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Sample records for 12-step naive treatment

  1. Climate for innovation, 12-step orientation, and tobacco cessation treatment.

    PubMed

    Muilenburg, Jessica L; Laschober, Tanja C; Eby, Lillian T

    2014-04-01

    This study examined the relationship between (1) three indicators of climate for innovation (clinician skills, absence of program obstacles, policy-related incentives) and adoption extensiveness of both behavioral treatments for tobacco cessation (TC) and system-level support for TC in substance use disorder treatment programs, (2) a program's 12-step treatment orientation and adoption extensiveness, and (3) whether 12-step treatment orientation moderates the relationship between climate for innovation and adoption extensiveness. Data were obtained from a random sample of 1006 program administrators. Hierarchical regression results showed that both absence of program obstacles and policy-related incentives are positively related to adoption extensiveness. Twelve-step treatment orientation is neither related to adoption extensiveness nor a moderator of the relationship between climate for innovation and adoption extensiveness. Although the adoption of both behavioral treatments for TC and system-level support for TC is not extensive, we conclude that a 12-step treatment orientation neither hampers nor promotes adoption extensiveness.

  2. Influence of Religiosity on 12-Step Participation and Treatment Response Among Substance-Dependent Adolescents*

    PubMed Central

    Kelly, John F.; Pagano, Maria E.; Stout, Robert L.; Johnson, Shannon M.

    2011-01-01

    Objective: Religious practices among adults are associated with more 12-step participation which, in turn, is linked to better treatment outcomes. Despite recommendations for adolescents to participate in mutual-help groups, little is known about how religious practices influence youth 12-step engagement and outcomes. This study examined the relationships among lifetime religiosity, during-treatment 12-step participation, and outcomes among adolescents, and tested whether any observed beneficial relation between higher religiosity and outcome could be explained by increased 12-step participation. Method: Adolescents (n = 195; 52% female, ages 14–18) court-referred to a 2-month residential treatment were assessed at intake and discharge. Lifetime religiosity was assessed with the Religious Background and Behaviors Questionnaire; 12-step assessments measured meeting attendance, step work (General Alcoholics Anonymous Tools of Recovery), and Alcoholics Anonymous (AA)/Narcotics Anonymous (NA)-related helping. Substance-related outcomes and psychosocial outcomes were assessed with toxicology screens, the Adolescent–Obsessive Compulsive Drinking Scale, the Children's Global Assessment Scale, and the Narcissistic Personality Inventory. Results: Greater lifetime formal religious practices at intake were associated with increased step work and AA/NA-related helping during treatment, which in turn were linked to improved substance outcomes, global functioning, and reduced narcissistic entitlement. Increased step work mediated the effect of religious practices on increased abstinence, whereas AA/NA-related helping mediated the effect of religiosity on reduced craving and entitlement. Conclusions: Findings extend the evidence for the protective effects of lifetime religious behaviors to an improved treatment response among adolescents and provide preliminary support for the 12-step proposition that helping others in recovery may lead to better outcomes. Youth with low or

  3. AN OVERVIEW OF THE EFFICACY OF THE 12-STEP GROUP THERAPY FOR SUBSTANCE ABUSE TREATMENT.

    PubMed

    Gamble, James; O'Lawrence, Henry

    2016-01-01

    This study was designed to determine if 12-Steps groups efficacy for substance abuse treatment significantly improve abstinence rates of heroin addicts in the short run and long run (1-year and 5-year period); and if abstinence rates are found to be lower for heroin addicts that have attended 12-Step groups at the 1-year mark, and if similar results would be expected at the 5-year mark. Secondary data from the Inter-University Consortium of Political and Social Research (ICPSR) was extracted and analyzed for the aforementioned hypothesis. Using SSPS to test the research hypothesis for the 1-Year Follow Up, the chi-square test shows a p-value below of .10, and the analysis determined that there was significant evidence to support the hypothesis that cases in a 12-Steps or self-help program have a higher success than cases not in a program for the 1-year follow up. For 5-Year Follow Up, the cases that attended a 12-Step program or a self-help program and about 27% went on to use heroin during the last 12 months compared to 34% cases that did not go to a program. PMID:27483978

  4. Characteristics of clinicians likely to refer clients to 12-Step programs versus a diversity of post-treatment options.

    PubMed

    Fenster, Judy

    2006-07-27

    Most clients in substance abuse treatment are referred for continuing care. However, post-treatment services vary widely in their approaches to helping individuals achieve better substance use outcomes. This study examined the attitudes of outpatient treatment staff who refer clients exclusively to 12-Step groups (12-Step subgroup) and staff who refer clients both to 12-Step groups and to other continuing care options (Diversity subgroup) toward seven mutual-aid and professional psychosocial post-treatment options: Twelve-Step Programs (12-Step), Cognitive-Behavioral Therapy (CBT), Moderation Management (MM), Smart Recovery((R)) (SMART), Psychodynamic-oriented Therapy (PSY), Secular Organizations for Sobriety (SOS), and Women for Sobriety (WFS). A large percentage of clinicians lacked knowledge about the effectiveness of all alternatives to 12-Step programs with the exception of CBT. Clinicians in the 12-Step subgroup were more likely than those in the Diversity subgroup to be unfamiliar with alternatives to 12-Step programs and to believe less strongly in the effectiveness of CBT and PSY. A logistic regression found beliefs about CBT effectiveness and clinician preference for the 12-Step model to be related to the likelihood of referring exclusively to 12-Step groups. Findings suggest that clinicians could benefit from information and training on assessing and referring clients to various options for continuing care.

  5. Assessing Fidelity of Treatment Delivery in Group and Individual 12-Step Facilitation

    PubMed Central

    Campbell, Barbara K.; Manuel, Jennifer K.; Manser, Sarah Turcotte; Peavy, K. Michelle; Stelmokas, Julija; McCarty, Dennis; Guydish, Joseph R.

    2012-01-01

    Twelve Step Facilitation (TSF) is an emerging, empirically supported treatment, the study of which will be strengthened by rigorous fidelity assessment. This report describes the development, reliability and concurrent validity of the Twelve Step Facilitation Adherence Competence Empathy Scale (TSF ACES), a comprehensive fidelity rating scale for group and individual TSF treatment developed for the National Drug Abuse Treatment Clinical Trials Network study, Stimulant Abuser Groups to Engage in 12-Step. Independent raters used TSF ACES to rate treatment delivery fidelity of 966 (97% of total) TSF group and individual sessions. TSF ACES summary measures assessed therapist treatment adherence, competence, proscribed behaviors, empathy and overall session performance. TSF ACES showed fair to good overall reliability; weighted kappa coefficients for 59 co-rated sessions ranged from .31–1.00, with a mean of .69. Reliability ratings for session summary measures were good to excellent (.69–.91). Internal consistency for the instrument was variable (.47–.71). Relationships of the TSF ACES summary measures with each other, as well as relationships of the summary measures with a measure of therapeutic alliance provided support for concurrent and convergent validity. Implications and future directions for use of TSF ACES in clinical trials and community treatment implementation are discussed. PMID:22944595

  6. Social Recovery Model: An 8-Year Investigation of Adolescent 12-step Group Involvement following Inpatient Treatment

    PubMed Central

    Kelly, John F.; Brown, Sandra A.; Abrantes, Ana; Kahler, Christopher; Myers, Mark

    2013-01-01

    Background Despite widespread use of 12-step treatment approaches and referrals to Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) by youth providers, little is known about the significance of these organizations in youth addiction recovery. Furthermore, existing evidence is based mostly on short-term follow-up and is limited methodologically. Methods Adolescent inpatients (N = 160; M age = 16, 40% female) were followed at 6-months, and at 1, 2, 4, 6, and 8 years post-treatment. Time-lagged, generalized estimating equations (GEE) modeled treatment outcome in relation to AA/NA attendance controlling for static and time-varying covariates. Robust regression (LOWESS) explored dose-response thresholds of AA/NA attendance on outcome. Results AA/NA attendance was common and intensive early post-treatment, but declined sharply and steadily over the 8-year period. Patients with greater addiction severity and those who believed they could not use substances in moderation were more likely to attend. Despite declining attendance, the effects related to AA/NA remained significant and consistent. Greater early participation was associated with better long-term outcomes. Conclusions Even though many youth discontinue AA/NA over time, attendees appear to benefit, and more severely substance-involved youth attend most. Successful early post-treatment engagement of youth in abstinence-supportive social contexts, such as AA/NA, may have long-term implications for alcohol and drug involvement into young adulthood. PMID:18557829

  7. Inmate Prerelease Assessment (IPASS) Aftercare Placement Recommendation as a Predictor of Rural Inmate's 12-Step Attendance and Treatment Entry Postrelease

    ERIC Educational Resources Information Center

    Oser, Carrie B.; Biebel, Elizabeth P.; Havens, Jennifer R.; Staton-Tindall, Michele; Knudsen, Hannah K.; Mooney, Jenny L.; Leukefeld, Carl G.

    2009-01-01

    The purpose of this study is to use the Criminal Justice Drug Abuse Treatment Studies' (CJ-DATS) Inmate Prerelease Assessment (IPASS), which recommends either intensive or nonintensive treatment after release, to predict rural offenders' 12-step attendance and treatment entry within six months of release from prison. IPASS scores indicated that…

  8. ATTITUDES AND BELIEFS ABOUT 12-STEP GROUPS AMONG ADDICTION TREATMENT CLIENTS AND CLINICIANS: TOWARD IDENTIFYING OBSTACLES TO PARTICIPATION

    PubMed Central

    Laudet, Alexandre B.

    2007-01-01

    Participation in 12-step groups (12SG) during and after formal treatment has been associated with positive outcome among substance users. However, the effectiveness of 12SG may be limited by high attrition rates and by low participation, areas on which there has been little research. Clinicians play an important role in fostering 12-step participation, and the insights which they develop in their practice can greatly contribute to informing the research process. Yet, little is known about clinicians’ attitudes about 12-step groups or about their experiences in referring clients. This study surveyed clients (N = 101) and clinicians (N = 102) in outpatient treatment programs to examine 12-step related attitudes and to identify potential obstacles to participation. Data collection was conducted between May 2001 and January 2002 in New York City. Both client and clinician samples were primarily African-American and Hispanic; 32% of clients reported substance use in the previous month, with crack and marijuana cited most frequently as primary drug problem. On average, clinicians had worked in the treatment field for 8 years. Both staff and clients viewed 12SG as a helpful recovery resource. Major obstacles to participation centered on motivation and readiness for change and on perceived need for help, rather than on aspects of the 12-step program often cited as points of resistance (e.g., religious aspect and emphasis on powerlessness). Clinicians also frequently cited convenience and scheduling issues as possible obstacles to attending 12SG. Clinical implications of these findings are discussed, including the importance of fostering motivation for change, the need to assess clients’ beliefs about and experiences with 12SG on a case by case basis, and to find goodness of fit between clients’ needs and inclinations on the one hand, and the tools and support available within 12-step groups on the other. PMID:14677780

  9. 12-Step Treatment for Alcohol and Substance Abuse Revisited: Best Available Evidence Suggests Lack of Effectiveness or Harm

    ERIC Educational Resources Information Center

    Miller, John Clark

    2008-01-01

    Approaches incorporating 12-Step beliefs and practices have dominated substance abuse treatment despite a lack of empirical support. Recent claims for effectiveness relying on results from a large, multisite research project in the U.S. were re-evaluated based on critical analysis of design, methodology, and construction of outcome measures.…

  10. Addiction, 12-Step Programs, and Evidentiary Standards for Ethically and Clinically Sound Treatment Recommendations: What Should Clinicians Do?

    PubMed

    Mendola, Annette; Gibson, Richard L

    2016-01-01

    Addiction is a complex phenomenon characterized by a loss of control and compulsive, habitual behavior. Since there is no single, specific cause for addiction, there is no single, standard treatment for it. A variety of approaches are used, including counseling, psychotherapy, medications, and mutual help groups (MHG). The best known and most widely available approach to addiction is 12-step (TS) programs of recovery, a variety of MHG. These have been lauded as lifesaving by some and criticized by others. We argue that TS programs are an appropriate mode of help for those seeking to quit an addiction but should not be the only approach considered.

  11. An Exploration of the Effect of On-Site 12-Step Meetings on Post-Treatment Outcomes among Polysubstance-Dependent Outpatient Clients

    ERIC Educational Resources Information Center

    Laudet, Alexandre; Stanick, Virginia; Sands, Brian

    2007-01-01

    Rates of return to active substance use after addiction treatment tend to be high; participation in 12-step fellowships (e.g., Alcoholics Anonymous) reduces relapse rates but many clients do not attend or attend for a short period only. This quasi-experimental study uses repeated measurement to explore the role of presence/absence of on-site…

  12. Alcoholics Anonymous attendance following 12-step treatment participation as a link between alcohol-dependent fathers' treatment involvement and their children's externalizing problems.

    PubMed

    Andreas, Jasmina Burdzovic; O'Farrell, Timothy J

    2009-01-01

    We investigated longitudinal associations between alcohol-dependent fathers' 12-step treatment involvement and their children's internalizing and externalizing problems (N = 125, M(age) = 9.8 +/- 3.1), testing the hypotheses that fathers' greater treatment involvement would benefit later child behavior and that this effect would be mediated by fathers' posttreatment behaviors. The initial association was established between fathers' treatment involvement and children's externalizing problems only, whereas Structural Equation Modeling (SEM) results supported mediating hypotheses. Fathers' greater treatment involvement predicted children's lower externalizing problems 12 months later, and fathers' posttreatment behaviors mediated this association: Greater treatment involvement predicted greater posttreatment Alcoholics Anonymous attendance, which in turn predicted greater abstinence. Finally, fathers' abstinence was associated with lower externalizing problems in children. Theoretical and practical implications of these findings are discussed. PMID:18715745

  13. Anterior Cingulate Volumetric Alterations in Treatment-Naive Adults with ADHD: A Pilot Study

    ERIC Educational Resources Information Center

    Makris, Nikos; Seidman, Larry J.; Valera, Eve M.; Biederman, Joseph; Monuteaux, Michael C.; Kennedy, David N.; Caviness, Verne S., Jr.; Bush, George; Crum, Katherine; Brown, Ariel B.; Faraone, Stephen V.

    2010-01-01

    Objective: We sought to examine preliminary results of brain alterations in anterior cingulate cortex (ACC) in treatment-naive adults with ADHD. The ACC is a central brain node for the integration of cognitive control and allocation of attention, affect and drive. Thus its anatomical alteration may give rise to impulsivity, hyperactivity and…

  14. The Effects of Age Composition of 12-Step Groups on Adolescent 12-Step Participation and Substance Use Outcome

    ERIC Educational Resources Information Center

    Kelly, John F.; Myers, Mark G.; Brown, Sandra A.; Myers, Mark

    2005-01-01

    Youth substance use disorder treatment programs frequently advocate integration into 12-Step fellowships to help prevent relapse. However, the effects of the predominantly adult composition of 12-step groups on adolescent involvement and substance use outcome remain unstudied. Greater knowledge could enhance the specificity of treatment…

  15. What Promotes Wisdom in 12-Step Recovery?

    PubMed

    DiGangi, Julia A; Majer, John M; Mendoza, Leslie; Droege, Jocelyn R; Jason, Leonard A; Contreras, Richard

    2014-01-01

    Research investigations on twelve-step groups such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) have addressed a number of resources associated with 12-step recovery. However, little is known about the role of wisdom, and whether aspects of 12-step participation might increase this resource among 12-step members. An exploratory analysis revealed that participants who reported having a "spiritual awakening" and considered themselves "members" of 12-step groups reported significantly higher levels of wisdom. Twelve-step meeting attendance was not significantly related to wisdom scores. Findings suggest certain aspects of 12-step involvement are associated with wisdom and may play a role in substance abuse recovery.

  16. A Discrete Choice Conjoint Experiment to Evaluate Parent Preferences for Treatment of Young, Medication Naive Children with ADHD

    ERIC Educational Resources Information Center

    Waschbusch, Daniel A.; Cunningham, Charles E.; Pelham, William E., Jr.; Rimas, Heather L.; Greiner, Andrew R.; Gnagy, Elizabeth M.; Waxmonsky, James; Fabiano, Gregory A.; Robb, Jessica A.; Burrows-MacLean, Lisa; Scime, Mindy; Hoffman, Martin T.

    2011-01-01

    The current study examined treatment preferences of 183 parents of young (average age = 5.8 years, SD = 0.6), medication naive children with ADHD. Preferences were evaluated using a discrete choice experiment in which parents made choices between different combinations of treatment characteristics, outcomes, and costs. Latent class analysis…

  17. The 12 Step Affiliation and Practices Scale: Development and initial validation of a measure assessing 12 step affiliation

    PubMed Central

    Klein, Audrey A.; Slaymaker, Valerie J.; Kelly, John F.

    2013-01-01

    Objective Research on instruments designed to measure endorsement of 12 step beliefs and practices among individuals with substance use disorders is virtually nonexistent. The goal of this study was to examine the psychometric properties of a novel instrument called the 12 Step Affiliation and Practices Scale (TSAPS) using a sample of young adults receiving 12 step-based residential treatment for alcohol and drug dependence. Method As part of a naturalistic treatment outcome study, 300 young adults receiving residential treatment completed the TSAPS and several other assessments during and after treatment. Analyses of the TSAPS examined its factor structure, internal consistency, sensitivity to change over time, and convergent and predictive validity. Results A maximum likelihood estimation factor analysis using oblique rotation produced 4 factors accounting for 61.16% of the variance. Internal consistency was very high and scores on the TSAPS significantly increased across the course of treatment. Convergent validity was demonstrated by relationships with scales of treatment attitudes, twelve step expectancies and commitment to sobriety. Predictive validity was also found, as evidenced by a relationship between total TSAPS score at 3 months post-treatment and percent of abstinent days at 6 months post-treatment. Conclusions The TSAPS shows promise as a psychometrically sound, internally reliable measure of 12 step affiliation and practices among individuals with substance dependence. PMID:21764222

  18. Gait and Balance in Treatment-Naive Active Alcoholics with and without a Lifetime Drug Codependence

    PubMed Central

    Fein, George; Smith, Stan; Greenstein, David

    2012-01-01

    Background Disturbed gait and balance are among the most consistent sequelae of chronic alcoholism. However, although a majority of alcoholics have never sought treatment, most investigations showing ataxia in alcohol dependent individuals have relied on samples drawn from treated populations. In addition, few studies have addressed the associations of codependence on other drugs with alcoholic gait and balance disturbance. Methods The present study employed the Walk-a-line Ataxia Battery (Fregly et al. 1972) to assess gait and balance in treatment-naive, actively drinking alcohol dependent men and women (TNA; n = 69) who were dependent on alcohol only (ALC; n = 43), or who also had a lifetime drug dependence (ALC+DRG; n = 26; i.e., methamphetamine, cocaine, opiates, and/or marijuana), compared with non-substance abusing controls (NSAC; n = 74). We also examined associations between lifetime alcohol use and age with gait and balance measures. Results Our main findings were 1) no evidence of disturbed gait and balance in ALC vs. NSAC and 2) significantly disturbed gait and balance in ALC+DRG, relative to both NSAC and ALC, along with steeper age-associated decline in gait and balance performance in ALC vs. ALC+DRG. Conclusions Our results provide evidence consistent with previous studies that TNA (without a lifetime drug codependence) may represent a population that is different and less impaired (including in gait and balance) than treated alcoholics. Additionally, we provide evidence that ALC+DRG, with greater alcohol use and family drinking density than ALC, have an accelerated effect of age on gait and balance disturbance compared to both NSAC and ALC. The ALC+DRG group likely represents a subset of TNA with different characteristics than ALC. PMID:22390787

  19. Serum soluble TWEAK levels are decreased in treatment naive noncirrhotic chronic hepatitis B patients.

    PubMed

    Asil, Mehmet; Dertli, Ramazan

    2016-09-01

    The mechanisms underlying hepatic inflammation and fibrogenesis in chronic hepatitis B (CHB) are complex and several cytokines are involved. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily which also acts as a cytokine. This study was conducted to evaluate serum soluble TWEAK (sTWEAK) levels in noncirrhotic CHB patients.Fifty-two treatment naive CHB patients and 30 healthy controls were included in the study and serum sTWEAK concentrations were measured using commercially available ELISA kits.Mean serum sTWEAK concentration was significantly lower in CHB group than healthy controls (189.6 ± 63.3 pg/mL in CHB group and 297.6 ± 61.5 pg/mL in control group, P < 0.001). According to the degree of necroinflammation in liver biopsies mean sTWEAK concentrations were found to be 168.14 ± 51.51, 206.96 ± 58.51, and 223.62 ± 78.88 pg/mL in patients with mild, moderate, and severe inflammation, respectively, and the difference between groups was statistically significant (P = 0.022). sTWEAK concentration was also found to be significantly higher in patients with advanced fibrosis in liver biopsy samples (169.59 ± 52.02 and 211.17 ± 68.22 pg/mL in patients with mild and advanced fibrosis, respectively, P = 0.016). Receiver operating characteristic (ROC) curves were obtained in CHB group to differentiate patients with advanced fibrosis from patients with mild fibrosis. Area under curve (AUC) was 0.676 (95% Cl; 0.526-0.825) for sTWEAK and for the specified cut-off value of 213.67 pg/mL sensitivity and specificity were 60% and 81.4%, respectively. ROC curve for sTWEAK to differentiate patients with severe inflammation revealed an AUC of 0.664 (95% Cl; 0.450-0.878). A cut-off value of 243.27 pg/mL yielded 54.5% sensitivity and 82.9% specificity.Serum sTWEAK concentration is decreased in treatment naive CHB patients. Further studies with simultaneous

  20. Attentional Control and Subjective Executive Function in Treatment-Naive Adults with Attention Deficit Hyperactivity Disorder

    PubMed Central

    Grane, Venke Arntsberg; Endestad, Tor; Pinto, Arnfrid Farbu; Solbakk, Anne-Kristin

    2014-01-01

    We investigated performance-derived measures of executive control, and their relationship with self- and informant reported executive functions in everyday life, in treatment-naive adults with newly diagnosed Attention Deficit Hyperactivity Disorder (ADHD; n = 36) and in healthy controls (n = 35). Sustained attentional control and response inhibition were examined with the Test of Variables of Attention (T.O.V.A.). Delayed responses, increased reaction time variability, and higher omission error rate to Go signals in ADHD patients relative to controls indicated fluctuating levels of attention in the patients. Furthermore, an increment in NoGo commission errors when Go stimuli increased relative to NoGo stimuli suggests reduced inhibition of task-irrelevant stimuli in conditions demanding frequent responding. The ADHD group reported significantly more cognitive and behavioral executive problems than the control group on the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). There were overall not strong associations between task performance and ratings of everyday executive function. However, for the ADHD group, T.O.V.A. omission errors predicted self-reported difficulties on the Organization of Materials scale, and commission errors predicted informant reported difficulties on the same scale. Although ADHD patients endorsed more symptoms of depression and anxiety on the Achenbach System of Empirically Based Assessment (ASEBA) than controls, ASEBA scores were not significantly associated with T.O.V.A. performance scores. Altogether, the results indicate multifaceted alteration of attentional control in adult ADHD, and accompanying subjective difficulties with several aspects of executive function in everyday living. The relationships between the two sets of data were modest, indicating that the measures represent non-redundant features of adult ADHD. PMID:25545156

  1. Attentional control and subjective executive function in treatment-naive adults with Attention Deficit Hyperactivity Disorder.

    PubMed

    Grane, Venke Arntsberg; Endestad, Tor; Pinto, Arnfrid Farbu; Solbakk, Anne-Kristin

    2014-01-01

    We investigated performance-derived measures of executive control, and their relationship with self- and informant reported executive functions in everyday life, in treatment-naive adults with newly diagnosed Attention Deficit Hyperactivity Disorder (ADHD; n = 36) and in healthy controls (n = 35). Sustained attentional control and response inhibition were examined with the Test of Variables of Attention (T.O.V.A.). Delayed responses, increased reaction time variability, and higher omission error rate to Go signals in ADHD patients relative to controls indicated fluctuating levels of attention in the patients. Furthermore, an increment in NoGo commission errors when Go stimuli increased relative to NoGo stimuli suggests reduced inhibition of task-irrelevant stimuli in conditions demanding frequent responding. The ADHD group reported significantly more cognitive and behavioral executive problems than the control group on the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). There were overall not strong associations between task performance and ratings of everyday executive function. However, for the ADHD group, T.O.V.A. omission errors predicted self-reported difficulties on the Organization of Materials scale, and commission errors predicted informant reported difficulties on the same scale. Although ADHD patients endorsed more symptoms of depression and anxiety on the Achenbach System of Empirically Based Assessment (ASEBA) than controls, ASEBA scores were not significantly associated with T.O.V.A. performance scores. Altogether, the results indicate multifaceted alteration of attentional control in adult ADHD, and accompanying subjective difficulties with several aspects of executive function in everyday living. The relationships between the two sets of data were modest, indicating that the measures represent non-redundant features of adult ADHD.

  2. 12-Step Interventions and Mutual Support Programs for Substance Use Disorders: An Overview

    PubMed Central

    Donovan, Dennis M.; Ingalsbe, Michelle H.; Benbow, James; Daley, Dennis C.

    2013-01-01

    Social workers and other behavioral health professionals are likely to encounter individuals with substance use disorders in a variety of practice settings outside of specialty treatment. 12-Step mutual support programs represent readily available, no cost community-based resources for such individuals; however, practitioners are often unfamiliar with such programs. The present article provides a brief overview of 12-Step programs, the positive substance use and psychosocial outcomes associated with active 12-Step involvement, and approaches ranging from ones that can be utilized by social workers in any practice setting to those developed for specialty treatment programs to facilitate engagement in 12-Step meetings and recovery activities. The goal is to familiarize social workers with 12-Step approaches so that they are better able to make informed referrals that match clients to mutual support groups that best meet the individual’s needs and maximize the likelihood of engagement and positive outcomes. PMID:23731422

  3. Efficacy and safety of maraviroc vs. efavirenz in treatment-naive patients with HIV-1: 5-year findings

    PubMed Central

    Cooper, David A.; Heera, Jayvant; Ive, Prudence; Botes, Mariette; Dejesus, Edwin; Burnside, Robert; Clumeck, Nathan; Walmsley, Sharon; Lazzarin, Adriano; Mukwaya, Geoffrey; Saag, Michael; van Der Ryst, Elna

    2014-01-01

    Objective: Maraviroc, a chemokine co-receptor type 5 (CCR5) antagonist, has demonstrated comparable efficacy and safety to efavirenz, each in combination with zidovudine/lamivudine, over 96 weeks in the Maraviroc vs. Efavirenz Regimens as Initial Therapy (MERIT) study. Here we report 5-year findings. Design: A randomized, double-blind, multicenter phase IIb/III study with an open-label extension phase. Methods: Treatment-naive patients with CCR5-tropic HIV-1 infection (Trofile) received maraviroc 300 mg twice daily or efavirenz 600 mg once daily, and zidovudine/lamivudine 300 mg/150 mg twice daily. After the last patient's week 96 visit, the study was unblinded and patients could enter a nominal 3-year open-label phase. Endpoints at the 5-year nominal visit (week 240) included proportion of patients (CCR5 tropism re-confirmed by enhanced sensitivity Trofile) with viral load (plasma HIV-1 RNA) below 50 and 400 copies/ml, and change from baseline in CD4+ cell count, as well as safety. Results: The proportion of patients maintaining viral load below 50 copies/ml was similar between treatment arms throughout the study and at week 240 (maraviroc 50.8% vs. efavirenz 45.9%). Maraviroc-treated patients had a greater increase from baseline in mean CD4+ cell count than efavirenz-treated patients at week 240 (293 vs. 271 cells/μl, respectively). Fewer patients on maraviroc vs. efavirenz experienced treatment-related adverse events (68.9 vs. 81.7%) and discontinued as a result of any adverse event (10.6 vs. 21.3%). Conclusion: Maraviroc maintained similar long-term antiviral efficacy to efavirenz over 5 years in treatment-naive patients with CCR5-tropic HIV-1. Maraviroc was generally well tolerated with no unexpected safety findings or evidence of long-term safety concerns. PMID:24983542

  4. High Prevalence of HIV Low Abundance Drug-Resistant Variants in a Treatment-Naive Population in North Rift Kenya.

    PubMed

    Cheriro, Winfrida; Kiptoo, Michael; Kikuvi, Gideon; Mining, Simeon; Emonyi, Wilfred; Songok, Elijah

    2015-12-01

    The advent of antiretroviral treatment (ART) has resulted in a dramatic reduction in AIDS-related morbidity and mortality. However, the emergence and spread of antiretroviral drug resistance (DR) threaten to negatively impact treatment regimens and compromise efforts to control the epidemic. It is recommended that surveillance of drug resistance occur in conjunction with scale-up efforts to ensure that appropriate first-line therapy is offered relative to the resistance that exists. However, standard resistance testing methods used in Sub-Saharan Africa rely on techniques that do not include low abundance DR variants (LADRVs) that have been documented to contribute to treatment failure. The use of next generation sequencing (NGS) has been shown to be more sensitive to LADRVS. We have carried out a preliminary investigation using NGS to determine the prevalence of LDRVS among a drug-naive population in North Rift Kenya. Antiretroviral-naive patients attending a care clinic in North Rift Kenya were requested to provide and with consent provided blood samples for DR analysis. DNA was extracted and amplified and nested PCR was conducted on the pol RT region using primers tagged with multiplex identifiers (MID). Resulting PCR amplicons were purified, quantified, and pyrosequenced using a GS FLX Titanium PicoTiterPlate (Roche). Valid pyrosequencing reads were aligned with HXB-2 and the frequency and distribution of nucleotide and amino acid changes were determined using an in-house Perl script. DR mutations were identified using the IAS-USA HIV DR mutation database. Sixty samples were successfully sequenced of which 26 were subtype A, 9 were subtype D, 2 were subtype C, and the remaining were recombinants. Forty-six (76.6%) had at least one drug resistance mutation, with 25 (41.6%) indicated as major and the remaining 21 (35%) indicated as minor. The most prevalent mutation was NRTI position K219Q/R (11/46, 24%) followed by NRTI M184V (5/46, 11%) and NNRTI K103N (4/46, 9

  5. Cultural points of resistance to the 12-Step recovery process.

    PubMed

    Smith, D E; Buxton, M E; Bilal, R; Seymour, R B

    1993-01-01

    This article addresses some of the key issues in developing culturally relevant approaches to drug abuse treatment and recovery, using the HAFC/Glide African-American Extended Family Program as a positive example of effective cultural adaptability within recovery. Cultural points of resistance to the recovery process are also addressed, including the perception that 12-Step fellowships are exclusive and confused with religion, confusion over surrender versus powerlessness, and concerns about low self-esteem, dysfunctional family structure, communication difficulties, and institutionalized and internalized racism. The authors also focus on professional resistance in other countries, where different treatment approaches and philosophies block the acceptance of a recovery concept in general and the 12-Step process in particular. In explicating these issues, addiction is presented as a multicultural problem in need of multicultural solutions. The challenge is to adapt the process of recovery to all cultures and races, to counter stereotypes on all sides, and to eliminate the perception that recovery only works for addicts from the White mainstream.

  6. Sub-Epidemics Explain Localized High Prevalence of Reduced Susceptibility to Rilpivirine in Treatment-Naive HIV-1-Infected Patients: Subtype and Geographic Compartmentalization of Baseline Resistance Mutations

    PubMed Central

    Van Laethem, Kristel; Gomes, Perpetua; Baele, Guy; Pineda-Peña, Andrea-Clemencia; Vandamme, Anne-Mieke; Camacho, Ricardo J.; Abecasis, Ana B.

    2016-01-01

    Abstract Objective: The latest nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) is indicated for human immunodeficiency virus type-1 (HIV-1) patients initiating antiretroviral treatment, but the extent of genotypic RPV resistance in treatment-naive patients outside clinical trials is poorly defined. Study Design: This retrospective observational study of clinical data from Belgium and Portugal evaluates genotypic information from HIV-1 drug-naive patients obtained for the purpose of drug resistance testing. Rilpivirine resistance-associated mutations (RPV-RAMs) were defined based on clinical trials, phenotypic studies, and expert-based resistance algorithms. Viral susceptibility to RPV alone and to the single-tablet regimen was estimated using expert-based resistance algorithms. Results: In 4,631 HIV-1 treatment-naive patients infected with diverse HIV-1 subtypes, major RPV-RAMs were detected in 4.6%, while complete viral susceptibility to RPV was estimated in 95% of patients. Subtype C- and F1-infected patients displayed the highest levels of reduced viral susceptibility at baseline, respectively 13.2% and 9.3%, mainly due to subtype- and geographic-dependent occurrence of RPV-RAMs E138A and A98G as natural polymorphisms. Strikingly, a founder effect in Portugal resulted in a 138A prevalence of 13.2% in local subtype C-infected treatment-naive patients. The presence of transmitted drug resistance did not impact our estimates. Conclusion: RPV is the first HIV-1 inhibitor for which, in the absence of transmitted drug resistance, intermediate or high-level genotypic resistance can be detected in treatment-naive patients. The extent of RPV susceptibility in treatment-naive patients differs depending on the HIV-1 subtype and dynamics of local compartmentalized epidemics. The highest prevalence of reduced susceptibility was found to be 15.7% in Portuguese subtype C-infected treatment-naive patients. In this context, even in the absence of

  7. Finger Tapping-Related Activation Differences in Treatment-Naive Pediatric Tourette Syndrome: A Comparison of the Preferred and Nonpreferred Hand

    ERIC Educational Resources Information Center

    Roessner, Veit; Wittfoth, Matthias; August, Julia M.; Rothenberger, Aribert; Baudewig, Jurgen; Dechent, Peter

    2013-01-01

    Background: Disturbances of motor circuitry are commonly encountered in Tourette syndrome (TS). The aim of this study was to investigate simple motor performance differences between boys with TS and healthy controls. Methods: We attempted to provide insight into motor network alterations by studying a group of treatment-naive patients suffering…

  8. Efficacy and safety of peginterferon alpha-2a/ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C.

    PubMed

    Njouom, Richard; Sartre, Michèle Tagni; Timba, Isabelle; Nerrienet, Eric; Tchendjou, Patrice; Pasquier, Christophe; Rousset, Dominique

    2008-12-01

    Data were examined from a day-to-day clinical practice in Yaounde, Cameroon to evaluate the efficacy and safety of peginterferon alfa-2a and ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C. Ninety adults with chronic hepatitis C (mean age, 53 +/- 8 years; 79% males; 37.8% genotype 1; 23.3% genotype 2; and 38.9% genotype 4) were given at least 12 weeks of combination therapy between February 2003 and August 2007. Of these, 54 completed the treatment and the 24-week follow up. Subsequently, 18 continued treatment and 18 (20%) discontinued the treatment, 6 (6.7%) due to adverse effects. An intention-to-treat analysis showed that 38 (52.8%) had an end-of-treatment virologic response and 34 (47.2%) had a sustained virologic response. Sustained virologic response were significantly higher among patients with hepatitis C virus (HCV) genotype 2 (83.4%) than in those with genotype 1 (31%) or genotype 4 (42.3%) (P < 0.05). Non HCV-2 genotype, pretreatment fibrosis score >2, HCV RNA level >8.0 x 10(5) IU/ml and a non-virologic response at 12 weeks of treatment were associated with poor sustained virologic response (P < 0.05). Thus, HCV can be treated in a Sub-Saharan African country. It indicates that Cameroonian HCV-1 and -4 patients have a poorer sustained virologic response than the published results for Western and Middle-East countries. Virus subtype may influence the treatment outcome, since there is a great genetic diversity within Cameroonian HCV-1 and -4 genotypes.

  9. Picturing neuroscience research through a human rights lens: imaging first-episode schizophrenic treatment-naive individuals.

    PubMed

    Eijkholt, Marleen; Anderson, James A; Illes, Judy

    2012-01-01

    In this paper we examine imaging research involving first-episode schizophrenic treatment-naive individuals (FESTNIs) through a legal human rights lens; in particular, the lens of the Additional Protocol to the Convention on Human Rights and Biomedicine Concerning Biomedical Research. We identify a number of ethical and legal hot spots highlighted by the Protocol, and offer a series of recommendations designed to ensure the human rights compatibility of this research. Subsequently, we argue that the lack of reporting on design elements related to ethical concerns frustrates commitments at the heart of the human rights approach, namely, transparency and openness to international scrutiny. To redress this problem, we introduce two norms for the first time: ethical transparency, and ethical reproducibility. When concluding, we offer a set of reporting guidelines designed to operationalize these norms in the context of imaging research involving FESTNIs. Though we will not make this case here, we believe that parallel reporting guidelines should be incorporated into other areas of research involving human subjects. PMID:22304987

  10. Brain Gray Matter Abnormalities in First-Episode, Treatment-Naive Children with Obsessive-Compulsive Disorder.

    PubMed

    Cheng, Bochao; Cai, Wu; Wang, Xiuli; Lei, Du; Guo, Yingkun; Yang, Xun; Wu, Qizhu; Gong, Jianping; Gong, Qiyong; Ning, Gang

    2016-01-01

    Although several magnetic resonance imaging (MRI) studies have been conducted in children with obsessive-compulsive disorder (OCD), the brain structural abnormalities in OCD, especially in children, are not yet well characterized. We aimed to identify gray matter (GM) abnormalities in the early stage of pediatric OCD and examine the relationship between these structural abnormalities with clinical characteristics. Examinations of 30 first-episode, treatment-naive pediatric OCD patients without any comorbidities and 30 matched healthy controls (HCs) were performed with 3.0 T magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) following Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) was used to conduct voxel-wise tests for group differences in regional gray matter volume (GMV). Compared to HCs, the patient group exhibited more GMV in the bilateral putamen and left orbitofrontal cortex (OFC) and less GMV in the left inferior parietal lobule (IPL). The GMV alternation in the right putamen of OCD patients was positively correlated with Hamilton Anxiety Rating Scale (HAM-A) scores, while the GMV alternation in the left IPL exhibited a trend to negatively correlate with HAM-A scores. Our current results suggest that the GM abnormalities were defined in the early stage of pediatric OCD. Moreover, these findings provided further evidence of brain GM abnormalities that are not only present in the classical fronto-striatal-thalamic circuit but also in the default mode network (DMN), which may represent the interaction of abnormally functional organization of both network in pediatric OCD. PMID:27445736

  11. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.

    PubMed

    Scholz, Alexander; Harter, Patrick N; Cremer, Sebastian; Yalcin, Burak H; Gurnik, Stefanie; Yamaji, Maiko; Di Tacchio, Mariangela; Sommer, Kathleen; Baumgarten, Peter; Bähr, Oliver; Steinbach, Joachim P; Trojan, Jörg; Glas, Martin; Herrlinger, Ulrich; Krex, Dietmar; Meinhardt, Matthias; Weyerbrock, Astrid; Timmer, Marco; Goldbrunner, Roland; Deckert, Martina; Braun, Christian; Schittenhelm, Jens; Frueh, Jochen T; Ullrich, Evelyn; Mittelbronn, Michel; Plate, Karl H; Reiss, Yvonne

    2015-12-14

    Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy.

  12. Reduced white matter integrity and its correlation with clinical symptom in first-episode, treatment-naive generalized anxiety disorder.

    PubMed

    Wang, Wei; Qian, Shaowen; Liu, Kai; Li, Bo; Li, Min; Xin, Kuolin; Sun, Gang

    2016-11-01

    The purpose of this study was to explore white matter microstructural alterations in the patients with generalized anxiety disorder (GAD) using diffusion tensor imaging (DTI) technique, and to assess neural associations with the symptom severity. Twenty-eight first-episode, treatment-naive GAD patients without co-morbidities and 28 matched healthy controls underwent DTI acquisition and clinical symptom assessments. Tract-based spatial statistics (TBSS) was used to analyze white matter microstructural abnormalities in patients with GAD, as well as their associations with clinical symptom scores in a voxel-wise manner. Compared to controls, patients showed decreased fractional anisotropy (FA) values in 7 clusters of white matter in bilateral uncinate fasciculus, body of corpus callosum, left middle cingulum (cingulate gyrus), bilateral anterior thalamic radiation and corona radiate, right anterior limb of internal capsule, bilateral inferior frontal-occipital fasciculus, bilateral superior and inferior longitudinal fasciculus, and increased mean diffusivity and radial diffusivity in widespread white matter regions. Reduced FA values in right uncinate fasciculus, left cingulum bundle showed significantly negative correlations with clinical symptom severity for Hamilton anxiety Rating Scale scores. Our findings suggest microstructural abnormalities in uncinate fasciculus and cingulum bundle play key roles in the underlying neural basis of GAD. PMID:27515289

  13. Brain Gray Matter Abnormalities in First-Episode, Treatment-Naive Children with Obsessive-Compulsive Disorder

    PubMed Central

    Cheng, Bochao; Cai, Wu; Wang, Xiuli; Lei, Du; Guo, Yingkun; Yang, Xun; Wu, Qizhu; Gong, Jianping; Gong, Qiyong; Ning, Gang

    2016-01-01

    Although several magnetic resonance imaging (MRI) studies have been conducted in children with obsessive-compulsive disorder (OCD), the brain structural abnormalities in OCD, especially in children, are not yet well characterized. We aimed to identify gray matter (GM) abnormalities in the early stage of pediatric OCD and examine the relationship between these structural abnormalities with clinical characteristics. Examinations of 30 first-episode, treatment-naive pediatric OCD patients without any comorbidities and 30 matched healthy controls (HCs) were performed with 3.0 T magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) following Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) was used to conduct voxel-wise tests for group differences in regional gray matter volume (GMV). Compared to HCs, the patient group exhibited more GMV in the bilateral putamen and left orbitofrontal cortex (OFC) and less GMV in the left inferior parietal lobule (IPL). The GMV alternation in the right putamen of OCD patients was positively correlated with Hamilton Anxiety Rating Scale (HAM-A) scores, while the GMV alternation in the left IPL exhibited a trend to negatively correlate with HAM-A scores. Our current results suggest that the GM abnormalities were defined in the early stage of pediatric OCD. Moreover, these findings provided further evidence of brain GM abnormalities that are not only present in the classical fronto–striatal–thalamic circuit but also in the default mode network (DMN), which may represent the interaction of abnormally functional organization of both network in pediatric OCD. PMID:27445736

  14. The treatment-naive microbiome in new-onset Crohn's disease.

    PubMed

    Gevers, Dirk; Kugathasan, Subra; Denson, Lee A; Vázquez-Baeza, Yoshiki; Van Treuren, Will; Ren, Boyu; Schwager, Emma; Knights, Dan; Song, Se Jin; Yassour, Moran; Morgan, Xochitl C; Kostic, Aleksandar D; Luo, Chengwei; González, Antonio; McDonald, Daniel; Haberman, Yael; Walters, Thomas; Baker, Susan; Rosh, Joel; Stephens, Michael; Heyman, Melvin; Markowitz, James; Baldassano, Robert; Griffiths, Anne; Sylvester, Francisco; Mack, David; Kim, Sandra; Crandall, Wallace; Hyams, Jeffrey; Huttenhower, Curtis; Knight, Rob; Xavier, Ramnik J

    2014-03-12

    Inflammatory bowel diseases (IBDs), including Crohn's disease (CD), are genetically linked to host pathways that implicate an underlying role for aberrant immune responses to intestinal microbiota. However, patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies. Using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases, we studied the microbiome in the largest pediatric CD cohort to date. An axis defined by an increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status. Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD. Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD.

  15. Compartmentalization of drug resistance-associated mutations in a treatment-naive HIV-infected female.

    PubMed

    Tirado, Grissell; Jove, Gloria; Kumar, Rakesh; Noel, Richard J; Reyes, Evelyn; Sepulveda, Gladys; Yamamura, Yasuhiro; Kumar, Anil

    2004-06-01

    Development of a drug-resistant variant of HIV-1 has been one of the major concerns contributing to the transmission of the virus. A 40-year-old woman presented to the clinic with micosis and oral candidiasis. The subject was referred for HIV-1 diagnosis. Subsequent investigations revealed a very low CD4 T cell count (48 cell/microl blood) and high plasma HIV-1 RNA load (4.33 x 10(5) copy/ml). A 1.3-kb pol fragment was sequenced in virus collected from plasma and the vaginal compartment. Plasma virus had no mutation in reverse transcriptase and one mutation in protease (L63P). On the other hand vaginal virus contained L63P and M184V mutations in protease and reverse transcriptase, respectively. These mutations were accompanied by several other mutations in previously identified CTL epitopic regions of the two genes. In the absence of antiretroviral treatment, a drug-resistant mutant was thought to develop because of immune pressure. This is the first report describing the role of immune pressure in the development of a drug-resistant virus.

  16. Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication.

    PubMed

    Kumarasinghe, Nishantha; Beveridge, Natalie J; Gardiner, Erin; Scott, Rodney J; Yasawardene, Surangi; Perera, Antoinette; Mendis, Jayan; Suriyakumara, Kanishka; Schall, Ulrich; Tooney, Paul A

    2013-08-01

    Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.

