NMDA Receptor-Mediated Motor Cortex Plasticity After 20 Hz Transcranial Alternating Current Stimulation.

Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations and excitability levels in the primary motor cortex (M1). These effects can last for more than an hour and an involvement of N-methyl-d-aspartate receptor (NMDAR) mediated synaptic plasticity has been suggested. However, to date the cortical mechanisms underlying tACS after-effects have not been explored. Here, we applied 20 Hz beta tACS to M1 while participants received either the NMDAR antagonist dextromethorphan or a placebo and the effects on cortical beta oscillations and excitability were explored. When a placebo medication was administered, beta tACS was found to increase cortical excitability and beta oscillations for at least 60 min, whereas when dextromethorphan was administered, these effects were completely abolished. These results provide the first direct evidence that tACS can induce NMDAR-mediated plasticity in the motor cortex, which contributes to our understanding of tACS-induced influences on human motor cortex physiology.

A composite of exhaled LTB4 , LXA4 , FeNO, and FEV1 as an "asthma classification ratio" characterizes childhood asthma.

BACKGROUND: Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma. METHODS: Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases. RESULTS: Exhaled LTB4 , LTE4 , PGE2, and LXA4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB4 , LXA4 , together with FeNO and FEV1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as "asthma classification ratio" was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively. CONCLUSIONS: In a pediatric study population in Taiwan, the levels of exhaled LTB4 , LTE4 , LXA4, and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4 , together with FeNO and FEV1 , best characterized childhood asthma.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

Role of primary T-cell immunodeficiency and hepatitis B coinfection on spontaneous clearance of hepatitis C: The BC Hepatitis Testers Cohort.

T-cell host immune response against hepatitis C virus (HCV) has been suggested to play an important role in determining HCV infection outcome. However, data from human studies are not available. This study examined the effect of primary T-cell deficiency along with other factors on the spontaneous clearance of HCV in a large population-based cohort in British Columbia, Canada. The BC Hepatitis Testers Cohort includes all individuals tested for HCV in BC in 1990-2013 linked with data on their medical visits, hospitalizations and prescription drugs. HCV-positive individuals with at least one valid HCV PCR test on/after HCV diagnosis (n=46 783) were included in this study. To examine factors associated with the spontaneous clearance of HCV, multivariable logistic regression was fitted on the full sample, and Cox proportional hazards model on the HCV seroconverters. Spontaneous clearance was observed in 25.1% (n=11 737) of those tested for HCV. After adjusting for potential confounders, the odds of spontaneous clearance of HCV was lower in people with primary T-cell immunodeficiency (adjusted odds ratio [aOR]: 0.55, 95% CI: 0.32-0.94), and higher in females (aOR: 1.61, 95% CI: 1.54-1.68) and in those coinfected with HBV (aOR: 2.31, 95% CI: 1.93-2.77). Similar results were observed in HCV seroconverters except HBV coinfection was not significant. In conclusion, primary T-cell immunodeficiency is associated with a lower spontaneous clearance of HCV while female sex and coinfection with HBV are associated with a higher spontaneous clearance.

The MNS glycophorin variant GP.Mur affects differential erythroid expression of Rh/RhAG transcripts.

BACKGROUND: The band 3 macrocomplex (also known as the ankyrin-associated complex) on the red cell membrane comprises two interacting subcomplexes: a band 3/glycophorin A subcomplex, and a Rh/RhAG subcomplex. Glycophorin B (GPB) is a component of the Rh/RhAG subcomplex that is also structurally associated with glycophorin A (GPA). Expression of glycophorin B-A-B hybrid GP.Mur enhances band 3 expression and is associated with lower levels of Rh-associated glycoprotein (RhAG) and Rh polypeptides. The goal of this study was to determine whether GP.Mur influenced erythroid Rh/RhAG expression at the transcript level. MATERIALS AND METHODS: GP.Mur was serologically determined in healthy participants from Taitung County, Taiwan. RNA was extracted from the reticulocyte-enriched fraction of peripheral blood, followed by reverse transcription and quantitative PCR for RhAG, RhD and RhCcEe. RESULTS: Quantification by real-time PCR revealed significantly fewer RhAG and RhCcEe transcripts in the reticulocytes from subjects with homozygous GYP*Mur. Independent from GYP.Mur, both RhAG and RhD transcript levels were threefold or higher than that of RhCcEe. Also, in GYP.Mur and the control samples alike, direct quantitative associations were observed between the transcript levels of RhAG and RhD, but not between that of RhAG and RhCcEe. CONCLUSION: Erythroid RhD and RhCcEe were differentially expressed at the transcript levels, which could be related to their different degrees of interaction or sensitivity to RhAG. Further, the reduction or absence of glycophorin B in GYP.Mur erythroid cells affected transcript expressions of RhAG and RhCcEe. Thus, GPB and GP.Mur differentially influenced Rh/RhAG expressions prior to protein translation.

