfaces and the adhesion abilities against foodborne pathogens. Bif. longum B6 (53.6%) and Lact. rhamnosus GG (46.5%) showed the highest hydrophobicity, while the least affinity to xylene was observed in Ped. acidilactici (10.4%). Bifidobacterium longum B6 showed the strongest coaggregation phenotype with Listeria monocytogenes (53.0%), Shigella boydii (42.0%) and Staphylococcus aureus (45.9%). Lactobacillus rhamnosus GG had the strong binding ability to Caco-2 cells and effectively inhibited the adhesion of L. monocytogenes, Salmonella Typhimurium, Sh. boydii and Staph. aureus to Caco-2 cells. The hydrophobicity was highly correlated with coaggregative abilities and competitive inhibition, suggesting a good relationship between in vitro adhesion and in vivo colonization. CONCLUSION: The results suggest that Bif. longum B6 and Lact. rhamnosus GG can be candidate probiotics available for human consumption. SIGNIFICANCE AND IMPACT OF THE STUDY: Because the use of probiotic strains has been more concerned with their beneficial effects in the GI tract, it is essential to examine the potential of probiotic strains based on the physicochemical properties in terms of bacterial-binding and adhesion capabilities.

ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation.

The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1 expression as a predictive marker of survival in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). ERCC1 expression was assessed by immunohistochemical staining. The median age of the 45 patients analysed was 56 years (range 27-75 years), and 82% were men; 73% of all specimens showed high expression of ERCC1. The overall tumour response rate after CCRT was 89%. The median follow-up was 53.6 months (95% CI, 34.5-72.7 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 58.7 and 61.3%, respectively. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 3-year PFS (83.3 vs 49.4%, P=0.036) and OS (91.7 vs 45.5%, P=0.013) rates. Multivariate analysis showed that low expression of ERCC1 was an independent predictor for prolonged survival (HR, 0.120; 95% CI, 0.016-0.934, P=0.043). These results suggest that ERCC1 expression might be a useful predictive marker of locally advanced SCCHN in patients treated with cisplatin-based CCRT.

STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression.

Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.

Effects of influent COD/N ratio and internal recycle ratio on nitrogen removal efficiency in the KNR process.

In this study, with the KNR process that has many advantages, the nitrogen removal efficiency of KNR was experimentally investigated at various COD/N ratios of influent conditions. The optimal operating condition of internal recycle ratio was evaluated. The TN removal efficiencies were 59.1, 72.5 and 75.9% at the COD/N ratios of 3, 5 and 7, respectively. These high removal efficiencies resulted from high denitrification rate in UMBR with high microorganism concentration. Furthermore, specific endogenous denitrification at MLVSS of 10.3 g/L that is similar to MLVSS in UMBR was over two times higher than that at MLVSS of 2.06 g/L. This result suggests that endogenous denitrification rate in UMBR is so high that the requirement of an external carbon source can be saved. As the internal recycle ratio increased from 100 to 400%, the TN removal efficiency also improved from 69.5 to 82.9%, and the optimal internal recycle ratio was 300%.

Modeling of extracellular polymeric substances and soluble microbial products production in a submerged membrane bioreactor at various SRTs.

Extracelluar polymeric substances (EPSs) and soluble microbial products (SMPs) produced by microbial cultures involved in membrane biofouling have been widely investigated. A mathematical model of EPS and SMP formation and degradation was established based on the activated sludge model no. 1 (ASM1) and was applied to the membrane bioreactor sludge with different sludge retention times (SRTs). The unified theory that the distinct products from the EPS and SMP overlapped each other was integrated into the ASM1. Two components, five processes and eight parameters were newly added to set up the model. To increase the accuracy of model simulation, microbial kinetic parameters were determined by respirometry method and applied to the model instead of microbial kinetic constant offered in ASM1. From the respirometry result, both of heterotroph and autotroph showed different yield value, growth rate and decay rate from activated sludge. There was no significant effect of SRT on SMP production and the experimental results showed good agreement with the predicted values by the model simulation. With the developed unified EPS and SMP model, EPS and SMP production could be simulated so well that it can be applied for the membrane biofouling control.

Concurrent Post-Transplantation Diabetes Mellitus in Renal Allograft Recipients With Immunoglobulin A Nephropathy.