  17. Gene expression profiling of CD4+ T cells in treatment-naive HIV, HCV mono- or co-infected Chinese

    PubMed Central

    2014-01-01

    Background Because of the shared transmission routes, co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HIV) is very common. Accumulated clinical evidence showed that one could alter the infectious course of the other virus in HIV and HCV co-infected individuals. However, little is known on the molecular basis of HIV/HCV interactions and their modulations on hosts. Methods In this study, treatment-naive HIV, HCV mono-/co-infected individuals with CD4+ T cell counts >300/μl were recruited and their gene expression profiles were investigated by microarray assays. The differentially expressed genes were identified and validated by quantitative real-time PCR (qRT-PCR). To further understand the biological meanings of the gene expression profiles in these three groups, GSEA analysis (version 2.0, Broad Institute http://www.broad.mit.edu/gsea) was performed. Results By gene set enrichment analysis, we revealed that gene sets of cell cycle progression, innate immune response and some transcription factors in CD4+ T cells were mainly affected by HIV; while genes associated with GPCR signaling were the major targets of HCV. Metabolic pathways were modulated by both HCV and HIV viruses. Conclusions This study for the first time offers gene profiling basis for HCV/HIV mono-/co- infections in human beings. HIV infection displayed the great impact on transcription profile of CD4+ T cells in HIV/HCV co-infected individuals. Genes related to cell cycle arrest were significantly mediated by HIV which may lead to dysfunction of CD4+ T cells and acceleration of HCV-related disease progression in the co-infections. PMID:24520951

  18. Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease.

    PubMed

    Gurram, B; Salzman, N H; Kaldunski, M L; Jia, S; Li, B U K; Stephens, M; Sood, M R; Hessner, M J

    2016-04-01

    The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. To understand more clearly the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naive paediatric IBD patients (n = 22 CD, n = 15 UC) and unrelated healthy controls (uHC, n = 10) were used to induce transcriptional responses in a healthy leucocyte population. After culture, gene expression was measured comprehensively with microarrays and analysed. Relative to uHC, plasma of CD and UC patients induced distinct responses consisting, respectively, of 985 and 895 regulated transcripts [|log2 ratio| ≥ 0·5 (1·4-fold); false discovery rates (FDR) ≤ 0·01]. The CD:uHC and UC:uHC signatures shared a non-random, commonly regulated, intersection of 656 transcripts (χ(2)  = P < 0·001) and were highly correlative [Pearson's correlation coefficient = 0·96, 95% confidence interval (CI) = 0.96, 0.97]. Despite sharing common genetic susceptibility loci, the IBD signature correlated negatively with that driven by plasma of type 1 diabetes (T1D) patients (Pearson's correlation coefficient = -0·51). Ontological analyses revealed the presence of an immunoregulatory plasma milieu in IBD, as transcripts for cytokines/chemokines, receptors and signalling molecules consistent with immune activation were under-expressed relative to uHC and T1D plasma. Multiplex enzyme-linked immunosorbent assay (ELISA) and receptor blockade studies confirmed transforming growth factor (TGF)-β and interleukin (IL)-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Through plasma-induced signature analysis, we have defined a unique, partially TGF-β/IL-10-dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness

  19. Stimulant Abuser Groups to Engage in 12-Step (STAGE-12): A Multisite Trial in the NIDA Clinical Trials Network

    PubMed Central

    Donovan, Dennis M.; Daley, Dennis C.; Brigham, Gregory S.; Hodgkins, Candace C.; Perl, Harold I.; Garrett, Sharon; Doyle, Suzanne; Floyd, Anthony S.; Knox, Patricia C.; Botero, Christopher; Kelly, Thomas; Killeen, Therese; Hayes, Carole; Baumhofer, Nicole Kau’i; Seamans, Cindy; Zammarelli, Lucy

    2012-01-01

    Aims The study evaluated the effectiveness of an 8-week combined group plus individual 12-step facilitative intervention on stimulant drug use and 12-step meeting attendance and service. Design Multisite randomized controlled trial, with assessments at baseline, mid-treatment, end of treatment, and 3- and 6-month post-randomization follow-ups (FU). Setting Intensive outpatient substance treatment programs. Participants Individuals with stimulant use disorders (n = 471) randomly assigned to treatment as usual (TAU) or TAU into which the STAGE-12 intervention was integrated. Measurements Urinalysis and self-reports of substance use and 12-step attendance and activities. Intervention Group sessions focused on increasing acceptance of 12-step principles; individual sessions incorporated an intensive referral procedure connecting participants to 12-step volunteers. Findings Compared to TAU, STAGE-12 participants had significantly greater odds of self-reported stimulant abstinence during the active 8-week treatment phase; however, among those who had not achieved abstinence during this period, STAGE-12 participants had more days of use. STAGE-12 participants had lower ASI Drug Composite scores at and a significant reduction from baseline to the 3-month FU, attended 12-step meetings on a greater number of days during the early phase of active treatment, engaged in more other types of 12-step activities throughout the active treatment phase and the entire FU period, and had more days of self-reported service at meetings from mid-treatment through the 6-month FU. Conclusions The present findings are mixed with respect to the impact of integrating the STAGE-12 intervention into intensive outpatient drug treatment compared to TAU on stimulant drug use. However, the results more clearly indicate that individuals in STAGE-12 had higher rates of 12-step meeting attendance and were engaged in more related activities throughout both the active treatment phase and the entire 6

  20. Step by Step: Avoiding Spiritual Bypass in 12-Step Work

    ERIC Educational Resources Information Center

    Cashwell, Craig S.; Clarke, Philip B.; Graves, Elizabeth G.

    2009-01-01

    With spirituality as a cornerstone, 12-step groups serve a vital role in the recovery community. It is important for counselors to be mindful, however, of the potential for clients to be in spiritual bypass, which likely will undermine the recovery process.

  1. Molecular Characterization of HBV Strains Circulating among the Treatment-Naive HIV/HBV Co-Infected Patients of Eastern India

    PubMed Central

    Saha, Debraj; Pal, Ananya; Biswas, Avik; Panigrahi, Rajesh; Sarkar, Neelakshi; Das, Dipanwita; Sarkar, Jayeeta; Guha, Subhasish Kamal; Saha, Bibhuti; Chakrabarti, Sekhar; Chakravarty, Runu

    2014-01-01

    Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant. PMID:24587360

  2. Improvement of cognitive flexibility and cingulate blood flow correlates after atypical antipsychotic treatment in drug-naive patients with first-episode schizophrenia.

    PubMed

    Pardo, Bernardo M; Garolera, Maite; Ariza, Mar; Pareto, Deborah; Salamero, Manel; Valles, Vicenç; Delgado, Luis; Alberni, Joan

    2011-12-30

    The aim of this study was to examine the changes in cognitive flexibility and associated cerebral blood flow in the anterior cingulate lobe of drug-naive patients with first-episode schizophrenia who were treated with atypical antipsychotics for 6 weeks. Single photon emission computed tomography (SPECT) images were obtained from 8 healthy subjects both at rest and while performing the flexibility subtest of the TAP (Test for Attentional Performance). SPECT images were obtained in parallel from 8 first-episode drug-naive schizophrenic patients while they were performing the same task both before and after 6 weeks of neuroleptic treatment. In the control group, an increase in the perfusion indices of the dorsal section of the anterior cingulate gyrus was observed in the activation condition. Task performance was altered and the level of perfusion of the brain region related to the task execution was significantly decreased in the patients at baseline. After treatment, there was a significant improvement in both task performance and the level of perfusion of the dorsal section of the anterior cingulate. We conclude that treatment with second-generation neuroleptics improves cognitive flexibility, and there was a relationship between such improvements and normalization of perfusion indices of the involved brain areas.

  3. Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades

    PubMed Central

    Doyle, Tomas; Dunn, David T.; Ceccherini-Silberstein, Francesca; De Mendoza, Carmen; Garcia, Frederico; Smit, Erasmus; Fearnhill, Esther; Marcelin, Anne-Genevieve; Martinez-Picado, Javier; Kaiser, Rolf; Geretti, Anna Maria

    2015-01-01

    Objectives The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade. Methods The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex). Results No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades. Conclusions No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed. PMID:26311843

  4. Characterization of Treatment-Naive HIV/HBV Co-Infected Patients Attending ART Clinic of a Tertiary Healthcare Centre in Eastern India

    PubMed Central

    Biswas, Avik; Panigrahi, Rajesh; Sarkar, Neelakshi; Sarkar, Jayeeta; Pal, Manisha; Guha, Subhasish Kamal; Saha, Bibhuti; Chakrabarti, Sekhar; Chakravarty, Runu

    2013-01-01

    Objective The study was designed to assess the hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection scenario among the human immunodeficiency virus (HIV) infected patients attending a tertiary healthcare unit in eastern India. Additionally, clinical and virological characterization of these viruses, prior to antiretroviral therapy (ART) initiation was also done for better understanding of the disease profile. Methods Pool of ART-naive HIV/HBV co-infected and HIV mono-infected patients, participating in two different studies, were included in this study. HBV DNA was detected by nested-PCR amplification followed by HBV genotype determination and HBV reverse transcriptase (RT) region amplification and direct sequencing for detecting drug resistance. Results The prevalence of HBsAg (11.3%) was higher compared to anti-HCV (1.9%) among the HIV infected ART-naive patients. Moreover, majority of the HBeAg positive HIV/HBV co-infected patients (87.7%) had HBV DNA ≥20,000 IU/ml with median HBV DNA significantly higher than that of HBeAg negative subjects (5.7 log10 IU/ml vs. 4.2 log10 IU/ml; p<0.0001). Multivariate analysis also showed that HBeAg-positive status was independently associated with higher HBV DNA level (p = <0.001). Notably, 60.9% of the HBeAg negative co-infected subjects had HBV DNA ≥2,000 IU/ml of which 37.0% had HBV DNA ≥20,000 IU/ml. Genotype HBV/D (68.2%) was the predominant genotype followed by HBV/A (24.3%) and HBV/C (7.5%). Anti-HBV drug resistant mutations were detected in two (3.8%) of the ART-naive patients. Conclusion The prevalence of HIV/HBV co-infection was relatively higher in our study subjects. HBeAg testing might provide clue for early treatment initiation. Furthermore, HBeAg negative patients are also associated with high HBV DNA levels and therefore require appropriate medical attention. Pre-treatment screening for anti-HBV drug resistant mutations is not necessary before ART initiation. PMID:24023688

  5. The General Alcoholics Anonymous Tools of Recovery: The Adoption of 12-Step Practices and Beliefs

    PubMed Central

    Greenfield, Brenna L.; Tonigan, J. Scott

    2013-01-01

    Working the 12 steps is widely prescribed for Alcoholics Anonymous (AA) members although the relative merits of different methods for measuring step-work have received minimal attention and even less is known about how step-work predicts later substance use. The current study (1) compared endorsements of step-work on an face-valid or direct measure, the Alcoholics Anonymous Inventory (AAI), with an indirect measure of step-work, the General Alcoholics Anonymous Tools of Recovery (GAATOR), (2) evaluated the underlying factor structure of the GAATOR and changes in step-work over time, (3) examined changes in the endorsement of step-work over time, and (4) investigated how, if at all, 12-step-work predicted later substance use. New AA affiliates (N = 130) completed assessments at intake, 3, 6, and 9 months. Significantly more participants endorsed step-work on the GAATOR than on the AAI for nine of the 12 steps. An exploratory factor analysis revealed a two-factor structure for the GAATOR comprising Behavioral Step-Work and Spiritual Step-Work. Behavioral Step-Work did not change over time, but was predicted by having a sponsor, while Spiritual Step-Work decreased over time and increases were predicted by attending 12-step meetings or treatment. Behavioral Step-Work did not prospectively predict substance use. In contrast, Spiritual Step-Work predicted percent days abstinent, an effect that is consistent with recent work on the mediating effects of spiritual growth, AA, and increased abstinence. Behavioral and Spiritual Step-Work appear to be conceptually distinct components of step-work that have distinct predictors and unique impacts on outcomes. PMID:22867293

  6. Intravenous immunoglobulin (IVIG) treatment for modulation of immune activation in human immunodeficiency virus type 1 infected therapy-naive individuals.

    PubMed

    Vermeulen, Joost N; Prins, Jan M; Bunnik, Evelien; Hack, C Erik; Jurriaans, Suzanne; Miedema, Frank; Lange, Joep M A; Schuitemaker, Hanneke

    2007-11-01

    We evaluated the ability of intravenous immunoglobulin (IVIG) to diminish immune hyperactivation, which is considered a major cause of CD4+ T cell loss during chronic HIV-1 infection and whether this affected CD4+ T cell counts and plasma HIV-1 RNA (pVL). Therefore, we treated six chronically HIV-1-infected, antiretroviral-therapy-naive patients with IVIG (0.4 g/kg) at weeks 0 and 4, with a follow-up of 12 weeks after the second dosage during which pVL, T cell numbers, and T cell activation were measured. At baseline median CD4+ T cell counts were 300 (range 200-460) x 10(6)/liter and median pVL was 5.0 (range 3.2-5.2) log10 copies/ml. IgG plasma levels peaked during the first days after administration. We observed a decrease in the percentage of activated (CD38+ HLA-DR+) CD4+ and CD8+ T cells [3.5% (range 1-7%) and 5% (1-10%), respectively (p = 0.027)], but no effect on the fraction of proliferating CD4+ or CD8+ T cells as measured by Ki67 expression. CD4+ T cell counts were significantly increased on day 4 (median +55 cells, range 0-150, p = 0.043). pVL was significantly increased on day 1 after IVIG infusion (median +0.13 log10, range 0.01-0.55, p = 0.028). All these parameters returned to baseline levels within 1 week after infusion. In conclusion, administration of IVIG caused a temporary decrease in T cell activation and an increase in CD4+ T cell counts, despite an increase in pVL. Our results support the hypothesis that T cell activation, rather than direct HIV-1 infection, mediates the loss of CD4+ T cells and suggest that immunomodulating therapy in HIV-1 infection could indeed be effective.

  7. The trouble with morality: the effects of 12-step discourse on addicts' decision-making.

    PubMed

    Frank, David

    2011-01-01

    Since its development in the 1960s, researchers have extensively scrutinized methadone maintenance treatment (MMT) as a medical response to heroin addiction. Studies consistently find that MMT is more successful than other treatment models in the reduction of opiate/opioid misuse, the transmission of diseases like HIV/AIDS and hepatitis C, and criminal arrest and conviction rates. Nonetheless, a significant portion of active and former heroin addicts view MMT negatively and-perhaps as a result-MMT is vastly underused. This study examines the effects of 12-Step discourses on the opinions and treatment decisions of active heroin addicts, addicts in MMT, and addicts in 12-Step treatment programs. The study finds the abstinence/morality based discourse of drug addiction and treatment is pervasive among addicts and their non-drug using relations and peers alike; moreover, addicts have internalized this narrative, oftentimes despite their own knowledge of MMT's success and positive personal experiences. The findings suggest that the dominance of abstinence/morality narratives contributes to MMT's poor reputation among, and low use rate by current and former heroin addicts and that the power of the dominant discourse is such that it produces a desire to buy into its values and tenets even when it is against the individual's interests to do so.

  8. The Trouble with Morality: The Effects of 12-Step Discourse on Addicts’ Decision-Making

    PubMed Central

    Frank, David

    2016-01-01

    Since its development in the 1960s, researchers have extensively scrutinized methadone maintenance treatment (MMT) as a medical response to heroin addiction. Studies consistently find that MMT is more successful than other treatment models in the reduction of opiate/opioid misuse, the transmission of diseases like HIV/AIDS and hepatitis C, and criminal arrest and conviction rates. Nonetheless, a significant portion of active and former heroin addicts view MMT negatively and—perhaps as a result—MMT is vastly underused. This study examines the effects of 12-Step discourses on the opinions and treatment decisions of active heroin addicts, addicts in MMT, and addicts in 12-Step treatment programs. The study finds the abstinence/morality based discourse of drug addiction and treatment is pervasive among addicts and their non-drug using relations and peers alike; moreover, addicts have internalized this narrative, oftentimes despite their own knowledge of MMT’s success and positive personal experiences. The findings suggest that the dominance of abstinence/morality narratives contributes to MMT’s poor reputation among, and low use rate by current and former heroin addicts and that the power of the dominant discourse is such that it produces a desire to buy into its values and tenets even when it is against the individual’s interests to do so. PMID:22111408

  9. A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency.

    PubMed

    Reiter, E O; Attie, K M; Moshang, T; Silverman, B L; Kemp, S F; Neuwirth, R B; Ford, K M; Saenger, P

    2001-10-01

    Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.

  10. Factors associated with mental health clinicians’f referrals to 12-step groups

    PubMed Central

    Rosenblum, Andrew; Fong, Chunki; Laudet, Alexandre; Uttaro, Thomas; Magura, Stephen

    2012-01-01

    As substance use and mental illness services are increasingly integrated, mental health professionals are presented with opportunities to refer greater numbers of dually-diagnosed clients to 12-step groups. This study examined the relationships among clinicians’ 12-step experiences, attitudes and referral practices in 6 NYC mental health clinics. A path analysis model showed that greater interest in learning about 12-step (12-step interest) directly predicted 12-step referral practices and that 12-step interest was predicted both by clinicians’ perception of the helpfulness of 12-Step groups and the severity of their patients’ problems with substance abuse. Clinicians’ responses to open-ended questions supported this model. Didactic and experiential education for clinicians in substance abuse and mutual aid would likely increase patient referrals to 12-step groups. PMID:22873191

  11. Analysis of Hepatitis B Virus Intrahepatic Covalently Closed Circular DNA and Serum Viral Markers in Treatment-Naive Patients with Acute and Chronic HBV Infection

    PubMed Central

    Zou, Zhengsheng; Liu, Yan; Li, Baosen; Sun, Ying; Li, Xiaodong; Liu, Shuhong; Cai, Shaoping; Yao, Weimin; Xin, Shaojie; Lu, Fengmin; Xu, Dongping

    2014-01-01

    Background This study aimed to investigate the relationships of intrahepatic cccDNA with serum HBsAg and with HBV DNA in treatment-naive patients throughout acute and chronic HBV infection. Methods A total of 120 patients who had a liver biopsy were enrolled, including 19 with acute hepatitis B (AHB), and 101 patients with chronic HBV infection (CHB) of whom were 10 in immune-tolerant (IT) phase, 59 in immune-clearance (IC) phase, 8 in low-replicative (LR) phase, and 24 in HBeAg-negative hepatitis (ENH) phase. Intrahepatic cccDNA, serum HBsAg and serum HBV DNA levels were comparatively analyzed. Results The median intrahepatic cccDNA levels were 0.18 4.80, 3.81, 0.22 and 0.97 copies/cell for patients with AHB, CHB-IT, CHB-IC, CHB-LR, and CHB-ENH, respectively. In AHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg (r = 0.665, P = 0.003), as well as serum HBV DNA (r = 0.536, P = 0.022). In CHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg in the IC phase (r = 0.392, P = 0.005), and with serum HBV DNA in the IC phase (r = 0.301, P = 0.036) and ENH phase (r = 0.588, P = 0.013). HBV replicative efficiency, defined as the ratio of serum HBV DNA to intrahepatic cccDNA, was obviously lower in AHB and CHB-LR patients than in CHB-IT, CHB-IC and CHB-ENH patients (0.70 and 0.53 vs. 1.12, 1.09 and 0.99, P<0.001, values were logarithmic transformed for analysis). In CHB-IC patients, HBV replicative efficiency was positively correlated with histological activity index of liver inflammation (r = 0.308, P = 0.009). Conclusion Serum HBsAg and HBV DNA levels may reflect the amount of active intrahepatic cccDNA in treatment-naive AHB and CHB-IC patients. Reduced intrahepatic cccDNA and HBV replicative efficiency may imply effective immune control of HBV infection. PMID:24551214

  12. Afatinib in Treatment-Naive Patients With EGFR-Mutated Lung Adenocarcinoma With Brain Metastasis: A Case Series.

    PubMed

    Li, Shih-Hong; Hsieh, Meng-Heng; Fang, Yueh-Fu

    2015-10-01

    Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) were previously the standard first-line treatments for lung cancers with activating EGFR mutations. The first-generation reversible EGFR TKIs, gefitinib and erlotinib, demonstrated substantial efficacy in the treatment of brain metastases from EGFR-mutated lung adenocarcinoma. However, the efficacy of afatinib, the second-generation irreversible EGFR TKI, as the first-line treatment in lung adenocarcinoma patients with brain metastasis has yet to be evaluated.Here, we report cases of 3 patients who received afatinib alone as the first-line treatment in combination with whole-brain radiotherapy or following surgical resection of brain metastases. All 3 patients had EGFR L858R mutation. The first patient had lung adenocarcinoma with brain metastasis and no neurologic symptoms. After consultation, she received afatinib as a first-line treatment. Chest computed tomography and brain magnetic resonance imaging (MRI) showed partial response. The second patient had lung adenocarcinoma accompanied with a metastatic brain lesion associated with seizures. This patient received whole-brain radiotherapy and afatinib treatment following brain MRI and subsequently showed significant regression of the brain metastasis. The third patient had strabismus of the right eye, and brain MRI showed a single tumor at the cerebellar pontine angle. This patient underwent surgical resection of the tumor followed by afatinib treatment. He refused adjuvant radiotherapy after surgery for brain metastasis. The brain MRI showed no recurrent brain metastasis, and the patient had relatively less neurologic deficiency.This series of 3 cases indicate that afatinib may be an appropriate first-line treatment alternative in patients having lung adenocarcinoma with EGFR mutations. Further retrospective analyses and prospective clinical trials are required to substantiate the efficacy of afatinib in the treatment of brain

  13. First-line therapy for treatment-naive patients with advanced/metastatic renal cell carcinoma: a systematic review of published randomized controlled trials.

    PubMed

    Takyar, Shweta; Diaz, Jose; Sehgal, Manu; Sapunar, Francisco; Pandha, Hardev

    2016-06-01

    In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine

  14. Interpersonal Climate of 12-step Groups Predicts Reductions in Alcohol Use

    PubMed Central

    Rynes, Kristina N.; Tonigan, J. Scott; Rice, Samara L.

    2013-01-01

    Research has shown that increases in the size of abstinence-based social networks helps explain the association between 12-step attendance and increased abstinence. This study investigated whether the quality of social interaction in 12-step groups also predicts reduced substance use. Participants reported their perceptions of engagedness, avoidance, and conflict in their 12-step groups and their substance use in four assessments. Results showed that perceptions of group engagedness, but not avoidance or conflict, decreased over time. Despite this, engagedness predicted increased 12-step-related behavior and decreased alcohol use. Findings suggest that positive group interaction plays an important role in 12-step affiliates’ recovery efforts. PMID:24039338

  15. Skill Training versus 12-Step Facilitation for Parents of Substance-Abusing Teens

    PubMed Central

    McGillicuddy, Neil B.; Rychtarik, Robert G.; Papandonatos, George D.

    2014-01-01

    Distressed parents (N = 85) with a substance-abusing adolescent not receiving treatment were randomized to 12 weeks of coping skill training (CST), 12-step facilitation (TSF), or delayed treatment control (DTC). At the end of treatment/delay, CST showed greater coping skillfulness than TSF, and both CST and TSF were more skillful than DTC. The percentage of parent problem days (PPD)—days when the adolescent’s substance use caused a problem—also was reduced in CST and TSF, relative to DTC. Both CST and TSF reported significantly reduced monthly PPD by the end of a 12-month follow-up. Skill training and TSF interventions appear equally effective for this underserved parent population. PMID:25306932

  16. Skill training versus 12-step facilitation for parents of substance-abusing teens.

    PubMed

    McGillicuddy, Neil B; Rychtarik, Robert G; Papandonatos, George D

    2015-03-01

    Distressed parents (N=85) with a substance-abusing adolescent not receiving treatment were randomized to 12 weeks of coping skill training (CST), 12-step facilitation (TSF), or delayed treatment control (DTC). At the end of treatment/delay, CST showed greater coping skillfulness than TSF, and both CST and TSF were more skillful than DTC. The percentage of parent problem days (PPD)-days when the adolescent's substance use caused a problem-also was reduced in CST and TSF, relative to DTC. Both CST and TSF reported significantly reduced monthly PPD by the end of a 12-month follow-up. Skill training and TSF interventions appear equally effective for this underserved parent population.

  17. Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a prospective randomized multicenter trial.

    PubMed

    de Leval, Jean; Boca, Philippe; Yousef, Enis; Nicolas, Hubert; Jeukenne, Michel; Seidel, Laurence; Bouffioux, Christian; Coppens, Luc; Bonnet, Pierre; Andrianne, Robert; Wlatregny, David

    2002-12-01

    The aim of this study was to compare the efficacy of total intermittent androgen deprivation (IAD) versus total continuous androgen deprivation (CAD) for treating patients with advanced prostate cancer in a phase III randomized trial. A total of 68 evaluable patients with hormone-naive advanced or relapsing prostate cancer were randomized to receive combined androgen blockade according to a continuous (n = 33) or intermittent (n = 35) regimen. Therapeutic monitoring was assessed by use of serum prostate-specific antigen (PSA) measurements. Patients in the CAD and IAD groups were equally stratified for age, biopsy Gleason score, and baseline serum PSA levels. The outcome variable was time to androgen-independence of the tumor, which was defined as increasing serum PSA levels despite androgen blockade. Mean follow-up was 30.8 months. The 35 IAD-treated patients completed 91 cycles, and 19 of them (54.3%) completed > or = 3 cycles. Median cycle length and percentage of time off therapy were 9.0 months and 59.5, respectively. The estimated 3-year progression rate was significantly lower in the IAD group (7.0% +/- 4.8%) than in the CAD group (38.9% +/- 11.2%, P = 0.0052). Our data suggest that IAD treatment may maintain the androgen-dependent state of advanced human prostate cancer, as assessed by PSA measurements, at least as long as CAD treatment. Further studies with longer follow-up times and larger patient cohorts are needed to determine the comparative impacts of CAD and IAD on survival.

  18. Toward Enhancing Twelve-Step Facilitation among young people: A systematic qualitative investigation of Young Adults’ 12-step Experiences

    PubMed Central

    Labbe, Allison K.; Slaymaker, Valerie; Kelly, John F.

    2014-01-01

    Background Twelve-Step Facilitation (TSF) interventions designed to enhance rates of engagement with 12-step mutual help organizations (MHOs) have shown efficacy among adults, but research provides little guidance on how to adapt TSF strategies for young people. Methods To inform TSF strategies for youth, this study used qualitative methods to investigate the self-reported experiences of 12-step participation, and reasons for non-attendance and discontinuation among young adults (18-24 yrs; N=302). Responses to open-ended questions following residential treatment were coded into rationally-derived domains. Results Young adults reported that cohesiveness, belonging, and instillation of hope were the most helpful aspects of attending 12-step groups; meeting structure and having to motivate oneself to attend meetings were the most common aspects young adults liked least; logistical barriers and low recovery motivation and interest were the most common reasons for discontinued attendance; and perceptions that one did not have a problem or needed treatment were cited most often as reasons for never attending. Conclusions Findings may inform and enhance strategies intended to engage young people with community-based recovery focused 12-step MHOs and ultimately improve recovery outcomes. PMID:25102256

  19. Platelet leukocyte aggregates and markers of platelet aggregation, immune activation and disease progression in HIV infected treatment naive asymptomatic individuals.

    PubMed

    Nkambule, Bongani B; Davison, Glenda; Ipp, Hayley

    2015-11-01

    Platelet aggregates play a crucial role in the immune defence mechanism against viruses. Increased levels of lipopolysaccharide have been reported in human immunodeficiency virus (HIV) infected individuals. Platelets are capable of interacting with bacterial LPS and subsequently forming platelet leukocyte aggregates (PLAs). This study aimed at determining the levels of circulating PLAs in treatment naïve HIV infected individuals and correlating them, with markers of immune activation, disease progression and platelet aggregation. Thirty-two HIV negative and 35 HIV positive individuals were recruited from a clinic in the Western Cape. Platelet monocyte and platelet neutrophil aggregates were measured using flow cytometry at baseline and were correlated with markers of platelet activation (CD62P); aggregation (CD36); monocyte and neutrophil activation (CD69); monocyte tissue factor expression (CD142); immune activation (CD38 on T+ cells); D-dimers (a marker of active coagulation); CD4 count and viral load. Platelet monocyte aggregates were also measured post stimulation with lipopolysaccharide. PMA levels were higher in HIV 25.26 (16.16-32.28) versus control 14.12 (8.36-18.83), p = 0.0001. PMAs correlated with %CD38/8 expression (r = 0.54624, p = 0.0155); CD4 count (r = -0.6964, p = 0.0039) viral load (r = 0.633, p < 0.009) and monocyte %CD69 expression (r = 0.757, p = 0.030). In addition the %PMAs correlated with platelet %CD36 (r = 0.606, p = 0.017). The HIV group showed increased levels of %CD62P 5.44 (2.72-11.87) versus control 1.15 (0.19-3.59), p < 0.0001; %CD36 22.53 (10.59-55.15) versus 11.01 (3.69-26.98), p = 0.0312 and tissue factor (CD142) MFI 4.84 (4.01-8.17) versus 1.74 (1.07-9.3), p = 0.0240. We describe increased levels of circulating PMAs which directly correlates with markers of immune activation, disease progression and platelet aggregation in HIV treatment naïve individuals.

  20. Safety and efficacy of tiotropium Respimat versus HandiHaler in patients naive to treatment with inhaled anticholinergics: a post hoc analysis of the TIOSPIR trial

    PubMed Central

    Wise, Robert; Calverley, Peter MA; Dahl, Ronald; Dusser, Daniel; Metzdorf, Norbert; Müller, Achim; Fowler, Andy; Anzueto, Antonio

    2015-01-01

    Background: Patients with chronic obstructive pulmonary disease (COPD) who were naive to anticholinergics before the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial may reflect patients seen in practice, in particular in primary care. In addition, investigating safety in these patients avoids the potential bias in patients who previously received anticholinergics and may be tolerant of their effects. Aims: The aim of this study was to evaluate whether patients naive to anticholinergic therapy who were treated with tiotropium Respimat 2.5 or 5 μg had different safety and efficacy outcomes than patients treated with tiotropium HandiHaler 18 μg. Methods: A post hoc analysis of patients who were not receiving anticholinergics before TIOSPIR (N=6,966/17,135) was conducted. Primary end points were risk of death from any cause and risk of COPD exacerbation. Secondary outcomes included severe exacerbation and major adverse cardiovascular events (MACE). Additional analysis of exacerbations was carried out in anticholinergic-naive patients with moderate (GOLD II) disease. Results: Anticholinergic-naive patients had less severe disease than the total TIOSPIR population. Discontinuations because of anticholinergic side effects were infrequent (0.9% overall). Similar to the primary study, patients in the tiotropium Respimat groups had no difference in the risk of death or risk of any or severe exacerbation than patients treated with tiotropium HandiHaler. Risk of MACE was similar across the Respimat and HandiHaler groups. Rates of exacerbations in the subgroup of patients with moderate disease were similar across the Respimat and HandiHaler groups. Conclusions: Tiotropium Respimat and HandiHaler have similar safety and efficacy profiles in patients who are naive to anticholinergic therapy. PMID:26540491

  1. Effectiveness of Making Alcoholics Anonymous Easier (MAAEZ), a group format 12-step facilitation approach

    PubMed Central

    Kaskutas, Lee Ann; Subbaraman, Mina; Witbrodt, Jane; Zemore, Sarah E.

    2009-01-01

    Most treatment programs recommend clients attend 12-step groups, but many drop out post-treatment. The effectiveness of “MAAEZ” (Making AA Easier), a manual-guided intervention designed to help clients connect with individuals encountered in AA, was tested using an “OFF/ON” design (n=508). MAAEZ effectiveness was determined by comparing abstinence rates of participants recruited during ON and OFF conditions, and studying the effect of the number of MAAEZ sessions attended. At 12 months, more clients in the ON condition (vs. OFF) reported past-30-day abstinence from alcohol (p=.012), drugs (p=.009), and both alcohol/ drugs (p=.045). In multivariate analyses, ON condition participants had significantly increased odds of abstinence from alcohol (OR=1.85) and from drugs (OR=2.21); abstinence odds also increased significantly for each additional MAAEZ session received. MAAEZ appeared especially effective for those with more prior AA exposure, severe psychiatric problems, and atheists/agnostics. MAAEZ represents an evidence-based intervention that is easily implemented in existing treatment programs. PMID:19339148

  2. Alcoholic Recovery and the 12 Steps: White Bison Presents a Native View.

    ERIC Educational Resources Information Center

    Simonelli, Richard

    1993-01-01

    Describes an alcohol recovery program offered by White Bison, Inc. (Colorado Springs), that integrates the 12 Steps of Alcoholics Anonymous with traditional Native American ceremonies and medicine wheel teachings symbolizing the life cycle. (LP)

  3. Coping Skills Training and 12-Step Facilitation for Women Whose Partner Has Alcoholism: Effects on Depression, the Partner's Drinking, and Partner Physical Violence

    ERIC Educational Resources Information Center

    Rychtarik, Robert G.; McGillicuddy, Neil B.

    2005-01-01

    Women (N = 171), distressed from their partners' untreated alcoholism, received either coping skills training (CST), 12-step facilitation (TSF), or delayed treatment (DTC). CST and TSF resulted in lower depression levels than DTC but did not differ from one another. Skill acquisition mediated the treatment effects of CST; Al-Anon attendance did…

  4. SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients

    PubMed Central

    Asselah, Tarik; Guyader, Dominique; Berg, Thomas; Schuchmann, Marcus; Mauss, Stefan; Ratziu, Vlad; Ferenci, Peter; Larrey, Dominique; Maieron, Andreas; Stern, Jerry O.; Ozan, Melek; Datsenko, Yakov; Böcher, Wulf Otto; Steinmann, Gerhard

    2014-01-01

    Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620). PMID:24709256

  5. The meaning of suffering in drug addiction and recovery from the perspective of existentialism, Buddhism and the 12-Step program.

    PubMed

    Chen, Gila

    2010-09-01

    The aim of the current article was to examine the meaning of suffering in drug addiction and in the recovery process. Negative emotions may cause primary suffering that can drive an individual toward substance abuse. At the same time, drugs only provide temporary relief, and over time, the pathological effects of the addiction worsen causing secondary suffering, which is a motivation for treatment. The 12-Step program offers a practical way to cope with suffering through a process of surrender. The act of surrender sets in motion a conversion experience, which involves a self-change including reorganization of one's identity and meaning in life. This article is another step toward understanding one of the several factors that contribute to the addict's motivation for treatment. This knowledge may be helpful for tailoring treatment that addresses suffering as a factor that initiates treatment motivation and, in turn, treatment success.

  6. Naive Theories of Social Groups

    ERIC Educational Resources Information Center

    Rhodes, Marjorie

    2012-01-01

    Four studies examined children's (ages 3-10, Total N = 235) naive theories of social groups, in particular, their expectations about how group memberships constrain social interactions. After introduction to novel groups of people, preschoolers (ages 3-5) reliably expected agents from one group to harm members of the other group (rather than…

  7. Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients

    PubMed Central

    Baril, Jean-Guy; Angel, Jonathan B.; Gill, M. John; Gathe, Joseph; Cahn, Pedro; van Wyk, Jean; Walmsley, Sharon

    2016-01-01

    Objective We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. Methods A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Results Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. Conclusions The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here

  8. 48-Week Efficacy and Safety of Dolutegravir Relative to Commonly Used Third Agents in Treatment-Naive HIV-1–Infected Patients: A Systematic Review and Network Meta-Analysis

    PubMed Central

    Patel, Dipen A.; Snedecor, Sonya J.; Tang, Wing Yu; Sudharshan, Lavanya; Lim, Jessica W.; Cuffe, Robert; Pulgar, Sonia; Gilchrist, Kim A.; Camejo, Rodrigo Refoios; Stephens, Jennifer; Nichols, Garrett

    2014-01-01

    Background A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1–infected patients. Methods A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed. Results Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions. Conclusion Three clinical

  9. Performance of HIV-1 Drug Resistance Testing at Low-Level Viremia and Its Ability to Predict Future Virologic Outcomes and Viral Evolution in Treatment-Naive Individuals

    PubMed Central

    Gonzalez-Serna, A.; Min, J. E.; Woods, C.; Chan, D.; Lima, V. D.; Montaner, J. S. G.; Harrigan, P. R.; Swenson, L. C.

    2014-01-01

    Background. Low-level viremia (LLV; human immunodeficiency virus [HIV-1] RNA 50–999 copies/mL) occurs frequently in patients receiving antiretroviral therapy (ART), but there are few or no data available demonstrating that HIV-1 drug resistance testing at a plasma viral load (pVL) <1000 copies/mL provides potentially clinically useful information. Here, we assess the ability to perform resistance testing by genotyping at LLV and whether it is predictive of future virologic outcomes in patients beginning ART. Methods. Resistance testing by genotyping at LLV was attempted on 4915 plasma samples from 2492 patients. A subset of previously ART-naive patients was analyzed who achieved undetectable pVL and subsequently rebounded with LLV (n = 212). A genotypic sensitivity score (GSS) was calculated based on therapy and resistance testing results by genotyping, and stratified according to number of active drugs. Results. Eighty-eight percent of LLV resistance assays produced useable sequences, with higher success at higher pVL. Overall, 16 of 212 (8%) patients had pretherapy resistance. Thirty-eight of 196 (19%) patients without pretherapy resistance evolved resistance to 1 or more drug classes, primarily the nucleoside reverse transcriptase (14%) and/or nonnucleoside reverse transcriptase (9%) inhibitors. Patients with resistance at LLV (GSS <3) had a 2.1-fold higher risk of virologic failure (95% confidence interval, 1.2- to 3.7-fold) than those without resistance (P = .007). Progressively lower GSS scores at LLV were associated with a higher increase in pVL over time (P < .001). Acquisition of additional resistance mutations to a new class of antiretroviral drugs during LLV was not found in a subset of patients. Conclusions. Routine HIV-1 genotyping of LLV samples can be performed with a reasonably high success rate, and the results appear predictive of future virologic outcomes. PMID:24429436

  10. Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients▿

    PubMed Central

    Marin-Niebla, Ana; Lopez-Cortes, Luis Fernando; Ruiz-Valderas, Rosa; Viciana, Pompeyo; Mata, Rosario; Gutierrez, Alicia; Pascual, Rosario; Rodriguez, Magdalena

    2007-01-01

    We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10 copies/ml. Median Cmax, area under the concentration-time curve from 0 to 24 h, and Cmin plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate Cmin levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI

  11. Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study

    PubMed Central

    Rossetti, Giuseppe; Pizzocri, Samuele; Brasca, Francesco; Pozzi, Marta; Beltrami, Laura M.; Bolla, Giovanni B.; Famiani, Roberta; Caimi, Barbara; Omboni, Stefano; Magrini, Fabio; Carugo, Stefano

    2008-01-01

    Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140–179 mm Hg and diastolic BP of 90–109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13

  12. Three Distinct Phases of HIV-1 RNA Decay in Treatment-Naive Patients Receiving Raltegravir-Based Antiretroviral Therapy: ACTG A5248

    PubMed Central

    Andrade, Adriana; Rosenkranz, Susan L.; Cillo, Anthony R.; Lu, Darlene; Daar, Eric S.; Jacobson, Jeffrey M.; Lederman, Michael; Acosta, Edward P.; Campbell, Thomas; Feinberg, Judith; Flexner, Charles; Mellors, John W.; Kuritzkes, Daniel R.

    2013-01-01

    Objective. The goal of this study was to define viral kinetics after initiation of raltegravir (RAL)–based antiretroviral therapy (ART). Methods. ART-naive patients received RAL, tenofovir disoproxil fumarate, and emtricitabine for 72 weeks. Human immunodeficiency virus type 1 (HIV-1) RNA were measured by ultrasensitive and single-copy assays, and first (d1)–, second (d2)–, and, third (d3)–phase decay rates were estimated by mixed-effects models. Decay data were compared to historical estimates for efavirenz (EFV)– and ritonavir/lopinavir (LPV/r)–based regimens. Results. Bi- and tri-exponential models for ultrasensitive assay (n = 38) and single-copy assay (n = 8) data, respectively, provided the best fits over 8 and 72 weeks. The median d1 with ultrasensitive data was 0.563/day (interquartile range [IQR], 0.501–0.610/day), significantly slower than d1 for EFV-based regimens [P < .001]). The median duration of d1 was 15.1 days, transitioning to d2 at an HIV-1 RNA of 91 copies/mL, indicating a longer duration of d1 and a d2 transition at lower viremia levels than with EFV. Median patient-specific decay estimates with the single-copy assay were 0.607/day (IQR, 0.582–0.653) for d1, 0.070/day (IQR, 0.042–0.079) for d2, and 0.0016/day (IQR, 0.0005–0.0022) for d3; the median d1 duration was 16.1 days, transitioning to d2 at 69 copies/mL. d3 transition occurred at 110 days, at 2.6 copies/mL, similar to values for LPV/r-based regimens. Conclusions. Models using single-copy assay data revealed 3 phases of decay with RAL-containing ART, with a longer duration of first-phase decay consistent with RAL-mediated blockade of productive infection from preintegration complexes. Clinical Trials Registration. NCT00660972. PMID:23801609

  13. Do social networks explain 12-step sponsorship effects? A prospective lagged mediation analysis.

    PubMed

    Rynes, Kristina N; Tonigan, J Scott

    2012-09-01

    Sponsorship is a basic and important part of the 12-step approach to recovery from substance abuse (Alcoholics Anonymous, 2005) and research has shown that having a sponsor is associated with increased involvement in 12-step programs and improved outcomes (Bond, Kaskutas, & Weisner, 2003; Tonigan & Rice, 2010). However, little is known about how sponsorship improves outcomes. Given research demonstrating bivariate associations between sponsorship and social support for abstinence (Majer, Jason, Ferrari, Venable, & Olson, 2002), we hypothesized that the association between having a sponsor and increased abstinence outcomes would be explained by increases in one's abstinence-based social network. Prospective fully lagged mediational analyses did not support this hypothesis and these results ran counter to findings of five previous studies (cf. Groh, Jason, & Keys, 2008). A review of these studies showed that researchers often used cross-sectional or partially lagged methods to test mediation and the mediational effect of the social network was small in magnitude. Results suggest that the prospective association between sponsorship and abstinence is not explained by increases in the abstinence-based social network and demonstrate the need for future studies to use rigorous and time-lagged methods to test social support for abstinence as a mediator of the effects of 12-step involvement. PMID:21895349

  14. 12-step participation and outcomes over 7 years among adolescent substance use patients with and without psychiatric comorbidity.

    PubMed

    Chi, Felicia W; Sterling, Stacy; Campbell, Cynthia I; Weisner, Constance

    2013-01-01

    This study examines the associations between 12-step participation and outcomes over 7 years among 419 adolescent substance use patients with and without psychiatric comorbidities. Although level of participation decreased over time for both groups, comorbid adolescents participated in 12-step groups at comparable or higher levels across time points. Results from mixed-effects logistic regression models indicated that for both groups, 12-step participation was associated with both alcohol and drug abstinence at follow-ups, increasing the likelihood of either by at least 3 times. Findings highlight the potential benefits of 12-step participation in maintaining long-term recovery for adolescents with and without psychiatric disorders. PMID:23327502

  15. 12-step participation and outcomes over 7 years among adolescent substance use patients with and without psychiatric comorbidity.

    PubMed

    Chi, Felicia W; Sterling, Stacy; Campbell, Cynthia I; Weisner, Constance

    2013-01-01

    This study examines the associations between 12-step participation and outcomes over 7 years among 419 adolescent substance use patients with and without psychiatric comorbidities. Although level of participation decreased over time for both groups, comorbid adolescents participated in 12-step groups at comparable or higher levels across time points. Results from mixed-effects logistic regression models indicated that for both groups, 12-step participation was associated with both alcohol and drug abstinence at follow-ups, increasing the likelihood of either by at least 3 times. Findings highlight the potential benefits of 12-step participation in maintaining long-term recovery for adolescents with and without psychiatric disorders.

  16. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus

    PubMed Central

    Thompson, Melanie; Saag, Michael; DeJesus, Edwin; Gathe, Joseph; Lalezari, Jay; Landay, Alan L.; Cade, Jerry; Enejosa, Jeffrey; Lefebvre, Eric; Feinberg, Judith

    2016-01-01

    Objective: To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults. Design: A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico). Methods: Study participants (HIV-1 RNA ≥1000 copies/ml, CD4+ cell count ≥200 cells/μl, C-C chemokine receptor type 5-tropic virus) were randomized 2 : 2 : 1 to CVC 100 mg (CVC100), CVC 200 mg (CVC200), or EFV 600 mg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48. Results: A total of 143 patients were randomized (CVC100, n = 59; CVC200, n = 56; EFV, n = 28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all P > 0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all P > 0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8 ng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC. Conclusion: CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC

  17. Applying an Ensemble Classification Tree Approach to the Prediction of Completion of a 12-Step Facilitation Intervention with Stimulant Abusers

    PubMed Central

    Doyle, Suzanne R.; Donovan, Dennis M.

    2014-01-01

    Aims The purpose of this study was to explore the selection of predictor variables in the evaluation of drug treatment completion using an ensemble approach with classification trees. The basic methodology is reviewed and the subagging procedure of random subsampling is applied. Methods Among 234 individuals with stimulant use disorders randomized to a 12-Step facilitative intervention shown to increase stimulant use abstinence, 67.52% were classified as treatment completers. A total of 122 baseline variables were used to identify factors associated with completion. Findings The number of types of self-help activity involvement prior to treatment was the predominant predictor. Other effective predictors included better coping self-efficacy for substance use in high-risk situations, more days of prior meeting attendance, greater acceptance of the Disease model, higher confidence for not resuming use following discharge, lower ASI Drug and Alcohol composite scores, negative urine screens for cocaine or marijuana, and fewer employment problems. Conclusions The application of an ensemble subsampling regression tree method utilizes the fact that classification trees are unstable but, on average, produce an improved prediction of the completion of drug abuse treatment. The results support the notion there are early indicators of treatment completion that may allow for modification of approaches more tailored to fitting the needs of individuals and potentially provide more successful treatment engagement and improved outcomes. PMID:25134038

  18. Therapeutic approach to the treatment-naive patient with hepatitis C virus genotype 1 infection: a step-by-step approach.