The prevalence, correlates, and help-seeking of eating disorders in Switzerland.

BACKGROUND: Eating disorders (EDs) have long-term physical and mental impacts on those affected. However, few population-based studies have estimated the prevalence of EDs. We aimed to estimate the lifetime and 12-month prevalence rates of EDs using DSM-IV criteria, and to examine differences against the DSM-5 criteria for anorexia. METHOD: A nationally representative sample of 10 038 residents in Switzerland was interviewed, and prevalence rates for anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) were assessed using WHO Composite International Diagnostic Interviews (WHO-CIDI). RESULTS: The lifetime prevalence rate for any ED was found to be 3.5%. Lifetime prevalence estimates for AN, BN, and/or BED were 1.2%, 2.4%, and 2.4%, respectively, among women and 0.2%, 0.9%, and 0.7%, respectively, among men. Utilizing the DSM-5 criteria, the prevalence of AN in women increased by more than 50%, from 1.2% to 1.9%. Among those meeting the criteria for any ED, only 49.4% of men and 67.9% of women had ever sought professional help about their problems with eating or weight. CONCLUSIONS: The higher prevalence of BN we detected relative to other studies should prompt further monitoring for a possible increasing trend. The female v. male ratios, especially for bulimia and BED, are decreasing. Given that more than half of those affected have never consulted any professional about their problems with eating or weight, routine inquiries about eating and weight by clinicians, school teachers/psychologists, and family members may help those who are at risk, especially among men.

Changes in living arrangement, daily smoking, and risky drinking initiation among young Swiss men: a longitudinal cohort study.

OBJECTIVES: The aim of this study was to assess the association between changes in living arrangement and the initiation of daily smoking and monthly risky single-occasion drinking (RSOD) in a cohort of young Swiss men. STUDY DESIGN: Longitudinal cohort study. METHODS: The sample consisted of 4662 young men drawn from the Cohort Study on Substance Use Risk Factors who lived with their family at baseline. Follow-up assessments occurred 15 months later. Multiple regression models were adjusted for individual and family factors (family model), as well as for individual and peer-related factors (peer model). RESULTS: Relative to those still living with their parents at follow-up (n = 3845), those who had moved out (n = 817) were considerably more likely to have taken up smoking or RSOD after adjusting for several individual, family, and peer-related variables: OR (daily smoking) = 1.67 (95% CI 1.15-2.41) (P = 0.007) and OR (monthly RSOD) = 1.42 (95% CI 1.08-1.88) (P = 0.012). The strongest family-related predictors of smoking initiation were family structure and the lack of parental regulation and the strongest peer-related factors alcohol/drug problems in peers. Meanwhile, the strongest peer-related predictors of RSOD initiation were peer pressure (misconduct), perceived social support from friends, and perceived social support from a significant other, whereas family factors were not associated with RSOD initiation. Further subanalyses were conducted to examine the impact of different living arrangement changes on substance use initiation and revealed that living with peers at follow-up was associated with the greatest risk. CONCLUSIONS: We identified a strong association between moving out of one's parents' home and daily smoking and monthly RSOD initiation in young Swiss men. Moving out to live with peers was an especially strong predictor of substance use initiation. Campaigns that aim to prevent heavy smoking and drinking should be intensified at the end of obligatory school.

Substance use capital: Social resources enhancing youth substance use.