BACKGROUND: The prevalence of post-transplantation immunoglobulin A nephropathy (PTIgAN) and diabetes mellitus (PTDM) increases with time after transplantation, and recognition and management of these conditions is becoming more important in renal allograft recipients as graft survival increases. METHODS: We explored the influence of concurrent PTDM on renal allograft histology and function in 111 cases with PTIgAN diagnosed from 2000 to 2010 at our institution. RESULTS: Sixteen patients (14.4%) had PTDM at the time of diagnosis of PTIgAN, which increased to 28 patients (25.2%) at the last follow-up (10.4 years after transplantation). Donor ages were younger in PTIgAN patients with concurrent PTDM. However, other clinical and demographic data were not significantly different between PTIgAN patients with and without PTDM. Histologically, Banff "mm" scores were higher and "M1" of the Oxford classification was more frequent in PTIgAN patients with concurrent PTDM than in patients without PTDM, but the difference did not reach statistical significance. Serum creatinine levels and proteinuria at the time of biopsy and overall graft survival did not vary according to the presence of PTDM both at biopsy and at the last follow-up. CONCLUSIONS: Concurrent PTDM does not significantly influence graft function or outcome for 10 years after transplantation in PTIgAN patients.

Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

A new member of alpha 1-adrenoceptor-coupled G alpha h (transglutaminase II) family in pig heart: purification and characterization.

We previously reported an identification of a 77-kDa GTP-binding protein that co-purified with the alpha 1-adrenoceptor following ternary complex formation. In the present paper, we report on the purification and characterization of this GTP-binding protein (termed G alpha h5) isolated from pig heart membranes. After solubilization of pig heart membranes with NaCl, G alpha h5 was purified by sequential chromatographies using DEAE-Cellulose, Q-Sepharose, and GTP-agarose columns. The protein displayed high-affinity GTP gamma S binding which is Mg(2+)-dependent and saturable. The relative order of affinity of nucleotide binding by G alpha h5 was GTP > GDP > ITP >> ATP > or = adenyl-5'-yl imidodiphosphate, which was similar to that observed for other heterotrimeric G-proteins involved in receptor signaling. Moreover, the G alpha h5 demonstrated transglutaminase (TGase) activity that was blocked either by EGTA or GTP gamma S. In support of these observations, the G alpha h5 was recognized by a specific antibody to G alpha h7 or TGase II, indicating a homology with G alpha h (TGase II) family. These results demonstrate that 77-kDa G alpha h5 from pig heart is an alpha 1-adrenoceptor-coupled G alpha h (TGase II) family which has species-specificity in molecular mass.

Differences in familism values and caregiving outcomes among Korean, Korean American, and White American dementia caregivers.

Recent theories have suggested that burden and distress among dementia caregivers may be higher in American culture, which emphasizes individualism, and lower in cultures with higher levels of familism. However, immigrants may experience higher levels of burden because of acculturation with attendant values, conflicts and stresses. Forty-four Korean caregivers and 32 Korean American caregivers were compared with 54 White American caregivers on sociodemographic variables, familism, burden, anxiety, and depression. Familism was highest in Korean caregivers and lowest in Whites, with Korean Americans in the middle. Koreans and Korean Americans reported higher levels of burden. Koreans showed higher levels of depression and of anxiety than White American caregivers, with Koreans and Korean Americans higher than Whites on anxiety. These results suggest a need for greater specificity in theories about familism values, with attention to the specific meaning of familism in different cultures.

The influence of system factors upon the macro-economic efficiency of health care: implications for the health policies of developing and developed countries.

This paper aims to clarify the global association of system factors with the attainment of health policy goals, through economic analyses of cross-country data. In the case of OECD (the Organization for Economic Co-operation and Development) data for 1990, the variation in total expenditure on health among 24 countries can be explained by various factors including Gross Domestic Product (GDP). Among these, the variables representing the level of public sector involvement through social protection or public-private mix within a health care system, such as the Public-to-Total Expenditure Ratio, Coverage Rate and Public Cost Sharing, are significantly negative when factors such as GDP are controlled. This suggests that countries attaining higher equity or accessibility are in a better position to gain higher cost-containment or macro-economic efficiency. The results of this study may be helpful for developing countries searching for a long-term health care system as well as for developed countries facing health care system reforms.