    PubMed

    Sherman, Kenneth E

    2012-11-01

    Recent advances in the treatment of hepatitis C virus infection (HCV) have led to high rates of viral cure. However, the use of newly approved protease inhibitors with activity against HCV still requires careful patient selection, counseling, and decision making before initiation of treatment. Laboratory work-up, staging of liver disease, and careful review of comorbid conditions is mandatory. Patients with cirrhosis may require treatment regimens that differ from those without cirrhosis. Because pegylated interferon alfa and ribavirin remain a key part of the treatment regimen, absolute and relative contraindications to their use must be considered. Management of common adverse events including anemia and rash must be embraced by the healthcare provider. PMID:22843782

  19. The Papez Circuit in First-Episode, Treatment-Naive Adults with Major Depressive Disorder: Combined Atlas-Based Tract-Specific Quantification Analysis and Voxel-Based Analysis

    PubMed Central

    Jiang, Wenyan; Gong, Gaolang; Wu, Feng; Kong, Lingtao; Chen, Kaiyuan; Cui, Wenhui; Ren, Ling; Fan, Guoguang; Sun, Wenge; Ma, Huan; Xu, Ke; Tang, Yanqing; Wang, Fei

    2015-01-01

    Previous findings suggest that the Papez Circuit may have a role in major depressive disorders. We used atlas-based tract-specific quantification analysis and voxel-based analysis to examine the integrity of white matter tracts involved in mood regulation (including tracts in the Papez Circuit). Diffusion tensor imaging acquired from 35 first-episode, treatment-naive adults with major depressive disorders and 34 healthy adult controls were compared. Our statistical approach compared structural integrity of 11 major white matter tracts between the major depressive disorder and adult controls, as well as illness duration influence in patients. Fractional anisotropy was decreased in the hippocampal cingulum and in the anterior thalamic radiation according to both analytical approaches, all of which were important tracts included in the Papez Circuit. Our results support the role of the Papez Circuit in major depressive disorders with the minimal probability of false positive due to similar findings in both analyses that have complementary advantages. Dysfunction of the Papez Circuit may be a potential marker for studying the pathogenesis of major depressive disorders. PMID:25996480

  20. Prevalence of HIV-1 Subtypes and Drug Resistance-Associated Mutations in HIV-1-Positive Treatment-Naive Pregnant Women in Pointe Noire, Republic of the Congo (Kento-Mwana Project).

    PubMed

    Bruzzone, Bianca; Saladini, Francesco; Sticchi, Laura; Mayinda Mboungou, Franc A; Barresi, Renata; Caligiuri, Patrizia; Calzi, Anna; Zazzi, Maurizio; Icardi, Giancarlo; Viscoli, Claudio; Bisio, Francesca

    2015-08-01

    The Kento-Mwana project was carried out in Pointe Noire, Republic of the Congo, to prevent mother-to-child HIV-1 transmission. To determine the prevalence of different subtypes and transmitted drug resistance-associated mutations, 95 plasma samples were collected at baseline from HIV-1-positive naive pregnant women enrolled in the project during the years 2005-2008. Full protease and partial reverse transcriptase sequencing was performed and 68/95 (71.6%) samples were successfully sequenced. Major mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors were detected in 4/68 (5.9%), 3/68 (4.4%), and 2/68 (2.9%) samples, respectively. Phylogenetic analysis of HIV-1 isolates showed a high prevalence of unique recombinant forms (24/68, 35%), followed by CRF45_cpx (7/68, 10.3%) and subsubtype A3 and subtype G (6/68 each, 8.8%). Although the prevalence of transmitted drug resistance mutations appears to be currently limited, baseline HIV-1 genotyping is highly advisable in conjunction with antiretroviral therapy scale-up in resource-limited settings to optimize treatment and prevent perinatal transmission. PMID:25970260

  1. The papez circuit in first-episode, treatment-naive adults with major depressive disorder: combined atlas-based tract-specific quantification analysis and voxel-based analysis.

    PubMed

    Jiang, Wenyan; Gong, Gaolang; Wu, Feng; Kong, Lingtao; Chen, Kaiyuan; Cui, Wenhui; Ren, Ling; Fan, Guoguang; Sun, Wenge; Ma, Huan; Xu, Ke; Tang, Yanqing; Wang, Fei

    2015-01-01

    Previous findings suggest that the Papez Circuit may have a role in major depressive disorders. We used atlas-based tract-specific quantification analysis and voxel-based analysis to examine the integrity of white matter tracts involved in mood regulation (including tracts in the Papez Circuit). Diffusion tensor imaging acquired from 35 first-episode, treatment-naive adults with major depressive disorders and 34 healthy adult controls were compared. Our statistical approach compared structural integrity of 11 major white matter tracts between the major depressive disorder and adult controls, as well as illness duration influence in patients. Fractional anisotropy was decreased in the hippocampal cingulum and in the anterior thalamic radiation according to both analytical approaches, all of which were important tracts included in the Papez Circuit. Our results support the role of the Papez Circuit in major depressive disorders with the minimal probability of false positive due to similar findings in both analyses that have complementary advantages. Dysfunction of the Papez Circuit may be a potential marker for studying the pathogenesis of major depressive disorders.

  2. Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

    PubMed Central

    Al-Mahtab, Mamun; Bazinet, Michel; Vaillant, Andrew

    2016-01-01

    Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2–7 log reductions of serum HBsAg, 3–9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10–1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which

  3. Systematic Review and Network Meta-Analysis of Randomized Controlled Trials: Comparative Effectiveness and Safety of Direct-Acting Antiviral Agents for Treatment-Naive Hepatitis C Genotype 1.

    PubMed

    Zhu, Gui-Qi; Zou, Zhuo-Lin; Zheng, Ji-Na; Chen, Da-Zhi; Zou, Tian-Tian; Shi, Ke-Qing; Zheng, Ming-Hua

    2016-03-01

    All possible direct-acting antiviral agent (DAA) regimens for treatment-naive hepatitis C genotype 1 were evaluated by many randomized controlled trials (RCTs). However, the optimum regimen remains inconclusive. We aim to compare interventions in terms of sustained virological response at 12 (SVR12) and 24 (SVR24) weeks after the end of treatment and adverse effects (AEs) (fatigue, headache, nausea, insomnia). PubMed, Embase, and the Cochrane Library were searched for RCTs until July 31, 2015. We estimated odds ratios (ORs) between treatments on clinical outcomes. Twenty-two eligible RCTs were included. Compared with peginterferon-ribavirin (PR), daclatasvir plus PR (OR 8.90, P < 0.001), faldaprevir plus PR (OR 3.72, P < 0.001), simeprevir plus PR (OR 3.59, P < 0.001), sofosbuvir plus PR (OR 4.69, P < 0.001) yield a significant effect in improving SVR12. Consistently, simeprevir plus PR (OR 3.49, P < 0.001), sofosbuvir plus PR (OR 4.51, P < 0.001), daclatasvir plus PR (OR 4.77, P < 0.001) also improved the rates of SVR24 significantly compared with PR. With respect to AEs, compared with PR, ledipasvir plus sofosbuvir plus PR (OR 2.13, P < 0.001) confer a significant AE in nausea, whereas daclatasvir plus PR (OR 0.20, P < 0.001 and OR 0.18, P < 0.001, respectively) lowered the incidence of fatigue and nausea significantly when compared with ledipasvir plus sofosbuvir plus PR. Daclatasvir plus PR was the most effective in SVR12 and SVR24, but caused an increased AEs profile (headache and insomnia). Combined ledipasvir with sofosbuvir or combination of PR was associated with higher incidence of fatigue and nausea. PMID:26945424

  4. New option for management of HIV-1 infection in treatment-naive patients: once-daily, fixed-dose combination of rilpivirine-emtricitabine-tenofovir

    PubMed Central

    Patel, Nimish; Miller, Christopher D

    2012-01-01

    Fixed-dose combination tablets have become an important therapy option for patients infected with the human immunodeficiency virus. Fixed-dose combination rilpivirine-tenofovir-emtricitabine is a recently approved therapy option that has been extensively studied within the treatment-naïve population. When compared with efavirenz-based therapy, improved tolerability with rilpivirine-based therapy was balanced by higher rates of virologic failure to provide similar overall efficacy rates within the intention-to-treat analysis. As a result, providers will need to balance the potential for improved tolerability with fixed-dose combination rilpivirine-tenofovir-emtricitabine against a higher potential for virologic failure, particularly among patients with baseline viral loads above 100,000 copies/mL. Current treatment guidelines have recommended that fixed-dose combination rilpivirine-tenofovir-emtricitabine be an alternative therapy option for treatment-naïve patients and advise caution in those patients with high viral loads at baseline. Similar to other non-nucleoside reverse transcriptase inhibitor-based regimens, there are a number of drug interaction concerns with fixed-dose combination rilpivirine-tenofovir-emtricitabine that will necessitate monitoring and, in some cases, appropriate management. Additionally, the emergence of drug resistance to fixed-dose combination rilpivirine-tenofovir-emtricitabine has been well documented in clinical studies and close attention will be necessary in order to protect current and future therapy options. Overall, fixed-dose combination rilpivirine-tenofovir-emtricitabine is poised to provide an important therapy option for patients when appropriately applied. PMID:22570576

  5. All-oral therapy with nucleotide inhibitors sofosbuvir and GS-0938 for 14 days in treatment-naive genotype 1 hepatitis C (nuclear).

    PubMed

    Lawitz, E J; Rodriguez-Torres, M; Denning, J; Mathias, A; Mo, H; Gao, B; Cornpropst, M T; Berrey, M M; Symonds, W T

    2013-10-01

    Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of -4.50 (-4.66, -4.24) in Cohort 1, -4.55 (-4.97, -4.13) in Cohort 2, -4.65 (-4.78, -4.17) in Cohort 3 and -4.43 (-4.81, -4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log(10) IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1-4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938-alone and in combination--were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.

  6. Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals

    PubMed Central

    Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpetua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.

    2015-01-01

    Objectives: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. Design: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. Methods: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. Results: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers – above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. Conclusion: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with

  7. The Naive Intuitive Statistician: A Naive Sampling Model of Intuitive Confidence Intervals

    ERIC Educational Resources Information Center

    Juslin, Peter; Winman, Anders; Hansson, Patrik

    2007-01-01

    The perspective of the naive intuitive statistician is outlined and applied to explain overconfidence when people produce intuitive confidence intervals and why this format leads to more overconfidence than other formally equivalent formats. The naive sampling model implies that people accurately describe the sample information they have but are…

  8. Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials

    PubMed Central

    Nelson, Mark; Amaya, Gerardo; Clumeck, Nathan; Arns da Cunha, Clovis; Jayaweera, Dushyantha; Junod, Patrice; Li, Taisheng; Tebas, Pablo; Stevens, Marita; Buelens, Annemie; Vanveggel, Simon; Boven, Katia

    2012-01-01

    Objectives The efficacy and hepatic safety of the non-nucleoside reverse transcriptase inhibitors rilpivirine (TMC278) and efavirenz were compared in treatment-naive, HIV-infected adults with concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in the pooled week 48 analysis of the Phase III, double-blind, randomized ECHO (NCT00540449) and THRIVE (NCT00543725) trials. Methods Patients received 25 mg of rilpivirine once daily or 600 mg of efavirenz once daily, plus two nucleoside/nucleotide reverse transcriptase inhibitors. At screening, patients had alanine aminotransferase/aspartate aminotransferase levels ≤5× the upper limit of normal. HBV and HCV status was determined at baseline by HBV surface antigen, HCV antibody and HCV RNA testing. Results HBV/HCV coinfection status was known for 670 patients in the rilpivirine group and 665 in the efavirenz group. At baseline, 49 rilpivirine and 63 efavirenz patients [112/1335 (8.4%)] were coinfected with either HBV [55/1357 (4.1%)] or HCV [57/1333 (4.3%)]. The safety analysis included all available data, including beyond week 48. Eight patients seroconverted during the study (rilpivirine: five; efavirenz: three). A higher proportion of patients achieved viral load <50 copies/mL (intent to treat, time to loss of virological response) in the subgroup without HBV/HCV coinfection (rilpivirine: 85.0%; efavirenz: 82.6%) than in the coinfected subgroup (rilpivirine: 73.5%; efavirenz: 79.4%) (rilpivirine, P = 0.04 and efavirenz, P = 0.49, Fisher's exact test). The incidence of hepatic adverse events (AEs) was low in both groups in the overall population (rilpivirine: 5.5% versus efavirenz: 6.6%) and was higher in HBV/HCV-coinfected patients than in those not coinfected (26.7% versus 4.1%, respectively). Conclusions Hepatic AEs were more common and response rates lower in HBV/HCV-coinfected patients treated with rilpivirine or efavirenz than in those who were not coinfected. PMID:22532465

  9. Naive Optics: Acting on Mirror Reflections

    ERIC Educational Resources Information Center

    Hecht, Heiko; Bertamini, Marco; Gamer, Matthias

    2005-01-01

    It is known that naive observers have striking misconceptions about mirror reflections. In 5 experiments, this article systematically extends the findings to graphic stimuli, to interactive visual tasks, and finally to tasks involving real mirrors. The results show that the perceptual knowledge of nonexpert adults is far superior to their…

  10. Coping Skills Training and 12-Step Facilitation for Women Whose Partner Has Alcoholism: Effects on Depression, the Partner’s Drinking, and Partner Physical Violence

    PubMed Central

    Rychtarik, Robert G.; McGillicuddy, Neil B.

    2015-01-01

    Women (N = 171), distressed from their partners’ untreated alcoholism, received either coping skills training (CST), 12-step facilitation (TSF), or delayed treatment (DTC). CST and TSF resulted in lower depression levels than DTC but did not differ from one another. Skill acquisition mediated the treatment effects of CST; Al-Anon attendance did not mediate the TSF effect. Lower depression levels were maintained at 12 months with no differences between groups. Partner drinking decreased from pretreatment to follow-up in the CST and TSF conditions. However, for partners with a history of relationship violence, drinking improved across follow-up in the CST condition but worsened in the TSF condition. Partner relationship violence was less in the CST condition. CST may be particularly useful for women experiencing physical violence from a partner with alcoholism. PMID:15796632

  11. Humility and 12-Step Recovery: A Prolegomenon for the Empirical Investigation of a Cardinal Virtue in Alcoholics Anonymous

    PubMed Central

    Post, Stephen G.; Pagano, Maria E.; Lee, Matthew T.; Johnson, Byron R.

    2016-01-01

    Alcoholics Anonymous (AA) offers a live stage to study how humility is worn by thousands for another day of sobriety and more freedom from the bondage of self. It has been the coauthors’ intent to emphasize the significance of humility as a cardinal virtue across the 12-Step program and as essential to all its key elements. The coauthors have placed this emphasis in the context of a wider theological history of thought as this converged on Bill W. and AA. In addition, the coauthors have offered a constructive developmental interpretation of the 12 Steps that relies on a model of four modulations of humility. Finally, the coauthors have reviewed in brief some approaches to the measurement of humility in this context, and suggest several aims for future research. PMID:27429509

  12. Do the Naive Know Best? The Predictive Power of Naive Ratings of Couple Interactions

    ERIC Educational Resources Information Center

    Baucom, Katherine J. W.; Baucom, Brian R.; Christensen, Andrew

    2012-01-01

    We examined the utility of naive ratings of communication patterns and relationship quality in a large sample of distressed couples. Untrained raters assessed 10-min videotaped interactions from 134 distressed couples who participated in both problem-solving and social support discussions at each of 3 time points (pre-therapy, post-therapy, and…

  13. The Preference for Symmetry in Flower-Naive and Not-so-Naive Bumblebees

    ERIC Educational Resources Information Center

    Plowright, C. M. S.; Evans, S. A.; Leung, J. Chew; Collin, C. A.

    2011-01-01

    Truly flower-naive bumblebees, with no prior rewarded experience for visits on any visual patterns outside the colony, were tested for their choice of bilaterally symmetric over asymmetric patterns in a radial-arm maze. No preference for symmetry was found. Prior training with rewarded black and white disks did, however, lead to a significant…

  14. Human Naive Embryonic Stem Cells: How Full Is the Glass?

    PubMed

    Wang, Yixuan; Gao, Shaorong

    2016-03-01

    Human naive embryonic stem cells in the ground state of pluripotency provide a new opportunity to study human developmental biology and potential clinical applications. Two studies now report related work in human naive stem cell derivation and DNA methylation analysis, with one reporting some differences from oocyte and blastocyst profiles. PMID:26942847

  15. Fuzzy Naive Bayesian for constructing regulated network with weights.

    PubMed

    Zhou, Xi Y; Tian, Xue W; Lim, Joon S

    2015-01-01

    In the data mining field, classification is a very crucial technology, and the Bayesian classifier has been one of the hotspots in classification research area. However, assumptions of Naive Bayesian and Tree Augmented Naive Bayesian (TAN) are unfair to attribute relations. Therefore, this paper proposes a new algorithm named Fuzzy Naive Bayesian (FNB) using neural network with weighted membership function (NEWFM) to extract regulated relations and weights. Then, we can use regulated relations and weights to construct a regulated network. Finally, we will classify the heart and Haberman datasets by the FNB network to compare with experiments of Naive Bayesian and TAN. The experiment results show that the FNB has a higher classification rate than Naive Bayesian and TAN.

  16. Mapping the route from naive pluripotency to lineage specification.

    PubMed

    Kalkan, Tüzer; Smith, Austin

    2014-12-01

    In the mouse blastocyst, epiblast cells are newly formed shortly before implantation. They possess a unique developmental plasticity, termed naive pluripotency. For development to proceed, this naive state must be subsumed by multi-lineage differentiation within 72 h following implantation. In vitro differentiation of naive embryonic stem cells (ESCs) cultured in controlled conditions provides a tractable system to dissect and understand the process of exit from naive pluripotency and entry into lineage specification. Exploitation of this system in recent large-scale RNAi and mutagenesis screens has uncovered multiple new factors and modules that drive or facilitate progression out of the naive state. Notably, these studies show that the transcription factor network that governs the naive state is rapidly dismantled prior to upregulation of lineage specification markers, creating an intermediate state that we term formative pluripotency. Here, we summarize these findings and propose a road map for state transitions in ESC differentiation that reflects the orderly dynamics of epiblast progression in the embryo. PMID:25349449

  17. Derivation of novel human ground state naive pluripotent stem cells.

    PubMed

    Gafni, Ohad; Weinberger, Leehee; Mansour, Abed AlFatah; Manor, Yair S; Chomsky, Elad; Ben-Yosef, Dalit; Kalma, Yael; Viukov, Sergey; Maza, Itay; Zviran, Asaf; Rais, Yoach; Shipony, Zohar; Mukamel, Zohar; Krupalnik, Vladislav; Zerbib, Mirie; Geula, Shay; Caspi, Inbal; Schneir, Dan; Shwartz, Tamar; Gilad, Shlomit; Amann-Zalcenstein, Daniela; Benjamin, Sima; Amit, Ido; Tanay, Amos; Massarwa, Rada; Novershtern, Noa; Hanna, Jacob H

    2013-12-12

    Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3β signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre-inactivation X chromosome state, and global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters. Upon withdrawal of 2i/LIF, naive mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include predominant use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalent domain acquisition on lineage regulatory genes. The feasibility of establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in mouse ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation

  18. Intestinal healing after anti-TNF induction therapy predicts long-term response to one-year treatment in patients with ileocolonic Crohn’s disease naive to anti-TNF agents

    PubMed Central

    Łykowska-Szuber, Liliana; Katulska, Katarzyna; Stawczyk-Eder, Kamila; Krela-Kaźmierczak, Iwona; Klimczak, Katarzyna; Szymczak, Aleksandra; Stajgis, Marek; Linke, Krzysztof

    2015-01-01

    Introduction Objective assessment of Crohn’s disease (CD) activity in patients treated with anti-tumour necrosis factor (anti-TNF) antibodies is crucial for the prediction of its long-term results. Mucosal healing estimated endoscopically has a strong predictive value; however, only combined assessment together with transmural healing in magnetic resonance enterography (MRE) gives full information about the whole spectrum of inflammatory lesions in CD. Aim To assess the usefulness of intestinal healing phenomenon in CD, defined as improvement both in endoscopy and MRE, after anti-TNF induction therapy, in predicting long-term results of 1-year treatment. Material and methods Twenty-six patients with ileocolonic CD were enrolled into the study. In this group a parallel assessment of disease activity was estimated before and after induction doses of anti-TNF antibodies with ileocolonoscopy and MRE by using appropriate scores. Subsequently the patients were treated until 12 months and then followed-up. The associations between intestinal healing (assessed in MRE and endoscopy), and mucosal and transmural healing with long-term results of 1-year anti-TNF therapy were analysed statistically. Results The median time of follow-up was 29 months (interquartile range – IQR: 14–46). Intestinal healing was significantly associated with favourable therapeutic outcomes (p = 0.02) and had 75% (IQR: 35–97%) sensitivity and 72% (IQR: 46–90%) specificity in predicting long-term remission. Other parameters were not useful (transmural healing) or their usefulness was of borderline significance (mucosal healing). Conclusions Dynamic assessment of intestinal healing is an accurate method in predicting long-term outcomes in CD patients responding to 1-year anti-TNF therapy.

  19. Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis

    PubMed Central

    Phillips, Andrew N; Cambiano, Valentina; Miners, Alec; Revill, Paul; Pillay, Deenan; Lundgren, Jens D; Bennett, Diane; Raizes, Elliott; Nakagawa, Fumiyo; De Luca, Andrea; Vitoria, Marco; Barcarolo, Jhoney; Perriens, Joseph; Jordan, Michael R; Bertagnolio, Silvia

    2016-01-01

    Summary Background With continued roll-out of antiretroviral therapy (ART) in resource-limited settings, evidence is emerging of increasing levels of transmitted drug-resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial levels of transmitted drug resistance. Methods We created a model of HIV transmission, progression, and the effects of ART, which accounted for resistance generation, transmission, and disappearance of resistance from majority virus in the absence of drug pressure. We simulated 5000 ART programmatic scenarios with different prevalence levels of detectable resistance in people starting ART in 2017 (t0) who had not previously been exposed to antiretroviral drugs. We used the model to predict cost-effectiveness of various potential changes in policy triggered by different prevalence levels of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) measured in the population starting ART. Findings Individual-level resistance testing before ART initiation was not generally a cost-effective option, irrespective of the cost-effectiveness threshold. At a cost-effectiveness threshold of US$500 per quality-adjusted life-year (QALY), no change in policy was cost effective (ie, no change in policy would involve paying less than $500 per QALY gained), irrespective of the prevalence of pretreatment NNRTI resistance, because of the increased cost of the policy alternatives. At thresholds of $1000 or higher, and with the prevalence of pretreatment NNRTI resistance greater than 10%, a policy to measure viral load 6 months after ART initiation became cost effective. The policy option to change the standard first-line treatment to a boosted protease inhibitor regimen became cost effective at a prevalence of NNRTI resistance higher than 15%, for cost-effectiveness thresholds greater than $2000. Interpretation Cost-effectiveness of potential policies to adopt in response

  20. Prescription of Opioids for Opioid-Naive Medical Inpatients

    PubMed Central

    Lail, Sharan; Sequeira, Kelly; Lieu, Jenny; Dhalla, Irfan A

    2014-01-01

    Background: Harms associated with prescription opioids are a major and increasing public health concern. Prescribing of opioids for inpatients may contribute to the problem, especially if primary care practitioners continue opioid therapy that is initiated in hospital. Objectives: To describe the extent and nature of opioid prescribing for opioid-naive patients (i.e., no use of opioids within 2 weeks before admission) on an internal medicine unit. Methods: This single-centre study involved chart review for opioid-naive patients admitted to the internal medicine unit of a large academic health sciences centre in Toronto, Ontario. Over 12 weeks, patients were prospectively identified for the study, and charts were later reviewed to characterize opioid use during the hospital stay and upon discharge. The primary outcomes were the proportions of opioid-naive patients for whom opioids were prescribed in hospital and upon discharge. Data on serious adverse events related to opioid use (e.g., need for naloxone or occurrence of falls) were also collected through chart review. Results: From July 4 to September 22, 2011, a total of 721 patients were admitted to the study unit, of whom 381 (53%) were classified as opioid-naive. Opioids were prescribed for 82 (22%) of these opioid-naive patients while they were in hospital. Among the opioid-naive patients, there were a total of 247 opioid prescriptions, with hydromorphone (110 prescriptions) and morphine (92 prescriptions) being the drugs most commonly prescribed. For 23 (28%) of the patients with a prescription for opioids in hospital (6% of all opioid-naive patients), an opioid was also prescribed upon discharge. The indication for opioids was documented in 16 (70%) of the 23 discharge prescriptions. No adverse events or deaths related to opioid use were identified during the hospital stays. Conclusions: Among opioid-naive patients admitted to the internal medicine unit, opioids were prescribed for about 1 in 5 patients, and

  1. Hepatic sarcoidosis complicating treatment-naive viral hepatitis

    PubMed Central

    Aravinthan, Aloysious; Gelson, William; Limbu, Anita; Brais, Rebecca; Richardson, Paul

    2012-01-01

    Hepatic sarcoidosis is usually asymptomatic but rarely leads to adverse liver-related outcome. Co-existence of viral hepatitis and hepatic sarcoidosis is a rare, but recognised phenomenon. Obtaining a balance between immune suppression and anti-viral therapy may be problematic. Immunosuppression in the presence of viral hepatitis can lead to rapid deterioration of liver disease. Similarly, anti-viral therapy may exacerbate granulomatous hepatitis. Here we present two cases of viral hepatitis co-existing with sarcoidosis that illustrate successful management strategies. In one, hepatitis B replication was suppressed with oral anti-viral therapy before commencing prednisolone. In the second, remission of hepatic sarcoidosis was achieved with prednisolone, before treating hepatitis C and obtaining a sustained virological response with pegylated interferon and ribavirin therapy. PMID:23355920

  2. "Naive" Native Speakers and Judgments of Oral Proficiency in Spanish.

    ERIC Educational Resources Information Center

    Barnwell, David

    A study addressed issues of concern in the use of the American Council on the Teaching of Foreign Languages (ACTFL)/Educational Testing Service (ETS) Language Proficiency Guidelines commonly used in determination of oral language proficiency. Specifically, potential discrepancies between the judgments of trained raters and "naive" native speakers…

  3. Expert and Naive Raters Using the PAG: Does it Matter?

    ERIC Educational Resources Information Center

    Cornelius, Edwin T.; And Others

    1984-01-01

    Questions the observed correlation between job experts and naive raters using the Position Analysis Questionnaire (PAQ); and conducts a replication of the Smith and Hakel study (1979) with college students (N=39). Concluded that PAQ ratings from job experts and college students are not equivalent and therefore are not interchangeable. (LLL)

  4. Naive vs. Sophisticated Methods of Forecasting Public Library Circulations.

    ERIC Educational Resources Information Center

    Brooks, Terrence A.

    1984-01-01

    Two sophisticated--autoregressive integrated moving average (ARIMA), straight-line regression--and two naive--simple average, monthly average--forecasting techniques were used to forecast monthly circulation totals of 34 public libraries. Comparisons of forecasts and actual totals revealed that ARIMA and monthly average methods had smallest mean…

  5. A Workshop for High School Students on Naive Set Theory

    ERIC Educational Resources Information Center

    Wegner, Sven-Ake

    2014-01-01

    In this article we present the prototype of a workshop on naive set theory designed for high school students in or around the seventh year of primary education. Our concept is based on two events which the author organized in 2006 and 2010 for students of elementary school and high school, respectively. The article also includes a practice report…

  6. Explanatory Coherence and Belief Revision in Naive Physics.

    ERIC Educational Resources Information Center

    Ranney, Michael; Thagard, Paul

    Students of reasoning have long tried to understand how people revise systems of beliefs. This paper maintains that people often change their beliefs in ways driven by considerations of explanatory coherence. In this report, a computational model is described of how experimental subjects revise their naive beliefs about physical motion. First,…

  7. Children's Conceptions of Mental Illness: A Naive Theory Approach

    ERIC Educational Resources Information Center

    Fox, Claudine; Buchanan-Barrow, Eithne; Barrett, Martyn

    2010-01-01

    This paper reports two studies that investigated children's conceptions of mental illness using a naive theory approach, drawing upon a conceptual framework for analysing illness representations which distinguishes between the identity, causes, consequences, curability, and timeline of an illness. The studies utilized semi-structured interviewing…

  8. Three Naive Questions: Addressed to the Modern Educational Optimism

    ERIC Educational Resources Information Center

    Krstic, Predrag

    2016-01-01

    This paper aims to question anew the popular and supposedly self-evident affirmation of education, in its modern incarnation as in its historical notion. The "naive" questions suggest that we have recently taken for granted that education ought to be for the masses, that it ought to be upbringing, and that it is better than ignorance.…

  9. Osteoporosis and multiple fractures in an antiretroviral-naive, HIV-positive child.

    PubMed

    Soler Palacin, P; Torrent, A; Rossich, R; Moraga, F A; Yeste, D; Carreño, J C; Encabo, G; Figueras, C

    2007-08-01

    As a result of the increased incidence of osteopenia and osteoporosis in HIV-infected patients, numerous publications have suggested that there may be a link between bone metabolism alterations and HIV infection. The early bone loss seen in these patients was initially attributed to the use of highly active antiretroviral treatment (HAART) that included protease inhibitors. Recent studies, however, have suggested that it may be a direct consequence of the viral infection on bone metabolism, persistent activation of pro-inflammatory cytokines (TNFa), or altered vitamin D metabolism secondary to the virus, combined with subsequent factors (e.g., antiretroviral treatment) that aggravate the bone demineralization. We present an antiretroviral-naive 6-year-old girl with vertically transmitted HIV infection who presented with severe osteoporosis and multiple pathological fractures of the vertebrae, ribs, and upper and lower limbs. The child was treated with HAART, appropriate nutritional support for her age, physiotherapy and rehabilitation, calcium and vitamin D supplements, and alendronate therapy. After 6 weeks of treatment, the intense pain and muscle atrophy had disappeared and she was able to walk unassisted. At 6 months, bone mass had increased by 72%. The interest of this case lies in the presence of severe osteoporosis and multiple pathological fractures in an HIVinfected naive child. To date, this condition has only been described in patients treated with antiretrovirals. Moreover, this is the first reported HIV-positive pediatric patient treated with bisphosphonates, which proved to be highly successful.

  10. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice

    PubMed Central

    Hogan, Thea; Gossel, Graeme; Yates, Andrew J.; Seddon, Benedict

    2015-01-01

    Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment. PMID:26607449

  11. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice.

    PubMed

    Hogan, Thea; Gossel, Graeme; Yates, Andrew J; Seddon, Benedict

    2015-12-15

    Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment.

  12. Children's naive theories of intelligence influence their metacognitive judgments.

    PubMed

    Miele, David B; Son, Lisa K; Metcalfe, Janet

    2013-01-01

    Recent studies have shown that the metacognitive judgments adults infer from their experiences of encoding effort vary in accordance with their naive theories of intelligence. To determine whether this finding extends to elementary schoolchildren, a study was conducted in which 27 third graders (M(age) = 8.27) and 24 fifth graders (M(age) = 10.39) read texts presented in easy- or difficult-to-encode fonts. The more children in both grades viewed intelligence as fixed, the less likely they were to interpret effortful or difficult encoding as a sign of increasing mastery and the more likely they were to report lower levels of comprehension as their perceived effort increased. This suggests that children may use naive theories of intelligence to make motivationally relevant inferences earlier than previously thought. PMID:23574195

  13. Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway

    SciTech Connect

    Managlia, Elizabeth Z. . E-mail: lalharth@rush.edu

    2006-07-05

    Interleukin (IL)-7 plays several roles critical to T cell maturation, survival, and homeostasis. Because of these functions, IL-7 is under investigation as an immune-modulator for therapeutic use in lymphopenic clinical conditions, including HIV. We reported that naive T cells, typically not permissive to HIV, can be productively infected when pre-treated with IL-7. We evaluated the mechanism by which IL-7-mediates this effect. IL-7 potently up-regulated the transcriptional factor NFAT, but had no effect on NF{kappa}B. Blocking NFAT activity using a number of reagents, such as Cyclosporin A, FK-506, or the NFAT-specific inhibitor known as VIVIT peptide, all markedly reduced IL-7-mediated induction of HIV replication in naive T cells. Additional neutralization of cytokines present in IL-7-treated cultures and/or those that have NFAT-binding sequences within their promotors indicated that IL-10, IL-4, and most significantly IFN{gamma}, all contribute to IL-7-induction of HIV productive replication in naive T cells. These data clarify the mechanism by which IL-7 can overcome the block to HIV productive infection in naive T cells, despite their quiescent cell status. These findings are relevant to the treatment of HIV disease and understanding HIV pathogenesis in the naive CD4+ T cell compartment, especially in light of the vigorous pursuit of IL-7 as an in vivo immune modulator.

  14. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells.

    PubMed

    van den Broek, Theo; Delemarre, Eveline M; Janssen, Willemijn J M; Nievelstein, Rutger A J; Broen, Jasper C; Tesselaar, Kiki; Borghans, Jose A M; Nieuwenhuis, Edward E S; Prakken, Berent J; Mokry, Michal; Jansen, Nicolaas J G; van Wijk, Femke

    2016-03-01

    The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants. PMID:26901814

  15. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells

    PubMed Central

    van den Broek, Theo; Delemarre, Eveline M.; Janssen, Willemijn J.M.; Nievelstein, Rutger A.J.; Broen, Jasper C.; Tesselaar, Kiki; Borghans, Jose A.M.; Nieuwenhuis, Edward E.S.; Prakken, Berent J.; Mokry, Michal; Jansen, Nicolaas J.G.

    2016-01-01

    The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants. PMID:26901814

  16. Schistosoma japonicum soluble egg antigens activate naive B cells to produce antibodies: definition of parasite mechanisms of immune deviation.

    PubMed Central

    Yamashita, T; Watanabe, T; Saito, S; Araki, Y; Sendo, F

    1993-01-01

    This study analysed the effect of Schistosoma japonicum egg antigens (SEA) on the activation of lymphocytes from naive mice. T cells were found to be unaffected by SEA. B cells, however, were activated by SEA without participation of adherent cells such as macrophages. B-cell activating factor(s) in SEA were distributed into a fraction of M(r) 120,000 and a fraction of M(r) 650,000 by gel filtration. However, a fraction of M(r) 120,000 demonstrated the presence of a limited number of components by polyacrylamide gel electrophoresis (PAGE) under non-denaturing conditions. These activating factor(s) were destroyed by peroxidase oxidation, heat treatment, chymotrypsin and trypsin digestion. These results indicate that the B-cell activating factor(s) in SEA contain both carbohydrate and protein. IgM antibodies were detected in the culture supernatant of SEA-activated B cells after 48 hr in culture, but IgG antibodies were undetected in culture. These antibodies did not react with SEA but reacted with sheep, horse, mouse red blood cells, carbonic anhydrase and autoantigens in myelinated nerve fibres of cerebrum as well as luminal surface and parietal cells of the stomach of naive mice. Thus our data demonstrated that SEA directly stimulates naive B cells to produce antibodies against heterophile and autologous antigens. Images Figure 5 Figure 6 Figure 7 PMID:8344698

  17. MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages.

    PubMed

    Saha, Banishree; Momen-Heravi, Fatemeh; Kodys, Karen; Szabo, Gyongyi

    2016-01-01

    Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGFβ and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages.

  18. A Combined Omics Approach to Generate the Surface Atlas of Human Naive CD4+ T Cells during Early T-Cell Receptor Activation*

    PubMed Central

    Graessel, Anke; Hauck, Stefanie M.; von Toerne, Christine; Kloppmann, Edda; Goldberg, Tatyana; Koppensteiner, Herwig; Schindler, Michael; Knapp, Bettina; Krause, Linda; Dietz, Katharina; Schmidt-Weber, Carsten B.; Suttner, Kathrin

    2015-01-01

    Naive CD4+ T cells are the common precursors of multiple effector and memory T-cell subsets and possess a high plasticity in terms of differentiation potential. This stem-cell-like character is important for cell therapies aiming at regeneration of specific immunity. Cell surface proteins are crucial for recognition and response to signals mediated by other cells or environmental changes. Knowledge of cell surface proteins of human naive CD4+ T cells and their changes during the early phase of T-cell activation is urgently needed for a guided differentiation of naive T cells and may support the selection of pluripotent cells for cell therapy. Periodate oxidation and aniline-catalyzed oxime ligation technology was applied with subsequent quantitative liquid chromatography-tandem MS to generate a data set describing the surface proteome of primary human naive CD4+ T cells and to monitor dynamic changes during the early phase of activation. This led to the identification of 173 N-glycosylated surface proteins. To independently confirm the proteomic data set and to analyze the cell surface by an alternative technique a systematic phenotypic expression analysis of surface antigens via flow cytometry was performed. This screening expanded the previous data set, resulting in 229 surface proteins, which were expressed on naive unstimulated and activated CD4+ T cells. Furthermore, we generated a surface expression atlas based on transcriptome data, experimental annotation, and predicted subcellular localization, and correlated the proteomics result with this transcriptional data set. This extensive surface atlas provides an overall naive CD4+ T cell surface resource and will enable future studies aiming at a deeper understanding of mechanisms of T-cell biology allowing the identification of novel immune targets usable for the development of therapeutic treatments. PMID:25991687

  19. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

    PubMed Central

    Fleischmann, Roy M; Huizinga, Tom W J; Kavanaugh, Arthur F; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F

    2016-01-01

    Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. Methods MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. Results Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. Conclusions Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. Trial registration number NCT01039688; Results. PMID:27493790

  20. Reconciling Longitudinal Naive T-Cell and TREC Dynamics during HIV-1 Infection

    PubMed Central

    Mugwagwa, Tendai; de Boer, Anne Bregje; Otto, Sigrid A.; Hazenberg, Mette D.; Tesselaar, Kiki; de Boer, Rob J.; Borghans, José A. M.

    2016-01-01

    Naive T cells in untreated HIV-1 infected individuals have a reduced T-cell receptor excision circle (TREC) content. Previous mathematical models have suggested that this is due to increased naive T-cell division. It remains unclear, however, how reduced naive TREC contents can be reconciled with a gradual loss of naive T cells in HIV-1 infection. We performed longitudinal analyses in humans before and after HIV-1 seroconversion, and used a mathematical model to investigate which processes could explain the observed changes in naive T-cell numbers and TRECs during untreated HIV-1 disease progression. Both CD4+ and CD8+ naive T-cell TREC contents declined biphasically, with a rapid loss during the first year and a much slower loss during the chronic phase of infection. While naive CD8+ T-cell numbers hardly changed during follow-up, naive CD4+ T-cell counts continually declined. We show that a fine balance between increased T-cell division and loss in the peripheral naive T-cell pool can explain the observed short- and long-term changes in TRECs and naive T-cell numbers, especially if T-cell turnover during the acute phase is more increased than during the chronic phase of infection. Loss of thymic output, on the other hand, does not help to explain the biphasic loss of TRECs in HIV infection. The observed longitudinal changes in TRECs and naive T-cell numbers in HIV-infected individuals are most likely explained by a tight balance between increased T-cell division and death, suggesting that these changes are intrinsically linked in HIV infection. PMID:27010200

  1. Naive Bayes-Guided Bat Algorithm for Feature Selection

    PubMed Central

    Taha, Ahmed Majid; Mustapha, Aida; Chen, Soong-Der

    2013-01-01

    When the amount of data and information is said to double in every 20 months or so, feature selection has become highly important and beneficial. Further improvements in feature selection will positively affect a wide array of applications in fields such as pattern recognition, machine learning, or signal processing. Bio-inspired method called Bat Algorithm hybridized with a Naive Bayes classifier has been presented in this work. The performance of the proposed feature selection algorithm was investigated using twelve benchmark datasets from different domains and was compared to three other well-known feature selection algorithms. Discussion focused on four perspectives: number of features, classification accuracy, stability, and feature generalization. The results showed that BANB significantly outperformed other algorithms in selecting lower number of features, hence removing irrelevant, redundant, or noisy features while maintaining the classification accuracy. BANB is also proven to be more stable than other methods and is capable of producing more general feature subsets. PMID:24396295

  2. Fatal attraction: sexually cannibalistic invaders attract naive native mantids

    PubMed Central

    Fea, Murray P.; Stanley, Margaret C.; Holwell, Gregory I.

    2013-01-01

    Overlap in the form of sexual signals such as pheromones raises the possibility of reproductive interference by invasive species on similar, yet naive native species. Here, we test the potential for reproductive interference through heterospecific mate attraction and subsequent predation of males by females of a sexually cannibalistic invasive praying mantis. Miomantis caffra is invasive in New Zealand, where it is widely considered to be displacing the only native mantis species, Orthodera novaezealandiae, and yet mechanisms behind this displacement are unknown. We demonstrate that native males are more attracted to the chemical cues of introduced females than those of conspecific females. Heterospecific pairings also resulted in a high degree of mortality for native males. This provides evidence for a mechanism behind displacement that has until now been undetected and highlights the potential for reproductive interference to greatly influence the impact of an invasive species. PMID:24284560

  3. Fatal attraction: sexually cannibalistic invaders attract naive native mantids.

    PubMed

    Fea, Murray P; Stanley, Margaret C; Holwell, Gregory I

    2013-01-01

    Overlap in the form of sexual signals such as pheromones raises the possibility of reproductive interference by invasive species on similar, yet naive native species. Here, we test the potential for reproductive interference through heterospecific mate attraction and subsequent predation of males by females of a sexually cannibalistic invasive praying mantis. Miomantis caffra is invasive in New Zealand, where it is widely considered to be displacing the only native mantis species, Orthodera novaezealandiae, and yet mechanisms behind this displacement are unknown. We demonstrate that native males are more attracted to the chemical cues of introduced females than those of conspecific females. Heterospecific pairings also resulted in a high degree of mortality for native males. This provides evidence for a mechanism behind displacement that has until now been undetected and highlights the potential for reproductive interference to greatly influence the impact of an invasive species. PMID:24284560

  4. The Persistence of "Solid" and "Liquid" Naive Conceptions: A Reaction Time Study

    ERIC Educational Resources Information Center

    Babai, Reuven; Amsterdamer, Anat

    2008-01-01

    The study explores whether the naive concepts of "solid" and "liquid" persist in adolescence. Accuracy of responses and reaction times where measured while 41 ninth graders classified different solids (rigid, non-rigid and powders) and different liquids (runny, dense) into solid or liquid. The results show that these naive conceptions affect…

  5. Naive Theory of Biology: The Pre-School Child's Explanation of Death

    ERIC Educational Resources Information Center

    Vlok, Milandre; de Witt, Marike W.

    2012-01-01

    This article explains the naive theory of biology that the pre-school child uses to explain the cause of death. The empirical investigation showed that the young participants do use a naive theory of biology to explain function and do make reference to "vitalistic causality" in explaining organ function. Furthermore, most of these participants…

  6. What Fits into a Mirror: Naive Beliefs about the Field of View

    ERIC Educational Resources Information Center

    Bianchi, Ivana; Savardi, Ugo

    2012-01-01

    Research on naive physics and naive optics have shown that people hold surprising beliefs about everyday phenomena that are in contrast with what they see. In this article, we investigated what adults expect to be the field of view of a mirror from various viewpoints. The studies presented here confirm that humans have difficulty dealing with the…

  7. Children and Adolescents' Understandings of Family Resemblance: A Study of Naive Inheritance Concepts

    ERIC Educational Resources Information Center

    Williams, Joanne M.

    2012-01-01

    This paper aims to provide developmental data on two connected naive inheritance concepts and to explore the coherence of children's naive biology knowledge. Two tasks examined children and adolescents' (4, 7, 10, and 14 years) conceptions of phenotypic resemblance across kin (in physical characteristics, disabilities, and personality traits). The…

  8. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

    PubMed

    Pulko, Vesna; Davies, John S; Martinez, Carmine; Lanteri, Marion C; Busch, Michael P; Diamond, Michael S; Knox, Kenneth; Bush, Erin C; Sims, Peter A; Sinari, Shripad; Billheimer, Dean; Haddad, Elias K; Murray, Kristy O; Wertheimer, Anne M; Nikolich-Žugich, Janko

    2016-08-01

    The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens. PMID:27270402

  9. Naive Pluripotent Stem Cells Derived Directly from Isolated Cells of the Human Inner Cell Mass

    PubMed Central

    Guo, Ge; von Meyenn, Ferdinand; Santos, Fatima; Chen, Yaoyao; Reik, Wolf; Bertone, Paul; Smith, Austin; Nichols, Jennifer

    2016-01-01

    Summary Conventional generation of stem cells from human blastocysts produces a developmentally advanced, or primed, stage of pluripotency. In vitro resetting to a more naive phenotype has been reported. However, whether the reset culture conditions of selective kinase inhibition can enable capture of naive epiblast cells directly from the embryo has not been determined. Here, we show that in these specific conditions individual inner cell mass cells grow into colonies that may then be expanded over multiple passages while retaining a diploid karyotype and naive properties. The cells express hallmark naive pluripotency factors and additionally display features of mitochondrial respiration, global gene expression, and genome-wide hypomethylation distinct from primed cells. They transition through primed pluripotency into somatic lineage differentiation. Collectively these attributes suggest classification as human naive embryonic stem cells. Human counterparts of canonical mouse embryonic stem cells would argue for conservation in the phased progression of pluripotency in mammals. PMID:26947977

  10. Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.

    PubMed

    Wilkins, Ed L; Cohen, Calvin J; Trottier, Benoit; Esser, Stefan; Smith, Don E; Haas, Bernhard; Brinson, Cynthia; Garner, Will; Chuck, Susan; Thorpe, David; De-Oertel, Shampa

    2016-01-01

    This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.