BACKGROUND: Social capital is described as a protective factor against youth substance use, but it may also be associated with behaviours that do not enhance health. The present study hypothesized that 'substance use capital', i.e. resources favourable to substance use, is a risk factor for substance use and misuse. METHODS: We used baseline data from the ongoing Cohort Study on Substance Use Risk Factors (C-SURF) that included a representative sample of young Swiss men (n=5623). Substance use (alcohol, cannabis, 15 illicit drugs, lifetime use, hazardous use and dependence), substance use capital (parental and peer attitudes towards substance use, parental and peer drug use, perceived norms of substance use) and aspects of social capital (relationships with parents and peers) were assessed. Logistic regressions were used to examine the associations between substance-related resources and social resources, and substance use. RESULTS: Results showed that substance-related resources were associated with an increased risk of substance use (OR between 1.25 and 4.67), whereas social resources' associations with substance use were commonly protective but weaker than substance-related resources. Thus, a drug-friendly environment facilitated substance use and misuse. Moreover, the results showed that peer environments were more drug-friendly than familial environments. CONCLUSION: In conclusion, this study highlighted a concept of 'substance use capital', which may be useful for advancing both theoretical and applied knowledge of substance use. Indeed, substance use is not only associated with a lack of social resources, but also with specific drug-friendly social resources coming from environment and background.

Designer germanium quantum dot phototransistor for near infrared optical detection and amplification.

We demonstrated a unique CMOS approach for the production of a high-performance germanium (Ge) quantum dot (QD) metal-oxide-semiconductor phototransistor. In the darkness, low off-state leakage (Ioff ∼ 0.27 pA µm(-2)), a high on-off current ratio (Ion/Ioff ∼ 10(6)), and good switching behaviors (subthreshold swing of 175 mV/dec) were measured on our Ge-QD phototransistor at 300 K, indicating good hetero-interfacial quality of the Ge-on-Si. Illumination makes a significant enhancement in the drain current of Ge QD phototransistors when biased at both the on- and off-states, which is a great benefit from Ge QD-mediated photoconductive and photovoltaic effects. The measured photocurrent-to-dark-current ratio (Iphoto/Idark) and the photoresponsivities from the Ge QD phototransistor are as high as 4.1 × 10(6) and 1.7 A W(-1), respectively, under an incident power of 0.9 mW at 850 nm illumination. A superior external quantum efficiency of 240% and a very fast temporal response time of 1.4 ns suggest that our Ge QD MOS phototransistor offers great promise as optical switches and transducers for Si-based optical interconnects.

M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine.

Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forced-swim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M1 and M2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and VU0255035 (N-[3-oxo-3-[4-(4-pyridinyl)-1-piper azinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide) with selectivity for M1 over M2 receptors also demonstrated activity in the forced-swim test, which was attenuated in M1 but not M2 receptor KO mice. An antagonist with selectivity of M2 over M1 receptors (SCH226206 [(2-amino-3-methyl-phenyl)-[4-[4-[[4-(3 chlorophenyl)sulfonylphenyl]methyl]-1-piperidyl]-1-piperidyl]methanone]) was also active in the forced-swim assay, and the effects were deleted in M2 (-/-) mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.

NO-releasing xanthine KMUP-1 bonded by simvastatin attenuates bleomycin-induced lung inflammation and delayed fibrosis.

BACKGROUND AND PURPOSE: Pulmonary fibrosis (PF) is a progressing lung injury initiated by pulmonary inflammation (PI). Bleomycin (BLM) is the most common pathogenesis of PF through early PI and extensive extracellular matrix deposition. This study is aimed to determine whether NO-releasing KMUP-1 inhibits PI and PF, and if so, the benefits of KMUP-1S resulted from simvastatin (SIM)-bonding to KMUP-1. EXPERIMENT APPROACH: C57BL/6 male mice were intra-tracheally administered BLM (4 U/kg) at day 0. KMUP-1 (1-5 mg/kg), KMUP-1S (2.5 mg/kg), SIM (5 mg/kg), Plus (KMUP-1 2.5 mg/kg + SIM 2.5 mg/kg), and clarithromycin (CAM, 10 mg/kg) were orally and daily administered for 7 and 28 days, respectively, to mice, sacrificed at day-7 and day-28 to isolate the lung tissues, for examining the inflammatory and fibrotic signaling and measuring the cell population and MMP-2/MMP-9 activity in broncholaveolar lavage fluid (BAL). KEY RESULTS: KMUP-1 and KUP-1S significantly decreased neutrophil counts in BAL fluid. Fibroblastic foci were histologically assessed by H&E and Masson's trichrome stain and treated with KMUP-1 and references. Lung tissues were determined the contents of collagen and the expressions of TGF-ß, α-SMA, HMGB1, CTGF, eNOS, p-eNOS, RhoA, Smad3, p-Smad3, MMP-2 and MMP-9 by Western blotting analyses, respectively. These changes areregulated by NO/cGMP and inhibited by various treatments. KMUP-1 and KMUP-1S predominantly prevented HMGB1/MMP-2 expression at day-7 and reduced TGF-ß/phosphorylated Smad3 and CTGF at day-28. CONCLUSIONS AND IMPLICATIONS: KMUP-1 and KMUP-S restore eNOS, inhibit iNOS/ROCKII/MMP-2/MMP-9, attenuate histologic collagen disposition and reduce BALF inflammatory cells, potentially useful for the treatment of BLM-lung PF.