  11. Telomere Length and Pulse Pressure in Newly Diagnosed, Antipsychotic-Naive Patients With Nonaffective Psychosis

    PubMed Central

    Fernandez-Egea, Emilio; Bernardo, Miguel; Heaphy, Christopher M.; Griffith, Jeffrey K.; Parellada, Eduard; Esmatjes, Enric; Conget, Ignacio; Nguyen, Linh; George, Varghese; Stöppler, Hubert; Kirkpatrick, Brian

    2009-01-01

    Introduction: Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP. Methods: Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test. Results: Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects. Discussion: These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension. PMID:19279086

  12. CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART

    PubMed Central

    Sauter, Rafael; Huang, Ruizhu; Ledergerber, Bruno; Battegay, Manuel; Bernasconi, Enos; Cavassini, Matthias; Furrer, Hansjakob; Hoffmann, Matthias; Rougemont, Mathieu; Günthard, Huldrych F; Held, Leonhard

    2016-01-01

    Abstract Plasma HIV viral load is related to declining CD4 lymphocytes. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized so far. We examine if CD8 cell count is a prognostic factor for CD4 cell counts during an HIV infection. A longitudinal analysis is conducted using data from the Swiss HIV cohort study collected between January 2000 and October 2014. Linear mixed regression models were applied to observations from HIV-1-infected treatment naive patients (NAIVE) and cART-treated patients to predict the short-term evolution of CD4 cell counts. For each subgroup, it was quantified to which extent CD8 cell counts or CD4/CD8 ratios are prognostic factors for disease progression. In both subgroups, 2500 NAIVE and 8902 cART patients, past CD4 cells are positively (P < 0.0001) and past viral load is negatively (P < 0.0001) associated with the outcome. Including additionally past CD8 cell counts improves the fit significantly (P < 0.0001) and increases the marginal explained variation 31.7% to 40.7% for the NAIVE and from 44.1% to 50.7% for the cART group. The past CD4/CD8 ratio (instead of the past CD8 level) is positively associated with the outcome, increasing the explained variation further to 41.8% for NAIVE and 51.9% for cART. PMID:27759638

  13. Risk Classification with an Adaptive Naive Bayes Kernel Machine Model

    PubMed Central

    Minnier, Jessica; Yuan, Ming; Liu, Jun S.; Cai, Tianxi

    2014-01-01

    Genetic studies of complex traits have uncovered only a small number of risk markers explaining a small fraction of heritability and adding little improvement to disease risk prediction. Standard single marker methods may lack power in selecting informative markers or estimating effects. Most existing methods also typically do not account for non-linearity. Identifying markers with weak signals and estimating their joint effects among many non-informative markers remains challenging. One potential approach is to group markers based on biological knowledge such as gene structure. If markers in a group tend to have similar effects, proper usage of the group structure could improve power and efficiency in estimation. We propose a two-stage method relating markers to disease risk by taking advantage of known gene-set structures. Imposing a naive bayes kernel machine (KM) model, we estimate gene-set specific risk models that relate each gene-set to the outcome in stage I. The KM framework efficiently models potentially non-linear effects of predictors without requiring explicit specification of functional forms. In stage II, we aggregate information across gene-sets via a regularization procedure. Estimation and computational efficiency is further improved with kernel principle component analysis. Asymptotic results for model estimation and gene set selection are derived and numerical studies suggest that the proposed procedure could outperform existing procedures for constructing genetic risk models. PMID:26236061

  14. Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats.

    PubMed

    Cohier, Camille; Chevillard, Lucie; Risède, Patricia; Roussel, Olivier; Mégarbane, Bruno

    2014-07-15

    Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P<0.05) without altering minute volume (VE). In combination to DZP, BUP/NLX significantly increased expiratory time (P<0.01) and decreased f (P<0.01), tidal volume (VT, P<0.001), and VE (P<0.001) while BUP only decreased VT (P<0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P<0.001) and decreased f (P<0.01) and VE (P<0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined. PMID:24769261

  15. Neisseria lactamica selectively induces mitogenic proliferation of the naive B cell pool via cell surface Ig.

    PubMed

    Vaughan, Andrew T; Brackenbury, Louise S; Massari, Paola; Davenport, Victoria; Gorringe, Andrew; Heyderman, Robert S; Williams, Neil A

    2010-09-15

    Neisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen Neisseria meningitidis, there is an absence of adaptive cell-mediated immunity to N. lactamica during the peak age of carriage. Instead, outer membrane vesicles derived from N. lactamica mediate a B cell-dependent proliferative response in mucosal mononuclear cells that is associated with the production of polyclonal IgM. We demonstrate in this study that this is a mitogenic human B cell response that occurs independently of T cell help and any other accessory cell population. The ability to drive B cell proliferation is a highly conserved property and is present in N. lactamica strains derived from diverse clonal complexes. CFSE staining of purified human tonsillar B cells demonstrated that naive IgD(+) and CD27(-) B cells are selectively induced to proliferate by outer membrane vesicles, including the innate CD5(+) subset. Neither purified lipooligosaccharide nor PorB from N. lactamica is likely to be responsible for this activity. Prior treatment of B cells with pronase to remove cell-surface Ig or treatment with BCR-specific Abs abrogated the proliferative response to N. lactamica outer membrane vesicles, suggesting that this mitogenic response is dependent upon the BCR.

  16. Presence of drug resistance mutations among drug-naive patients in Morocco.

    PubMed

    Annaz, Hicham El; Recordon-Pinson, Patricia; Baba, Nabil; Sedrati, Omar; Mrani, Saad; Fleury, Hervé

    2011-08-01

    The aim of the present study was to determine viral subtypes and resistance mutations to antiretroviral treatment (ART) in HIV-1-infected treatment-naive patients from Rabat, Morocco during the period 2005-2009. The protease and reverse transcriptase (RT) genes were sequenced, the phylogenetic trees were inferred, and the resistance-associated mutations to NRTIs, NNRTIs, and PIs were recorded according to the international list of surveillance drug resistance mutations (SDRMs). The viral subtypes were subtype B (74%), CRF02_AG (15%), A1 (6%), C (2%), F1 (1%), CRF09 (1%), and CRF25_cpx (1%). The presence of DRMs was found in four (5.06%) of 91 patients; resistance mutations to NRTIs were M184V and T215I/S revertant mutations; resistance to NNRTIs was associated with K103N and resistance to PIs with V82A. These findings have relevant implications for the local molecular mapping of HIV-1 and future ART surveillance studies in the region.

  17. Characterization of the finch embryo supports evolutionary conservation of the naive stage of development in amniotes.

    PubMed

    Mak, Siu-Shan; Alev, Cantas; Nagai, Hiroki; Wrabel, Anna; Matsuoka, Yoko; Honda, Akira; Sheng, Guojun; Ladher, Raj K

    2015-09-11

    Innate pluripotency of mouse embryos transits from naive to primed state as the inner cell mass differentiates into epiblast. In vitro, their counterparts are embryonic (ESCs) and epiblast stem cells (EpiSCs), respectively. Activation of the FGF signaling cascade results in mouse ESCs differentiating into mEpiSCs, indicative of its requirement in the shift between these states. However, only mouse ESCs correspond to the naive state; ESCs from other mammals and from chick show primed state characteristics. Thus, the significance of the naive state is unclear. In this study, we use zebra finch as a model for comparative ESC studies. The finch blastoderm has mESC-like properties, while chick blastoderm exhibits EpiSC features. In the absence of FGF signaling, finch cells retained expression of pluripotent markers, which were lost in cells from chick or aged finch epiblasts. Our data suggest that the naive state of pluripotency is evolutionarily conserved among amniotes.

  18. Improving Naive Bayes with Online Feature Selection for Quick Adaptation to Evolving Feature Usefulness

    SciTech Connect

    Pon, R K; Cardenas, A F; Buttler, D J

    2007-09-19

    The definition of what makes an article interesting varies from user to user and continually evolves even for a single user. As a result, for news recommendation systems, useless document features can not be determined a priori and all features are usually considered for interestingness classification. Consequently, the presence of currently useless features degrades classification performance [1], particularly over the initial set of news articles being classified. The initial set of document is critical for a user when considering which particular news recommendation system to adopt. To address these problems, we introduce an improved version of the naive Bayes classifier with online feature selection. We use correlation to determine the utility of each feature and take advantage of the conditional independence assumption used by naive Bayes for online feature selection and classification. The augmented naive Bayes classifier performs 28% better than the traditional naive Bayes classifier in recommending news articles from the Yahoo! RSS feeds.

  19. Do naive juvenile seabirds forage differently from adults?

    PubMed Central

    Riotte-Lambert, Louise; Weimerskirch, Henri

    2013-01-01

    Foraging skills of young individuals are assumed to be inferior to those of adults. The reduced efficiency of naive individuals may be the primary cause of the high juvenile mortality and explain the deferment of maturity in long-lived species. However, the study of juvenile and immature foraging behaviour has been limited so far. We used satellite telemetry to compare the foraging movements of juveniles, immatures and breeding adult wandering albatrosses Diomedea exulans, a species where foraging success is positively influenced by the distance covered daily. We showed that juveniles are able to use favourable winds as soon as the first month of independence, but cover shorter distances daily and spend more time sitting on water than adults during the first two months after fledging. These reduced movement capacities do not seem to be the cause of higher juvenile mortality. Moreover, juveniles almost never restrict their movement to specific areas, as adults and immatures frequently do over shelf edges or oceanic zones, which suggest that the location of appropriate areas is learned through experience. Immatures and adults have equivalent movement capacities, but when they are central place foragers, i.e. when adults breed or immatures come to the colony to display and pair, immatures make shorter trips than adults. The long duration of immaturity in this species seems to be related to a long period of learning to integrate the foraging constraints associated with reproduction and central place foraging. Our results indicate that foraging behaviour of young albatrosses is partly innate and partly learned progressively over immaturity. The first months of learning appear critical in terms of survival, whereas the long period of immaturity is necessary for young birds to attain the skills necessary for efficient breeding without fitness costs. PMID:23926153

  20. Insulin Degludec Versus Insulin Glargine in Insulin-Naive Patients With Type 2 Diabetes

    PubMed Central

    Zinman, Bernard; Philis-Tsimikas, Athena; Cariou, Bertrand; Handelsman, Yehuda; Rodbard, Helena W.; Johansen, Thue; Endahl, Lars; Mathieu, Chantal

    2012-01-01

    OBJECTIVE To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9−4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis. RESULTS In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI −0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar. CONCLUSIONS Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. PMID:23043166

  1. Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents

    PubMed Central

    Matera, Emilia; Petruzzelli, Maria G.; Simone, Marta; Lamanna, Anna L.; Pastore, Adriana; Palmieri, Vincenzo O.; Margari, Francesco

    2015-01-01

    The aim of this prospective observational study was to investigate the variations of serum prolactin hormone (PRL) in a sample of 34 drug-naive patients (mean age 13 years) who started risperidone therapy assuming that several factors may favor the increase in serum PRL. Serum PRL and hyperprolactinemia clinical signs were examined at baseline (T0) and after almost 3 months of treatment (T1). We considered sex, pubertal status, risperidone dosage, psychiatric diagnosis, and any personal/family history of autoimmune diseases. The mean serum PRL value increased between T0 and T1 (P=0.004). The mean serum PRL was higher in females in the pubertal/postpubertal stage and for risperidone dosage up 1 mg/day. Hyperprolactinemia was found in 20% of patients at T0 and in 38% of patients at T1 (P=0.03). The mean serum PRL increase was greater in early-onset schizophrenia spectrum psychosis patients compared with no-early-onset schizophrenia spectrum psychosis patients (P=0.04). The increase in PRL was higher in patients with a personal and a family history of autoimmune diseases. This study suggests that the increase in serum PRL in patients treated with risperidone may be linked not only to the drug and its dosage but also to several risk factors such as sex, pubertal stage, psychiatric disease, and autoimmune disorders. PMID:25514607

  2. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study

    PubMed Central

    Stellbrink, Hans-Jürgen; Reynes, Jacques; Lazzarin, Adriano; Voronin, Eugene; Pulido, Federico; Felizarta, Franco; Almond, Steve; Clair, Marty St; Flack, Nancy; Min, Sherene

    2013-01-01

    Objective: To evaluate the efficacy and safety/tolerability of dolutegravir (DTG, S/GSK1349572), a potent inhibitor of HIV integrase, through the full 96 weeks of the SPRING-1 study. Design: ING112276 (SPRING-1) was a 96-week, randomized, partially blinded, phase IIb dose-ranging study. Methods: Treatment-naive adults with HIV received DTG 10, 25, or 50 mg once daily or efavirenz (EFV) 600 mg once daily (control arm) combined with investigator-selected dual nucleos(t)ide reverse transcriptase inhibitor backbone regimen (tenofovir/emtricitabine or abacavir/lamivudine). The primary endpoint of the study was the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, based on time to loss of virologic response at 16 weeks (conducted for the purpose of phase III dose selection), with a planned analysis at 96 weeks. Safety and tolerability were also assessed. Results: Of 208 participants randomized to treatment, 205 received study drug. At week 96, the proportion of participants achieving plasma HIV-1 RNA less than 50 copies/ml was 79, 78, and 88% for DTG 10, 25, and 50 mg, respectively, compared with 72% for EFV. The median increase from baseline in CD4+ cells was 338 cells/μl with DTG (all treatment groups combined) compared with 301 cells/μl with EFV (P = 0.155). No clinically significant dose-related trends in adverse events were observed, and fewer participants who received DTG withdrew because of adverse events (3%) compared with EFV (10%). Conclusion: Throughout the 96 weeks of the SPRING-1 study, DTG demonstrated sustained efficacy and favorable safety/tolerability in treatment-naive individuals with HIV-1. PMID:23807273

  3. Impaired processing speed and attention in first-episode drug naive schizophrenia with deficit syndrome.

    PubMed

    Chen, Ce; Jiang, Wenhui; Zhong, Na; Wu, Jin; Jiang, Haifeng; Du, Jiang; Li, Ye; Ma, Xiancang; Zhao, Min; Hashimoto, Kenji; Gao, Chengge

    2014-11-01

    Although first-episode drug naive patients with schizophrenia are known to show cognitive impairment, the cognitive performances of these patients, who suffer deficit syndrome, compared with those who suffer non-deficit syndrome is undetermined. The aim of this study was to compare cognitive performances in first-episode drug-naive schizophrenia with deficit syndrome or non-deficit syndrome. First-episode drug naive patients (n=49) and medicated patients (n=108) with schizophrenia, and age, sex, and education matched healthy controls (n=57 for the first-episode group, and n=128 for the medicated group) were enrolled. Patients were divided into deficit or non-deficit syndrome groups, using the Schedule for Deficit Syndrome. Cognitive performance was assessed using the CogState computerized cognitive battery. All cognitive domains in first-episode drug naive and medicated patients showed significant impairment compared with their respective control groups. Furthermore, cognitive performance in first-episode drug naive patients was significantly worse than in medicated patients. Interestingly, the cognitive performance markers of processing speed and attention, in first-episode drug naive patients with deficit syndrome, were both significantly worse than in equivalent patients without deficit syndrome. In contrast, no differences in cognitive performance were found between the two groups of medicated patients. In conclusion, this study found that first-episode drug naive schizophrenia with deficit syndrome showed significantly impaired processing speed and attention, compared with patients with non-deficit syndrome. These findings highlight processing speed and attention as potential targets for pharmacological and psychosocial interventions in first-episode schizophrenia with deficit syndrome, since these domains are associated with social outcomes.

  4. Evaluation of the skin sensitization potential of chemicals using expression of co-stimulatory molecules, CD54 and CD86, on the naive THP-1 cell line.

    PubMed

    Yoshida, Y; Sakaguchi, H; Ito, Y; Okuda, M; Suzuki, H

    2003-04-01

    It has been known that dendritic cells (DCs) including Langerhans cells (LCs) play a critical role in the skin sensitization process. Many attempts have been made to develop in vitro sensitization tests that employ DCs derived from peripheral blood mononuclear cells (PBMC-DC) or CD34+ hematopoietic progenitor cells (CD34+ HPC) purified from cord blood or bone marrow. However, the use of the DCs in in vitro methods has been difficult due to the nature of these cells such as low levels in the source and/or donor-to-donor variability. In our studies, we employed the human monocytic leukemia cell line, THP-1, in order to avoid some of these difficulties. At the start, we examined whether treatment of the cells with various cytokines could produce DCs from THP-1. Treatment of THP-1 cells with cytokines such as GM-CSF, IL-4, TNF-alpha, and/or PMA did induce some phenotypic changes in THP-1 cells that were characteristic of DCs. Subsequently, responses to a known sensitizer, dinitrochlorobenzene (DNCB), and a non-sensitizer, dimethyl sulfoxide (DMSO) or sodium lauryl sulfate (SLS), on the expression of co-stimulatory molecules, CD54 and CD86, were examined between the naive cells and the cytokine-treated cells. Interestingly, the naive THP-1 cells responded only to DNCB and the response to the sensitizer was more distinct than cytokine-treated THP-1 cells. Similar phenomena were also observed in the human myeloid leukemia cell line, KG-1. Furthermore, with treatment of DNCB, naive THP-1 cells showed augmented expression of HLA, CD80 and secretion of IL-1 beta. The response of THP-1 cells to a sensitizer was similar to that of LCs/DCs. Upon demonstrating the differentiation of monocyte cells in our system, we then evaluated a series of chemicals, including known sensitizers and non-sensitizers, for their potential to augment CD54 and CD86 expression on naive THP-1 cells. Indeed, known sensitizers such as PPD and 2-MBT significantly augmented CD54 and CD86 expression in a

  5. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson’s Disease

    PubMed Central

    Kustrimovic, Natasa; Rasini, Emanuela; Legnaro, Massimiliano; Bombelli, Raffaella; Aleksic, Iva; Blandini, Fabio; Comi, Cristoforo; Mauri, Marco; Minafra, Brigida; Riboldazzi, Giulio; Sanchez-Guajardo, Vanesa; Marino, Franca; Cosentino, Marco

    2016-01-01

    Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D1-like DR decrease, while in T memory cells D2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs. PMID:27652978

  6. Effects of neuropeptide FF and related peptides on the antinociceptive activities of VD-hemopressin(α) in naive and cannabinoid-tolerant mice.

    PubMed

    Pan, Jia-Xin; Wang, Zi-Long; Li, Ning; Zhang, Nan; Wang, Pei; Tang, Hong-Hai; Zhang, Ting; Yu, Hong-Ping; Zhang, Run; Zheng, Ting; Fang, Quan; Wang, Rui

    2015-11-15

    Neuropeptide FF (NPFF) system has recently been reported to modulate cannabinoid-induced antinociception. The aim of the present study was to further investigate the roles of NPFF system in the antinociceptive effects induced by intracerebroventricular (i.c.v.) administration of mouse VD-hemopressin(α), a novel endogenous agonist of cannabinoid CB1 receptor, in naive and VD-hemopressin(α)-tolerant mice. The effects of NPFF system on the antinociception induced by VD-hemopressin(α) were investigated in the radiant heat tail-flick test in naive mice and VD-hemopressin(α)-tolerant mice. The cannabinoid-tolerant mice were produced by given daily injections of VD-hemopressin(α) (20 nmol, i.c.v.) for 5 days and the antinociception was measured on day 6. In naive mice, intracerebroventricular injection of NPFF dose-dependently attenuated central analgesia of VD-hemopressin(α). In contrast, neuropeptide VF (NPVF) and D.NP(N-Me)AFLFQPQRF-NH2 (dNPA), two highly selective agonists for Neuropeptide FF1 and Neuropeptide FF2 receptors, enhanced VD-hemopressin(α)-induced antinociception in a dose-dependent manner. In addition, the VD-hemopressin(α)-modulating activities of NPFF and related peptides were antagonized by the Neuropeptide FF receptors selective antagonist 1-adamantanecarbonyl-RF-NH2 (RF9). In VD-hemopressin(α)-tolerant mice, NPFF failed to modify VD-hemopressin(α)-induced antinociception. However, both neuropeptide VF and dNPA dose-dependently potentiated the antinociception of VD-hemopressin(α) and these cannabinoid-potentiating effects were reduced by RF9. The present works support the cannabinoid-modulating character of NPFF system in naive and cannabinoid-tolerant mice. In addition, the data suggest that a chronic cannabinoid treatment modifies the pharmacological profiles of NPFF, but not the cannabinoid-potentiating effects of neuropeptide VF and dNPA.

  7. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis.

    PubMed

    Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H Leighton; Katz, Jonathan D; Finkelman, Fred D; Hildeman, David A

    2007-07-01

    We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2(-/-) mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim(+/-)Bcl-2(-/-) mice, but were largely restored in Bim(-/-)Bcl-2(-/-) mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim(-/-), T cells. Further, T cells from Bim(+/-)Bcl-2(-/-) mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8(+) T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4(+) T cells did not. In contrast, Bim(+/-)Bcl-2(-/-) mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim(+/-)Bcl-2(-/-) mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.

  8. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

    PubMed Central

    Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H. Leighton; Katz, Jonathan D.; Finkelman, Fred D.; Hildeman, David A.

    2007-01-01

    We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells. PMID:17591857

  9. Adenoviral transduction of naive CD4 T cells to study Treg differentiation.

    PubMed

    Warth, Sebastian C; Heissmeyer, Vigo

    2013-08-13

    Regulatory T cells (Tregs) are essential to provide immune tolerance to self as well as to certain foreign antigens. Tregs can be generated from naive CD4 T cells in vitro with TCR- and co-stimulation in the presence of TGFβ and IL-2. This bears enormous potential for future therapies, however, the molecules and signaling pathways that control differentiation are largely unknown. Primary T cells can be manipulated through ectopic gene expression, but common methods fail to target the most important naive state of the T cell prior to primary antigen recognition. Here, we provide a protocol to express ectopic genes in naive CD4 T cells in vitro before inducing Treg differentiation. It applies transduction with the replication-deficient adenovirus and explains its generation and production. The adenovirus can take up large inserts (up to 7 kb) and can be equipped with promoters to achieve high and transient overexpression in T cells. It effectively transduces naive mouse T cells if they express a transgenic Coxsackie adenovirus receptor (CAR). Importantly, after infection the T cells remain naive (CD44(low), CD62L(high)) and resting (CD25(-), CD69(-)) and can be activated and differentiated into Tregs similar to non-infected cells. Thus, this method enables manipulation of CD4 T cell differentiation from its very beginning. It ensures that ectopic gene expression is already in place when early signaling events of the initial TCR stimulation induces cellular changes that eventually lead into Treg differentiation.

  10. Pluripotency-associated miR-290/302 family of microRNAs promote the dismantling of naive pluripotency

    PubMed Central

    Gu, Kai-Li; Zhang, Qiang; Yan, Ying; Li, Ting-Ting; Duan, Fei-Fei; Hao, Jing; Wang, Xi-Wen; Shi, Ming; Wu, Da-Ren; Guo, Wen-Ting; Wang, Yangming

    2016-01-01

    The molecular mechanism controlling the dismantling of naive pluripotency is poorly understood. Here we show that microRNAs (miRNAs) have important roles during naive to primed pluripotency transition. Dgcr8−/− embryonic stem cells (ESCs) failed to completely silence the naive pluripotency program, as well as to establish the primed pluripotency program during differentiation. miRNA profiling revealed that expression levels of a large number of miRNAs changed dynamically and rapidly during naive to primed pluripotency transition. Furthermore, a miRNA screen identified numerous miRNAs promoting naive to primed pluripotency transition. Unexpectedly, multiple miRNAs from miR-290 and miR-302 clusters, previously shown as pluripotency-promoting miRNAs, demonstrated the strongest effects in silencing naive pluripotency. Knockout of both miR-290 and miR-302 clusters but not either alone blocked the silencing of naive pluripotency program. Mechanistically, the miR-290/302 family of miRNAs may facilitate the exit of naive pluripotency in part by promoting the activity of MEK pathway and through directly repressing Akt1. Our study reveals miRNAs as an important class of regulators potentiating ESCs to transition from naive to primed pluripotency, and uncovers context-dependent functions of the miR-290/302 family of miRNAs at different developmental stages. PMID:26742694

  11. Consistent Safety and Infectivity in Sporozoite Challenge Model of Plasmodium vivax in Malaria-Naive Human Volunteers

    PubMed Central

    Herrera, Sócrates; Solarte, Yezid; Jordán-Villegas, Alejandro; Echavarría, Juan Fernando; Rocha, Leonardo; Palacios, Ricardo; Ramírez, Óscar; Vélez, Juan D.; Epstein, Judith E.; Richie, Thomas L.; Arévalo-Herrera, Myriam

    2011-01-01

    A safe and reproducible Plasmodium vivax infectious challenge method is required to evaluate the efficacy of malaria vaccine candidates. Seventeen healthy Duffy (+) and five Duffy (−) subjects were randomly allocated into three (A–C) groups and were exposed to the bites of 2–4 Anopheles albimanus mosquitoes infected with Plasmodium vivax derived from three donors. Duffy (−) subjects were included as controls for each group. Clinical manifestations of malaria and parasitemia were monitored beginning 7 days post-challenge. All Duffy (+) volunteers developed patent malaria infection within 16 days after challenge. Prepatent period determined by thick smear, was longer for Group A (median 14.5 d) than for Groups B and C (median 10 d/each). Infected volunteers recovered rapidly after treatment with no serious adverse events. The bite of as low as two P. vivax-infected mosquitoes provides safe and reliable infections in malaria-naive volunteers, suitable for assessing antimalarial and vaccine efficacy trials. PMID:21292872

  12. The Persistence of Solid and Liquid Naive Conceptions: A Reaction Time Study

    NASA Astrophysics Data System (ADS)

    Babai, Reuven; Amsterdamer, Anat

    2008-12-01

    The study explores whether the naive concepts of solid and liquid persist in adolescence. Accuracy of responses and reaction times where measured while 41 ninth graders classified different solids (rigid, non-rigid and powders) and different liquids (runny, dense) into solid or liquid. The results show that these naive conceptions affect adolescences' classifications in terms of both accuracy and reaction time. The rate of correct classifications of non-rigid solids and powders was significantly lower than of rigid solids. Lower rate of success was also found for classification of dense liquids compared with runny liquids. In addition, the reaction time results of correct classifications for non-rigid solids and powders were longer than those for rigid solids and, likewise, reaction times for dense liquids were longer than for runny ones. These results suggest that reasoning processes associated with correct classification of objects that are not consistent with the naive conceptions are more demanding.

  13. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition.

    PubMed

    Sperber, Henrik; Mathieu, Julie; Wang, Yuliang; Ferreccio, Amy; Hesson, Jennifer; Xu, Zhuojin; Fischer, Karin A; Devi, Arikketh; Detraux, Damien; Gu, Haiwei; Battle, Stephanie L; Showalter, Megan; Valensisi, Cristina; Bielas, Jason H; Ericson, Nolan G; Margaretha, Lilyana; Robitaille, Aaron M; Margineantu, Daciana; Fiehn, Oliver; Hockenbery, David; Blau, C Anthony; Raftery, Daniel; Margolin, Adam A; Hawkins, R David; Moon, Randall T; Ware, Carol B; Ruohola-Baker, Hannele

    2015-12-01

    For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs).  Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development. PMID:26571212

  14. Hepatitis B and hepatitis C virus infections among antiretroviral-naive and -experienced HIV co-infected adults.

    PubMed

    Manyazewal, Tsegahun; Sisay, Zufan; Biadgilign, Sibhatu; Abegaz, Woldaregay Erku

    2014-05-01

    Most HIV positive people have not been tested for viral hepatitis and their treatments have not been optimized for possible co-infections. The aim of this study was to investigate the serological pattern of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among antiretroviral (ARV)-naive and -experienced HIV co-infected adults in Addis Ababa, Ethiopia. A total of 500 frozen HIV positive serum and plasma samples collected from ARV-naive (n = 250) and -experienced (n = 250) adults were randomly selected and screened for HBsAg, anti-HBs, HBeAg and anti-HCV using rapid two-site sandwich immunochromatographic assay. The test was performed at Aklilu Lemma Institute of Pathobiology, Addis Ababa University. Positive specimens for HBsAg and anti-HCV markers were further confirmed using third generation ELISA. Of the 500 specimens tested, 15 (3 %), 58 (11.6 %), 3 (0.6 %), 18 (3.6 %), 3 (0.6 %) and 1 (0.2 %) were positive for HBsAg, anti-HBs, HBeAg, anti-HCV, HBsAg and HBeAg, and HBsAg and anti-HBs markers, respectively. No specimen tested positive for both HBeAg and anti-HBs, and 442 (88.4 %) individuals were non-immune to HBV. Of the 250 ARV-naive individuals, 8 (3.2 %), 33 (13.2 %), 2 (0.8 %), 10 (4 %), 2 (0.8 %), and 1 (0.4 %) were positive for HBsAg, anti-HBs, HBeAg, anti-HCV, HBsAg and HBeAg, and HBsAg and anti-HBs markers, respectively. Of the 250 ARV-experienced individuals, 7 (2.8 %), 25 (10 %), 1 (0.4 %), 8 (3.2 %), 1 (0.4 %), and 0 (0 %) were positive for HBsAg, Anti-HBs, HBeAg, anti-HCV, HBsAg and HBeAg, and HBsAg and anti-HBs markers, respectively. In summary, seroprevalence of HIV/HBV and HIV/HCV co-infections was lower in Addis Ababa, Ethiopia, than in Sub-Saharan Africa and globally. HBV and HCV infections were not significantly different between HIV positive subjects who were or who were not on ARV. This suggests that the two groups have equal chance of being infected with these two viruses; despite

  15. In Vivo HIV-1 Hypermutation and Viral Loads Among Antiretroviral-Naive Brazilian Patients

    PubMed Central

    de Lima-Stein, Mariana Leão; Alkmim, Wagner Tadeu; Bizinoto, Maria Clara de Souza; Lopez, Luis Fernandez; Burattini, Marcelo Nascimento; Maricato, Juliana Terzi; Giron, Leila; Sucupira, Maria Cecília Araripe; Diaz, Ricardo Sobhie

    2014-01-01

    Abstract Hypermutation alludes to an excessive number of specific guanine-to-adenine (G- >A) substitutions in proviral DNA and this phenomenon is attributed to the catalytic activity of cellular APOBECs. Population studies relating hypermutation and the progression of infection by human immunodeficiency virus type 1 (HIV-1) have been performed to elucidate the effect of hypermutation on the natural course of HIV-1 infection. However, the many different approaches employed to assess hypermutation in nucleotide sequences render the comparison of results difficult. This study selected 157 treatment-naive patients and sought to correlate the hypermutation level of the proviral sequences in clinical samples with demographic variables, HIV-1 RNA viral load, and the level of CD4+ T cells. Nested touchdown polymerase chain reaction (PCR) was performed with specific primers to detect hypermutation in the region of HIV-1 integrase, and the amplified sequences were run in agarose gels with HA-Yellow. The analysis of gel migration patterns using the k-means clustering method was validated by its agreement with the results obtained with the software Hypermut. Hypermutation was found in 31.2% of the investigated samples, and a correlation was observed between higher hypermutation levels and higher viral load levels. These findings suggest a high frequency of hypermutation detection in a Brazilian cohort, which can reflect a particular characteristic of this population, but also can result from the method approach by aiming at hypermutation-sensitive sites. Furthermore, we found that hypermutation events are pervasive during HIV-1 infection as a consequence of high viral replication, reflecting its role during disease progression. PMID:25065371

  16. Testing the Development of Linguistic Knowledge in Adult Naive Learners of American Sign Language

    ERIC Educational Resources Information Center

    Von Pein, Margreta; Altarriba, Jeanette

    2011-01-01

    The present study was designed to investigate the ways in which notions of semantics and phonology are acquired by adult naive learners of American Sign Language (ASL) when they are first exposed to a set of simple signs. First, a set of ASL signs was tested for nontransparency and a set of signs was selected for subsequent use. Next, a set of…

  17. 'Educated' dendritic cells act as messengers from memory to naive T helper cells.

    PubMed

    Alpan, Oral; Bachelder, Eric; Isil, Eda; Arnheiter, Heinz; Matzinger, Polly

    2004-06-01

    Ingested antigens lead to the generation of effector T cells that secrete interleukin 4 (IL-4) rather than interferon-gamma (IFN-gamma) and are capable of influencing naive T cells in their immediate environment to do the same. Using chimeric mice generated by aggregation of two genotypically different embryos, we found that the conversion of a naive T cell occurs only if it can interact with the same antigen-presenting cell, although not necessarily the same antigen, as the effector T cell. Using a two-step culture system in vitro, we found that antigen-presenting dendritic cells can act as 'temporal bridges' to relay information from orally immunized memory CD4 T cells to naive CD4 T cells. The orally immunized T cells use IL-4 and IL-10 (but not CD40 ligand) to 'educate' dendritic cells, which in turn induce naive T cells to produce the same cytokines as those produced by the orally immunized memory T cells.

  18. Is Children's Naive Knowledge Consistent?: A Comparison of the Concepts of Sound and Heat

    ERIC Educational Resources Information Center

    Lautrey, Jacques; Mazens, Karine

    2004-01-01

    The aim of this study was to shed some light on the organization of naive knowledge, and on the process of conceptual change in everyday physics, more specifically regarding the concepts of sound and heat. Eighty-three 8-year-old children were interviewed individually in order to see if they attributed the properties of objects (such as…

  19. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

    PubMed Central

    Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony J.; Yamamoto, Tori N.; Cruz, Anthony C.; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Thomas, Stacy K.; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Siegel, Richard M.; Restifo, Nicholas P.

    2015-01-01

    Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell–T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory–induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell–based immunotherapies. PMID:26657860

  20. The Effect of Naive Ideas on Students' Reasoning about Electricity and Magnetism

    ERIC Educational Resources Information Center

    Leppavirta, Johanna

    2012-01-01

    Traditional multiple-choice concept inventories measure students' critical conceptual understanding and are designed to reveal students' naive or alternate ideas. The overall scores, however, give little information about the state of students' knowledge and the consistency of reasoning. This study investigates whether students have consistent…

  1. Characterization of the finch embryo supports evolutionary conservation of the naive stage of development in amniotes

    PubMed Central

    Mak, Siu-Shan; Alev, Cantas; Nagai, Hiroki; Wrabel, Anna; Matsuoka, Yoko; Honda, Akira; Sheng, Guojun; Ladher, Raj K

    2015-01-01

    Innate pluripotency of mouse embryos transits from naive to primed state as the inner cell mass differentiates into epiblast. In vitro, their counterparts are embryonic (ESCs) and epiblast stem cells (EpiSCs), respectively. Activation of the FGF signaling cascade results in mouse ESCs differentiating into mEpiSCs, indicative of its requirement in the shift between these states. However, only mouse ESCs correspond to the naive state; ESCs from other mammals and from chick show primed state characteristics. Thus, the significance of the naive state is unclear. In this study, we use zebra finch as a model for comparative ESC studies. The finch blastoderm has mESC-like properties, while chick blastoderm exhibits EpiSC features. In the absence of FGF signaling, finch cells retained expression of pluripotent markers, which were lost in cells from chick or aged finch epiblasts. Our data suggest that the naive state of pluripotency is evolutionarily conserved among amniotes. DOI: http://dx.doi.org/10.7554/eLife.07178.001 PMID:26359635

  2. Observation of the naive-T-odd Sivers effect in deep-inelastic scattering.

    PubMed

    Airapetian, A; Akopov, N; Akopov, Z; Aschenauer, E C; Augustyniak, W; Avetissian, A; Avetisyan, E; Bacchetta, A; Ball, B; Bianchi, N; Blok, H P; Böttcher, H; Bonomo, C; Borissov, A; Bryzgalov, V; Burns, J; Capiluppi, M; Capitani, G P; Cisbani, E; Ciullo, G; Contalbrigo, M; Dalpiaz, P F; Deconinck, W; De Leo, R; De Nardo, L; De Sanctis, E; Diefenthaler, M; Di Nezza, P; Dreschler, J; Düren, M; Ehrenfried, M; Elbakian, G; Ellinghaus, F; Elschenbroich, U; Fabbri, R; Fantoni, A; Felawka, L; Frullani, S; Gabbert, D; Gapienko, G; Gapienko, V; Garibaldi, F; Gharibyan, V; Giordano, F; Gliske, S; Hadjidakis, C; Hartig, M; Hasch, D; Hill, G; Hillenbrand, A; Hoek, M; Holler, Y; Hristova, I; Imazu, Y; Ivanilov, A; Jackson, H E; Jo, H S; Joosten, S; Kaiser, R; Keri, T; Kinney, E; Kisselev, A; Korotkov, V; Kozlov, V; Kravchenko, P; Lagamba, L; Lamb, R; Lapikás, L; Lehmann, I; Lenisa, P; Linden-Levy, L A; López Ruiz, A; Lorenzon, W; Lu, X-G; Lu, X-R; Ma, B-Q; Mahon, D; Makins, N C R; Manaenkov, S I; Manfré, L; Mao, Y; Marianski, B; Martinez de la Ossa, A; Marukyan, H; Miller, C A; Miyachi, Y; Movsisyan, A; Murray, M; Mussgiller, A; Nappi, E; Naryshkin, Y; Nass, A; Negodaev, M; Nowak, W-D; Pappalardo, L L; Perez-Benito, R; Reimer, P E; Reolon, A R; Riedl, C; Rith, K; Rosner, G; Rostomyan, A; Rubin, J; Ryckbosch, D; Salomatin, Y; Sanftl, F; Schäfer, A; Schnell, G; Schüler, K P; Seitz, B; Shibata, T-A; Shutov, V; Stancari, M; Statera, M; Steijger, J J M; Stenzel, H; Stewart, J; Stinzing, F; Taroian, S; Terkulov, A; Trzcinski, A; Tytgat, M; Vandenbroucke, A; van der Nat, P B; Van Haarlem, Y; Van Hulse, C; Varanda, M; Veretennikov, D; Vikhrov, V; Vilardi, I; Vogel, C; Wang, S; Yaschenko, S; Ye, H; Ye, Z; Yen, S; Yu, W; Zeiler, D; Zihlmann, B; Zupranski, P

    2009-10-01

    Azimuthal single-spin asymmetries of leptoproduced pions and charged kaons were measured on a transversely polarized hydrogen target. Evidence for a naive-T-odd, transverse-momentum-dependent parton distribution function is deduced from nonvanishing Sivers effects for pi(+), pi(0), and K(+/-), as well as in the difference of the pi(+) and pi(-) cross sections. PMID:19905623

  3. Children's Naive Theories of Intelligence Influence Their Metacognitive Judgments

    ERIC Educational Resources Information Center

    Miele, David B.; Son, Lisa K.; Metcalfe, Janet

    2013-01-01

    Recent studies have shown that the metacognitive judgments adults infer from their experiences of encoding effort vary in accordance with their naive theories of intelligence. To determine whether this finding extends to elementary schoolchildren, a study was conducted in which 27 third graders (M[subscript age] = 8.27) and 24 fifth graders…

  4. An Investigation of Factors Affecting the Degree of Naive Impetus Theory Application

    ERIC Educational Resources Information Center

    Liu, Xiufeng; MacIsaac, Dan

    2005-01-01

    This study investigates factors affecting the degree of novice physics students application of the naive impetus theory. Six hundred and fourteen first-year university engineering physics students answered the Force Concept Inventory as a pre-test for their calculus-based course. We examined the degree to which students consistently applied the…

  5. Corpus Callosum Anatomy in Chronically Treated and Stimulant Naive ADHD

    ERIC Educational Resources Information Center

    Schnoebelen, Sarah; Semrud-Clikeman, Margaret; Pliszka, Steven R.

    2010-01-01

    Objective: To determine the effect of chronic stimulant treatment on corpus callosum (CC) size in children with ADHD using volumetric and area measurements. Previously published research indicated possible medication effects on specific areas of the CC. Method: Measurements of the CC from anatomical MRIs were obtained from children aged 9-16 in…

  6. From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD.

    PubMed

    Brandenburg, Vincent M; D'Haese, Patrick; Deck, Annika; Mekahli, Djalila; Meijers, Björn; Neven, Ellen; Evenepoel, Pieter

    2016-02-01

    Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology. PMID:25735207

  7. Effects of Dopamine D2/D3 Blockade on Human Sensory and Sensorimotor Gating in Initially Antipsychotic-Naive, First-Episode Schizophrenia Patients

    PubMed Central

    Düring, Signe; Glenthøj, Birte Y; Andersen, Gitte Saltoft; Oranje, Bob

    2014-01-01

    It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits. PMID:24954063

  8. Differentiation of IL-17-producing effector and regulatory human T cells from lineage-committed naive precursors.

    PubMed

    Mercer, Frances; Khaitan, Alka; Kozhaya, Lina; Aberg, Judith A; Unutmaz, Derya

    2014-08-01

    A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17(+) Tregs differentiate from naive precursors remains unclear. In this study, we show that IL-17-producing T cells can differentiate from CCR6(+) naive T cell precursors in the presence of IL-2, IL-1β, TGF-β, and IL-23. CCR6(+) naive T cells are present in adult peripheral and umbilical cord blood and in both conventional T naive and FOXP3(+) naive Treg subsets. IL-17(+) cells derived from CCR6(+) naive Tregs (referred to as IL-17(+) Tregs) express FOXP3 but not HELIOS, another Treg-associated transcription factor, and these cells display suppressor capacity and a surface phenotype resembling memory Tregs. Remarkably, the IL-17(+) Treg compartment was preferentially reduced relative to the canonical Th17 and Treg compartments in a subset of HIV(+) subjects, suggesting a specific perturbation of this subset during the course of disease. Our findings that CCR6(+) naive precursors contain a predetermined reservoir to replenish IL-17-secreting cells may have implications in balancing the Th17 and IL-17(+) Treg compartments that are perturbed during HIV infection and potentially in other inflammatory diseases.

  9. Relatively High Prevalence of Drug Resistance Among Antiretroviral-Naive Patients from Henan, Central China

    PubMed Central

    Li, Lingnuo; Sun, Binlian; Zeng, Haiyan; Sun, Zhiwu; Sun, Guoqing

    2014-01-01

    Abstract To elucidate the prevalence of HIV-1 subtypes and transmitted drug resistance in Henan, central China, HIV-1-positive blood samples from 187 antiretroviral-naive patients were collected in our study from August 2009 to November 2010. Subtype B′ (92.0%, 172 of 187) remains the predominant HIV-1 subtype in Henan province and was prevalent in all risk populations and geographic regions. Of 98 pol sequences 67 (68.4%) harbored drug resistance mutations, and only 14 (14.3%, 14 of 98) sequences have mutations associated with significantly reduced phenotypic susceptibility to antiretroviral drugs. The unexpectedly high percentage of drug resistance in Henan province is mainly due to the prevalence of minor mutations in the protease and integrase regions, especially A71T/V and L68V/I/IM/LV. In all, we detected a relatively high prevalence of drug resistance with unique mutation distributions among antiretroviral-naive patients from Henan province. PMID:23800338

  10. Abnormal causal connectivity by structural deficits in first-episode, drug-naive schizophrenia at rest.

    PubMed

    Guo, Wenbin; Liu, Feng; Liu, Jianrong; Yu, Liuyu; Zhang, Jian; Zhang, Zhikun; Xiao, Changqing; Zhai, Jinguo; Zhao, Jingping

    2015-01-01

    Anatomical deficits and resting-state functional connectivity (FC) alterations in prefrontal-thalamic-cerebellar circuit have been implicated in the neurobiology of schizophrenia. However, the effect of structural deficits in schizophrenia on causal connectivity of this circuit remains unclear. This study was conducted to examine the causal connectivity biased by structural deficits in first-episode, drug-naive schizophrenia patients. Structural and resting-state functional magnetic resonance imaging (fMRI) data were obtained from 49 first-episode, drug-naive schizophrenia patients and 50 healthy controls. Data were analyzed by voxel-based morphometry and Granger causality analysis. The causal connectivity of the integrated prefrontal-thalamic (limbic)-cerebellar (sensorimotor) circuit was partly affected by structural deficits in first-episode, drug-naive schizophrenia as follows: (1) unilateral prefrontal-sensorimotor connectivity abnormalities (increased driving effect from the left medial prefrontal cortex [MPFC] to the sensorimotor regions); (2) bilateral limbic-sensorimotor connectivity abnormalities (increased driving effect from the right anterior cingulate cortex [ACC] to the sensorimotor regions and decreased feedback from the sensorimotor regions to the right ACC); and (3) bilateral increased and decreased causal connectivities among the sensorimotor regions. Some correlations between the gray matter volume of the seeds, along with their causal effects and clinical variables (duration of untreated psychosis and symptom severity), were also observed in the patients. The findings indicated the partial effects of structural deficits in first-episode, drug-naive schizophrenia on the prefrontal-thalamic (limbic)-cerebellar (sensorimotor) circuit. Schizophrenia may reinforce the driving connectivities from the left MPFC or right ACC to the sensorimotor regions and may disrupt bilateral causal connectivities among the sensorimotor regions.

  11. Naive (commonsense) geography and geobrowser usability after ten years of Google Earth

    NASA Astrophysics Data System (ADS)

    Hamerlinck, J. D.

    2016-04-01

    In 1995, the concept of ‘naive geography’ was formally introduced as an area of cognitive geographic information science representing ‘the body of knowledge that people have about the surrounding geographic world’ and reflecting ‘the way people think and reason about geographic space and time, both consciously and subconsciously’. The need to incorporate such commonsense knowledge and reasoning into design of geospatial technologies was identified but faced challenges in formalizing these relationships and processes in software implementation. Ten years later, the Google Earth geobrowser was released, marking the beginning of a new era of open access to, and application of, geographic data and information in society. Fast-forward to today, and the opportunity presents itself to take stock of twenty years of naive geography and a decade of the ubiquitous virtual globe. This paper introduces an ongoing research effort to explore the integration of naive (or commonsense) geography concepts in the Google Earth geobrowser virtual globe and their possible impact on Google Earth's usability, utility, and usefulness. A multi-phase methodology is described, combining usability reviews and usability testing with use-case scenarios involving the U.S.-Canadian Yellowstone to Yukon Initiative. Initial progress on a usability review combining cognitive walkthroughs and heuristics evaluation is presented.

  12. Reinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency

    PubMed Central

    Chen, Hongwei; Aksoy, Irène; Gonnot, Fabrice; Osteil, Pierre; Aubry, Maxime; Hamela, Claire; Rognard, Cloé; Hochard, Arnaud; Voisin, Sophie; Fontaine, Emeline; Mure, Magali; Afanassieff, Marielle; Cleroux, Elouan; Guibert, Sylvain; Chen, Jiaxuan; Vallot, Céline; Acloque, Hervé; Genthon, Clémence; Donnadieu, Cécile; De Vos, John; Sanlaville, Damien; Guérin, Jean- François; Weber, Michael; Stanton, Lawrence W; Rougeulle, Claire; Pain, Bertrand; Bourillot, Pierre-Yves; Savatier, Pierre

    2015-01-01

    Leukemia inhibitory factor (LIF)/STAT3 signalling is a hallmark of naive pluripotency in rodent pluripotent stem cells (PSCs), whereas fibroblast growth factor (FGF)-2 and activin/nodal signalling is required to sustain self-renewal of human PSCs in a condition referred to as the primed state. It is unknown why LIF/STAT3 signalling alone fails to sustain pluripotency in human PSCs. Here we show that the forced expression of the hormone-dependent STAT3-ER (ER, ligand-binding domain of the human oestrogen receptor) in combination with 2i/LIF and tamoxifen allows human PSCs to escape from the primed state and enter a state characterized by the activation of STAT3 target genes and long-term self-renewal in FGF2- and feeder-free conditions. These cells acquire growth properties, a gene expression profile and an epigenetic landscape closer to those described in mouse naive PSCs. Together, these results show that temporarily increasing STAT3 activity is sufficient to reprogramme human PSCs to naive-like pluripotent cells. PMID:25968054

  13. Ensemble of Chaotic and Naive Approaches for Performance Enhancement in Video Encryption

    PubMed Central

    Chandrasekaran, Jeyamala; Thiruvengadam, S. J.

    2015-01-01

    Owing to the growth of high performance network technologies, multimedia applications over the Internet are increasing exponentially. Applications like video conferencing, video-on-demand, and pay-per-view depend upon encryption algorithms for providing confidentiality. Video communication is characterized by distinct features such as large volume, high redundancy between adjacent frames, video codec compliance, syntax compliance, and application specific requirements. Naive approaches for video encryption encrypt the entire video stream with conventional text based cryptographic algorithms. Although naive approaches are the most secure for video encryption, the computational cost associated with them is very high. This research work aims at enhancing the speed of naive approaches through chaos based S-box design. Chaotic equations are popularly known for randomness, extreme sensitivity to initial conditions, and ergodicity. The proposed methodology employs two-dimensional discrete Henon map for (i) generation of dynamic and key-dependent S-box that could be integrated with symmetric algorithms like Blowfish and Data Encryption Standard (DES) and (ii) generation of one-time keys for simple substitution ciphers. The proposed design is tested for randomness, nonlinearity, avalanche effect, bit independence criterion, and key sensitivity. Experimental results confirm that chaos based S-box design and key generation significantly reduce the computational cost of video encryption with no compromise in security. PMID:26550603

  14. Joint decision and Naive Bayes learning for detection of space multi-target

    NASA Astrophysics Data System (ADS)

    Huang, Tao; Li, Zhulian; Zhou, Yu; Xiong, Yaoheng; Zhang, Haitao

    2014-07-01

    In the photoelectric tracking system, the detection of space multi-target is crucial for target localization and tracking. The difficulties include the interferences from CCD smear and strong noise, the few characteristics of spot-like targets and the challenge of multiple targets. In this paper, we propose a hybrid algorithm of joint decision and Naive Bayes (JD-NB) learning, and present the duty ratio feature to discriminate the target and smear blocks. Firstly, we extract the proper features and train the parameters of the Naive Bayes classifier. Secondly, target blocks are preliminarily estimated with the Naive Bayes. Lastly, the 4-adjacent blocks of the candidate target blocks are jointed to analyze the distribution pattern and the true target blocks are secondarily extracted by the method of pattern matching. Experimental results indicate that the proposed JD-NB algorithm not only possesses a high recognition rate of better than 90% for the target block, but also effectively overcomes the disturbance of the smear block. Moreover, it performs well in the detection of small and faint targets when the SNR of the block is higher than about 0.014.

  15. Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis.

    PubMed

    Boroviak, Thorsten; Loos, Remco; Lombard, Patrick; Okahara, Junko; Behr, Rüdiger; Sasaki, Erika; Nichols, Jennifer; Smith, Austin; Bertone, Paul

    2015-11-01

    Naive pluripotency is manifest in the preimplantation mammalian embryo. Here we determine transcriptome dynamics of mouse development from the eight-cell stage to postimplantation using lineage-specific RNA sequencing. This method combines high sensitivity and reporter-based fate assignment to acquire the full spectrum of gene expression from discrete embryonic cell types. We define expression modules indicative of developmental state and temporal regulatory patterns marking the establishment and dissolution of naive pluripotency in vivo. Analysis of embryonic stem cells and diapaused embryos reveals near-complete conservation of the core transcriptional circuitry operative in the preimplantation epiblast. Comparison to inner cell masses of marmoset primate blastocysts identifies a similar complement of pluripotency factors but use of alternative signaling pathways. Embryo culture experiments further indicate that marmoset embryos utilize WNT signaling during early lineage segregation, unlike rodents. These findings support a conserved transcription factor foundation for naive pluripotency while revealing species-specific regulatory features of lineage segregation. PMID:26555056

  16. Ensemble of Chaotic and Naive Approaches for Performance Enhancement in Video Encryption.

    PubMed

    Chandrasekaran, Jeyamala; Thiruvengadam, S J

    2015-01-01

    Owing to the growth of high performance network technologies, multimedia applications over the Internet are increasing exponentially. Applications like video conferencing, video-on-demand, and pay-per-view depend upon encryption algorithms for providing confidentiality. Video communication is characterized by distinct features such as large volume, high redundancy between adjacent frames, video codec compliance, syntax compliance, and application specific requirements. Naive approaches for video encryption encrypt the entire video stream with conventional text based cryptographic algorithms. Although naive approaches are the most secure for video encryption, the computational cost associated with them is very high. This research work aims at enhancing the speed of naive approaches through chaos based S-box design. Chaotic equations are popularly known for randomness, extreme sensitivity to initial conditions, and ergodicity. The proposed methodology employs two-dimensional discrete Henon map for (i) generation of dynamic and key-dependent S-box that could be integrated with symmetric algorithms like Blowfish and Data Encryption Standard (DES) and (ii) generation of one-time keys for simple substitution ciphers. The proposed design is tested for randomness, nonlinearity, avalanche effect, bit independence criterion, and key sensitivity. Experimental results confirm that chaos based S-box design and key generation significantly reduce the computational cost of video encryption with no compromise in security. PMID:26550603

  17. Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis

    PubMed Central

    Boroviak, Thorsten; Loos, Remco; Lombard, Patrick; Okahara, Junko; Behr, Rüdiger; Sasaki, Erika; Nichols, Jennifer; Smith, Austin; Bertone, Paul

    2015-01-01

    Summary Naive pluripotency is manifest in the preimplantation mammalian embryo. Here we determine transcriptome dynamics of mouse development from the eight-cell stage to postimplantation using lineage-specific RNA sequencing. This method combines high sensitivity and reporter-based fate assignment to acquire the full spectrum of gene expression from discrete embryonic cell types. We define expression modules indicative of developmental state and temporal regulatory patterns marking the establishment and dissolution of naive pluripotency in vivo. Analysis of embryonic stem cells and diapaused embryos reveals near-complete conservation of the core transcriptional circuitry operative in the preimplantation epiblast. Comparison to inner cell masses of marmoset primate blastocysts identifies a similar complement of pluripotency factors but use of alternative signaling pathways. Embryo culture experiments further indicate that marmoset embryos utilize WNT signaling during early lineage segregation, unlike rodents. These findings support a conserved transcription factor foundation for naive pluripotency while revealing species-specific regulatory features of lineage segregation. PMID:26555056

  18. The BMP Pathway Participates in Human Naive CD4+ T Cell Activation and Homeostasis

    PubMed Central

    Martínez, Víctor G.; Sacedón, Rosa; Hidalgo, Laura; Valencia, Jaris; Fernández-Sevilla, Lidia M.; Hernández-López, Carmen

    2015-01-01

    Bone Morphogenetic Proteins (BMPs) form a group of secreted factors that belongs to the TGF-β superfamily. Among different roles in a number of immune cell types, BMPs are known to regulate T cell development within the thymus, although the role of BMP signaling in human mature T cells remains elusive. In this study, we demonstrate that canonical BMP signaling is necessary during two critical events that regulate the size and function of human naive CD4+ T cell population: activation and homeostasis. Upon stimulation via TCR, naive CD4+ T cells upregulate the expression of BMP ligands triggering canonical BMP signaling in CD25+ cells. Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling. Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis. Moreover, upregulation of two critical receptors for T cell homeostasis, CXCR4 and CCR9, triggered by IL-7 is also abrogated in the absence of BMP signaling. Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application. PMID:26110906

  19. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude.

    PubMed

    Moon, James J; Chu, H Hamlet; Pepper, Marion; McSorley, Stephen J; Jameson, Stephen C; Kedl, Ross M; Jenkins, Marc K

    2007-08-01

    Cell-mediated immunity stems from the proliferation of naive T lymphocytes expressing T cell antigen receptors (TCRs) specific for foreign peptides bound to host major histocompatibility complex (MHC) molecules. Because of the tremendous diversity of the T cell repertoire, naive T cells specific for any one peptide:MHC complex (pMHC) are extremely rare. Thus, it is not known how many naive T cells of any given pMHC specificity exist in the body or how that number influences the immune response. By using soluble pMHC class II (pMHCII) tetramers and magnetic bead enrichment, we found that three different pMHCII-specific naive CD4(+) T cell populations vary in frequency from 20 to 200 cells per mouse. Moreover, naive population size predicted the size and TCR diversity of the primary CD4(+) T cell response after immunization with relevant peptide. Thus, variation in naive T cell frequencies can explain why some peptides are stronger immunogens than others. PMID:17707129

  20. D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with (11C)raclopride

    SciTech Connect

    Farde, L.; Wiesel, F.A.; Stone-Elander, S.; Halldin, C.; Nordstroem, A.L.H.; Hall, H.; Sedvall, G. )

    1990-03-01

    Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and ({sup 11}C)raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.

  1. A Naive-Bayes model observer for detection and localization of perfusion defects in cardiac SPECT-MPI

    NASA Astrophysics Data System (ADS)

    Parages, Felipe M.; O'Connor, J. Michael; Pretorius, P. Hendrik; Brankov, Jovan G.

    2014-03-01

    Model observers (MO) are widely used in medical imaging to act as surrogates of human observers in task-based image quality evaluation, frequently towards optimization of reconstruction algorithms. In SPECT myocardial perfusion imaging (MPI), a realistic task-based approach involves detection and localization of perfusion defects, as well as a subsequent assessment of defect severity. In this paper we explore a machine-learning MO based on Naive- Bayes classification (NB-MO). NB-MO uses a set of polar-map image features to predict lesion detection, localization and severity scores given by five human readers for a set of simulated 3D SPECT-MPI patients. The simulated dataset included lesions with different sizes, perfusion-reduction ratios, and locations. Simulated projections were reconstructed using two readily used methods namely: FBP and OSEM. For validation, a multireader multi-case (MRMC) analysis of alternative free-response ROC (AFROC) curve was performed for NB-MO and human observers. For comparison, we also report performances of a statistical Hotelling Observer applied on polar-map images. Results show excellent agreement between NB-MO and humans, as well as model's good generalization between different reconstruction treatments.

  2. Risk of erectile dysfunction in transfusion-naive thalassemia men: a nationwide population-based retrospective cohort study.

    PubMed

    Chen, Yu-Guang; Lin, Te-Yu; Lin, Cheng-Li; Dai, Ming-Shen; Ho, Ching-Liang; Kao, Chia-Hung

    2015-04-01

    Based on the mechanism of pathophysiology, thalassemia major or transfusion-dependent thalassemia patients may have an increased risk of developing organic erectile dysfunction resulting from hypogonadism. However, there have been few studies investigating the association between erectile dysfunction and transfusion-naive thalassemia populations. We constructed a population-based cohort study to elucidate the association between transfusion-naive thalassemia populations and organic erectile dysfunction. This nationwide population-based cohort study involved analyzing data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified men with transfusion-naive thalassemia and selected a comparison cohort that was frequency-matched with these according to age, and year of diagnosis thalassemia at a ratio of 1 thalassemia man to 4 control men. We analyzed the risks for transfusion-naive thalassemia men and organic erectile dysfunction by using Cox proportional hazards regression models. In this study, 588 transfusion-naive thalassemia men and 2337 controls were included. Total 12 patients were identified within the thalassaemia group and 10 within the control group. The overall risks for developing organic erectile dysfunction were 4.56-fold in patients with transfusion-naive thalassemia men compared with the comparison cohort after we adjusted for age and comorbidities. Our long-term cohort study results showed that in transfusion-naive thalassemia men, there was a higher risk for the development of organic erectile dysfunction, particularly in those patients with comorbidities.

  3. The sudden emergence of pathogenicity in insect–fungus symbioses threatens naive forest ecosystems

    PubMed Central

    Hulcr, Jiri; Dunn, Robert R.

    2011-01-01

    Invasive symbioses between wood-boring insects and fungi are emerging as a new and currently uncontrollable threat to forest ecosystems, as well as fruit and timber industries throughout the world. The bark and ambrosia beetles (Curculionidae: Scolytinae and Platypodinae) constitute the large majority of these pests, and are accompanied by a diverse community of fungal symbionts. Increasingly, some invasive symbioses are shifting from non-pathogenic saprotrophy in native ranges to a prolific tree-killing in invaded ranges, and are causing significant damage. In this paper, we review the current understanding of invasive insect–fungus symbioses. We then ask why some symbioses that evolved as non-pathogenic saprotrophs, turn into major tree-killers in non-native regions. We argue that a purely pathology-centred view of the guild is not sufficient for explaining the lethal encounters between exotic symbionts and naive trees. Instead, we propose several testable hypotheses that, if correct, lead to the conclusion that the sudden emergence of pathogenicity is a new evolutionary phenomenon with global biogeographical dynamics. To date, evidence suggests that virulence of the symbioses in invaded ranges is often triggered when several factors coincide: (i) invasion into territories with naive trees, (ii) the ability of the fungus to either overcome resistance of the naive host or trigger a suicidal over-reaction, and (iii) an ‘olfactory mismatch’ in the insect whereby a subset of live trees is perceived as dead and suitable for colonization. We suggest that individual cases of tree mortality caused by invasive insect–fungus symbionts should no longer be studied separately, but in a global, biogeographically and phylogenetically explicit comparative framework. PMID:21752822

  4. Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Björklund, Andreas T; Clancy, Trevor; Goodridge, Jodie P; Béziat, Vivien; Schaffer, Marie; Hovig, Eivind; Ljunggren, Hans-Gustaf; Ljungman, Per T; Malmberg, Karl-Johan

    2016-02-01

    Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high-resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56(bright), NKG2A(+), NKG2C(+), and CD57(+) NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A(+)CD57(-)NKG2C(-)) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03-0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9-12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6-33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1-77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9-12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7-11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12-0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01-0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT. PMID:26746188

  5. QCD evolution of naive-time-reversal-odd parton distribution functions

    NASA Astrophysics Data System (ADS)

    Kang, Zhong-Bo; Qiu, Jian-Wei

    2012-07-01

    We reexamine the derivation of the leading order QCD evolution equations of twist-3 quark-gluon correlation functions, Tq,F (x , x) and Tq,F (σ) (x , x), which are the first transverse-momentum-moment of the naive-time-reversal-odd parton distribution functions - the Sivers and Boer-Mulders function, respectively. The evolution equations were derived by several groups with apparent differences. We identify the sources that are responsible for the differences, and are able to reconcile the results from various groups.

  6. QCD Evolution of Naive-Time Quark-Gluon Correlation Functions

    NASA Astrophysics Data System (ADS)

    Kang, Zhong-Bo; Qiu, Jian-Wei

    In this talk, we examine the existing calculations of QCD evolution kernels for the scale dependence of two sets of twist-3 quark-gluon correlation functions, Tq,F(x, x) and T(σ ){q, F}(x, x), which are the first transverse-momentum-moment of the naive-time-reversal-odd Sivers and Boer-Mulders function, respectively. The evolution kernels at the leading order in strong coupling constant αs were derived by several groups with apparent differences. We identify the sources of discrepancies and are able to reconcile the results from various groups.

  7. Maraviroc 150 mg daily plus lopinavir/ritonavir, a nucleoside/nucleotide reverse transcriptase inhibitor-sparing regimen for HIV-infected naive patients: 48-week final results of VEMAN study.

    PubMed

    Nozza, S; Galli, L; Antinori, A; Chiappetta, S; Mazzotta, F; Zaccarelli, M; Ottou, S; De Battista, D; Pogliaghi, M; Di Pietro, M; Malnati, M; Ripa, M; Bonora, S; Lazzarin, A

    2015-05-01

    Non-conventional strategies with nucleoside/nucleotide reverse transcriptase inhibitor-sparing regimens in antiretroviral naive human immunodeficiency virus (HIV) -infected patients have been explored in clinical trials. A prospective, open-label, randomized (1:1), multicentre, proof-of-concept trial (VEMAN study, EUDRACT number 2008-006287-11) was conducted assigning HIV-infected naive patients to once-daily maraviroc plus lopinavir/ritonavir (MVC group) or to tenofovir/emtricitabine plus lopinavir/ritonavir (TDF/FTC group). Clinical and laboratory data were collected at baseline, and after 4, 12, 24, 36 and 48 weeks with the objective to evaluate the 48-week virological and immunological efficacy. HIV-1 DNA load and CD4(+) T-cell subsets were analysed on frozen peripheral blood mononuclear cells collected at baseline, 4 and 48 weeks to explore the trend in HIV reservoirs. Fifty patients were randomized and included in the analysis. During follow up, HIV-1 RNA decreased similarly in both groups and, at week 48, all patients in the MVC group and 22/24 (96%) in the TDF/FTC group had < 50 copies/ml of HIV-1 RNA. CD4(+) trend during follow up was higher in maraviroc-treated patients (MVC group: 286 (183-343) versus TDF/FTC group: 199 (125-285); Mann-Whitney U-test: p 0.033). A significant 48-week increase of CCR5(+) CD4(+) T cells and CD4(+) effector memory cells was observed among maraviroc-treated patients (Wilcoxon signed rank test: p 0.016 and p 0.007, respectively). No significant variations were found in naive and central memory CD4(+) T cells. Among naive patients with an R5 virus, treatment with maraviroc and lopinavir/ritonavir was shown to provide a virological response compared to a triple therapy and a greater immunological benefit.

  8. TLR activation excludes circulating naive CD8+ T cells from gut-associated lymphoid organs in mice.

    PubMed

    Heidegger, Simon; Kirchner, Sophie-Kathrin; Stephan, Nicolas; Bohn, Bernadette; Suhartha, Nina; Hotz, Christian; Anz, David; Sandholzer, Nadja; Stecher, Bärbel; Rüssmann, Holger; Endres, Stefan; Bourquin, Carole

    2013-05-15

    The trafficking of effector T cells is tightly regulated by the expression of site-specific sets of homing molecules. In contrast, naive T cells are generally assumed to express a uniform pattern of homing molecules and to follow a random distribution within the blood and secondary lymphoid organs. In this study, we demonstrate that systemic infection fundamentally modifies the trafficking of circulating naive CD8(+) T cells. We show that on naive CD8(+) T cells, the constitutive expression of the integrin α4β7 that effects their entry into GALT is downregulated following infection of mice with Salmonella typhimurium. We further show that this downregulation is dependent on TLR signaling, and that the TLR-activated naive CD8(+) T cells are blocked from entering GALT. This contrasts strongly with Ag-experienced effector T cells, for which TLR costimulation in the GALT potently upregulates α4β7 and enhances trafficking to intestinal tissues. Thus, TLR activation leads to opposite effects on migration of naive and effector CD8(+) T cells. Our data identify a mechanism that excludes noncognate CD8(+) T cells from selected immune compartments during TLR-induced systemic inflammation. PMID:23589622

  9. TLR activation excludes circulating naive CD8+ T cells from gut-associated lymphoid organs in mice.

    PubMed

    Heidegger, Simon; Kirchner, Sophie-Kathrin; Stephan, Nicolas; Bohn, Bernadette; Suhartha, Nina; Hotz, Christian; Anz, David; Sandholzer, Nadja; Stecher, Bärbel; Rüssmann, Holger; Endres, Stefan; Bourquin, Carole

    2013-05-15

    The trafficking of effector T cells is tightly regulated by the expression of site-specific sets of homing molecules. In contrast, naive T cells are generally assumed to express a uniform pattern of homing molecules and to follow a random distribution within the blood and secondary lymphoid organs. In this study, we demonstrate that systemic infection fundamentally modifies the trafficking of circulating naive CD8(+) T cells. We show that on naive CD8(+) T cells, the constitutive expression of the integrin α4β7 that effects their entry into GALT is downregulated following infection of mice with Salmonella typhimurium. We further show that this downregulation is dependent on TLR signaling, and that the TLR-activated naive CD8(+) T cells are blocked from entering GALT. This contrasts strongly with Ag-experienced effector T cells, for which TLR costimulation in the GALT potently upregulates α4β7 and enhances trafficking to intestinal tissues. Thus, TLR activation leads to opposite effects on migration of naive and effector CD8(+) T cells. Our data identify a mechanism that excludes noncognate CD8(+) T cells from selected immune compartments during TLR-induced systemic inflammation.

  10. The Role of Social Supports, Spirituality, Religiousness, Life Meaning and Affiliation with 12-Step Fellowships in Quality of Life Satisfaction Among Individuals in Recovery from Alcohol and Drug Problems

    PubMed Central

    Laudet, Alexandre B.; Morgen, Keith; White, William L.

    2006-01-01

    SUMMARY Many recovering substance users report quitting drugs because they wanted a better life. The road of recovery is the path to a better life but a challenging and stressful path for most. There has been little research among recovering persons in spite of the numbers involved, and most research has focused on substance use outcomes. This study examines stress and quality of life as a function of time in recovery, and uses structural equation modeling to test the hypothesis that social supports, spirituality, religiousness, life meaning, and 12-step affiliation buffer stress toward enhanced life satisfaction. Recovering persons (N = 353) recruited in New York City were mostly inner-city ethnic minority members whose primary substance had been crack or heroin. Longer recovery time was significantly associated with lower stress and with higher quality of life. Findings supported the study hypothesis; the ‘buffer’ constructs accounted for 22% of the variance in life satisfaction. Implications for research and clinical practice are discussed. PMID:16892161

  11. Notch Signaling Regulates Antigen Sensitivity of Naive CD4+ T Cells by Tuning Co-stimulation

    PubMed Central

    Laky, Karen; Evans, Sharron; Perez-Diez, Ainhoa

    2015-01-01

    SUMMARY Adaptive immune responses begin when naive CD4+ T cells engage peptide+major histocompatibility complex class II and co-stimulatory molecules on antigen-presenting cells (APCs). Notch signaling can influence effector functions in differentiated CD4+ T helper and T regulatory cells. Whether and how ligand-induced Notch signaling influences the initial priming of CD4+ T cells has not been addressed. We have found that Delta Like Ligand 4 (DLL4)-induced Notch signaling potentiates phosphatidylinositol 3-OH kinase (PI3K)-dependent signaling downstream of the T cell receptor+CD28, allowing naive CD4+ T cells to respond to lower doses of antigen. In vitro, DLL4-deficient APCs were less efficient stimulators of CD4+ T cell activation, metabolism, proliferation, and cytokine secretion. With deletion of DLL4 from CD11c+ APCs in vivo, these deficits translated to an impaired ability to mount an effective CD4+-dependent anti-tumor response. These data implicate Notch signaling as an important regulator of adaptive immune responses. PMID:25607460

  12. Personality matters: individual variation in reactions of naive bird predators to aposematic prey.

    PubMed

    Exnerová, Alice; Svádová, Katerina Hotová; Fucíková, Eva; Drent, Pieter; Stys, Pavel

    2010-03-01

    Variation in reactions to aposematic prey is common among conspecific individuals of bird predators. It may result from different individual experience but it also exists among naive birds. This variation may possibly be explained by the effect of personality--a complex of correlated, heritable behavioural traits consistent across contexts. In the great tit (Parus major), two extreme personality types have been defined. 'Fast' explorers are bold, aggressive and routine-forming; 'slow' explorers are shy, non-aggressive and innovative. Influence of personality type on unlearned reaction to aposematic prey, rate of avoidance learning and memory were tested in naive, hand-reared great tits from two opposite lines selected for exploration (slow against fast). The birds were subjected to a sequence of trials in which they were offered aposematic adult firebugs (Pyrrhocoris apterus). Slow birds showed a greater degree of unlearned wariness and learned to avoid the firebugs faster than fast birds. Although birds of both personality types remembered their experience, slow birds were more cautious in the memory test. We conclude that not only different species but also populations of predators that differ in proportions of personality types may have different impacts on survival of aposematic insects under natural conditions.

  13. Cortical thinning in drug-naive Parkinson's disease patients with depression.

    PubMed

    Luo, ChunYan; Song, Wei; Chen, Qin; Yang, Jing; Gong, QiYong; Shang, Hui-Fang

    2016-10-01

    To shed more light on the contribution of brain structural changes to PD-related depressive symptoms, this study conducted cortical thickness analysis in drug-naive PD patients with and without depression. We recruited 27 PD patients with depression (PD-Dep), 29 PD patients without depression (PD-NDep), and 56 normal controls. T1 weighted magnetic resonance imaging and surface-based morphometric analyses were performed to examine morphometric abnormalities in PD patients and their relationship to depression. We found decreased thickness in the left prefrontal cortex in PD-Dep group compared with PD-NDep group. No significant difference was found between PD patients and controls. In addition, we found there is a trend of inverse correlation between the structural changes and the score of depressive symptom in depressed PD patients. This study demonstrates that cortical thinning in prefrontal area in drug-naive PD patients with depression and highlights the critical role of prefrontal region in the depression associated with PD. PMID:27485171

  14. Characterization of lymphocyte subtypes in scabietic skin lesions of naive and sensitized dogs.

    PubMed

    Arlian, L G; Rapp, C M; Stemmer, B L; Morgan, M S; Moore, P F

    1997-03-01

    We delineated the density of cells expressing CD4, CD8, CD21 and CD45RA antigens in the cellular infiltrates in the epidermis, dermis and follicular epithelium in scabietic skin lesions of naive hosts and sensitized hosts that expressed resistance to scabies infestation. No cells expressing CD21 (B-lymphocytes and follicular dendritic cells) were present in the epidermis and only a few were occasionally present in the dermis during both the first and second infestations. Naive T-cells (CD45RA+) and CD8+ cells (cytotoxic and suppressor T-lymphocytes) were present in varying densities in the infiltrates throughout the epidermis, dermis and follicular epithelium with no apparent differences in density and the rate of appearance between sensitizing and challenge infestations. CD4+ cells were abundant in fluctuating densities in the dermis, epidermis, and follicular epidermis during the sensitizing infestation and these cells became the dominant cell type early during the challenge infestation. The density of CD4+ cells in the infiltrate was much greater during the challenge than during the sensitization infestation. This population of CD4+ cells consisted of both T-helper/inducer cells and neutrophils and the large increase in their numbers during the challenge suggested they played a key role in the successful immune/inflammatory response that resulted in resistance to scabies infestation.

  15. Naive CD8+ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics

    PubMed Central

    Neller, Michelle A; Ladell, Kristin; McLaren, James E; Matthews, Katherine K; Gostick, Emma; Pentier, Johanne M; Dolton, Garry; Schauenburg, Andrea JA; Koning, Dan; Fontaine Costa, Ana Isabel CA; Watkins, Thomas S; Venturi, Vanessa; Smith, Corey; Khanna, Rajiv; Miners, Kelly; Clement, Mathew; Wooldridge, Linda; Cole, David K; van Baarle, Debbie; Sewell, Andrew K; Burrows, Scott R; Price, David A; Miles, John J

    2015-01-01

    Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this ‘ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8+ T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment. PMID:25801351

  16. Renal abnormalities among HIV-infected, antiretroviral naive children, Harare, Zimbabwe: a cross-sectional study

    PubMed Central

    2013-01-01

    Background Data on the prevalence of renal and urine abnormalities among HIV-infected children in Sub-Saharan Africa are limited. We set out to determine the prevalence of proteinuria; low estimated glomerular filtration rate (eGFR), urinary tract infection and associated factors among HIV-infected antiretroviral therapy (ART) naive children, aged 2–12 years, attending the paediatric HIV clinic at a tertiary hospital in Harare. Methods Consecutive ART naive children attending the clinic between June and October 2009 were recruited. Detailed medical history was obtained and a complete physical examination was performed. Children were screened for urinary tract infection and for significant persistent proteinuria. Serum creatinine was used to estimate GFR using the modified Counahan-Barratt formula. The Student’s t-test was used to analyse continuous variables and the chi-square or Fisher’s exact test was used to analyse categorical data. Logistic regression was performed to assess the relationship between study factors and urine abnormalities, persistent proteinuria and the eGFR. Results Two hundred and twenty children were enrolled into the study. The median age was 90 months (Q1=65.5; Q3=116.5). The prevalence of urinary tract infection was 9.5%. Escherichia coli was the predominant organism. There was uniform resistance to cotrimoxazole. Persistent proteinuria (urine protein to creatinine ratio greater than 0.2, a week apart) was found in 5% of the children. Seventy-five children (34.6%) had mild to moderate renal impairment shown by a low eGFR (30 to <90ml/min/1.73m2). Persistent proteinuria was more likely to be found in children who were wasted, weight-for-height (WHZ) z-score <−2 (p=0.0005). Children with WHO clinical stage 4 were more likely to have a low eGFR than children with less advanced stages (OR 2.68; CI 1.24-5.80). Urine abnormalities were more likely to be observed in children with WHO clinical stages 3 and 4 (OR 2.20; CI 1

  17. Neural Correlates of Aggression in Medication-Naive Children with ADHD: Multivariate Analysis of Morphometry and Tractography.

    PubMed

    Cha, Jiook; Fekete, Tomer; Siciliano, Francesco; Biezonski, Dominik; Greenhill, Laurence; Pliszka, Steven R; Blader, Joseph C; Roy, Amy Krain; Leibenluft, Ellen; Posner, Jonathan

    2015-06-01

    Aggression is widely observed in children with attention deficit/hyperactivity disorder (ADHD) and has been frequently linked to frustration or the unsatisfied anticipation of reward. Although animal studies and human functional neuroimaging implicate altered reward processing in aggressive behaviors, no previous studies have documented the relationship between fronto-accumbal circuitry-a critical cortical pathway to subcortical limbic regions-and aggression in medication-naive children with ADHD. To address this, we collected behavioral measures and parental reports of aggression and impulsivity, as well as structural and diffusion MRI, from 30 children with ADHD and 31 healthy controls (HC) (mean age, 10±2.1 SD). Using grey matter morphometry and probabilistic tractography combined with multivariate statistical modeling (partial least squares regression and support vector regression), we identified anomalies within the fronto-accumbal circuit in childhood ADHD, which were associated with increased aggression. More specifically, children with ADHD showed reduced right accumbal volumes and frontal-accumbal white matter connectivity compared with HC. The magnitude of the accumbal volume reductions within the ADHD group was significantly correlated with increased aggression, an effect mediated by the relationship between the accumbal volume and impulsivity. Furthermore, aggression, but not impulsivity, was significantly explained by multivariate measures of fronto-accumbal white matter connectivity and cortical thickness within the orbitofrontal cortex. Our multi-modal imaging, combined with multivariate statistical modeling, indicates that the fronto-accumbal circuit is an important substrate of aggression in children with ADHD. These findings suggest that strategies aimed at probing the fronto-accumbal circuit may be beneficial for the treatment of aggressive behaviors in childhood ADHD.

  18. Reduced error signalling in medication-naive children with ADHD: associations with behavioural variability and post-error adaptations

    PubMed Central

    Plessen, Kerstin J.; Allen, Elena A.; Eichele, Heike; van Wageningen, Heidi; Høvik, Marie Farstad; Sørensen, Lin; Worren, Marius Kalsås; Hugdahl, Kenneth; Eichele, Tom

    2016-01-01

    Background We examined the blood-oxygen level–dependent (BOLD) activation in brain regions that signal errors and their association with intraindividual behavioural variability and adaptation to errors in children with attention-deficit/hyperactivity disorder (ADHD). Methods We acquired functional MRI data during a Flanker task in medication-naive children with ADHD and healthy controls aged 8–12 years and analyzed the data using independent component analysis. For components corresponding to performance monitoring networks, we compared activations across groups and conditions and correlated them with reaction times (RT). Additionally, we analyzed post-error adaptations in behaviour and motor component activations. Results We included 25 children with ADHD and 29 controls in our analysis. Children with ADHD displayed reduced activation to errors in cingulo-opercular regions and higher RT variability, but no differences of interference control. Larger BOLD amplitude to error trials significantly predicted reduced RT variability across all participants. Neither group showed evidence of post-error response slowing; however, post-error adaptation in motor networks was significantly reduced in children with ADHD. This adaptation was inversely related to activation of the right-lateralized ventral attention network (VAN) on error trials and to task-driven connectivity between the cingulo-opercular system and the VAN. Limitations Our study was limited by the modest sample size and imperfect matching across groups. Conclusion Our findings show a deficit in cingulo-opercular activation in children with ADHD that could relate to reduced signalling for errors. Moreover, the reduced orienting of the VAN signal may mediate deficient post-error motor adaptions. Pinpointing general performance monitoring problems to specific brain regions and operations in error processing may help to guide the targets of future treatments for ADHD. PMID:26441332

  19. A Public Database of Memory and Naive B-Cell Receptor Sequences

    PubMed Central

    Sherwood, Anna M.; Vignali, Marissa; Carlson, Christopher S.; Greenberg, Philip D.; Duerkopp, Natalie; Emerson, Ryan O.; Robins, Harlan S.

    2016-01-01

    The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics. PMID:27513338

  20. A Public Database of Memory and Naive B-Cell Receptor Sequences.

    PubMed

    DeWitt, William S; Lindau, Paul; Snyder, Thomas M; Sherwood, Anna M; Vignali, Marissa; Carlson, Christopher S; Greenberg, Philip D; Duerkopp, Natalie; Emerson, Ryan O; Robins, Harlan S

    2016-01-01

    The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics. PMID:27513338

  1. Enrichment of a bipotent hepatic progenitor cell from naive adult liver tissue

    SciTech Connect

    Wright, Natasha; Samuelson, Lisa; Walkup, Maggie H.; Chandrasekaran, Prakash; Gerber, David A.

    2008-02-08

    Background/Aim: Recent interest in the liver stem cell field has led to the identification and characterization of several hepatic progenitor cell populations from fetal and adult tissues. We isolated a hepatic progenitor cell from naive adult liver and the current studies focus on differentiation and growth. Results: A Sca-1{sup +} hepatic progenitor cell was identified within the liver parenchyma. This cell expresses numerous liver related genes and transcription found in the developing and/or adult liver. It is located in the peri-portal region and expresses markers associated with undifferentiated hepatic cell populations, mature hepatocytes and biliary cells which distinguish it from the Sca-1{sup -} fraction. Conclusion: This hepatic progenitor cell from uninjured liver has features of both hepatocytic and biliary populations and demonstrates proliferative potential. Further studies will focus on sca-HPC subsets and conditions that regulate differentiation towards hepatic or biliary lineages.

  2. Schistosoma mansoni: migration potential of normal and radiation attenuated parasites in naive guinea pigs

    SciTech Connect

    Kamiya, H.; McLaren, D.J.

    1987-02-01

    Compressed tissue autoradiography using (75Se)selenomethionine labelled parasites has been used to investigate the migration potential of normal and radiation attenuated cercariae of Schistosoma mansoni in naive guinea pigs. By Day 14 after infection. 44% of normal parasites were detected as reduced silver foci in the liver; this value corresponded well with the number of liver parasites recovered by retrograde perfusion of the hepatic portal system on Day 42 (42% of the challenge). In contrast, cercariae subjected to 50 krad of gamma irradiation failed to migrate out of the skin. The migration capacity of 20 krad irradiated parasites was less severely affected in that about half of the challenge parasites reached the lungs, but virtually none moved to the liver. These data are discussed in relation to the kinetics of immunity induced in guinea pigs by infection or vaccination with normal or radiation attenuated parasites.

  3. Targeted Help for Spoken Dialogue Systems: Intelligent Feedback Improves Naive Users' Performance

    NASA Technical Reports Server (NTRS)

    Hockey, Beth Ann; Lemon, Oliver; Campana, Ellen; Hiatt, Laura; Aist, Gregory; Hieronymous, Jim; Gruenstein, Alexander; Dowding, John

    2003-01-01

    We present experimental evidence that providing naive users of a spoken dialogue system with immediate help messages related to their out-of-coverage utterances improves their success in using the system. A grammar-based recognizer and a Statistical Language Model (SLM) recognizer are run simultaneously. If the grammar-based recognizer suceeds, the less accurate SLM recognizer hypothesis is not used. When the grammar-based recognizer fails and the SLM recognizer produces a recognition hypothesis, this result is used by the Targeted Help agent to give the user feed-back on what was recognized, a diagnosis of what was problematic about the utterance, and a related in-coverage example. The in-coverage example is intended to encourage alignment between user inputs and the language model of the system. We report on controlled experiments on a spoken dialogue system for command and control of a simulated robotic helicopter.

  4. Divergent responses of exposed and naive Pacific tree frog tadpoles to invasive predatory crayfish.

    PubMed

    Pease, Katherine M; Wayne, Robert K

    2014-01-01

    Invasive predators can devastate native species and ecosystems. However, native species may be able to coexist with invasive predators through a variety of mechanisms, such as changes in morphology or behavior due to a plastic response or selection on fixed anti-predator traits. We examined whether exposed and naive populations of Pacific tree frog tadpoles (Pseudacris regilla) display divergent morphological and behavioral traits in response to the invasive predatory red swamp crayfish (Procambarus clarkii). Tadpoles were collected from three study streams with and three without crayfish, in the Santa Monica Mountains of Southern California. We analyzed tadpole morphology and tested anti-predator behavior and survival in the laboratory. Tadpoles from streams with crayfish had shallower, narrower tails than tadpoles from streams without crayfish. Tadpoles from streams with and without crayfish were less active after exposure to crayfish chemical cues. The divergent morphology of naive and exposed tadpoles is consistent with tadpoles exhibiting a plastic response to crayfish or undergoing selection from crayfish predation. In laboratory predation experiments, we found no difference in survival between tadpoles from streams with and without crayfish but tadpoles that survived predation had deeper tail muscles than those that were killed or injured. Our results suggest that deeper tails are advantageous in the presence of crayfish, yet tadpoles from crayfish streams had shallower tails than those from crayfish-free streams. Shallower tails may have an alternative unmeasured advantage or there may be a physiological constraint to developing deeper tails in the wild. These results highlight the ability of a native frog to respond to an invasive predatory crayfish, potentially allowing for coexistence.

  5. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells.

    PubMed

    Berard, Marion; Brandt, Katja; Bulfone-Paus, Silvia; Tough, David F

    2003-05-15

    IL-15 stimulates the proliferation of memory phenotype CD44(high)CD8(+) T cells and is thought to play a key role in regulating the turnover of these cells in vivo. We have investigated whether IL-15 also has the capacity to affect the life span of naive phenotype (CD44(low)) CD8(+) T cells. We report that IL-15 promotes the survival of both CD44(low) and CD44(high) CD8(+) T cells, doing so at much lower concentrations than required to induce proliferation of CD44(high) cells. Rescue from apoptosis was associated with the up-regulation of Bcl-2 in both cell types, whereas elevated expression of Bcl-x(L) was observed among CD44(high) but not CD44(low) CD8(+) cells. An investigation into the role of IL-15R subunits in mediating the effects of IL-15 revealed distinct contributions of the alpha- and beta- and gamma-chains. Most strikingly, IL-15R alpha was not essential for either induction of proliferation or promotion of survival by IL-15, but did greatly enhance the sensitivity of cells to low concentrations of IL-15. By contrast, the beta- and gamma-chains of the IL-15R were absolutely required for the proliferative and pro-survival effects of IL-15, although it was not necessary for CD44(high)CD8(+) cells to express higher levels of IL-15R beta than CD44(low) cells to proliferate in response to IL-15. These results show that IL-15 has multiple effects on CD8 T cells and possesses the potential to regulate the life span of naive as well as memory CD8(+) T cells. PMID:12734346

  6. Visualizing Non Infectious and Infectious Anopheles gambiae Blood Feedings in Naive and Saliva-Immunized Mice

    PubMed Central

    Choumet, Valerie; Attout, Tarik; Chartier, Loïc; Khun, Huot; Sautereau, Jean; Robbe-Vincent, Annie; Brey, Paul; Huerre, Michel; Bain, Odile

    2012-01-01

    Background Anopheles gambiae is a major vector of malaria and lymphatic filariasis. The arthropod-host interactions occurring at the skin interface are complex and dynamic. We used a global approach to describe the interaction between the mosquito (infected or uninfected) and the skin of mammals during blood feeding. Methods Intravital video microscopy was used to characterize several features during blood feeding. The deposition and movement of Plasmodium berghei sporozoites in the dermis were also observed. We also used histological techniques to analyze the impact of infected and uninfected feedings on the skin cell response in naive mice. Results The mouthparts were highly mobile within the skin during the probing phase. Probing time increased with mosquito age, with possible effects on pathogen transmission. Repletion was achieved by capillary feeding. The presence of sporozoites in the salivary glands modified the behavior of the mosquitoes, with infected females tending to probe more than uninfected females (86% versus 44%). A white area around the tip of the proboscis was observed when the mosquitoes fed on blood from the vessels of mice immunized with saliva. Mosquito feedings elicited an acute inflammatory response in naive mice that peaked three hours after the bite. Polynuclear and mast cells were associated with saliva deposits. We describe the first visualization of saliva in the skin by immunohistochemistry (IHC) with antibodies directed against saliva. Both saliva deposits and sporozoites were detected in the skin for up to 18 h after the bite. Conclusion This study, in which we visualized the probing and engorgement phases of Anopheles gambiae blood meals, provides precise information about the behavior of the insect as a function of its infection status and the presence or absence of anti-saliva antibodies. It also provides insight into the possible consequences of the inflammatory reaction for blood feeding and pathogen transmission. PMID

  7. Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice

    PubMed Central

    Brachman, Rebecca A.; Lehmann, Michael L.; Maric, Dragan

    2015-01-01

    We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2−/− mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice. The mice receiving lymphocytes from defeated donors showed less anxiety, more social behavior, and increased hippocampal cell proliferation compared with those receiving no cells or cells from unstressed donors. Mice receiving stressed immune cells had reduced pro-inflammatory cytokine levels in the blood relative to the other groups, an effect opposite to the elevated donor pro-inflammatory cytokine profile. Furthermore, mice receiving stressed immune cells had microglia skewed toward an anti-inflammatory, neuroprotective M2-like phenotype, an effect opposite the stressed donors' M1-like pro-inflammatory profile. However, stress had no effect on lymphocyte surface marker profiles in both donor and recipient mice. The data suggest that chronic stress-induced changes in the adaptive immune system, contrary to conferring anxiety and depressive behavior, protect against the deleterious effects of stress. Improvement in affective behavior is potentially mediated by reduced peripheral pro-inflammatory cytokine load, protective microglial activity, and increased hippocampal cell proliferation. The data identify the peripheral adaptive immune system as putatively involved in the mechanisms underlying stress resilience and a potential basis for developing novel rapid-acting antidepressant therapies. PMID:25632130

  8. Short Communication: Transmitted HIV Drug Resistance in Antiretroviral-Naive Pregnant Women in North Central Nigeria

    PubMed Central

    Sagay, Atiene S.; Chaplin, Beth; Chebu, Philippe; Musa, Jonah; Okpokwu, Jonathan; Hamel, Donald J.; Pam, Ishaya C.; Agbaji, Oche; Samuels, Jay; Meloni, Seema; Sankale, Jean-Louis; Okonkwo, Prosper; Kanki, Phyllis

    2014-01-01

    Abstract The World Health Organization (WHO) recommends periodic surveillance of transmitted drug resistance (TDR) in communities in which antiretroviral therapy (ART) has been scaled-up for greater than 3 years. We conducted a survey of TDR mutations among newly detected HIV-infected antiretroviral (ARV)-naive pregnant women. From May 2010 to March 2012, 38 ARV-naive pregnant women were recruited in three hospitals in Jos, Plateau state, north central Nigeria. Eligible subjects were recruited using a modified version of the binomial sequential sampling technique recommended by WHO. HIV-1 genotyping was performed and HIV-1 drug resistance mutations were characterized according to the WHO 2009 surveillance drug resistance mutation (SDRM) list. HIV subtypes were determined by phylogenetic analysis. The women's median age was 25.5 years; the median CD4+ cell count was 317 cells/μl and the median viral load of 16 was 261 copies/ml. Of the 38 samples tested, 34 (89%) were successfully genotyped. The SDRM rate was <5% for all ART drug classes, with 1/34 (2.9%) for NRTIs/NNRTIs and none for protease inhibitors 0/31 (0%). The specific SDRMs detected were M41L for nucleoside reverse transcriptase inhibitors (NRTIs) and G190A for nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIV-1 subtypes detected were CRF02_AG (38.2%), G′ (41.2%), G (14.7%), CRF06-CPX (2.9%), and a unique AG recombinant form (2.9%). The single ARV-native pregnant woman with SDRMs was infected with HIV-1 subtype G′. Access to ART has been available in the Jos area for over 8 years. The prevalence of TDR lower than 5% suggests proper ART administration, although continued surveillance is warranted. PMID:24164431

  9. Predicting Ecstasy Use among Young People at Risk: A Prospective Study of Initially Ecstasy-Naive Subjects

    ERIC Educational Resources Information Center

    Vervaeke, Hylke K.E.; Benschop, Annemieke; Van Den Brink, Wim; Korf, Dirk J.