The association between campylobacteriosis, agriculture and drinking water: a case-case study in a region of British Columbia, Canada, 2005-2009.

We studied the association between drinking water, agriculture and sporadic human campylobacteriosis in one region of British Columbia (BC), Canada. We compared 2992 cases of campylobacteriosis to 4816 cases of other reportable enteric diseases in 2005-2009 using multivariate regression. Cases were geocoded and assigned drinking water source, rural/urban environment and socioeconomic status (SES) according to the location of their residence using geographical information systems analysis methods. The odds of campylobacteriosis compared to enteric disease controls were higher for individuals serviced by private wells than municipal surface water systems (odds ratio 1·4, 95% confidence interval 1·1-1·8). In rural settings, the odds of campylobacteriosis were higher in November (P = 0·014). The odds of campylobacteriosis were higher in individuals aged ⩾15 years, especially in those with higher SES. In this region of BC, campylobacteriosis risk, compared to other enteric diseases, seems to be mediated by vulnerable drinking water sources and rural factors. Consideration should be given to further support well-water users and to further study the microbiological impact of agriculture on water.

Hepatitis A outbreak in British Columbia, Canada: the roles of established surveillance, consumer loyalty cards and collaboration, February to May 2012.

Non-travel-related hepatitis A is rare in Canada. We describe a hepatitis A outbreak investigation in British Columbia in February to May 2012 in which exposure history was collected from nine confirmed non-travel-related cases. Suspected foods were tested for hepatitis A virus (HAV): a frozen fruit blend was identified as a common exposure for six of the nine cases using supermarket loyalty cards. Consumption of the product was confirmed in each case. Genetic analysis confirmed HAV genotype 1B in the six exposed cases. Of the three non-exposed cases, the virus could not be genotyped for two of them; the virus from the other case was found to be genotype 1A and this case was therefore not considered part of the outbreak. HAV was detected by PCR from pomegranate seeds, a component of the identified frozen fruit blend. Historically low levels of HAV infection in British Columbia triggered early recognition of the outbreak. Loyalty card histories facilitated product identification and a trace-back investigation implicated imported pomegranate seeds.

Veterinary echocardiographers' preferences for left atrial size assessment in cats: the BENEFIT project.

INTRODUCTION/OBJECTIVES: Veterinary echocardiographers' preferences for left atrial (LA) size assessment in cats have not been systematically investigated. The primary aim of this prospective exploratory study was to investigate echocardiographers' preferences concerning LA size assessment in cats. A secondary aim was to investigate echocardiographers' preferences for assessing LA size in subgroups based on geographic, demographic, and professional profiles. ANIMALS, MATERIALS, AND METHODS: An online survey instrument was designed, verified, and distributed globally to veterinary echocardiographers. RESULTS: A total of 655 veterinary echocardiographers from six continents and 54 countries, working in specialty practice (56%) and in general practice (38%), provided data. Linear two-dimensional (2D) technique was favored by most echocardiographers (n = 612) for LA size assessment. Most commonly, respondents combined linear 2D with subjective assessment (n = 227), while 209 used linear 2D-based methods alone. Most echocardiographers using linear 2D-based methods preferred the right parasternal short-axis view and to index the LA to the aorta (Ao). Approximately 10% of the respondents obtained LA dimensions from a right parasternal long-axis four-chamber view. Approximately one-third of echocardiographers that made linear measurements from 2D echocardiograms shared the same preferences regarding cat position, acquisition view, indexing method and time point identification for the LA measurement. The responses were comparably homogeneous across geographic location, level of training, years performing echocardiography, and type of practice. DISCUSSION/CONCLUSION: Most veterinary echocardiographers assessed LA size in cats using linear 2D echocardiography from a right parasternal short-axis view, and indexed LA to Ao. Respondents' preferences were similar over geographic, demographic, and professional backgrounds.