    2008-01-01

    Our aim is to identify predictors of first-time ecstasy use in a prospective study among young people at risk. As part of the multidisciplinary Netherlands XTC Toxicity Study (NeXT), we monitored 188 subjects aged up to 18 years who were ecstasy-naive at baseline but seemed likely to start taking ecstasy in the near future. After an 11- to…

  10. Effects of Training on Naive Listeners' Judgments of the Speech Intelligibility of Children with Severe-to-Profound Hearing Loss

    ERIC Educational Resources Information Center

    Ellis, Lee W.; Beltyukova, Svetlana A.

    2008-01-01

    Purpose: This study examined the effects of feedback training, familiarization training, and no training on naive listeners' word identification (WI) and magnitude estimation scaling (MES) judgments of the speech intelligibility of children with severe-to-profound hearing impairments. Method: Depending on the training group, listeners received a…

  11. Effects of Noise Suppression on Intelligibility: Experts' Opinions and Naive Normal-Hearing Listeners' Performance

    ERIC Educational Resources Information Center

    Hilkhuysen, Gaston L. M.; Gaubitch, Nikolay; Huckvale, Mark

    2013-01-01

    Purpose: In this study, the authors investigated how well experts can adjust the settings of a commercial noise-reduction system to optimize the intelligibility for naive normal-hearing listeners. Method: In Experiment 1, 5 experts adjusted parameters for a noise-reduction system while aiming to optimize intelligibility. The stimuli consisted of…

  12. The Galileo Bias: A Naive Conceptual Belief That Influences People's Perceptions and Performance in a Ball-Dropping Task

    ERIC Educational Resources Information Center

    Oberle, Crystal D.; McBeath, Michael K.; Madigan, Sean C.; Sugar, Thomas G.

    2005-01-01

    This research introduces a new naive physics belief, the Galileo bias, whereby people ignore air resistance and falsely believe that all objects fall at the same rate. Survey results revealed that this bias is held by many and is surprisingly strongest for those with formal physics instruction. In 2 experiments, 98 participants dropped ball pairs…

  13. An Overview of the Effectiveness of Adolescent Substance Abuse Treatment Models.

    ERIC Educational Resources Information Center

    Muck, Randolph; Zempolich, Kristin A.; Titus, Janet C.; Fishman, Marc; Godley, Mark D.; Schwebel, Robert

    2001-01-01

    Describes current approaches to adolescent substance abuse treatment, including the 12-step treatment approach, behavioral treatment approach, family-based treatment approach, and therapeutic community approach. Summarizes research that assesses the effectiveness of these models, offering findings from the Center for Substance Abuse Treatment's…

  14. Efavirenz-Based Regimens in Antiretroviral-Naive HIV-Infected Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Kryst, Joanna; Kawalec, Paweł; Pilc, Andrzej

    2015-01-01

    Efavirenz, a non-nucleoside reverse-transcriptase inhibitor (NNRTI) is one of the most commonly prescribed antiretroviral drugs. The present article provides a systematic overview and meta-analysis of clinical trials comparing efavirenz and other active drugs currently recommended for treatment of HIV-infected, antiretroviral-naive patients. Electronic databases (Pubmed, Embase, the Cochrane Library, Trip Database) were searched up till 23 December 2013 for randomized controlled clinical trials published as a peer-reviewed papers, and concerning efavirenz-based regimens used as initial treatment for HIV infection. Thirty-four studies were included in the systematic review, while twenty-six trials were suitable for the meta-analysis. Efavirenz was compared with drugs from four different classes: NNRTIs other than efavirenz (nevirapine or rilpivirine), integrase strand transfer inhibitors (InSTIs), ritonavir-boosted protease inhibitors (bPI) and chemokine (C-C motif) receptor 5 (CCR5) antagonists (maraviroc), all of them were added to the background regimen. Results of the current meta-analysis showed that efavirenz-based regimens were equally effective as other recommended regimens based on NNRTI, ritonavir-boosted PI or CCR5 antagonist in terms of efficacy outcomes (disease progression and/or death, plasma viral HIV RNA <50 copies/ml) while statistically significant more patients treated with InSTI achieved plasma viral load <50 copies/ml at week 48. In comparison with both InSTI-based and CCR5-based therapy, efavirenz-based treatment was associated with a higher risk of therapy discontinuation due to adverse events. However, comparisons of efevirenz-based treatment with InSTI-based and CCR5-based therapy were based on a limited number of trials, therefore, conclusions from these two comparisons must be confirmed in further reliable randomized controlled studies. Results of our meta-analysis support the present clinical guidelines for antiretroviral-naive, HIV

  15. 1,25-dihydroxyvitamin D{sub 3} impairs NF-{kappa}B activation in human naive B cells

    SciTech Connect

    Geldmeyer-Hilt, Kerstin; Heine, Guido; Hartmann, Bjoern; Baumgrass, Ria; Radbruch, Andreas; Worm, Margitta

    2011-04-22

    Highlights: {yields} In naive B cells, VDR activation by calcitriol results in reduced NF-{kappa}B p105 and p50 protein expression. {yields} Ligating the VDR with calcitriol causes reduced nuclear translocation of NF-{kappa}B p65. {yields} Reduced nuclear amount of p65 after calcitriol incubation results in reduced binding of p65 on the p105 promoter. {yields} Thus, vitamin D receptor signaling may reduce or prevent activation of B cells and unwanted immune responses, e.g. in IgE dependent diseases such as allergic asthma. -- Abstract: 1{alpha},25-dihydroxyvitamin D{sub 3} (calcitriol), the bioactive metabolite of vitamin D, modulates the activation and inhibits IgE production of anti-CD40 and IL-4 stimulated human peripheral B cells. Engagement of CD40 results in NF-{kappa}B p50 activation, which is essential for the class switch to IgE. Herein, we investigated by which mechanism calcitriol modulates NF-{kappa}B mediated activation of human naive B cells. Naive B cells were predominantly targeted by calcitriol in comparison with memory B cells as shown by pronounced induction of the VDR target gene cyp24a1. Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naive B cells. This effect is mediated by impaired nuclear translocation of p65 and consequently reduced binding of p65 to its binding site in the p105 promoter. Our data indicate that the vitamin D receptor reduces NF-{kappa}B activation by interference with NF-{kappa}B p65 and p105. Thus, the vitamin D receptor inhibits costimulatory signal transduction in naive B cells, namely by reducing CD40 signaling.

  16. Using an Integrated Naive Bayes Calssifier for Crawling Relevent Data on the Web

    NASA Astrophysics Data System (ADS)

    Mihsra, A.

    2015-12-01

    In our experiments (at JPL, NASA) for DARPA Memex project, we wanted to crawl a large amount of data for various domains. A big challenge was data relevancy in the crawled data. More than 50% of the data was irrelevant to the domain at hand. One immediate solution was to use good seeds (seeds are the initial urls from where the program starts to crawl) and make sure that the crawl remains into the original host urls. This although a very efficient technique, fails under two conditions. One when you aim to reach deeper into the web; into new hosts (not in the seed list) and two when the website hosts myriad content types eg. a News website.The relevancy calculation used to be a post processing step i.e. once we had finished crawling, we trained a NaiveBayes Classifier and used it to find a rough relevancy of the web pages that we had. Integrating the relevancy into the crawling rather than after it was very important because crawling takes resources and time. To save both we needed to get an idea of relevancy of the whole crawl during run time and be able to steer its course accordingly. We use Apache Nutch as the crawler, which uses a plugin system to incorporate any new implementations and hence we built a plugin for Nutch.The Naive Bayes Parse Plugin works in the following way. It parses every page and decides, using a trained model (which is built in situ only once using the positive and negative examples given by the user in a very simple format), if it is relevant; If true, then it allows all the outlinks from that page to go to the next round of crawling; If not, then it gives the urls a second chance to prove themselves by checking some commonly expected words in the url relevant to that domain. This two tier system is very intuitive and efficient in focusing the crawl. In our initial test experiments over 100 seed urls, the results were astonishingly good with a recall of 98%.The same technique can be applied to geo-informatics. This will help scientists

  17. Effects of ziprasidone, SCH23390 and SB277011 on spatial memory in the Morris water maze test in naive and MK-801 treated mice.

    PubMed

    Tanyeri, Pelin; Buyukokuroglu, Mehmet Emin; Mutlu, Oguz; Ulak, Güner; Akar, Füruzan Yildiz; Celikyurt, Ipek Komsuoglu; Erden, Bekir Faruk

    2015-11-01

    Introduction: Patients with schizophrenia have cognitive dysfunctions; positive psychotic symptoms are the primary purposes for schizophrenia treatment. Improvements in cognitive function should be a characteristic of all newly developed drugs for the treatment of schizophreniawith dementia. Thus,we investigated the effects of the second-generation antipsychotic ziprasidone, dopamine D1 antagonist SCH-23390 and dopamine D3 antagonist SB-277011 on spatial learning and memory. Materials and methods: Male inbred mice were used. The effects of ziprasidone, SCH-23390 and SB-277011 were investigated using the Morris water maze test. Results: Ziprasidone (0.5 and 1mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on the time spent in the target quadrant in naive mice.MK-801 (0.1mg/kg) significantly decreased the time spent in the target quadrant. The time spent in the target quadrant was significantly prolonged by Ziprasidone (0.5 and 1 mg/kg) and SCH-23390 (0.1 mg/kg), but not with SB-277011 (20 mg/kg) in MK-801-treated mice. Ziprasidone (0.5 and 1mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on themean distance to the platformin naivemice.MK-801 significantly increased themean distance to the platform. Ziprasidone (1 mg/kg) and SCH-23390 (0.1 mg/kg) significantly decreased the mean distance to the platform in MK-801-treated mice, but SB-277011 (20 mg/kg) didn't. MK-801 significantly increased the total distance moved. Ziprasidone (0.5 and 1 mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on the total distance moved in naive mice. Ziprasidone (1 mg/kg) and SCH-23390 (0.1 mg/kg) significantly decreased the total distance moved in MK-801-treated mice, but SB-277011 (20 mg/kg) didn't. Conclusions: The second-generation antipsychotic drug ziprasidone and D1 antagonist SCH23390, but not the D3 antagonist SB277011, might be clinically useful for the treatment of

  18. Factors influencing medication adherence beliefs and self-efficacy in persons naive to antiretroviral therapy: a multicenter, cross-sectional study.

    PubMed

    Reynolds, Nancy R; Testa, Marcia A; Marc, Linda G; Chesney, Margaret A; Neidig, Judith L; Smith, Scott R; Vella, Stefano; Robbins, Gregory K

    2004-06-01

    It is widely recognized that adherence to antiretroviral therapy is critical to long-term treatment success, yet rates of adherence to antiretroviral medications are frequently subtherapeutic. Beliefs about antiretroviral therapy and psychosocial characteristics of HIV-positive persons naive to therapy may influence early experience with antiretroviral medication adherence and therefore could be important when designing programs to improve adherence to antiretroviral therapy. As part of a multicenter AIDS Clinical Trial Group (ACTG 384) study, 980 antiretroviral-naive subjects (82% male, 47% White, median age 36 years, and median CD4 cell count 278 cells/mm3) completed a self-administered questionnaire prior to random treatment assignment of initial antiretroviral medications. Measures of symptom distress, general health and well-being, and personal and situational factors including demographic characteristics, social support, self-efficacy, depression, stress, and current adherence to (nonantiretroviral) medications were recorded. Associations among variables were explored using correlation and regression analyses. Beliefs about the importance of antiretroviral adherence and ability to take antiretroviral medications as directed (adherence self-efficacy) were generally positive. Fifty-six percent of the participants were "extremely sure" of their ability to take all medications as directed and 48% were "extremely sure" that antiretroviral nonadherence would cause resistance, but only 37% were as sure that antiretroviral therapy would benefit their health. Less-positive beliefs about antiretroviral therapy adherence were associated with greater stress, depression, and symptom distress. More-positive beliefs about antiretroviral therapy adherence were associated with better scores on health perception, functional health, social-emotional-cognitive function, social support, role function, younger age, and higher education (r values = 0.09-0.24, all p < .001). Among

  19. Tameness and stress physiology in a predator-naive island species confronted with novel predation threat

    PubMed Central

    Rödl, Thomas; Berger, Silke; Michael Romero, L; Wikelski, Martin

    2006-01-01

    Tame behaviour, i.e. low wariness, in terrestrial island species is often attributed to low predation pressure. However, we know little about its physiological control and its flexibility in the face of predator introductions. Marine iguanas (Amblyrhynchus cristatus) on the Galápagos Islands are a good model to study the physiological correlates of low wariness. They have lived virtually without predation for 5–15 Myr until some populations were first confronted with feral cats and dogs some 150 years ago. We tested whether and to what extent marine iguanas can adjust their behaviour and endocrine stress response to novel predation threats. Here, we show that a corticosterone stress response to experimental chasing is absent in naive animals, but is quickly restored with experience. Initially, low wariness also increases with experience, but remains an order of magnitude too low to allow successful escape from introduced predators. Our data suggest that the ability of marine iguanas to cope with predator introductions is limited by narrow reaction norms for behavioural wariness rather than by constraints in the underlying physiological stress system. In general, we predict that island endemics show flexible physiological stress responses but are restricted by narrow behavioural plasticity. PMID:17476779

  20. Radiosensitivity of CD45RO+ memory and CD45RO- naive T cells in culture.

    PubMed

    Uzawa, A; Suzuki, G; Nakata, Y; Akashi, M; Ohyama, H; Akanuma, A

    1994-01-01

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4+ helper and CD8+ killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO+ memory and CD45RO- naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO+ cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity.

  1. A Naive Bayes machine learning approach to risk prediction using censored, time-to-event data.

    PubMed

    Wolfson, Julian; Bandyopadhyay, Sunayan; Elidrisi, Mohamed; Vazquez-Benitez, Gabriela; Vock, David M; Musgrove, Donald; Adomavicius, Gediminas; Johnson, Paul E; O'Connor, Patrick J

    2015-09-20

    Predicting an individual's risk of experiencing a future clinical outcome is a statistical task with important consequences for both practicing clinicians and public health experts. Modern observational databases such as electronic health records provide an alternative to the longitudinal cohort studies traditionally used to construct risk models, bringing with them both opportunities and challenges. Large sample sizes and detailed covariate histories enable the use of sophisticated machine learning techniques to uncover complex associations and interactions, but observational databases are often 'messy', with high levels of missing data and incomplete patient follow-up. In this paper, we propose an adaptation of the well-known Naive Bayes machine learning approach to time-to-event outcomes subject to censoring. We compare the predictive performance of our method with the Cox proportional hazards model which is commonly used for risk prediction in healthcare populations, and illustrate its application to prediction of cardiovascular risk using an electronic health record dataset from a large Midwest integrated healthcare system.

  2. Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes

    PubMed Central

    1996-01-01

    Upon activation, B lymphocytes can change the isotype of the antibody they express by immunoglobulin (Ig) isotype switch recombination. In previous studies on the regulation of human IgG expression, we demonstrated that interleukin 10 (IL-10) could stimulate IgG1 and IgG3 secretion by human CD40-activated naive (sIgD+) tonsillar B cells. To assess whether IL-10 actually promotes the DNA recombination underlying switching to these isotypes, we examined the effect of IL-10 on the generation of reciprocal products that form DNA circles as by-products of switch recombination. The content of reciprocal products characteristic of mu-gamma recombination was elevated after culture of CD40-activated tonsillar sIgD+ B cells with either IL-4 or IL-10, although high levels of IgG secretion were observed only with IL-10. Unlike IL-4, IL-10 did not induce reciprocal products of mu-epsilon and gamma-epsilon switch recombination. These results demonstrate that IL- 10 promotes both switching to gamma and IgG secretion. PMID:8642297

  3. Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents.

    PubMed

    Dahlström, M; Ahonen, A; Ebeling, H; Torniainen, P; Heikkilä, J; Moilanen, I

    2000-09-01

    Cumulative data suggest depression in adulthood being connected to reduced availability of brain serotonin while the role of dopamine remains less specific. Prospective studies have shown a continuity of depressive episodes from childhood to adulthood, combined with poor social function and excess mortality. The object of this study was to examine whether alterations in brain serotonin and/or dopamine transporter levels are already present in depressive children and adolescents. We examined 41 drug-naive patients (aged 7-17) by single photon emission tomography (SPET) using iodine-123-labelled 23-carbomethoxy-3P3(iodophenyl) tropane [123I]beta-CIT as a tracer for monoamine transporters. In addition to the ordinary clinical examination, the patients were given a structured interview and information was gathered from teachers and parents with questionnaires. The diagnoses were established by consensus evaluation between three child psychiatrists. To test the serotonin hypothesis and the dopamine hypothesis regarding depression in children and adolescents, the series was divided into groups with depression present (31) and no depression present (10). In this study, the depressive child and adolescent patients had significantly higher serotonin transporter availability (P < 0.02) in the hypothalamic/midbrain area. Age did not correlate to the hypothalamic/midbrain serotonin transporter binding ratio. No significant difference in dopamine transporter availability in striatum was found between the depressive and the nondepressive children and adolescents.

  4. Common Spatial Pattern Patches: online evaluation on BCI-naive users.

    PubMed

    Sannelli, Claudia; Vidaurre, Carmen; Müller, Klaus-Robert; Blankertz, Benjamin

    2012-01-01

    Brain-Computer Interfaces (BCI) based on the voluntary modulation of sensorimotor rhythms (SMRs) induced by motor imagery are very prominent because allow a continuous control of the external device. Nevertheless, the design of a SMR-based BCI system that provides every user with a reliable BCI control from the first session, i.e., without extensive training, is still a big challenge. Considerable advances in this direction have been made by the machine learning co-adaptive calibration approach, which combines online adaptation techniques with subject learning in order to offer the user a feedback from the beginning of the experiment. Recently, based on offline analyses, we proposed the novel Common Spatial Patterns Patches (CSPP) technique as a good candidate to improve the co-adaptive calibration. CSPP is an ensemble of localized spatial filters, each of them optimized on subject-specific data by CSP analysis. Here, the evaluation of CSPP in online operation is presented for the first time. Results on three BCI-naive participants show indeed promising results. All three users reach the threshold criterion of 70% accuracy within one session, even one candidate for whom the weak SMR at rest predicted deficient BCI control. Concurrent recordings of the SMR during a relax condition as well as the course of BCI performance indicate a clear learning effect.

  5. Tuberous sclerosis complex 1 (Tsc1) enforces quiescence of naive T cells to promote immune homeostasis and function

    PubMed Central

    Yang, Kai; Neale, Geoffrey; Green, Douglas R.; He, Weifeng; Chi, Hongbo

    2011-01-01

    The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescence program in naive T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that resulted in loss of conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naive T cell quiescence to facilitate adaptive immune function. PMID:21765414

  6. Capacity of a natural strain of woodchuck hepatitis virus, WHVNY, to induce acute infection in naive adult woodchucks.

    PubMed

    Freitas, Natalia; Lukash, Tetyana; Dudek, Megan; Litwin, Sam; Menne, Stephan; Gudima, Severin O

    2015-07-01

    Woodchuck hepatitis virus (WHV) is often used as surrogate to study mechanism of HBV infection. Currently, most infections are conducted using strains WHV7 or WHV8 that have very high sequence identity. This study focused on natural strain WHVNY that is more genetically distant from WHV7. Three naive adult woodchucks inoculated with WHVNY developed productive acute infection with long lasting viremia. However, only one of two woodchucks infected with WHV7 at the same multiplicity demonstrated productive liver infection. Quantification of intracellular WHV RNA and DNA replication intermediates; percentages of core antigen-positive hepatocytes; and serum relaxed circular DNA showed that strains WHVNY and WHV7 displayed comparable replication levels and capacities to induce acute infection in naive adult woodchucks. Strain WHVNY was therefore validated as valuable reagent to analyze the mechanism of hepadnavirus infection, especially in co- and super-infection settings, which required discrimination between two related virus genomes replicating in the same liver. PMID:25979221

  7. Using naive Bayes classifier for classification of convective rainfall intensities based on spectral characteristics retrieved from SEVIRI

    NASA Astrophysics Data System (ADS)

    Hameg, Slimane; Lazri, Mourad; Ameur, Soltane

    2016-07-01

    This paper presents a new algorithm to classify convective clouds and determine their intensity, based on cloud physical properties retrieved from the Spinning Enhanced Visible and Infrared Imager (SEVIRI). The convective rainfall events at 15 min, 4 × 5 km spatial resolution from 2006 to 2012 are analysed over northern Algeria. The convective rain classification methodology makes use of the relationship between cloud spectral characteristics and cloud physical properties such as cloud water path (CWP), cloud phase (CP) and cloud top height (CTH). For this classification, a statistical method based on `naive Bayes classifier' is applied. This is a simple probabilistic classifier based on applying `Bayes' theorem with strong (naive) independent assumptions. For a 9-month period, the ability of SEVIRI to classify the rainfall intensity in the convective clouds is evaluated using weather radar over the northern Algeria. The results indicate an encouraging performance of the new algorithm for intensity differentiation of convective clouds using SEVIRI data.

  8. Conditioning of naive CD4(+) T cells for enhanced peripheral Foxp3 induction by nonspecific bystander inflammation.

    PubMed

    Thompson, Lucas J; Lai, Jen-Feng; Valladao, Andrea C; Thelen, Tennille D; Urry, Zoe L; Ziegler, Steven F

    2016-03-01

    Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines affect the immune system in a context-dependent manner. Here we show that nonspecific bystander inflammation conditions naive CD4(+) T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This results in inhibition of immune responses in vivo via a Foxp3-dependent effect on antigen-specific naive CD4(+) T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the idea that early tuning of the immune system by infection affects the long-term quality of immune regulation. PMID:26752376

  9. Reduced antigen concentration and costimulatory blockade increase IFN-gamma secretion in naive CD8+ T cells.

    PubMed

    Hall, Håkan T L; Petrovic, Jelena; Höglund, Petter

    2004-11-01

    CD8+ T cells are killer cells but also major producers of IFN-gamma. We have investigated the effects of peptide antigen titration and costimulatory blockade on IFN-gamma production and proliferation by naive CD8+ T cells. Mature dendritic cells (DC) pulsed with high amounts of agonist peptide triggered proliferation but little IFN-gamma secretion in individual T cells. In contrast, immature DC pulsed with similar amounts of peptide induced IFN-gamma secretion in a larger fraction of T cells but triggered less proliferation. Blocking B7.2 or lowering the amount of peptide on mature DC led to a response similar to that induced by immature DC, suggesting that differences in stimulatory strength were responsible for the different responses. Using splenic antigen-presenting cells (APC) we demonstrate that reducing the amount of peptide in combination with B7 blockage enhanced IFN-gamma secretion and decreased proliferation in naive CD8+ T cells in an additive way. Our data suggest that IFN-gamma secretion and proliferation are independently and inversely controlled by stimulatory strength in naive CD8+ T cells. This may enable CD8+ T cells to respond with IFN-gamma secretion to immature APC with few peptide ligands consistent with an early immunoregulatory role of CD8+ T cells.

  10. A Chemokine Expressed in Lymphoid High Endothelial Venules Promotes the Adhesion and Chemotaxis of Naive T Lymphocytes

    NASA Astrophysics Data System (ADS)

    Gunn, Michael D.; Tangemann, Kirsten; Tam, Carmen; Cyster, Jason G.; Rosen, Steven D.; Williams, Lewis T.

    1998-01-01

    Preferential homing of naive lymphocytes to secondary lymphoid organs is thought to involve the action of chemokines, yet no chemokine has been shown to have either the expression pattern or the activities required to mediate this process. Here we show that a chemokine represented in the EST database, secondary lymphoid-tissue chemokine (SLC), is expressed in the high endothelial venules of lymph nodes and Peyer's patches, in the T cell areas of spleen, lymph nodes, and Peyer's patches, and in the lymphatic endothelium of multiple organs. SLC is a highly efficacious chemoattractant for lymphocytes with preferential activity toward naive T cells. Moreover, SLC induces firm adhesion of naive T lymphocytes via β 2 integrin binding to the counter receptor, intercellular adhesion molecule-1, a necessary step for lymphocyte recruitment. SLC is the first chemokine demonstrated to have the characteristics required to mediate homing of lymphocytes to secondary lymphoid organs. In addition, the expression of SLC in lymphatic endothelium suggests that the migration of lymphocytes from tissues into efferent lymphatics may be an active process mediated by this molecule.

  11. Isolation and cultivation of naive-like human pluripotent stem cells based on HERVH expression.

    PubMed

    Wang, Jichang; Singh, Manvendra; Sun, Chuanbo; Besser, Daniel; Prigione, Alessandro; Ivics, Zoltán; Hurst, Laurence D; Izsvák, Zsuzsanna

    2016-02-01

    The ability to derive and stably maintain ground-state human pluripotent stem cells (hPSCs) that resemble the cells seen in vivo in the inner cell mass has the potential to be an invaluable tool for researchers developing stem cell-based therapies. To date, derivation of human naive-like pluripotent stem cell lines has been limited to a small number of lineages, and their long-term culturing remains problematic. We describe a protocol for genetic and phenotypic tagging, selecting and maintaining naive-like hPSCs. We tag hPSCs by GFP, expressed by the long terminal repeat (LTR7) of HERVH endogenous retrovirus. This simple and efficient protocol has been reproduced with multiple hPSC lines, including embryonic and induced pluripotent stem cells, and it takes ∼6 weeks. By using the reporter, homogeneous hPSC cultures can be derived, characterized and maintained for the long term by repeated re-sorting and re-plating steps. The HERVH-expressing cells have a similar, but nonidentical, expression pattern to other naive-like cells, suggesting that alternative pluripotent states might exist. PMID:26797457

  12. Naive T-cells in myelodysplastic syndrome display intrinsic human telomerase reverse transcriptase (hTERT) deficiency.

    PubMed

    Yang, L; Mailloux, A; Rollison, D E; Painter, J S; Maciejewski, J; Paquette, R L; Loughran, T P; McGraw, K; Makishima, H; Radhakrishnan, R; Wei, S; Ren, X; Komrokji, R; List, A F; Epling-Burnette, P K

    2013-04-01

    Telomeres are specialized structures providing chromosome integrity during cellular division along with protection against premature senescence and apoptosis. Accelerated telomere attrition in patients with myelodysplastic syndrome (MDS) occurs by an undefined mechanism. Although the MDS clone originates within the myeloid compartment, T-lymphocytes display repertoire contraction and loss of naive T-cells. The replicative lifespan of T-cells is stringently regulated by telomerase activity. In MDS cases, we show that purified CD3+ T-cells have significantly shorter telomere length and reduced proliferative capacity upon stimulation compared with controls. To understand the mechanism, telomerase enzymatic activity and telomerase reverse transcriptase (hTERT), gene expression were compared in MDS cases (n=35) and healthy controls (n=42) within different T-cell compartments. Telomerase activity is greatest in naive T-cells illustrating the importance of telomere repair in homeostatic repertoire regulation. Compared with healthy controls, MDS cases had lower telomerase induction (P<0.0001) that correlated with significantly lower hTERT mRNA (P<0.0001), independent of age and disease stratification. hTERT mRNA deficiency affected naive but not memory T-cells, and telomere erosion in MDS occurred without evidence of an hTERT-promoter mutation, copy number variation or deletion. Telomerase insufficiency may undermine homeostatic control within the hematopoietic compartment and promote a change in the T-cell repertoire in MDS.

  13. Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba.

    PubMed

    Pérez, Lissette; Kourí, Vivian; Alemán, Yoan; Abrahantes, Yeisel; Correa, Consuelo; Aragonés, Carlos; Martínez, Orlando; Pérez, Jorge; Fonseca, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Dekeersmaeker, Nathalie; Imbrechts, Stijn; Beheydt, Gertjan; Vinken, Lore; Soto, Yudira; Álvarez, Alina; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2013-06-01

    In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007-2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%-4.8%) in 2003 versus 12.5% (CI 7.2%-14.5%) in 2007-2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%-17.0%) in 2007-2011 versus 3.8% (CI 0.9%-4.7%) in 2003 (OR 3.9, CI 1.5-17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the

  14. Low-Dose Pharmacokinetics and Oral Bioavailability of Dichloroacetate in Naive and GST-zeta Depleted Rats

    SciTech Connect

    Saghir, Shakil A.; Schultz, Irv R. )

    2002-01-01

    Pharmacokinetics of dichloroacetate (DCA) in naive and glutathione-S-transferase-zeta (GSTzeta) depleted rats was studied at doses approaching human daily exposure levels. In vitro metabolism of DCA by rat and human liver cytosol was also compared. Jugular vein cannulated male Fischer-344 rats were administered (i.v or gavage) with graded doses of DCA ranging from 0.05-20 mg/kg and time-course blood samples collected from the cannula. GSTzeta was depleted by exposing rats to DCA (0.2 g/L DCA) in drinking water for 7 days. Elimination of DCA by naive rats was so rapid that only the 1-20 mg/kg i.v. and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit. GSTzeta depletion slowed DCA elimination from plasma allowing kinetic analysis of doses as low as 0.05 mg/kg. DCA elimination was strongly dose-dependent in the naive rats with total body clearance declining with increasing dose. In the GSTzeta depleted rats, the pharmacokinetics became line ar at doses No.1 mg/kg. All oral doses were rapidly absorbed without any lag time. At higher oral doses (?5 mg/kg in GSTzeta depleted and?20 mg/kg in naive), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Virtually all the dose was eliminated through metabolic clearance; the rate of urinary elimination of DCA was < 1 ml h-1kg-1. A maximum of 1.0?0.3% dose was recovered in urine within 24 h in the GSTzeta depleted rats dosed i.v. with 20 mg/kg. The rate of in vitro metabolism of DCA by human cytosol was statistically similar to the GSTzeta depleted rats (p > 0.3), which supported the use of GSTzeta depleted rats as a model for assessing kinetics of DCA in humans. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GSTzeta depleted rats. Oral bioavailability of DCA to humans through consumption of drinking water was predicted to be a maximum of 0.05%.

  15. Low-dose pharmacokinetics and oral bioavailability of dichloroacetate in naive and GST-zeta-depleted rats.

    PubMed Central

    Saghir, Shakil A; Schultz, Irvin R

    2002-01-01

    We studied the pharmacokinetics of dichloroacetate (DCA) in naive rats and rats depleted of glutathione S-transferase-zeta (GST-zeta), at doses approaching human daily exposure levels. We also compared in vitro metabolism of DCA by rat and human liver cytosol. Jugular vein-cannulated male Fischer-344 rats received graded doses of DCA ranging from 0.05 to 20 mg/kg (intravenously or by gavage), and we collected time-course blood samples from the cannulas. GST-zeta activity was depleted by exposing rats to 0.2 g/L DCA in drinking water for 7 days before initiation of pharmacokinetic studies. Elimination of DCA by naive rats was so rapid that only 1-20 mg/kg intravenous and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit of 6 ng/mL. GST-zeta depletion slowed DCA elimination from plasma, allowing kinetic analysis of doses as low as 0.05 mg/kg. DCA elimination was strongly dose dependent in the naive rats, with total body clearance declining with increasing dose. In the GST-zeta-depleted rats, the pharmacokinetics became linear at doses less than or equal to 1 mg/kg. Virtually all of the dose was eliminated through metabolic clearance; the rate of urinary elimination was < 1 mL/hr/kg. At higher oral doses (less than or equal to 5 mg/kg in GST-zeta-depleted and 20 mg/kg in naive rats), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GST-zeta- depleted rats. Oral bioavailability of DCA in humans through consumption of drinking water was predicted to be very low and < 1%. The use of the GST-zeta-depleted rat as a model for assessing the kinetics of DCA in humans is supported by the similarity in pharmacokinetic parameter estimates and rate of in vitro metabolism of DCA by human and GST-zeta-depleted rat liver cytosol. PMID:12153755

  16. Naive Treg-like CCR7(+) mononuclear cells indicate unfavorable prognosis in hepatocellular carcinoma.

    PubMed

    Shi, Jie-Yi; Duan, Meng; Sun, Qi-Man; Yang, Liuxiao; Wang, Zhi-Chao; Mynbaev, Ospan A; He, Yi-Feng; Wang, Ling-Yan; Zhou, Jian; Tang, Qi-Qun; Cao, Ya; Fan, Jia; Wang, Xiao-Ying; Gao, Qiang

    2016-07-01

    Chemokine receptor-like 1 (CCRL1) has the potential in creating a low level of CCL19 and CCL21 to hinder CCR7(+) cell tracking to tumor tissue. Previously, we found a tumor suppressive role of CCRL1 by impairing CCR7-related chemotaxis of tumor cells in human hepatocellular carcinoma (HCC). Here, we reported a contribution of CCR7(+) mononuclear cells in the tumor microenvironment to the progression of disease. Immunohistochemistry was used to investigate the distribution and clinical significance of CCR7(+) cells in a cohort of 240 HCC patients. Furthermore, the phenotype, composition, and functional status of CCR7(+) cells were determined by flow cytometry, immunofluorescence, and in vitro co-culture assays. We found that CCR7(+) mononuclear cells were dispersed around tumor tissue and negatively related to tumoral expression of CCRL1 (P < 0.001, r = 0.391). High density of CCR7(+) mononuclear cells positively correlated with the absence of tumor capsule, vascular invasion, and poor differentiation (P < 0.05). Survival analyses revealed that increased number of CCR7(+) mononuclear cells was significantly associated with worse survival and increased recurrence. We found that CCR7(+) mononuclear cells featured a naive Treg-like phenotype (CD45RA(+)CD25(+)FOXP3(+)) and possessed tumor-promoting potential by producing TGF-β1. Moreover, CCR7(+) cells were also composed of several immunocytes, a third of which were CD8(+) T cells. CCR7(+) Treg-like cells facilitate tumor growth and indicate unfavorable prognosis in HCC patients, but fortunately, their tracking to tumor tissue is under the control of CCRL1. PMID:26813566

  17. Learning the Hang Power Clean: Kinetic, Kinematic, and Technical Changes in Four Weightlifting Naive Athletes.

    PubMed

    Haug, William B; Drinkwater, Eric J; Chapman, Dale W

    2015-07-01

    The investment in learning required to reach benefit with weightlifting training is currently not well understood in elite athletes. The purpose of this investigation was to quantify changes in vertical jump power production and kinematic variables in hang power clean (HPC) performance during the learning process from a naive state in a multiple single-subject research design. Four elite athletes undertook HPC learning for approximately 20-30 minutes twice per week over a 169-day period. Changes in parameters of vertical power production during squat jump (SJ) and countermovement jump (CMJ) were monitored from baseline (day 0) and at 3 additional occasions. Hang power clean movement kinematics and bar path traces were monitored from day 35 and at 3 additional occasions particular to the individual's periodized training plan. Descriptive statistics were reported within athletes as mean ± SD. We observed a 14.1-35.7% (SJ) and a -14.4 to 20.5% (CMJ) gain in peak power across the 4 jump testing occasions with improvements over the first 4 weeks (SJ: 9.2-32.6%; CMJ: -2.91 to 20.79%). Changes in HPC movement kinematics and barbell path traces occurred for each athlete indicating a more rearward-directed center of pressure over the concentric phase, greater double knee bend during the transition phase, decreased maximal plantar flexion, and minimal vertical displacement of body mass with HPC learning. Considering the minimal investment of 4 weeks to achieve increases in vertical power production, the benefits of training with HPC justified the associated time costs for these 4 elite athletes.

  18. Synaptic fatigue at the naive perforant path-dentate granule cell synapse in the rat.

    PubMed

    Abrahamsson, Therése; Gustafsson, Bengt; Hanse, Eric

    2005-12-15

    Synaptic activation at low frequency is often used to probe synaptic function and synaptic plasticity, but little is known about how such low-frequency activation itself affects synaptic transmission. In the present study, we have examined how the perforant path-dentate granule cell (PP-GC) synapse adapts to low-frequency activation from a previously non-activated (naive) state. Stimulation at 0.2 Hz in acute slices from developing rats (7-12 days old) caused a gradual depression of the AMPA EPSC (at -80 mV) to about half within 50 stimuli. This synaptic fatigue was unaffected by the NMDA and metabotropic glutamate (mGlu) receptor antagonists d-AP5 and LY-341495. A smaller component of this synaptic fatigue was readily reversible when switching to very low-frequency stimulation (0.033-0.017 Hz) and is attributed to a reversible decrease in release probability, which is probably due to depletion of readily releasable vesicles. Thus, it was expressed to the same extent by AMPA and NMDA EPSCs, and was associated with a decrease in quantal content (measured as 1/CV(2)) with no change in the paired-pulse ratio. The larger component of the synaptic fatigue was not readily reversible, was selective for AMPA EPSCs and was associated with a decrease in 1/CV(2), thus probably representing silencing of AMPA signalling in a subset of synapses. In adult rats (> 30 days old), the AMPA silencing had disappeared while the low-frequency depression remained unaltered. The present study has thus identified two forms of synaptic plasticity that contribute to fatigue of synaptic transmission at low frequencies at the developing PP-GC synapse; AMPA silencing and a low-frequency depression of release probability.

  19. Epidemiological profile of naive HIV-1/AIDS patients in Istanbul: the largest case series from Turkey.

    PubMed

    Yemisen, Mucahit; Aydın, Ozlem Altuntas; Gunduz, Alper; Ozgunes, Nail; Mete, Bilgul; Ceylan, Bahadir; Karaosmanoglu, Hayat Kumbasar; Yildiz, Dilek; Sargin, Fatma; Ozaras, Resat; Tabak, Fehmi

    2014-01-01

    The aim of the study was to report the epidemiological profile of HIV-1 positive patients from, Istanbul, Turkey, which has one of the lowest HIV-1/AIDS prevalences in Europe. The patients were followed by ACTHIV-IST group which was established by the Infectious Diseases Departments of five teaching hospitals (three university hospitals and two public hospitals) in Istanbul, Turkey. The HIV-1 positive patients were added to the standard patient files in all of the centers; these files were then transferred to the ACTHIV-IST database in the Internet. A total of 829 naiv-untreated HIV-1 positive patients were chosen from the database. The number of male patients was 700 (84.4%) and the mean age of the patients was 37 years (range, 17-79). In our study group 348 (42%) of the patients were married and 318 (38.7%) of the patients were single. The probable route of transmission was heterosexual intercourse in 437 (52.7%) patients and homosexual intercourse in 256 (30.9%) patients. In 519 (62.6%) patients the diagnose was made due to a screening test and in 241 (29.1%) patients, the diagnose was made due to an HIV-related/non-related disease. The mean CD4+ T cell number in 788 of the patients was 357.8/mm(3) (±271.1), and the median viral load in 698 of the patients was 100,000 copies/mL (20-9,790,000). In Turkey, the number of HIV-1 positive patients is still low and to diagnose with a screening test is the most common way of diagnostic route.

  20. Advances in Alcoholism Treatment

    PubMed Central

    Huebner, Robert B.; Kantor, Lori Wolfgang

    2011-01-01

    Researchers are working on numerous and varied approaches to improving the accessibility, quality, effectiveness, and cost-effectiveness of treatment for alcohol use disorders (AUDs). This overview article summarizes the approaches reviewed in this issue, including potential future developments for alcoholism treatment, such as medications development, behavioral therapy, advances in technology that are being used to improve treatment, integrated care of patients with AUDs and co-occurring disorders, the role of 12-step programs in the broader realm of treatment, treating patients with recurring and chronic alcohol dependence, strategies to close the gap between treatment need and treatment utilization, and how changes in the health care system may affect the delivery of treatment. This research will not only reveal new medications and behavioral therapies but also will contribute to new ways of approaching current treatment problems. PMID:23580014

  1. Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+ T cells in aged humans

    PubMed Central

    van der Geest, Kornelis S M; Abdulahad, Wayel H; Teteloshvili, Nato; Tete, Sarah M; Peters, Jorieke H; Horst, Gerda; Lorencetti, Pedro G; Bos, Nicolaas A; Lambeck, Annechien; Roozendaal, Caroline; Kroesen, Bart-Jan; Koenen, Hans J P M; Joosten, Irma; Brouwer, Elisabeth; Boots, Annemieke M H

    2015-01-01

    Insight into the maintenance of naive T cells is essential to understand defective immune responses in the context of aging and other immune compromised states. In humans, naive CD4+ T cells, in contrast to CD8+ T cells, are remarkably well retained with aging. Here, we show that low-affinity TCR engagement is the main driving force behind the emergence and accumulation of naive-like CD4+ T cells with enhanced sensitivity to IL-2 in aged humans. In vitro, we show that these CD45RA+CD25dimCD4+ T cells can develop from conventional naive CD25−CD4+ T cells upon CD3 cross-linking alone, in the absence of costimulation, rather than via stimulation by the homeostatic cytokines IL-2, IL-7, or IL-15. In vivo, TCR engagement likely occurs in secondary lymphoid organs as these cells were detected in lymph nodes and spleen where they showed signs of recent activation. CD45RA+CD25dimCD4+ T cells expressed a broad TCRVβ repertoire and could readily differentiate into functional T helper cells. Strikingly, no expansion of CD45RA+CD25dimCD8+ T cells was detected with aging, thereby implying that maintenance of naive CD4+ T cells is uniquely regulated. Our data provide novel insight into the homeostasis of naive T cells and may guide the development of therapies to preserve or restore immunity in the elderly. PMID:26010129

  2. A selective androgen receptor modulator enhances male-directed sexual preference, proceptive behavior, and lordosis behavior in sexually experienced, but not sexually naive, female rats.

    PubMed

    Kudwa, A E; López, F J; McGivern, R F; Handa, R J

    2010-06-01

    Androgens influence many aspects of reproductive behavior, including sexual preference of females for males. In oophorectomized women with sexual desire disorder, testosterone patches improve libido, but their use is limited because of adverse side effects. Selective androgen receptor modulators offer an improved safety profile for both sexes: enhancing libido and muscle and bone growth in a manner similar to steroidal androgens but with fewer adverse effects, such as hirsutism, acne, and prostate growth. The current study investigated the action of a novel selective androgen receptor modulator (LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one]) on male-directed sexual preference, proceptivity, and lordosis behavior of female rats. LGD-3303 is a nonsteroidal, nonaromatizable, highly selective ligand for the androgen receptor and effectively crosses the blood-brain barrier. Gonadectomized female rats were treated with LGD-3303 (3-30 mg/kg) or vehicle by daily oral gavage. Results showed that LGD-3303 treatment enhanced sexual preference of females for males but only if females had previous sexual experience. This occurred after 1 or 7 d of treatment. In contrast, preference for males was inhibited by LGD-3303 treatments of sexually naive females. The LGD-3303 increase in male preference was blocked by pretreatment with the androgen receptor antagonist flutamide. LGD-3303 treatment increased lordosis and proceptivity behaviors in ovariectomized females primed with suboptimal doses of estradiol benzoate plus progesterone. These data support the concept that LGD-3303 can stimulate aspects of female sexual behavior and may serve as a potential therapeutic for women with sexual desire disorders.

  3. Treatment

    MedlinePlus

    ... Prevention Treatment 2003 U.S. Outbreak African Rodent Importation Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox ... Examining Animals with Suspected Monkeypox African Rodent Importation Ban Resources Related Links Poxvirus Molluscum Contagiosum Orf Virus ( ...

  4. Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

    PubMed

    Mao, Zhongping Lily; Modi, Nishit B

    2016-08-01

    Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.