Veterinary echocardiographers' preferences for left atrial size assessment in dogs: the BENEFIT project.

INTRODUCTION/OBJECTIVES: Veterinary echocardiographers' preferences for left atrial (LA) size assessment in dogs have never been systematically investigated. The primary aim of this international survey study was to investigate echocardiographers' preferences for LA size assessment in dogs. The secondary aim was to investigate echocardiographers' preferences for assessing LA size in subgroups based on geographic, demographic, and professional profiles. ANIMALS, MATERIALS, AND METHODS: An online survey instrument was designed, verified, and distributed globally to the veterinary echocardiographers. RESULTS: A total of 670 echocardiographers from 54 countries on six continents completed the survey. Most echocardiographers (n = 621) used linear two-dimensional (2D)-based methods to assess LA size, 379 used subjective assessment, and 151 used M-mode-based methods. Most commonly, echocardiographers combined linear 2D-based methods with subjective assessment (n = 222), whereas 191 used linear 2D-based methods alone. Most echocardiographers (n = 436) using linear 2D-based methods preferred the right parasternal short-axis view and indexed the LA to the aorta. Approximately 30% (n = 191) of the echocardiographers who performed linear measurements from 2D echocardiograms shared the same preferences regarding dog position, acquisition view, indexing method, and identification of the time-point used for the measurement. The responses were comparably homogeneous across geographic location, training level, years of performing echocardiography, and type of practice. DISCUSSION/CONCLUSION: Most veterinary echocardiographers assessed LA size in dogs using linear 2D echocardiography from a right parasternal short-axis view, and by indexing the LA to the aorta. The respondents' preferences were similar across geographic, demographic, and professional backgrounds.

Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans.

Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm(2) has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI and ICF towards inhibition. No significant changes were observed in the other protocols. Sham tDCS did not induce significant MEP alterations. These results suggest that an enhancement of tDCS intensity does not necessarily increase efficacy of stimulation, but might also shift the direction of excitability alterations. This should be taken into account for applications of the stimulation technique using different intensities and durations in order to achieve stronger or longer lasting after-effects.

Plasma sphingolipids are biomarkers of metabolic syndrome in non-human primates maintained on a Western-style diet.

BACKGROUND: The intake of a Western diet enriched in animal fat has been shown to be a major risk factor for Type 2 diabetes and obesity. Previous rodent studies have indicated that these conditions may be triggered by the accumulation of the sphingolipid ceramide in insulin-sensitive tissues. However, data are lacking in this regard from both humans and non-human primates. OBJECTIVE: Here we have investigated the relationship between plasma ceramides and metabolic syndrome in Rhesus macaques fed a high-fat and high-fructose (HFFD) 'western' diet. METHODS: We investigated this relationship in cohorts of monkeys fed a HFFD for a period of 8 months to 5 years. Animals were classified as control, pre-diabetic or diabetic based on fasting plasma parameters and insulin sensitivity. RESULTS: HFFD treatment produced significant increases in body weight and body fat and also resulted in a decline in insulin sensitivity. In parallel to the reduction in insulin sensitivity, significant increases in both plasma ceramide and dihydroceramide levels were observed, which further increased as animals progressed to the diabetic state. Plasma levels of the rare sphingolipid C18:0 deoxysphinganine, a marker of increased metabolic flux through serine palmitoyl transferase (SPT), were also elevated in both pre- and diabetic animals. Furthermore, plasma serine levels were significantly elevated in diabetic monkeys, which may indicate a shift in SPT substrate selectivity from serine to alanine or glycine. In contrast, branch chain amino acids were unchanged in pre-diabetic non-human primates, and only plasma valine levels were elevated in diabetic animals. CONCLUSION: Together, these data indicate that HFFD induces de novo synthesis of ceramides in non-human primates, and that increased production of plasma ceramides is significantly correlated with the decline in insulin sensitivity.