  5. Dose‐Response Analysis of the Effect of Carbidopa‐Levodopa Extended‐Release Capsules (IPX066) in Levodopa‐Naive Patients With Parkinson Disease

    PubMed Central

    Mao, Zhongping Lily

    2016-01-01

    Abstract Parkinson disease is an age‐related disorder of the central nervous system principally due to loss of dopamine‐producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose‐response relationship is established for carbidopa‐levodopa extended‐release capsules (IPX066) in levodopa‐naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double‐blind, parallel‐group, dose‐ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn‐Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half‐life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half‐life. The quantitative model allowed description of the entire time course of response to clinical trial intervention. PMID:26632091

  6. A prospective multicentre study to evaluate the efficacy and tolerability of osmotic release oral system (OROS®) hydromorphone in opioid-naive cancer patients: Results of the Korean South West Oncology Group study

    PubMed Central

    Song, Eun-Kee; Shim, Hyunjeong; Han, Hye-Suk; Sun, DerSheng; Lee, Soon-Il; Kang, Myung Hee; Lee, KyuTaek; Cho, DoYeun; Cho, In Sung; Park, Suk Young; Kim, Samyong; Yim, Chang-Yeol

    2015-01-01

    BACKGROUND: Osmotic release oral system (OROS®) hydromorphone is a potent, long-acting opioid analgesic, effective and safe for controlling cancer pain in patients who have received other strong opioids. To date, few studies have examined the efficacy of hydromorphone for pain relief in opioid-naive cancer patients. OBJECTIVES: A prospective, open-label, multicentre trial was conducted to determine the efficacy and tolerability of OROS hydromorphone as a single and front-line opioid therapy for patients experiencing moderate to severe cancer pain. METHODS: OROS hydromorphone was administered to patients who had not previously received strong, long-acting opioids. The baseline evaluation (visit 1) was followed by two evaluations (visits 2 and 3) performed two and 14 weeks later, respectively. The starting dose of OROS hydromorphone was 4 mg/day and was increased every two days when pain control was insufficient. Immediate-release hydromorphone was the only accepted alternative strong opioid for relief of breakthrough pain. The efficacy, safety and tolerability of OROS hydromorphone, including the effects on quality of life, and patients’ and investigators’ global impressions on pain relief were evaluated. The primary end point was pain intensity difference (PID) at visit 2 relative to visit 1 (expressed as %PID). RESULTS: A total of 107 patients were enrolled in the present study. An improvement in pain intensity of >50% (≥50% PID) was observed in 51.0% of the full analysis set and 58.6% of the per-protocol set. The mean pain score, measured using a numerical rating scale, was significantly reduced after two weeks of treatment, and most adverse events were manageable. Quality of life also improved, and >70% of patients and investigators were satisfied with the treatment. CONCLUSIONS: OROS hydromorphone provided effective pain relief and improved quality of life in opioid-naive cancer patients. As a single and front-line treatment, OROS hydromorphone delivered

  7. Transmitted Drug Resistance Among Antiretroviral-Naive Patients with Established HIV Type 1 Infection in Santo Domingo, Dominican Republic and Review of the Latin American and Caribbean Literature

    PubMed Central

    Taylor, Barbara S.; Rojas Fermín, Rita A.; Reyes, Emily Virginia; Vaughan, Catherine; José, Lina; Javier, Carmen; Franco Estévez, Ramona; Donastorg Cabral, Yeycy; Batista, Arelis; Lie, Yolanda; Coakley, Eoin; Hammer, Scott M.; Brudney, Karen

    2012-01-01

    Abstract Emergence of HIV resistance is a concerning consequence of global scale-up of antiretroviral therapy (ART). To date, there is no published information about HIV resistance from the Dominican Republic. The study's aim was to determine the prevalence of transmitted drug resistance (TDR) to reverse transcriptase and protease inhibitors in a sample of chronically HIV-1-infected patients in one clinic in Santo Domingo. The data are presented in the context of a review of the TDR literature from Latin America and the Caribbean. Genotype testing was successfully performed on 103 treatment-naive adults planning to initiate antiretroviral therapy; the World Health Organization (WHO) list of surveillance drug resistance mutations (SDRM) was used to determine the presence of TDR mutations. WHO SDRM were identified in eight patients (7.8%); none had received sdNVP. There were no significant differences in epidemiologic or clinical variables between those with or without WHO SDRM. The prevalence of WHO SDRM was 1.0% and 6.8% for nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. No WHO SDRMs for protease inhibitors were identified. Among 12 studies of TDR in the region with a sample size of at least 100 subjects, the reported prevalence of SDRM ranged from 2.8% to 8.1%. The most commonly identified SDRM was K103N. This information adds to our understanding of the epidemiology of TDR in the region and the possible role such mutations could play in undermining first-line treatment. Ongoing surveillance is clearly needed to better understand the TDR phenomenon in the Caribbean. PMID:21851324

  8. Functional connectivity between the amygdala and prefrontal cortex in medication-naive individuals with major depressive disorder

    PubMed Central

    Kong, Lingtao; Chen, Kaiyuan; Tang, Yanqing; Wu, Feng; Driesen, Naomi; Womer, Fay; Fan, Guoguang; Ren, Ling; Jiang, Wenyan; Cao, Yang; Blumberg, Hilary P.; Xu, Ke; Wang, Fei

    2013-01-01

    Background Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic resonance imaging (fMRI) to investigate amygdala–PFC functional connectivity during emotional face processing in medication-naive individuals with MDD. Methods Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups. Results Our study included 28 individuals with MDD and 30 controls. Decreased amygdala–left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition (p < 0.05, corrected). No significant differences were found in amygdala connectivity to any cerebral regions between the MDD and control groups for the happy or neutral conditions. Limitations All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population. Conclusion Medication-naive individuals with MDD showed decreased amygdala–left rPFC functional connectivity in response to negative emotional stimuli, suggesting that abnormalities in amygdala–left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD. PMID:24148846

  9. Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite.

    PubMed

    Stanisic, Danielle I; Gerrard, John; Fink, James; Griffin, Paul M; Liu, Xue Q; Sundac, Lana; Sekuloski, Silvana; Rodriguez, Ingrid B; Pingnet, Jolien; Yang, Yuedong; Zhou, Yaoqi; Trenholme, Katharine R; Wang, Claire Y T; Hackett, Hazel; Chan, Jo-Anne A; Langer, Christine; Hanssen, Eric; Hoffman, Stephen L; Beeson, James G; McCarthy, James S; Good, Michael F

    2016-09-01

    Plasmodium falciparum is the most virulent human malaria parasite because of its ability to cytoadhere in the microvasculature. Nonhuman primate studies demonstrated relationships among knob expression, cytoadherence, and infectivity. This has not been examined in humans. Cultured clinical-grade P. falciparum parasites (NF54, 7G8, and 3D7B) and ex vivo-derived cell banks were characterized. Knob and knob-associated histidine-rich protein expression, CD36 adhesion, and antibody recognition of parasitized erythrocytes (PEs) were evaluated. Parasites from the cell banks were administered to malaria-naive human volunteers to explore infectivity. For the NF54 and 3D7B cell banks, blood was collected from the study participants for in vitro characterization. All parasites were infective in vivo However, infectivity of NF54 was dramatically reduced. In vitro characterization revealed that unlike other cell bank parasites, NF54 PEs lacked knobs and did not cytoadhere. Recognition of NF54 PEs by immune sera was observed, suggesting P. falciparum erythrocyte membrane protein 1 expression. Subsequent recovery of knob expression and CD36-mediated adhesion were observed in PEs derived from participants infected with NF54. Knobless cell bank parasites have a dramatic reduction in infectivity and the ability to adhere to CD36. Subsequent infection of malaria-naive volunteers restored knob expression and CD36-mediated cytoadherence, thereby showing that the human environment can modulate virulence.

  10. Cultivation and qPCR Detection of Pathogenic and Antibiotic-Resistant Bacterial Establishment in Naive Broiler Houses.

    PubMed

    Brooks, J P; McLaughlin, M R; Adeli, A; Miles, D M

    2016-05-01

    Conventional commercial broiler production involves the rearing of more than 20,000 broilers in a single confined space for approximately 6.5 wk. This environment is known for harboring pathogens and antibiotic-resistant bacteria, but studies have focused on previously established houses with mature litter microbial populations. In the current study, a set of three naive houses were followed from inception through 11 broiler flocks and monitored for ambient climatic conditions, bacterial pathogens, and antibiotic resistance. Within the first 3 wk of the first flock cycle, 100% of litter samples were positive for and , whereas was cultivation negative but PCR positive. Antibiotic resistance genes were ubiquitously distributed throughout the litter within the first flock, approaching 10 to 10 genomic units g. Preflock litter levels were approximately 10 CFU g for heterotrophic plate count bacteria, whereas midflock levels were >10 colony forming units (CFU) g; other indicators demonstrated similar increases. The influence of intrahouse sample location was minor. In all likelihood, given that preflock levels were negative for pathogens and antibiotic resistance genes and 4 to 5 Log lower than flock levels for indicators, incoming birds most likely provided the colonizing microbiome, although other sources were not ruled out. Most bacterial groups experienced a cyclical pattern of litter contamination seen in other studies, whereas microbial stabilization required approximately four flocks. This study represents a first-of-its-kind view into the time required for bacterial pathogens and antibiotic resistance to colonize and establish in naive broiler houses. PMID:27136163

  11. Naive CD8⁺ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics.

    PubMed

    Neller, Michelle A; Ladell, Kristin; McLaren, James E; Matthews, Katherine K; Gostick, Emma; Pentier, Johanne M; Dolton, Garry; Schauenburg, Andrea J A; Koning, Dan; Fontaine Costa, Ana Isabel C A; Watkins, Thomas S; Venturi, Vanessa; Smith, Corey; Khanna, Rajiv; Miners, Kelly; Clement, Mathew; Wooldridge, Linda; Cole, David K; van Baarle, Debbie; Sewell, Andrew K; Burrows, Scott R; Price, David A; Miles, John J

    2015-08-01

    Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this 'ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8(+) T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment.

  12. Genetic diversity on the integrase region of the pol gene among HIV type 1-infected patients naive for integrase inhibitors in São Paulo City, Brazil.

    PubMed

    Arruda, Liã Bárbara; Fonseca, Luiz Augusto M; Duarte, Alberto J S; Casseb, Jorge

    2010-01-01

    The presence of mutations associated with integrase inhibitor (INI) resistance among INI-naive patients may play an important clinical role in the use of those drugs Samples from 76 HIV-1-infected subjects naive to INIs were submitted to direct sequencing. No differences were found between naive (25%) subjects and subjects on HAART (75%). No primary mutation associated with raltegravir or elvitegravir resistance was found. However, 78% of sequences showed at least one accessory mutation associated with resistance. The analysis of the 76 IN sequences showed a high polymorphic level on this region among Brazilian HIV-1-infected subjects, including a high prevalence of aa substitutions related to INI resistance. The impact of these findings remains unclear and further studies are necessary to address these questions.

  13. Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer

    PubMed Central

    Forero-Torres, Andres; Infante, Jeffrey R; Waterhouse, David; Wong, Lucas; Vickers, Selwyn; Arrowsmith, Edward; He, Aiwu Ruth; Hart, Lowell; Trent, David; Wade, James; Jin, Xiaoping; Wang, Qiang; Austin, TaShara; Rosen, Michael; Beckman, Robert; von Roemeling, Reinhard; Greenberg, Jonathan; Saleh, Mansoor

    2013-01-01

    Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. PMID:24403266

  14. Comparative analysis of drug resistance mutations in the human immunodeficiency virus reverse transcriptase gene in patients who are non-responsive, responsive and naive to antiretroviral therapy.

    PubMed

    Misbah, Mohammad; Roy, Gaurav; Shahid, Mudassar; Nag, Nalin; Kumar, Suresh; Husain, Mohammad

    2016-05-01

    Drug resistance mutations in the Pol gene of human immunodeficiency virus 1 (HIV-1) are one of the critical factors associated with antiretroviral therapy (ART) failure in HIV-1 patients. The issue of resistance to reverse transcriptase inhibitors (RTIs) in HIV infection has not been adequately addressed in the Indian subcontinent. We compared HIV-1 reverse transcriptase (RT) gene sequences to identify mutations present in HIV-1 patients who were ART non-responders, ART responders and drug naive. Genotypic drug resistance testing was performed by sequencing a 655-bp region of the RT gene from 102 HIV-1 patients, consisting of 30 ART-non-responding, 35 ART-responding and 37 drug-naive patients. The Stanford HIV Resistance Database (HIVDBv 6.2), IAS-USA mutation list, ANRS_09/2012 algorithm, and Rega v8.02 algorithm were used to interpret the pattern of drug resistance. The majority of the sequences (96 %) belonged to subtype C, and a few of them (3.9 %) to subtype A1. The frequency of drug resistance mutations observed in ART-non-responding, ART-responding and drug-naive patients was 40.1 %, 10.7 % and 20.58 %, respectively. It was observed that in non-responders, multiple mutations were present in the same patient, while in responders, a single mutation was found. Some of the drug-naive patients had more than one mutation. Thymidine analogue mutations (TAMs), however, were found in non-responders and naive patients but not in responders. Although drug resistance mutations were widely distributed among ART non-responders, the presence of resistance mutations in the viruses of drug-naive patients poses a big concern in the absence of a genotyping resistance test. PMID:26801790

  15. Association of Abnormal Liver Function Parameters with HIV Serostatus and CD4 Count in Antiretroviral-Naive Rwandan Women

    PubMed Central

    Hoover, Donald R.; Shi, Qiuhu; Mutimura, Eugene; Rudakemwa, Emmanuel; Ndacyayisenga, Victorien; Gakindi, Léonard; Mulvihill, Michael; Sinayobye, Jean D'Amour; Musabeyezu, Emmanuel; Anastos, Kathryn

    2015-01-01

    Abstract We determined the associations of HIV infection/CD4 count with markers of hepatocellular damage [elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and liver synthetic function (decreased albumin) in HIV-infected (HIV+) antiretroviral therapy (ART)-naive and uninfected (HIV−) Rwandan women. In 2005, 710 HIV+ ART-naive and 226 HIV− women enrolled in the Rwanda Women's Interassociation Study and Assessment. Liver enzymes were measured with abnormality defined as either AST or ALT ≥1.25 times the upper limit of normal. Low serum albumin level was defined as <3.5 g/dl. Multivariable logistic regression analysis identified independent predictors of elevated AST/ALT and low serum albumin. HIV− women had the lowest prevalence (6.6%) of abnormal AST/ALT, with the highest prevalence (16.4%) in HIV+ women with CD4 <200 cells/μl (p=0.01). The odds of having serum albumin <3.5 g/dl was 5.7-fold higher in HIV+ than HIV− women (OR=5.68, 95% CI: 3.32–9.71). The risk of low albumin decreased from low to high CD4 count, with OR=2.62, 95% CI: 1.66, 4.14 and OR=1.57, 95% CI: 1.01, 2.43 in HIV+ women with a CD4 count <200 and 200–350 cells/μl, respectively vs. HIV+ with CD4 >350 (p<0.001 and p<0.05 for all comparisons). Our findings suggest that HIV-associated liver damage may occur in ART-naive patients. Although liver abnormality prevalences in this cohort of HIV-infected Rwandan women are less than reported in developed countries, caution is needed for risk assessment measures to monitor and screen HIV-infected patients pre- and post-ART initiation in African clinical settings to curtail potential risks associated with HIV infection. PMID:25924728

  16. The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression

    PubMed Central

    Atsumi, Tatsuya; Yamamoto, Kazuhiko; Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Tanaka, Yoshiya; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Yasuda, Shinsuke; Yamanishi, Yuji; Kita, Yasuhiko; Matsubara, Tsukasa; Iwamoto, Masahiro; Shoji, Toshiharu; Okada, Toshiyuki; Miyasaka, Nobuyuki; Koike, Takao

    2016-01-01

    Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTX-naive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone. Methods MTX-naive, early RA patients with ≤12 months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1:1 to CZP+MTX or PBO+MTX for 52 weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52. Results 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3 months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p<0.001) and week 24 (mTSS CFB=0.26 vs 0.86; p=0.003). Clinical remission rates (Simple Disease Activity Index, Boolean and DAS28 (ESR)) of the CZP+MTX group were significantly higher compared with those of the PBO+MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX. Conclusions In MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms, demonstrating the efficacy of CZP in these patients. Trial registration number (NCT01451203). PMID:26139005

  17. Correlation between HIV viral load and aminotransferases as liver damage markers in HIV infected naive patients: a concordance cross-sectional study

    PubMed Central

    Mata-Marín, José Antonio; Gaytán-Martínez, Jesús; Grados-Chavarría, Bernardo Horacio; Fuentes-Allen, José Luis; Arroyo-Anduiza, Carla Ileana; Alfaro-Mejía, Alfredo

    2009-01-01

    Abnormalities in liver function tests could be produced exclusively by direct inflammation in hepatocytes, caused by the human immunodeficiency virus (HIV). Mechanisms by which HIV causes hepatic damage are still unknown. Our aim was to determine the correlation between HIV viral load, and serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatic damage in HIV naive infected patients. We performed a concordance cross-sectional study. Patients with antiviral treatment experience, hepatotoxic drugs use or co-infection were excluded. We used a Pearson's correlation coefficient to calculate the correlation between aminotransferases serum levels with HIV viral load. We enrolled 59 patients, 50 men and 9 women seen from 2006 to 2008. The mean (± SD) age of our subjects was 34.24 ± 9.5, AST 37.73 ± 29.94 IU/mL, ALT 43.34 ± 42.41 IU/mL, HIV viral load 199,243 ± 292,905 copies/mL, and CD4+ cells count 361 ± 289 cells/mm3. There was a moderately strong, positive correlation between AST serum levels and HIV viral load (r = 0.439, P < 0.001); and a weak correlation between ALT serum levels and HIV viral load (r = 0.276, P = 0.034); after adjusting the confounders in lineal regression model the correlation remained significant. Our results suggest that there is an association between HIV viral load and aminotransferases as markers of hepatic damage; we should improved recognition, diagnosis and potential therapy of hepatic damage in HIV infected patients. PMID:19878552

  18. Prevalence and Outcomes of Hepatitis B Coinfection and Associated Liver Disease Among Antiretroviral Therapy-Naive Individuals in a Rural Tanzanian Human Immunodeficiency Virus Cohort

    PubMed Central

    Ramírez-Mena, Adrià; Glass, Tracy R.; Winter, Annja; Kimera, Namvua; Ntamatungiro, Alex; Hatz, Christoph; Tanner, Marcel; Battegay, Manuel; Furrer, Hansjakob; Wandeler, Gilles; Letang, Emilio

    2016-01-01

    Background. We evaluated the prevalence of chronic hepatitis B virus (HBV) infection and liver fibrosis/cirrhosis in human immunodeficiency virus (HIV)-infected individuals enrolled in a rural Tanzanian prospective cohort and assessed hepatic fibrosis progression 12–24 months after antiretroviral treatment (ART) initiation. Methods. All ART-naive HIV-infected adults ≥15-year-old enrolled in the Kilombero and Ulanga Antiretroviral Cohort who started ART between 2005 and 2015 were included. Pre-ART factors associated with significant liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] >1.5) and cirrhosis (APRI > 2.0) were identified using logistic regression. Results. Of 3097 individuals screened, 227 (7.3%; 95% CI, 6.4–8.2) were hepatitis B surface antigen (HBsAg) positive. Before ART initiation, 9.1% individuals had significant liver fibrosis and 5.3% had cirrhosis. Human immunodeficiency virus/HBV-coinfected individuals were more likely to have an APRI score indicating significant fibrosis (14.2% vs 8.7%, P = .03) and cirrhosis (9.2% vs 4.9%, P = .03) than HBV-uninfected patients. CD4 cell count <200 cell/μL and alcohol consumption were independently associated with pre-ART APRI score, indicating significant fibrosis and cirrhosis in multivariable analyses. Among individuals with elevated APRI measurements pre- and 12–24 months post-ART initiation, 53 of 57 (93.0%) of HIV-monoinfected and 4 of 5 (80.0%) of HIV/HBV-coinfected had a regression to APRI < 1.5. Conclusions. Hepatic fibrosis and cirrhosis were common in our cohort, especially among HIV/HBV-coinfected individuals. The APRI improved in most patients. Pre-ART HBsAg screening and early onset of tenofovir-based ART for HIV/HBV-coinfection should be prioritized in sub-Saharan Africa.

  19. Evaluating preferences for profiles of glucagon-like peptide-1 receptor agonists among injection-naive type 2 diabetes patients in Japan

    PubMed Central

    Gelhorn, Heather L; Bacci, Elizabeth D; Poon, Jiat Ling; Boye, Kristina S; Suzuki, Shuichi; Babineaux, Steven M

    2016-01-01

    Objective The objective of this study was to use a discrete choice experiment (DCE) to estimate patients’ preferences for the treatment features, safety, and efficacy of two specific glucagon-like peptide-1 receptor agonists, dulaglutide and liraglutide, among patients with type 2 diabetes mellitus (T2DM) in Japan. Methods In Japan, patients with self-reported T2DM and naive to treatment with self-injectable medications were administered a DCE through an in-person interview. The DCE examined the following six attributes of T2DM treatment, each described by two levels: “dosing frequency”, “hemoglobin A1c change”, “weight change”, “type of delivery system”, “frequency of nausea”, and “frequency of hypoglycemia”. Part-worth utilities were estimated using logit models and were used to calculate the relative importance (RI) of each attribute. A chi-square test was used to determine the differences in preferences for the dulaglutide versus liraglutide profiles. Results The final evaluable sample consisted of 182 participants (mean age: 58.9 [standard deviation =10.0] years; 64.3% male; mean body mass index: 26.1 [standard deviation =5.0] kg/m2). The RI values for the attributes in rank order were dosing frequency (44.1%), type of delivery system (26.3%), frequency of nausea (15.1%), frequency of hypoglycemia (7.4%), weight change (6.2%), and hemoglobin A1c change (1.0%). Significantly more participants preferred the dulaglutide profile (94.5%) compared to the liraglutide profile (5.5%; P<0.0001). Conclusion This study elicited the preferences of Japanese T2DM patients for attributes and levels representing the actual characteristics of two existing glucagon-like peptide-1 receptor agonists. In this comparison, dosing frequency and type of delivery system were the two most important characteristics, accounting for >70% of the RI. These findings are similar to those of a previous UK study, providing information about patients’ preferences that

  20. Characteristics of naturally acquired avian malaria infections in naive juvenile African black-footed penguins (Spheniscus demersus).

    PubMed

    Graczyk, T K; Cranfield, M R; McCutchan, T F; Bicknese, E J

    1994-01-01

    Antibody responses to naturally acquired Plasmodium relictum and P. elongatum infections, blood parasitemia, and disease signs were investigated in 23 naive juvenile African black-footed penguins (Spheniscus demersus). Anti-Plasmodium spp. immunoglobulins were detected by enzyme-linked immunosorbent assay (ELISA) using P. falciparum antigens. All birds rapidly developed antibody to P. relictum and P. elongatum. Five penguins showed detectable parasitemia and signs of the disease. Parasitemia was not related to the timing of the maximal antibody response or to the antibody titer. Two of the five parasitemic birds died and gross examination revealed splenomegaly, hepatomegaly, and congested, edematous lungs. Although the other 17 birds were clearly exposed to the disease, none showed signs of infection. No subsequent episode of parasitemia was observed in individual penguins. A comparison of the fate of 1993 penguins with those from other years showed a great variability in the proportion of birds exhibiting signs of malaria.

  1. The Galileo bias: a naive conceptual belief that influences people's perceptions and performance in a ball-dropping task.

    PubMed

    Oberle, Crystal D; McBeath, Michael K; Madigan, Sean C; Sugar, Thomas G

    2005-07-01

    This research introduces a new naive physics belief, the Galileo bias, whereby people ignore air resistance and falsely believe that all objects fall at the same rate. Survey results revealed that this bias is held by many and is surprisingly strongest for those with formal physics instruction. In 2 experiments, 98 participants dropped ball pairs varying in volume and/or mass from a height of 10 m, with the goal of both balls hitting the ground simultaneously. The majority of participants in both experiments adopted a single strategy consistent with the Galileo bias, showing no improvement across trials. Yet, for participants reporting intentions of dropping both balls at the same time, the differences between release points were significantly greater than 0 ms. These findings support separate but interacting cognition and perception-action systems.

  2. Glutamatergic Metabolites, Volume and Cortical Thickness in Antipsychotic-Naive Patients with First-Episode Psychosis: Implications for Excitotoxicity.

    PubMed

    Plitman, Eric; Patel, Raihaan; Chung, Jun Ku; Pipitone, Jon; Chavez, Sofia; Reyes-Madrigal, Francisco; Gómez-Cruz, Gladys; León-Ortiz, Pablo; Chakravarty, M Mallar; de la Fuente-Sandoval, Camilo; Graff-Guerrero, Ariel

    2016-09-01

    Neuroimaging studies investigating patients with schizophrenia often report appreciable volumetric reductions and cortical thinning, yet the cause of these deficits is unknown. The association between subcortical and cortical structural alterations, and glutamatergic neurometabolites is of particular interest due to glutamate's capacity for neurotoxicity; elevated levels may be related to neuroanatomical compromise through an excitotoxic process. To this end, we explored the relationships between glutamatergic neurometabolites and structural measures in antipsychotic-naive patients experiencing their first non-affective episode of psychosis (FEP). Sixty antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls underwent a magnetic resonance imaging session, which included a T1-weighted volumetric image and proton magnetic resonance spectroscopy in the precommissural dorsal caudate. Group differences in precommissural caudate volume (PCV) and cortical thickness (CT), and the relationships between glutamatergic neurometabolites (ie, glutamate+glutamine (Glx) and glutamate) and these structural measures, were examined. PCV was decreased in the FEP group (p<0.001), yet did not differ when controlling for total brain volume. Cortical thinning existed in the FEP group within frontal, parietal, temporal, occipital, and limbic regions at a 5% false discovery rate. Glx levels were negatively associated with PCV only in the FEP group (p=0.018). The observed relationship between Glx and PCV in the FEP group is supportive of a focal excitotoxic mechanism whereby increased levels of glutamatergic markers are related to local structural losses. This process may be related to the prominent structural deficits that exist in patients with schizophrenia. PMID:27272768

  3. Anti-idiotypic nanobody as citrinin mimotope from a naive alpaca heavy chain single domain antibody library.

    PubMed

    Xu, Yang; Xiong, Liang; Li, Yanping; Xiong, Yonghua; Tu, Zhui; Fu, Jinheng; Chen, Bo

    2015-07-01

    Compared with peptide-based mimotope, anti-idiotypic antibodies (AIds) are considered as promising biosynthetic surrogate antigen because these antibodies display stable protein conformation. Nevertheless, conventional AIds are generated by immunizing animals with heterologous idiotypic antibody in vivo; isolated AIds commonly exhibit a higher affinity to primary antibodies than target analytes because AIds undergo an affinity-matured process during immune responses, resulting in low sensitivity in competitive immunoassay. In the present study, an anti-citrinin monoclonal antibody (anti-CIT McAb) was designed as primary antibody; one β-type AI alpaca heavy chain single domain antibody (β-AI VHH) was selected as a citrinin (CIT) surrogate from a naive phage-displayed VHH library. The affinity constant (K D) of obtained β-AI VHH to anti-CIT McAb (160 nM) is 2.35 times lower than that of CIT and ovalbumin conjugates (CIT-OVA) to anti-CIT McAb (68 nM). The developed VHH-based enzyme-linked immunosorbent assay (V-ELISA) can be used to perform dynamic linear detection of CIT in 10% (v/v) methanol/PBS from 5.0 to 300.0 ng/mL, with a median inhibitory concentration (IC50) of 44.6 ng/mL (n = 3); this result was twice as good as that of indirect competitive ELISA (ic-ELISA, IC50 = 96.2 ng/mL) with CIT-OVA as a coating antigen. Moreover, the precision of V-ELISA was evaluated by analyzing average recoveries and coefficient of variations of CIT-spiked cereal sample; the reliability of V-ELISA was also validated with a conventional ic-ELISA. In summary, the proposed strategy has a great potential for panning other β-AI VHH toward small organic molecules from a naive VHH library.

  4. Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells

    PubMed Central

    Smith, Kellie N.; Mailliard, Robbie B.; Piazza, Paolo A.; Fischer, Will; Korber, Bette T.; Fecek, Ronald J.; Ratner, Deena; Gupta, Phalguni; Mullins, James I.

    2016-01-01

    ABSTRACT Curing HIV-1 infection will require elimination of persistent cellular reservoirs that harbor latent virus in the face of combination antiretroviral therapy (cART). Proposed immunotherapeutic strategies to cure HIV-1 infection include enhancing lysis of these infected cells by cytotoxic T lymphocytes (CTL). A major challenge in this strategy is overcoming viral immune escape variants that have evaded host immune control. Here we report that naive CD8+ T cells from chronic HIV-1-infected participants on long-term cART can be primed by dendritic cells (DC). These DC must be mature, produce high levels of interleukin 12p70 (IL-12p70), be responsive to CD40 ligand (CD40L), and be loaded with inactivated, autologous HIV-1. These DC-primed CD8+ T cell responders produced high levels of gamma interferon (IFN-γ) in response to a broad range of both conserved and variable regions of Gag and effectively killed CD4+ T cell targets that were either infected with the autologous latent reservoir-associated virus or loaded with autologous Gag peptides. In contrast, HIV-1-specific memory CD8+ T cells stimulated with autologous HIV-1-loaded DC produced IFN-γ in response to a narrow range of conserved and variable Gag peptides compared to the primed T cells and most notably, displayed significantly lower cytolytic function. Our findings highlight the need to selectively induce new HIV-1-specific CTL from naive precursors while avoiding activation of existing, dysfunctional memory T cells in potential curative immunotherapeutic strategies for HIV-1 infection. PMID:27247230

  5. Naive Students' Conceptual Development and Beliefs: The Need for Multiple Analyses to Determine What Contributes to Student Success in a University Introductory Physics Course

    ERIC Educational Resources Information Center

    Chu, Hye-Eun; Treagust, David F.; Chandrasegaran, A. L.

    2008-01-01

    This research involved naive physics learners who were interested in majoring in science or engineering. In a semester-long quasi-experimental study, open-ended pretests and weekly interviews were used to analyse the progressive development of students' conceptions relating to sound and wave motion. Semi-structured interviews were also conducted…

  6. Acute Neuropsychological Effects of Methylphenidate in Stimulant Drug-Naive Boys with ADHD II--Broader Executive and Non-Executive Domains

    ERIC Educational Resources Information Center

    Rhodes, Sinead M.; Coghill, David R.; Matthews, Keith

    2006-01-01

    Background: Accumulating evidence supports methylphenidate-induced enhancement of neuropsychological functioning in attention deficit hyperactivity disorder (ADHD). The present study was designed to investigate the acute effects of the psychostimulant drug, methylphenidate (MPH), on neuropsychological performance in stimulant naive boys with ADHD.…

  7. Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial

    PubMed Central

    Rodbard, H W; Cariou, B; Zinman, B; Handelsman, Y; Philis-Tsimikas, A; Skjøth, T V; Rana, A; Mathieu, C

    2013-01-01

    Aims The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. Methods This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9–4.9 mmol/l. Results At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI −1 to 3) [0.07% (95% CI −0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). Conclusions In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine. PMID:23952326

  8. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    PubMed Central

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = -33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = -33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 681750 ng/mL). Conclusion Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study.

  9. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    PubMed Central

    Montaner, Julio S.G.; Schutz, Malte; Schwartz, Robert; Jayaweera, Dushyantha T.; Burnside, Alfred F.; Walmsley, Sharon; Saag, Michael S.

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = −33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = −33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 68-1750 ng/mL). Conclusions Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study. PMID:16926775

  10. Dexamethasone and Monophosphoryl Lipid A-Modulated Dendritic Cells Promote Antigen-Specific Tolerogenic Properties on Naive and Memory CD4+ T Cells

    PubMed Central

    Maggi, Jaxaira; Schinnerling, Katina; Pesce, Bárbara; Hilkens, Catharien M.; Catalán, Diego; Aguillón, Juan C.

    2016-01-01

    Tolerogenic dendritic cells (DCs) are a promising tool to control T cell-mediated autoimmunity. Here, we evaluate the ability of dexamethasone-modulated and monophosphoryl lipid A (MPLA)-activated DCs [MPLA-tolerogenic DCs (tDCs)] to exert immunomodulatory effects on naive and memory CD4+ T cells in an antigen-specific manner. For this purpose, MPLA-tDCs were loaded with purified protein derivative (PPD) as antigen and co-cultured with autologous naive or memory CD4+ T cells. Lymphocytes were re-challenged with autologous PPD-pulsed mature DCs (mDCs), evaluating proliferation and cytokine production by flow cytometry. On primed-naive CD4+ T cells, the expression of regulatory T cell markers was evaluated and their suppressive ability was assessed in autologous co-cultures with CD4+ effector T cells and PPD-pulsed mDCs. We detected that memory CD4+ T cells primed by MPLA-tDCs presented reduced proliferation and proinflammatory cytokine expression in response to PPD and were refractory to subsequent stimulation. Naive CD4+ T cells were instructed by MPLA-tDCs to be hyporesponsive to antigen-specific restimulation and to suppress the induction of T helper cell type 1 and 17 responses. In conclusion, MPLA-tDCs are able to modulate antigen-specific responses of both naive and memory CD4+ T cells and might be a promising strategy to “turn off” self-reactive CD4+ effector T cells in autoimmunity.

  11. Dexamethasone and Monophosphoryl Lipid A-Modulated Dendritic Cells Promote Antigen-Specific Tolerogenic Properties on Naive and Memory CD4+ T Cells

    PubMed Central

    Maggi, Jaxaira; Schinnerling, Katina; Pesce, Bárbara; Hilkens, Catharien M.; Catalán, Diego; Aguillón, Juan C.

    2016-01-01

    Tolerogenic dendritic cells (DCs) are a promising tool to control T cell-mediated autoimmunity. Here, we evaluate the ability of dexamethasone-modulated and monophosphoryl lipid A (MPLA)-activated DCs [MPLA-tolerogenic DCs (tDCs)] to exert immunomodulatory effects on naive and memory CD4+ T cells in an antigen-specific manner. For this purpose, MPLA-tDCs were loaded with purified protein derivative (PPD) as antigen and co-cultured with autologous naive or memory CD4+ T cells. Lymphocytes were re-challenged with autologous PPD-pulsed mature DCs (mDCs), evaluating proliferation and cytokine production by flow cytometry. On primed-naive CD4+ T cells, the expression of regulatory T cell markers was evaluated and their suppressive ability was assessed in autologous co-cultures with CD4+ effector T cells and PPD-pulsed mDCs. We detected that memory CD4+ T cells primed by MPLA-tDCs presented reduced proliferation and proinflammatory cytokine expression in response to PPD and were refractory to subsequent stimulation. Naive CD4+ T cells were instructed by MPLA-tDCs to be hyporesponsive to antigen-specific restimulation and to suppress the induction of T helper cell type 1 and 17 responses. In conclusion, MPLA-tDCs are able to modulate antigen-specific responses of both naive and memory CD4+ T cells and might be a promising strategy to “turn off” self-reactive CD4+ effector T cells in autoimmunity. PMID:27698654

  12. Criminal typology of veterans entering substance abuse treatment.

    PubMed

    Schultz, Nicole R; Blonigen, Daniel; Finlay, Andrea; Timko, Christine

    2015-07-01

    Criminal justice involvement among veterans is a critical and timely concern, yet little is known about criminal histories and clinical characteristics among veterans seeking treatment for substance use disorders (SUDs). The present study examined criminal typology, clinical characteristics, treatment utilization, and 12-step mutual-help group (MHG) participation among veterans (N = 332) at intake to SUD treatment at the Department of Veterans Affairs (VA), and 6 months and 1 year post-intake. Cluster analysis yielded three types of criminal histories mild-(78.9%), moderate (13.6%), and severe (7.5%)-distinguished by type of offense, number of convictions, and number of months incarcerated. At intake, participants with mild criminal histories reported more alcohol problems and fewer legal and employment problems than participants with moderate and severe criminal histories. Participants with severe criminal histories were most likely to attend a 12-step MHG meeting in the year post-intake, but all groups had high attendance. When only participants who had attended at least one meeting in the year post-intake were compared, participants with mild criminal histories worked more steps and were more involved in 12-step practices. All groups improved between baseline and follow-up and did not differ at follow-ups on substance use or other clinical outcomes. Multiple regressions identified treatment utilization and MHG attendance, but not baseline criminal history, as significant predictors of improved substance use problem severity at follow-up. Outpatient treatment and 12-step MHG attendance appear to be important components of recovery for veterans with varying criminal histories. Clinicians in SUD treatment programs should screen for criminal histories at treatment intake to ensure appropriate treatment planning.

  13. Identification of Germinal Center B Cells in Blood from HIV-infected Drug-naive Individuals in Central Africa

    PubMed Central

    Béniguel, Lydie; Bégaud, Evelyne; Cognasse, Fabrice; Gabrié, Philippe; Mbolidi, Christophe D.; Sabido, Odile; Marovich, Mary A.; deFontaine, Christiane; Frésard, Anne; Lucht, Frédéric; Genin, Christian; Garraud, Olivier

    2004-01-01

    To better understand the pathophysiology of B cell populations—the precursors of antibody secreting cells—during chronic human immunodeficiency virus (HIV) infection, we examined the phenotype of circulating B cells in newly diagnosed Africans. We found that all African individuals displayed low levels of naive B cells and of memory-type CD27+ B cells, and high levels of differentiated B cells. On the other hand, HIV-infected African patients had a population of germinal center B cells (i.e. CD20+, sIgM-, sIgD+, CD77+, CD138±), which are generally restricted to lymph nodes and do not circulate unless the lymph node architecture is altered. The first observations could be linked to the tropical environment whereas the presence of germinal center B cells may be attributable to chronic exposure to HIV as it is not observed in HIV-negative African controls and HAART treated HIV-infected Europeans. It may impact the management of HIV infection in countries with limited access to HIV drugs and urges consideration for implementation of therapeutic vaccines. PMID:15154608

  14. From Naive to Primed Pluripotency: In Vitro Conversion of Mouse Embryonic Stem Cells in Epiblast Stem Cells.

    PubMed

    Tosolini, Matteo; Jouneau, Alice

    2016-01-01

    Mouse embryonic stem cells (ESCs) derive from the inner cell mass (ICM) of a blastocyst at E3.5 while mouse epiblast stem cells (EpiSCs) derive from the late epiblast of a post-implantation embryo at E5.5-E7.5. Both cells are able to differentiate into derivatives of the three germs layers but only ESCs are able to produce chimeras when they are introduced into a blastocyst. To support the naive state of pluripotency, ESC culture requires Leukemia inhibitory factor (Lif) and either serum or inhibitors of Erk and Gsk3 pathways (2i) while the primed pluripotency of EpiSCs is maintained using Activin A and Fibroblast Growth Factor 2 (FGF2). It is possible to obtain EpiSCs in vitro starting from ESCs but also to induce ESCs starting from EpiSCs even if this second process is very difficult and inefficient. In this protocol we describe how we perform the process of conversion from ESCs to EpiSCs.

  15. Aberrant functional organization in schizophrenia: analysis of EEG coherence during rest and photic stimulation in drug-naive patients.

    PubMed

    Wada, Y; Nanbu, Y; Kikuchi, M; Koshino, Y; Hashimoto, T

    1998-01-01

    EEG coherence provides a measure of functional correlations between two EEG signals. The present study was conducted to examine intrahemispheric EEG coherence at rest and during photic stimulation (PS) in 18 drug-naive patients with paranoid schizophrenia and 30 control subjects. Compared with the controls, the schizophrenic patients had significantly higher intrahemispheric coherence of the resting EEG for the delta band, although no significant group differences were found for other frequency bands. EEG analysis during PS showed that the patients also had significantly higher EEG coherence over the left posterior regions. In this study, we also examined the changes in intrahemispheric coherence from rest to the stimulus condition (i.e., PS-related coherence reactivity); the patients were found to show significantly smaller changes, with significant group differences being also confined to the posterior regions in the left hemisphere. These findings provide evidence that schizophrenic patients have abnormal EEG coherence in both resting and stimulus conditions and suggest more diffuse, undifferentiated functional organization within hemispheres. In addition, diminished coherence reactivity suggests a failure of PS-related functional reorganization in schizophrenia.

  16. Perception of acoustic cues to Tokyo Japanese pitch-accent contrasts in native Japanese and naive English listeners.

    PubMed

    Shport, Irina A

    2015-07-01

    This study examines how native language shapes the perception of a prosodic contrast. In Tokyo Japanese, a high-low pitch accent is a lexical property of a word, and the F0 fall after the peak associated with the accented syllable is the fundamental cue to accent perception. In English, pitch accents do not create lexically contrastive F0 patterns. A hypothesis that English listeners naive to Japanese use the F0 fall cue less than Japanese listeners was tested in two experiments. The alignment of F0 peak, the presence and magnitude of F0 fall were manipulated in a trisyllabic nonword to resynthesize Japanese 1st-syllable accented, 2nd-syllable accented, and unaccented patterns. In an AX-discrimination experiment, both listener groups showed sensitivity to the presence of F0 fall at every peak location. In a categorization experiment, the English group did not use the F0 fall cue in decisions about whether the 1st or the 2nd syllable sounded more prominent. The Japanese group relied on the F0 fall information, some listeners much heavily than others. These findings suggest that one's native language constrains how much attention the prosodic dimension of F0 change receives and that individual listeners may have qualitatively different perceptual strategies.

  17. Perception of acoustic cues to Tokyo Japanese pitch-accent contrasts in native Japanese and naive English listeners.

    PubMed

    Shport, Irina A

    2015-07-01

    This study examines how native language shapes the perception of a prosodic contrast. In Tokyo Japanese, a high-low pitch accent is a lexical property of a word, and the F0 fall after the peak associated with the accented syllable is the fundamental cue to accent perception. In English, pitch accents do not create lexically contrastive F0 patterns. A hypothesis that English listeners naive to Japanese use the F0 fall cue less than Japanese listeners was tested in two experiments. The alignment of F0 peak, the presence and magnitude of F0 fall were manipulated in a trisyllabic nonword to resynthesize Japanese 1st-syllable accented, 2nd-syllable accented, and unaccented patterns. In an AX-discrimination experiment, both listener groups showed sensitivity to the presence of F0 fall at every peak location. In a categorization experiment, the English group did not use the F0 fall cue in decisions about whether the 1st or the 2nd syllable sounded more prominent. The Japanese group relied on the F0 fall information, some listeners much heavily than others. These findings suggest that one's native language constrains how much attention the prosodic dimension of F0 change receives and that individual listeners may have qualitatively different perceptual strategies. PMID:26233031

  18. Surveillance of transmitted HIV drug resistance in antiretroviral-naive patients aged less than 25 years, in Bangkok, Thailand.

    PubMed

    Sungkanuparph, Somnuek; Pasomsub, Ekawat; Chantratita, Wasun

    2014-01-01

    Emergence of transmitted HIV drug resistance (TDR) is a concern after global scale-up of antiretroviral therapy (ART). World Health Organization had developed threshold survey method for surveillance of TDR in resource-limited countries. ART in Thailand has been scaling up for >10 years. To evaluate the current TDR in Thailand, a cross-sectional study was conducted among antiretroviral-naive HIV-infected patients aged <25 years who newly visited infectious disease clinic in a university hospital, in 2011. HIV genotypic-resistance test was performed. World Health Organization 2009 surveillance drug-resistance mutations were used to define TDR. Of 50 patients, the prevalence of TDR was 4%. Of 2 patients with TDR, 1 had K103N and the other had Y181C mutations. Transmitted HIV drug resistance is emerging in Thailand after a decade of rapid scale-up of ART. Interventions to prevent TDR at the population level are essentially needed in Thailand. Surveillance for TDR in Thailand has to be regularly performed.

  19. Discrimination of Mine Seismic Events and Blasts Using the Fisher Classifier, Naive Bayesian Classifier and Logistic Regression

    NASA Astrophysics Data System (ADS)

    Dong, Longjun; Wesseloo, Johan; Potvin, Yves; Li, Xibing

    2016-01-01

    Seismic events and blasts generate seismic waveforms that have different characteristics. The challenge to confidently differentiate these two signatures is complex and requires the integration of physical and statistical techniques. In this paper, the different characteristics of blasts and seismic events were investigated by comparing probability density distributions of different parameters. Five typical parameters of blasts and events and the probability density functions of blast time, as well as probability density functions of origin time difference for neighbouring blasts were extracted as discriminant indicators. The Fisher classifier, naive Bayesian classifier and logistic regression were used to establish discriminators. Databases from three Australian and Canadian mines were established for training, calibrating and testing the discriminant models. The classification performances and discriminant precision of the three statistical techniques were discussed and compared. The proposed discriminators have explicit and simple functions which can be easily used by workers in mines or researchers. Back-test, applied results, cross-validated results and analysis of receiver operating characteristic curves in different mines have shown that the discriminator for one of the mines has a reasonably good discriminating performance.

  20. From Naive to Primed Pluripotency: In Vitro Conversion of Mouse Embryonic Stem Cells in Epiblast Stem Cells.

    PubMed

    Tosolini, Matteo; Jouneau, Alice

    2016-01-01

    Mouse embryonic stem cells (ESCs) derive from the inner cell mass (ICM) of a blastocyst at E3.5 while mouse epiblast stem cells (EpiSCs) derive from the late epiblast of a post-implantation embryo at E5.5-E7.5. Both cells are able to differentiate into derivatives of the three germs layers but only ESCs are able to produce chimeras when they are introduced into a blastocyst. To support the naive state of pluripotency, ESC culture requires Leukemia inhibitory factor (Lif) and either serum or inhibitors of Erk and Gsk3 pathways (2i) while the primed pluripotency of EpiSCs is maintained using Activin A and Fibroblast Growth Factor 2 (FGF2). It is possible to obtain EpiSCs in vitro starting from ESCs but also to induce ESCs starting from EpiSCs even if this second process is very difficult and inefficient. In this protocol we describe how we perform the process of conversion from ESCs to EpiSCs. PMID:25720370

  1. Interference-driven spacer acquisition is dominant over naive and primed adaptation in a native CRISPR–Cas system

    PubMed Central

    Staals, Raymond H. J.; Jackson, Simon A.; Biswas, Ambarish; Brouns, Stan J. J.; Brown, Chris M.; Fineran, Peter C.

    2016-01-01

    CRISPR–Cas systems provide bacteria with adaptive immunity against foreign nucleic acids by acquiring short, invader-derived sequences called spacers. Here, we use high-throughput sequencing to analyse millions of spacer acquisition events in wild-type populations of Pectobacterium atrosepticum. Plasmids not previously encountered, or plasmids that had escaped CRISPR–Cas targeting via point mutation, are used to provoke naive or primed spacer acquisition, respectively. The origin, location and order of spacer acquisition show that spacer selection through priming initiates near the site of CRISPR–Cas recognition (the protospacer), but on the displaced strand, and is consistent with 3′–5′ translocation of the Cas1:Cas2-3 acquisition machinery. Newly acquired spacers determine the location and strand specificity of subsequent spacers and demonstrate that interference-driven spacer acquisition (‘targeted acquisition') is a major contributor to adaptation in type I-F CRISPR–Cas systems. Finally, we show that acquisition of self-targeting spacers is occurring at a constant rate in wild-type cells and can be triggered by foreign DNA with similarity to the bacterial chromosome. PMID:27694798

  2. Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

    PubMed Central

    Serrano, Lisa Marie; Pfeiffer, Timothy; Olivares, Simon; Numbenjapon, Tontanai; Bennitt, Jennifer; Kim, Daniel; Smith, David; McNamara, George; Al-Kadhimi, Zaid; Rosenthal, Joseph; Forman, Stephen J.; Jensen, Michael C.; Cooper, Laurence J. N.