Impaired phagocytosis and susceptibility to infection in pediatric-onset systemic lupus erythematosus.

OBJECTIVES: Impaired function of polymorphonuclear cells (PMNs) in systemic lupus erythematosus (SLE) leads to severe gram-positive and gram-negative bacterial infection, and to major morbidity and mortality. Few studies have focused on the association of impaired function of PMNs and SLE patients' susceptibility to infection. This study aimed to analyze function of PMNs in peroxidase production, chemotaxis, and phagocytosis in pediatric-onset SLE with severe infection. METHODS: This study compared function of PMNs among pediatric-onset SLE patients with and without histories of severe infection and in normal control subjects. Human peripheral blood PMNs were isolated from patients and controls. Function of PMNs was measured by analyzing peroxidase, chemotaxis, and phagocytic activities. Different disease activity and severity, and drug use in newly diagnosed SLE patients were also compared. RESULTS: In total, 34 SLE patients (12 patients with severe infection, 22 patients without infection) and 25 healthy controls were analyzed. There were no differences in function of PMNs between SLE patients with or without severe infection. Regardless of infection status, medication, and disease activity, SLE patients had impaired phagocytic ability against Salmonella-specific lipopolysaccharides (LPS) compared with normal controls (p < 0.01). The use of immunosuppressants did not influence phagocytic ability against Salmonella-derived LPS. CONCLUSIONS: Immunosuppressant agents do not influence phagocytic ability against Salmonella in SLE subjects. Impaired phagocytosis against Salmonella is prominent in pediatric-onset SLE subjects, which may result in the high prevalence of Salmonella infection. There is no deficiency of peroxidase production and chemotaxis activity among SLE subjects.

Arecoline-stimulated placenta growth factor production in gingival epithelial cells: modulation by curcumin.

OBJECTIVE: Placenta growth factor (PlGF) is associated with the progression and prognosis of oral cancer. MATERIALS AND METHODS: This study used ELISA, quantitative polymerase chain reaction, and Western blotting to study the arecoline-stimulated (PlGF) protein or mRNA expression in human gingival epithelial S-G cells. RESULTS: Arecoline, a major areca nut alkaloid and an oral carcinogen, could stimulate PlGF protein synthesis in S-G cells in a dose- and time-dependent manner. The levels of PlGF protein secretion increased about 3.1- and 3.8-fold after 24-h exposure to 0.4 and 0.8 mM arecoline, respectively. Pretreatment with antioxidant N-acetyl-l-cysteine (NAC) and ERK inhibitor PD98059, but not NF-κB inhibitor Bay 11-7082, JNK inhibitor SP600125, p38 MAPK inhibitor SB203580, and PI3-K inhibitor LY294002, significantly reduced arecoline-induced PlGF protein synthesis. ELISA analyses demonstrated that NAC and PD98059 reduced about 43% and 38% of the arecoline-induced PlGF protein secretion, respectively. However, combined treatment with NAC and PD98059 did not show additive effect. Moreover, 10 µM curcumin and 4 mM NAC significantly inhibited arecoline-induced ERK activation. Furthermore, 10 µM curcumin completely blocked arecoline-induced PlGF mRNA expression. CONCLUSION: Arecoline-induced PlGF synthesis is probably mediated by reactive oxygen species/ERK pathways, and curcumin may be an useful agent in controlling oral carcinogenesis.

A bacteria injection scheme for in situ bioaugmentation.

This article presents an innovative design for inoculating the desired organisms to stratified geological layers at desired rates during in-situ bioaugmentation. The new delivery system consists of intermittent porous tubes connected in series with impermeable polyethylene tubes that run horizontally in each stratified layer of a contaminated aquifer. A bioaugmentation test using the new delivery system was conducted to inject an enriched culture of Escherichia coli (E. coli). Results of the test indicated that the distribution of E. coli through each porous tube was fairly uniform. A mathematical model previously developed to calculate the distribution of water flow through each porous tube was modified to calculate the distribution of E. coli. Geological layers often have different hydraulic conductivities. By controlling the permeability and the length of porous tubes placed in stratified layers, the new design provides a means to selectively deliver aqueous bacteria to various layers at desired rates according to aquifer heterogeneity.