    2006-01-01

    Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)–derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse. PMID:16352804

  3. HIV-1 Transmitted Drug Resistance Mutations in Newly Diagnosed Antiretroviral-Naive Patients in Turkey.

    PubMed

    Sayan, Murat; Sargin, Fatma; Inan, Dilara; Sevgi, Dilek Y; Celikbas, Aysel K; Yasar, Kadriye; Kaptan, Figen; Kutlu, Selda; Fisgin, Nuriye T; Inci, Ayse; Ceran, Nurgul; Karaoglan, Ilkay; Cagatay, Atahan; Celen, Mustafa K; Koruk, Suda T; Ceylan, Bahadir; Yildirmak, Taner; Akalın, Halis; Korten, Volkan; Willke, Ayse

    2016-01-01

    HIV-1 replication is rapid and highly error-prone. Transmission of a drug-resistant HIV-1 strain is possible and occurs within the HIV-1-infected population. In this study, we aimed to determine the prevalence of transmitted drug resistance mutations (TDRMs) in 1,306 newly diagnosed untreated HIV-1-infected patients from 21 cities across six regions of Turkey between 2010 and 2015. TDRMs were identified according to the criteria provided by the World Health Organization's 2009 list of surveillance drug resistance mutations. The HIV-1 TDRM prevalence was 10.1% (133/1,306) in Turkey. Primary drug resistance mutations (K65R, M184V) and thymidine analogue-associated mutations (TAMs) were evaluated together as nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations. NRTI TDRMs were found in 8.1% (107/1,306) of patients. However, TAMs were divided into three categories and M41L, L210W, and T215Y mutations were found for TAM1 in 97 (7.4%) patients, D67N, K70R, K219E/Q/N/R, T215F, and T215C/D/S mutations were detected for TAM2 in 52 (3.9%) patients, and M41L + K219N and M41L + T215C/D/S mutations were detected for the TAM1 + TAM2 profile in 22 (1.7%) patients, respectively. Nonnucleoside reverse transcriptase inhibitor-associated TDRMs were detected in 3.3% (44/1,306) of patients (L100I, K101E/P, K103N/S, V179F, Y188H/L/M, Y181I/C, and G190A/E/S) and TDRMs to protease inhibitors were detected in 2.3% (30/1,306) of patients (M46L, I50V, I54V, Q58E, L76V, V82A/C/L/T, N83D, I84V, and L90M). In conclusion, long-term and large-scale monitoring of regional levels of HIV-1 TDRMs informs treatment guidelines and provides feedback on the success of HIV-1 prevention and treatment efforts. PMID:26414663

  4. Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade

    PubMed Central

    Ebdrup, Bjørn H.; Raghava, Jayachandra M.; Nielsen, Mette Ø.; Rostrup, Egill; Glenthøj, Birte

    2016-01-01

    matter were not evaluated. Conclusion Antipsychotic-naive patients with schizophrenia displayed subtle deficits in white matter, and psychotic symptoms appeared specifically associated with frontal fasciculi integrity. Six weeks of amisulpride treatment normalized white matter. Potential re-myelinating effects of dopamine D2/3 receptor antagonism warrant further clarification. PMID:26599135

  5. ING116070: A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in Cerebrospinal Fluid in HIV-1–Infected, Antiretroviral Therapy–Naive Subjects

    PubMed Central

    Letendre, Scott L.; Mills, Anthony M.; Tashima, Karen T.; Thomas, Deborah A.; Min, Sherene S.; Chen, Shuguang; Song, Ivy H.; Piscitelli, Stephen C.

    2014-01-01

    Background. Dolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF). Methods. ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy–naive, HIV-1–infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16. Results. Thirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non–drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4–23 ng/mL) at week 2 and 13 ng/mL (4–18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were −3.42 and −3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16. Conclusions. The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199. PMID:24944232

  6. Visual cortex activation in late-onset, Braille naive blind individuals: an fMRI study during semantic and phonological tasks with heard words.

    PubMed

    Burton, Harold; McLaren, Donald G

    2006-01-01

    Visual cortex activity in the blind has been shown in Braille literate people, which raise the question of whether Braille literacy influences cross-modal reorganization. We used fMRI to examine visual cortex activation during semantic and phonological tasks with auditory presentation of words in two late-onset blind individuals who lacked Braille literacy. Multiple visual cortical regions were activated in the Braille naive individuals. Positive BOLD responses were noted in lower tier visuotopic (e.g., V1, V2, VP, and V3) and several higher tier visual areas (e.g., V4v, V8, and BA 37). Activity was more extensive and cross-correlation magnitudes were greater during the semantic compared to the phonological task. These results with Braille naive individuals plausibly suggest that visual deprivation alone induces visual cortex reorganization. Cross-modal reorganization of lower tier visual areas may be recruited by developing skills in attending to selected non-visual inputs (e.g., Braille literacy, enhanced auditory skills). Such learning might strengthen remote connections with multisensory cortical areas. Of necessity, the Braille naive participants must attend to auditory stimulation for language. We hypothesize that learning to attend to non-visual inputs probably strengthens the remaining active synapses following visual deprivation, and thereby, increases cross-modal activation of lower tier visual areas when performing highly demanding non-visual tasks of which reading Braille is just one example.

  7. Background level of risk and the survival of predator-naive prey: can neophobia compensate for predator naivety in juvenile coral reef fishes?

    PubMed

    Ferrari, Maud C O; McCormick, Mark I; Meekan, Mark G; Chivers, Douglas P

    2015-01-22

    Neophobia--the generalized fear response to novel stimuli--provides the first potential strategy that predator-naive prey may use to survive initial predator encounters. This phenotype appears to be highly plastic and present in individuals experiencing high-risk environments, but rarer in those experiencing low-risk environments. Despite the appeal of this strategy as a 'solution' for prey naivety, we lack evidence that this strategy provides any fitness benefit to prey. Here, we compare the relative effect of environmental risk (high versus low) and predator-recognition training (predator-naive versus predator-experienced individuals) on the survival of juvenile fish in the wild. We found that juveniles raised in high-risk conditions survived better than those raised in low-risk conditions, providing the first empirical evidence that environmental risk, in the absence of any predator-specific information, affects the way naive prey survive in a novel environment. Both risk level and experience affected survival; however, the two factors did not interact, indicating that the information provided by both factors did not interfere or enhance each other. From a mechanistic viewpoint, this indicates that the combination of the two factors may increase the intensity, and hence efficacy, of prey evasion strategies, or that both factors provide qualitatively separate benefits that would result in an additive survival success.

  8. Dynorphin A-(1-13)-morphine interactions: quantitative and qualitative EEG properties differ in morphine-naive vs. morphine-tolerant rats.

    PubMed

    Meng, Y; Young, G A

    1994-01-01

    The effects of dynorphin A-(1-13) on cumulative IV morphine-induced EEG and EEG power spectra were studied in naive and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling ICV and IV cannulae. In naive rats, dynorphin A-(1-13) quantitatively decreased cumulative IV morphine-induced EEG spectral power as well as qualitatively shifting the relative distribution of spectral power to predominantly faster frequencies. In morphine-tolerant rats, the quantitative and qualitative EEG properties were identical to those in dynorphin A-(1-13) pretreated morphine-naive rats. Thus, dynorphin A-(1-13) pretreatment apparently produced instantaneous acute morphine tolerance. Furthermore, in morphine-tolerant rats, dynorphin A-(1-13) pretreatment quantitatively increased morphine-induced EEG power without qualitatively changing the relative distribution of EEG spectral power. This latter effect may be due to a summation of increased endogenous levels of dynorphin A-(1-13) associated with the development of morphine tolerance and the experimentally administered dynorphin A-(1-13). These results indicate that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. That is, quantitative changes may reflect the number of receptors that are activated, while qualitative changes may reflect the nature of the receptor-effector coupling.

  9. Background level of risk and the survival of predator-naive prey: can neophobia compensate for predator naivety in juvenile coral reef fishes?

    PubMed

    Ferrari, Maud C O; McCormick, Mark I; Meekan, Mark G; Chivers, Douglas P

    2015-01-22

    Neophobia--the generalized fear response to novel stimuli--provides the first potential strategy that predator-naive prey may use to survive initial predator encounters. This phenotype appears to be highly plastic and present in individuals experiencing high-risk environments, but rarer in those experiencing low-risk environments. Despite the appeal of this strategy as a 'solution' for prey naivety, we lack evidence that this strategy provides any fitness benefit to prey. Here, we compare the relative effect of environmental risk (high versus low) and predator-recognition training (predator-naive versus predator-experienced individuals) on the survival of juvenile fish in the wild. We found that juveniles raised in high-risk conditions survived better than those raised in low-risk conditions, providing the first empirical evidence that environmental risk, in the absence of any predator-specific information, affects the way naive prey survive in a novel environment. Both risk level and experience affected survival; however, the two factors did not interact, indicating that the information provided by both factors did not interfere or enhance each other. From a mechanistic viewpoint, this indicates that the combination of the two factors may increase the intensity, and hence efficacy, of prey evasion strategies, or that both factors provide qualitatively separate benefits that would result in an additive survival success. PMID:25621337

  10. Intrinsic differences in the initiation of B cell receptor signaling favor responses of human IgG(+) memory B cells over IgM(+) naive B cells.

    PubMed

    Davey, Angel M; Pierce, Susan K

    2012-04-01

    The acquisition of long-lived memory B cells (MBCs) is critical for the defense against many infectious diseases. Despite their importance, little is known about how Ags trigger human MBCs, even though our understanding of the molecular basis of Ag activation of B cells in model systems has advanced considerably. In this study, we use quantitative, high-resolution, live-cell imaging at the single-cell and single-molecule levels to describe the earliest Ag-driven events in human isotype-switched, IgG-expressing MBCs and compare them with those in IgM-expressing naive B cells. We show that human MBCs are more robust than naive B cells at each step in the initiation of BCR signaling, including interrogation of Ag-containing membranes, formation of submicroscopic BCR oligomers, and recruitment and activation of signaling-associated kinases. Despite their robust response to Ag, MBCs remain highly sensitive to FcγRIIB-mediated inhibition. We also demonstrate that in the absence of Ag, a portion of MBC receptors spontaneously oligomerized, and phosphorylated kinases accumulated at the membrane and speculate that heightened constitutive signaling may play a role in maintaining MBC longevity. Using high-resolution imaging, we have provided a description of the earliest events in the Ag activation of MBCs and evidence for acquired cell-intrinsic differences in the initiation of BCR signaling in human naive and MBCs.

  11. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques

    PubMed Central

    Conaghan, Philip G; Østergaard, Mikkel; Bowes, Michael A; Wu, Chunying; Fuerst, Thomas; Irazoque-Palazuelos, Fedra; Soto-Raices, Oscar; Hrycaj, Pawel; Xie, Zhiyong; Zhang, Richard; Wyman, Bradley T; Bradley, John D; Soma, Koshika; Wilkinson, Bethanie

    2016-01-01

    Objectives To explore the effects of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)—with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand. Methods In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant. Results In total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were −1.55 (90% CI −2.52 to −0.58) for tofacitinib + MTX and −1.74 (−2.72 to −0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were −0.63 (−1.58 to 0.31) for tofacitinib + MTX and −0.52 (−1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy. Conclusions These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage. Trial registration number NCT01164579. PMID:27002108

  12. CD46 measles virus receptor polymorphisms influence receptor protein expression and primary measles vaccine responses in naive Australian children.

    PubMed

    Clifford, Holly D; Hayden, Catherine M; Khoo, Siew-Kim; Zhang, Guicheng; Le Souëf, Peter N; Richmond, Peter

    2012-05-01

    Despite the availability of measles vaccines, infants continue to die from measles. Measles vaccine responses vary between individuals, and poor immunogenicity is likely to preclude protection against measles. CD46 is a ubiquitously expressed specific receptor for vaccine strains of measles virus. CD46 polymorphisms have not been functionally investigated but may affect CD46 protein expression, which in turn may mediate primary measles antibody responses in infants. In a cohort of children aged 12 to 14 months from Perth, Australia (n = 137), after their first dose of measles-mumps-rubella (MMR) vaccine, CD46 polymorphisms were genotyped, and postvaccination measles IgG and CD46 protein expression before and after measles lysate stimulation of cells were measured. Three CD46 variants (rs7144, rs11118580, and rs2724384) were significantly associated with measles virus-specific IgG levels (P = 0.008, P = 0.026, and P = 0.018, respectively). There were significant differences between CD46 rs7144 genotypes and CD46 protein expression on T cells, as well as the downregulation of CD46 and T-cell frequency after measles lysate stimulation. We show that CD46 polymorphisms were associated with primary measles antibody responses in naive infants. We also report the first association of a measles virus receptor polymorphism with functional effects on the receptor, suggesting a possible mechanism through which antibody responses are altered. Elucidating all of the interconnecting genetic factors that alter primary measles vaccine responses may be important for identifying children at risk of poor immunogenicity or vaccine failure and for the future design of vaccine strategies to help these children.

  13. Biomarker identification and cancer classification based on microarray data using Laplace naive Bayes model with mean shrinkage.

    PubMed

    Wu, Meng-Yun; Dai, Dao-Qing; Shi, Yu; Yan, Hong; Zhang, Xiao-Fei

    2012-01-01

    Biomarker identification and cancer classification are two closely related problems. In gene expression data sets, the correlation between genes can be high when they share the same biological pathway. Moreover, the gene expression data sets may contain outliers due to either chemical or electrical reasons. A good gene selection method should take group effects into account and be robust to outliers. In this paper, we propose a Laplace naive Bayes model with mean shrinkage (LNB-MS). The Laplace distribution instead of the normal distribution is used as the conditional distribution of the samples for the reasons that it is less sensitive to outliers and has been applied in many fields. The key technique is the L1 penalty imposed on the mean of each class to achieve automatic feature selection. The objective function of the proposed model is a piecewise linear function with respect to the mean of each class, of which the optimal value can be evaluated at the breakpoints simply. An efficient algorithm is designed to estimate the parameters in the model. A new strategy that uses the number of selected features to control the regularization parameter is introduced. Experimental results on simulated data sets and 17 publicly available cancer data sets attest to the accuracy, sparsity, efficiency, and robustness of the proposed algorithm. Many biomarkers identified with our method have been verified in biochemical or biomedical research. The analysis of biological and functional correlation of the genes based on Gene Ontology (GO) terms shows that the proposed method guarantees the selection of highly correlated genes simultaneously

  14. Differential brain glucose metabolic patterns in antipsychotic-naive first-episode schizophrenia with and without auditory verbal hallucinations

    PubMed Central

    Horga, Guillermo; Parellada, Eduard; Lomeña, Francisco; Fernández-Egea, Emilio; Mané, Anna; Font, Mireia; Falcón, Carles; Konova, Anna B.; Pavia, Javier; Ros, Domènec; Bernardo, Miguel

    2011-01-01

    Background Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication. Methods The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences. Results We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error–corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal–parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < −3.3). Limitations The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings. Conclusion Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the

  15. Models of Alcohol and Other Drug Treatment for Consideration When Working with Deaf and Hard of Hearing Individuals.

    ERIC Educational Resources Information Center

    Guthmann, Debra

    This paper discusses several models for treating chemical dependency in individuals who are deaf or hard of hearing. It begins by describing the 12-step model, a comprehensive, multi-disciplinary approach to the treatment of addiction which is abstinence oriented and based on the principles of Alcoholics Anonymous. This model includes group…

  16. Killing of naive T cells by CD95L-transfected dendritic cells (DC): in vivo study using killer DC-DC hybrids and CD4(+) T cells from DO11.10 mice.

    PubMed

    Kusuhara, Masahiro; Matsue, Keiko; Edelbaum, Dale; Loftus, Julie; Takashima, Akira; Matsue, Hiroyuki

    2002-04-01

    Dendritic cells (DC) play the dual task of initiating cellular immunity against potentially harmful foreign antigens (Ag), while maintaining immunological tolerance to self-Ag and environmental Ag. As an approach to induce Ag-specific suppression, we and others introduced CD95 ligand (L) cDNA into DC. The resulting "killer" DC delivered apoptotic signals, instead of activation signals, to primed CD4(+) T cells in vitro and induced Ag-specific immunosuppression in vivo. To study the impact of killer DC on naive T cells, the fate of Ag-reactive T cells and the extent of their depletion after killer DC treatment, we performed in vitro and in vivo reconstitution experiments using: (a) killer DC-DC hybrids created between CD95L-transduced XS106 DC clone (A/J origin) and splenic DC from BALB/c mice, (b) CD4(+) T cells isolated from DO11.10 transgenic mice (BALB/c background), and (c) OVA(323-339) peptide as relevant Ag. Ovalbumin (OVA)-pulsed killer DC-DC hybrids inhibited DO11.10 T cell activation triggered by conventional DC, instead of inducing their activation. Rapid apoptosis of T cells was observed after co-culture with OVA-pulsed killer DC-DC hybrids, but not with non-pulsed killer DC-DC hybrids or OVA-pulsed control DC-DC hybrids. For in vivo reconstitution, (BALB/cxA/J)F1 mice received subcutaneous administration of killer DC-DC hybrids, followed by intravenous inoculation of DO11.10 T cells. Killer DC-DC hybrids migrated preferentially to draining lymph nodes albeit with relatively low efficiency (0.5-1% recovery) and they induced significant, but incomplete (30-40%) killing of DO11.10 T cells in this location. These results document the abilities of CD95L-transduced DC to trigger apoptosis of naive T cells in an Ag-specific manner, to overrule T cell activation signals delivered by conventional DC, and to reduce local frequencies of Ag-reactive T cells in vivo. Our data also uncover two major limitations (relatively low homing efficiency and incomplete

  17. Domains and Naive Theories

    PubMed Central

    Gelman, Susan A.; Noles, Nicholaus S.

    2013-01-01

    Human cognition entails domain-specific cognitive processes that influence memory, attention, categorization, problem-solving, reasoning, and knowledge organization. This review examines domain-specific causal theories, which are of particular interest for permitting an examination of how knowledge structures change over time. We first describe the properties of commonsense theories, and how commonsense theories differ from scientific theories, illustrating with children’s classification of biological and non-biological kinds. We next consider the implications of domain-specificity for broader issues regarding cognitive development and conceptual change. We then examine the extent to which domain-specific theories interact, and how people reconcile competing causal frameworks. Future directions for research include examining how different content domains interact, the nature of theory change, the role of context (including culture, language, and social interaction) in inducing different frameworks, and the neural bases for domain-specific reasoning. PMID:24187603

  18. Naive Analysis of Variance

    ERIC Educational Resources Information Center

    Braun, W. John

    2012-01-01

    The Analysis of Variance is often taught in introductory statistics courses, but it is not clear that students really understand the method. This is because the derivation of the test statistic and p-value requires a relatively sophisticated mathematical background which may not be well-remembered or understood. Thus, the essential concept behind…

  19. Induction of cross-priming of naive CD8+ T lymphocytes by recombinant bacillus Calmette-Guerin that secretes heat shock protein 70-major membrane protein-II fusion protein.

    PubMed

    Mukai, Tetsu; Maeda, Yumi; Tamura, Toshiki; Matsuoka, Masanori; Tsukamoto, Yumiko; Makino, Masahiko

    2009-11-15

    Because Mycobacterium bovis bacillus Calmette-Guérin (BCG) unconvincingly activates human naive CD8(+) T cells, a rBCG (BCG-70M) that secretes a fusion protein comprising BCG-derived heat shock protein (HSP)70 and Mycobacterium leprae-derived major membrane protein (MMP)-II, one of the immunodominant Ags of M. leprae, was newly constructed to potentiate the ability of activating naive CD8(+) T cells through dendritic cells (DC). BCG-70M secreted HSP70-MMP-II fusion protein in vitro, which stimulated DC to produce IL-12p70 through TLR2. BCG-70M-infected DC activated not only memory and naive CD8(+) T cells, but also CD4(+) T cells of both types to produce IFN-gamma. The activation of these naive T cells by BCG-70M was dependent on the MHC and CD86 molecules on BCG-70M-infected DC, and was significantly inhibited by pretreatment of DC with chloroquine. Both brefeldin A and lactacystin significantly inhibited the activation of naive CD8(+) T cells by BCG-70M through DC. Thus, the CD8(+) T cell activation may be induced by cross-presentation of Ags through a TAP- and proteosome-dependent cytosolic pathway. When naive CD8(+) T cells were stimulated by BCG-70M-infected DC in the presence of naive CD4(+) T cells, CD62L(low)CD8(+) T cells and perforin-producing CD8(+) T cells were efficiently produced. MMP-II-reactive CD4(+) and CD8(+) memory T cells were efficiently produced in C57BL/6 mice by infection with BCG-70M. These results indicate that BCG-70M activated DC, CD4(+) T cells, and CD8(+) T cells, and the combination of HSP70 and MMP-II may be useful for inducing better T cell activation.

  20. Absorption, Distribution, Metabolism, Excretion, and Toxicity Evaluation in Drug Discovery. 14. Prediction of Human Pregnane X Receptor Activators by Using Naive Bayesian Classification Technique.

    PubMed

    Shi, Huali; Tian, Sheng; Li, Youyong; Li, Dan; Yu, Huidong; Zhen, Xuechu; Hou, Tingjun

    2015-01-20

    The activation of pregnane X receptor (PXR), a member of the nuclear receptor (NR) superfamily, can mediate potential drug-drug interactions, and therefore, prediction of PXR activation is of great importance for evaluating drug metabolism and toxicity. In this study, based on 532 structurally diverse compounds, we present a comprehensive analysis with the aim to build accurate classification models for distinguishing PXR activators from nonactivators by using a naive Bayesian classification technique. First, the distributions of eight important molecular physicochemical properties of PXR activators versus nonactivators were compared, illustrating that the hydrophobicity-related molecular descriptors (AlogP and log D) show slightly better capability to discriminate PXR activators from nonactivators than the others. Then, based on molecular physicochemical properties, VolSurf descriptors, and molecular fingerprints, naive Bayesian classifiers were developed to separate PXR activators from nonactivators. The results demonstrate that the introduction of molecular fingerprints is quite essential to enhance the prediction accuracy of the classifiers. The best Bayesian classifier based on the 21 physicochemical properties, VolSurf descriptors, and LCFC_10 fingerprints descriptors yields a prediction accuracy of 92.7% for the training set based on leave-one-out (LOO) cross-validation and of 85.2% for the test set. Moreover, by exploring the important structural fragments derived from the best Bayesian classifier, we observed that flexibility is an important structural pattern for PXR activation. In addition, chemical compounds containing more halogen atoms, unsaturated alkanes chains relevant to π-π stacking, and fewer nitrogen atoms tend to be PXR activators. We believe that the naive Bayesian classifier can be used as a reliable virtual screening tool to predict PXR activation in the drug design and discovery pipeline.

  1. Effect of Metformin Glycinate on Glycated Hemoglobin A1c Concentration and Insulin Sensitivity in Drug-Naive Adult Patients with Type 2 Diabetes Mellitus

    PubMed Central

    Martínez-Abundis, Esperanza; Robles-Cervantes, José A.; Ramos-Zavala, Maria G.; Barrera-Durán, Carmelita; González-Canudas, Jorge

    2012-01-01

    Abstract Aim This study evaluated the effect of metformin glycinate on glycated hemoglobin A1c (A1C) concentration and insulin sensitivity in drug-naive adult patients with type 2 diabetes mellitus (T2DM). Subjects and Methods A randomized, double-blind, placebo-controlled clinical trial was carried out in 20 patients with drug-naive T2DM. Ten subjects received metformin glycinate (1,050.6 mg) once daily during the first month and force-titrated twice daily during the second month. Ten additional patients received placebo as the control group. Before and after the intervention, metabolic profile including A1C and insulin sensitivity (euglycemic-hyperinsulinemic clamp technique) was estimated. Results A1C concentrations decreased significantly with metformin glycinate administration (8.0±0.7% vs. 7.1±0.9%, P=0.008) before and after the intervention, respectively. There were significant differences in changes from baseline of A1C between groups (0.0±0.7% vs. −1.0±0.5% for placebo and metformin glycinate groups, respectively; P=0.004). A reduction of ≥1% in A1C levels was reached in 60.0% of patients with metformin glycinate administration (P=0.02). Insulin sensitivity was not modified by the intervention. Conclusions Administration of metformin glycinate during a 2-month period showed a greater decrease in A1C concentrations than placebo in a selected group of drug-naive adult patients with T2DM. PMID:22974412

  2. BAFF/APRIL Inhibition Decreases Selection of Naive but Not Antigen-Induced Autoreactive B Cells in Murine Systemic Lupus Erythematosus

    PubMed Central

    Huang, Weiqing; Moisini, Ioana; Bethunaickan, Ramalingam; Sahu, Ranjit; Akerman, Meredith; Eilat, Dan; Lesser, Martin; Davidson, Anne

    2011-01-01

    BAFF inhibition is a new B cell-directed therapeutic strategy for autoimmune disease. Our purpose was to analyze the effect of BAFF/APRIL availability on the naive and Ag-activated B cell repertoires in systemic lupus erythematosus, using the autoreactive germline D42 H chain (glD42H) site-directed transgenic NZB/W mouse. In this article, we show that the naive Vκ repertoire in both young and diseased glD42H NZB/W mice is dominated by five L chains that confer no or low-affinity polyreactivity. In contrast, glD42H B cells expressing L chains that confer high-affinity autoreactivity are mostly deleted before the mature B cell stage, but are positively selected and expanded in the germinal centers (GCs) as the mice age. Of these, the most abundant is VκRF (Vκ16-104*01), which is expressed by almost all IgG anti-DNA hybridomas derived from the glD42H mouse. Competition with nonautoreactive B cells or BAFF/APRIL inhibition significantly inhibited selection of glD42H B cells at the late transitional stage, with only subtle effects on the glD42H-associated L chain repertoire. However, glD42H/VκRF-encoded B cells were still vastly overrepresented in the GC, and serum IgG anti-DNA Abs arose with only a slight delay. Thus, although BAFF/APRIL inhibition increases the stringency of negative selection of the naive autoreactive B cell repertoire in NZB/W mice, it does not correct the major breach in B cell tolerance that occurs at the GC checkpoint. PMID:22102726

  3. Naive time-reversal odd phenomena in semi-inclusive deep-inelastic scattering from light-cone constituent quark models

    SciTech Connect

    Barbara Pasquini, Peter Schweitzer

    2011-06-01

    We present results for leading-twist azimuthal asymmetries in semi-inclusive lepton-nucleon deep-inelastic scattering due to naively time-reversal odd transverse-momentum dependent parton distribution functions from the light-cone constituent quark model. We carefully discuss the range of applicability of the model, especially with regard to positivity constraints and evolution effects. We find good agreement with available experimental data from COMPASS and HERMES, and present predictions to be tested in forthcoming experiments at Jefferson Lab.

  4. Long-term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV type 1-infected antiretroviral-naive patients: week 192 results from a phase IIb randomized trial.

    PubMed

    Wilkin, Aimee; Pozniak, Anton L; Morales-Ramirez, Javier; Lupo, Sergio H; Santoscoy, Mario; Grinsztejn, Beatriz; Ruxrungtham, Kiat; Rimsky, Laurence T; Vanveggel, Simon; Boven, Katia

    2012-05-01

    TMC278-C204 (NCT00110305), a 96-week trial of the nonnucleoside reverse transcription inhibitor (NNRTI) rilpivirine (RPV, TMC278) in 368 HIV-1-infected, treatment-naive patients, was extended to investigate long-term safety and efficacy. Week 192 analysis results are presented. This was a long-term follow-up of a Phase IIb, randomized trial. No significant RPV dose-response relationships with respect to the primary endpoint (composite ITT-TLOVR algorithm) were observed at week 48 or 96. All RPV-treated patients were switched to open-label 75 mg qd at week 96 and then to 25 mg qd, the Phase III dose, at approximately week 144 as it gave the best benefit-risk balance. All control patients continued receiving open-label efavirenz (EFV) 600 mg qd. At week 192, 59% of RPV- and 61% of EFV-treated patients maintained confirmed viral load <50 copies/ml (ITT-TLOVR algorithm). The mean changes from baseline in CD4 cell count were similar in both groups (RPV: 210 cells/mm(3) vs. EFV: 225 cells/mm(3)). No new safety concerns were noted between week 48 and 192. In the week 192 analysis, RPV compared with EFV was associated with a lower overall incidence of grade 2-4 adverse events (AEs) at least possibly related to treatment, including rash (p<0.001) and neurologic AEs (p<0.05 Fisher's exact test, post hoc analyses) Incidences of serious AEs, grade 3 or 4 AEs, and discontinuations due to AEs were similar across groups. Increases in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were significantly lower with RPV than with EFV. RPV continued to show sustained efficacy similar to EFV at week 192 with a generally more favorable safety profile. PMID:21902621

  5. An Analysis of Document Category Prediction Responses to Classifier Model Parameter Treatment Permutations within the Software Design Patterns Subject Domain

    ERIC Educational Resources Information Center

    Pankau, Brian L.

    2009-01-01

    This empirical study evaluates the document category prediction effectiveness of Naive Bayes (NB) and K-Nearest Neighbor (KNN) classifier treatments built from different feature selection and machine learning settings and trained and tested against textual corpora of 2300 Gang-Of-Four (GOF) design pattern documents. Analysis of the experiment's…

  6. Group Cognitive-Behavioral Therapy Versus Sertraline for the Treatment of Children and Adolescents with Obsessive-Compulsive Disorder

    ERIC Educational Resources Information Center

    Asbahr, Fernando Ramos; Castillo, Ana Regina; Ito, Ligia Montenegro; Latorre, Maria do Rosario Dias de Oliveira; Moreira, Michele Nunes; Lotufo-Neto, Francisco

    2005-01-01

    Objective: To compare the effectiveness of group cognitive-behavioral therapy (GCBT) and of sertraline in treatment-naive children and adolescents with obsessive-compulsive disorder. Method: Between 2000 and 2002, 40 subjects between 9 and 17 years old were randomized to receive GCBT (n = 20) or sertraline (n = 20). GCBT consisted of a…

  7. The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells.

    PubMed

    Miyazaki, Masaki; Rivera, Richard R; Miyazaki, Kazuko; Lin, Yin C; Agata, Yasutoshi; Murre, Cornelis

    2011-08-21

    It is established that the transcription factor E2A and its antagonist Id3 modulate the checkpoints consisting of the precursor to the T cell antigen receptor (pre-TCR) and the TCR. Here we demonstrate that Id3 expression was higher beyond the pre-TCR checkpoint, remained high in naive T cells and showed a bimodal pattern in the effector-memory population. We show how E2A promoted T lineage specification and how pre-TCR-mediated signaling affected E2A genome-wide occupancy. Thymi in Id3-deficient mice had aberrant development of effector-memory cells, higher expression of the chemokine receptor CXCR5 and the transcriptional repressor Bcl-6 and, unexpectedly, T cell-B cell conjugates and B cell follicles. Collectively, our data show how E2A acted globally to orchestrate development into the T lineage and that Id3 antagonized E2A activity beyond the pre-TCR checkpoint to enforce the naive fate of T cells.

  8. Patients with first-episode, drug-naive schizophrenia and subjects at ultra-high risk of psychosis shared increased cerebellar-default mode network connectivity at rest

    PubMed Central

    Wang, Houliang; Guo, Wenbin; Liu, Feng; Wang, Guodong; Lyu, Hailong; Wu, Renrong; Chen, Jindong; Wang, Shuai; Li, Lehua; Zhao, Jingping

    2016-01-01

    Increased cerebellar-default mode network (DMN) connectivity has been observed in first-episode, drug-naive patients with schizophrenia. However, it remains unclear whether increased cerebellar-DMN connectivity starts earlier than disease onset. Thirty-four ultra-high risk (UHR) subjects, 31 first-episode, drug-naive patients with schizophrenia and 37 healthy controls were enrolled for a resting-state scan. The imaging data were analyzed using the seed-based functional connectivity (FC) method. Compared with the controls, UHR subjects and patients with schizophrenia shared increased connectivity between the right Crus I and bilateral posterior cingulate cortex/precuneus and between Lobule IX and the left superior medial prefrontal cortex. There are positive correlations between the right Crus I-bilateral precuneus connectivity and clinical variables (Structured Interview for Prodromal Syndromes/Positive and Negative Symptom Scale negative symptoms/total scores) in the UHR subjects. Increased cerebellar-DMN connectivity shared by the UHR subjects and the patients not only highlights the importance of the DMN in the pathophysiology of psychosis but also may be a trait alteration for psychosis. PMID:27188233

  9. Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings.

    PubMed

    Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Xiao, Changqing; Zhao, Jingping

    2015-11-26

    Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed - right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed - bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia.

  10. The TLR9 ligand CpG promotes the acquisition of Plasmodium falciparum-specific memory B cells in malaria-naive individuals.

    PubMed

    Crompton, Peter D; Mircetic, Marko; Weiss, Greta; Baughman, Amy; Huang, Chiung-Yu; Topham, David J; Treanor, John J; Sanz, Iñaki; Lee, F Eun-Hyung; Durbin, Anna P; Miura, Kazutoyo; Narum, David L; Ellis, Ruth D; Malkin, Elissa; Mullen, Gregory E D; Miller, Louis H; Martin, Laura B; Pierce, Susan K

    2009-03-01

    Despite the central role of memory B cells (MBC) in protective immune responses, little is understood about how they are acquired in naive individuals in response to Ag exposure, and how this process is influenced by concurrent activation of the innate immune system's TLR. In this longitudinal study of malaria-naive individuals, we examined the MBC response to two candidate malaria vaccines administered with or without CpG, a TLR9 ligand. We show that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response. We observed that the percentage of vaccine-specific MBC present at the time of reimmunization predicts vaccine-specific Ab levels 14 days later; and that at steady-state, there is a positive correlation between vaccine-specific MBC and Ab levels. An examination of the total circulating MBC and plasma cell pools also suggests that MBC differentiate into plasma cells through polyclonal activation, independent of Ag specificity. These results provide important insights into the human MBC response, which can inform the development of vaccines against malaria and other pathogens that disrupt immunological memory. PMID:19234231

  11. Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings

    PubMed Central

    Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Xiao, Changqing; Zhao, Jingping

    2015-01-01

    Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed – right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed – bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia. PMID:26608842

  12. Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment

    PubMed Central

    Nagai, Norihiro; Suzuki, Misa; Uchida, Atsuro; Kurihara, Toshihide; Kamoshita, Mamoru; Minami, Sakiko; Shinoda, Hajime; Tsubota, Kazuo; Ozawa, Yoko

    2016-01-01

    The prognosis of neovascular age-related macular degeneration (AMD) has been improved by anti-vascular endothelial growth factor treatments, including intravitreal aflibercept (IVA) treatment. However, many patients remain incurable. In this study, we retrospectively evaluated non-responsiveness to IVA monotherapy at 12 months in 133 eyes of 133 AMD patients. Sixty-two patients were initially treatment-naive, and 71 had received other treatments before IVA (the treatment-switched group). Mean best-corrected visual acuity (BCVA) was improved in the treatment-naive group but not in the treatment-switched group, although mean central retinal thickness (CRT) decreased in both groups. The respective percentages of non-responders as determined by worsened BCVA in the treatment-naive and treatment-switched groups were 8.1% and 15.5%, and via fundus findings, they were 12.9% and 8.5%. Multivariate analyses adjusted for age, gender, CRT, and greatest linear dimension showed that serous pigment epithelial detachment (PED) at baseline was associated with non-responsiveness in both groups as determined by BCVA and by fundus findings, and fibrovascular PED measurements indicated no response as determined by fundus findings in the treatment-switched group. The results reported herein may assist the formulation of appropriate treatment protocols for AMD patients. PMID:27403807

  13. Pharmacologic treatments for women with addictions.

    PubMed

    Bogenschutz, Michael P; Geppert, Cynthia M A

    2003-09-01

    Physicians have a growing array of pharmacotherapies available for the treatment of substance use disorders. These medications are of central importance in the treatment of opioid and nicotine dependence and are of growing importance in the treatment of alcohol and stimulant dependence. Pharmacotherapy alone is rarely sufficient treatment for substance use disorder; appropriate psychosocial treatment or mutual help (eg, 12-step) participation is almost always indicated whether or not pharmacotherapy is used. Specialized facilities, licensing, and training are necessary for the use of some of the pharmacotherapies discussed in this article. The obstetrician gynecologist must determine the scope of his or her own practice in this area (ie, when to treat and when to refer) based on interest, training and experience, and available resources.

  14. Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden

    PubMed Central

    Simard, Julia F; Asker Hagelberg, Charlotte; Askling, Johan

    2016-01-01

    Objective To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor treatment, and in the general population. Design Population based cohort study. Setting Nationwide data from Sweden. Participants Cohort of patients with rheumatoid arthritis naive to biologics (n=46 409), cohort of patients with rheumatoid arthritis starting TNF inhibitor treatment as first biologic in 1998-2012 (n=12 558), and matched general population comparator cohort, identified through national quality of care and health registers. Main outcome measure Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12). Results For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks. Conclusion A small to moderately increased risk of basal cell cancer was seen in biologics-naive rheumatoid arthritis patients, with no further effect of TNF inhibitors. For squamous cell cancer, the risk was nearly doubled in biologics-naive patients, with a further 30% increase in risk among patients treated with TNF inhibitors; this translates to one additional case for every 1600 years of treatment experience, assuming that this association reflected causality

  15. Time course of cyclosporine and ist motabolites in blood, liver and spleen of naive Lewis rats: comparison with preliminary data obtained in transplanted animals.

    PubMed

    Wacher, V J; Liu, T; Roberts, J P; Ascher, N L; Benet, L Z

    1995-05-01

    the time course of intravenously administered cyclosporine (1 mg kg-1) and its metabolite AM1, AM9, and AM1c were examined in the blood, liver, and spleen of naive Lewis rats. Cyclosporine concentration versus time data for all three tissues were qualitatively similar, following a biexponential model C = Ae-gamma 1t + Be-gamma 2t with maximum cyclosporine concentrations reached at 1 h. Whole-blood cyclosporine clearance, terminal half-life, mean residence time, steady state volume of distribution, and hepatic extraction ratio (calculated from blood data) were similar to previously reported results. Cyclosporine in the liver showed the largest area under the concentration-time curve, mean residence time, and disposition and terminal half-lives. Spleen cyclosporine mean residence time and and terminal half-life were not significantly different from blood parameters. Metabolites AM1, AM9, and AM1c showed almost parallel time courses in all three tissues. The hydroxylated derivative AM9 was the major metabolite found in all tissues, with twofold greater levels in the liver compared to the blood and spleen. Slightly less AM1 was found in the liver relative to blood and spleen, where it was present in equal amounts. AM1c levels in the liver were not different from those in the spleen and were greater than observed for blood. The results obtained above were reflected in preliminary studies using liver transplanted rats treated with multiple doses of cyclosporine. Both blood and liver biopsy levels of CyA, AM1, and AM9 post-transplant showed twofold to fourfold decreases from day 3 ( samples taken 4 h post-CyA-dose) and concentrations were not significantly different from similarly sampled naive controls. More importantly, the metabolite/CyA ratios did not vary significantly between liver and blood in the two groups. For naive rats, and liver transplanted animals not undergoing rejection, changes in blood cyclosporine levels seem to predict variations in tissue

  16. Habit Learning by Naive Macaques Is Marked by Response Sharpening of Striatal Neurons Representing the Cost and Outcome of Acquired Action Sequences.

    PubMed

    Desrochers, Theresa M; Amemori, Ken-ichi; Graybiel, Ann M

    2015-08-19

    Over a century of scientific work has focused on defining the factors motivating behavioral learning. Observations in animals and humans trained on a wide range of tasks support reinforcement learning (RL) algorithms as accounting for the learning. Still unknown, however, are the signals that drive learning in naive, untrained subjects. Here, we capitalized on a sequential saccade task in which macaque monkeys acquired repetitive scanning sequences without instruction. We found that spike activity in the caudate nucleus after each trial corresponded to an integrated cost-benefit signal that was highly correlated with the degree of naturalistic untutored learning by the monkeys. Across learning, neurons encoding both cost and outcome gradually acquired increasingly sharp phasic trial-end responses that paralleled the development of the habit-like, repetitive saccade sequences. Our findings demonstrate an integrated cost-benefit signal by which RL and its neural correlates could drive naturalistic behaviors in freely behaving primates. PMID:26291166

  17. Clinical significance of increased cerebellar default-mode network connectivity in resting-state patients with drug-naive somatization disorder

    PubMed Central

    Wang, Houliang; Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Li, Lehua; Zhao, Jingping

    2016-01-01

    Abstract The cerebellum has been proven to be connected to the brain network, as in the default-mode network (DMN), among healthy subjects and patients with psychiatric disorders. However, whether or not abnormal cerebellar DMN connectivity exists and what its clinical significance is among drug-naive patients with somatization disorder (SD) at rest remain unclear. A total of 25 drug-naive patients with SD and 28 healthy controls were enrolled for a resting-state scan. The imaging data were analyzed using the seed-based functional connectivity (FC) method. Compared with the controls, patients with SD showed increased left/right Crus I-left/right angular gyrus (AG) connectivity and Lobule IX-left superior medial prefrontal cortex (MPFC) connectivity. The FC values of the left/right Crus I-right AG connectivity of the patients were positively correlated with their scores in the somatization subscale of the symptom checklist-90 (Scl-90). A trend level of correlations was observed between the FC values of the left Crus I-left AG connectivity of the patients and their scores for the somatization subscale of Scl-90, as well as between the FC values of their Lobule IX-left superior MPFC connectivity and their scores for the Eysenck personality questionnaire (EPQ) extraversion. Our findings show the increased cerebellar DMN connectivity in patients with SD and therefore highlight the importance of the DMN in the neurobiology of SD. Increased cerebellar DMN connectivities are also correlated with their somatization severity and personality, both of which bear clinical significance. PMID:27428190

  18. High-Dose-Rate Brachytherapy of a Single Implant With Two Fractions Combined With External Beam Radiotherapy for Hormone-Naive Prostate Cancer

    SciTech Connect

    Sato, Morio Mori, Takashi; Shirai, Shintaro; Kishi, Kazushi; Inagaki, Takeshi; Hara, Isao

    2008-11-15

    Purpose: To evaluate the preliminary outcomes of high-dose-rate (HDR) brachytherapy of a single implant with two fractions and external beam radiotherapy (EBRT) for hormone-naive prostate cancer. Methods and Materials: Between March 2000 and Sept 2003, a total of 53 patients with tumor Stage T1c-T3b N0 M0 prostate cancer were treated with HDR brachytherapy boost doses (7.5 Gy/fraction) and 50-Gy EBRT during a 5.5-week period. Median follow-up was 61 months. Patients were divided into groups with localized (T1c-T2b) and advanced disease (T3a-T3b). We used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition for biochemical failure. According to recommendations of the Radiation Therapy Oncology Group-ASTRO Phoenix Consensus Conference, biochemical failure-free control rates (BF-FCRs) at 3 years were investigated as 2 years short of the median follow-up. Results: Between April 2000 and Sept 2007, Common Terminology Criteria for Adverse Events Version 2.0 late Grade 2 genitourinary and gastrointestinal toxicity rates were 0% and 3.8%, respectively. Erectile preservation was 25% at 5 years. Overall survival was 88.1% and cause-specific survival was 100%. At 3 years, ASTRO BF-FCRs of the localized and advanced groups were 100% and 42%, respectively (p = 0.001). Conclusions: The HDR brachytherapy of a single implant with two fractions plus EBRT is effective in treating patients with localized hormone-naive prostate cancer, with the least genitourinary and gastrointestinal toxicities; however, longer median BF-FCR follow-up is required to assess these findings.

  19. Reproductive and economic impact following controlled introduction of cattle persistently infected with bovine viral diarrhea virus into a naive group of heifers.

    PubMed

    Rodning, S P; Givens, M D; Marley, M S D; Zhang, Y; Riddell, K P; Galik, P K; Hathcock, T L; Gard, J A; Prevatt, J W; Owsley, W F

    2012-10-15

    The reproductive impact following controlled introduction of animals persistently infected (PI) with bovine viral diarrhea virus (BVDV) was evaluated in BVDV-naive heifers. Heifers were randomly allocated into two groups: an unexposed control herd (n = 34) and a herd exposed to five persistently infected (PI) animals for 7 mo, beginning 50 days before the breeding season (n = 34). Initiation of the BVDV-challenge was timed to mimic either direct contact with PI calves born in the previous calving season or accidental introduction of PI herd additions prior to the breeding season. The PI animals represented BVDV Types 1a (n = 3), 1b (n = 1) and 2 (n = 1). Two BVDV-free, seropositive bulls were used in each group for 78 days breeding seasons. In both groups, 33 of 34 heifers became pregnant, with similar distribution of fetal ages. Two heifers in each group aborted (etiology undetermined). In addition, one calf was born dead and one calf died 3 days post-partum in the BVDV-exposed group. One calf in the unexposed group died 4 mo post-partum. No calves, including the stillborn calf and the two calves that died prior to weaning, were persistently infected with BVDV. In summary, introduction of PI cattle to a group of BVDV-naive heifers 50 days prior to the breeding season did not negatively impact reproductive performance. To the contrary, the active immunity that developed following field exposure to BVDV provided effective reproductive and fetal protection during the breeding season and subsequent gestations, despite continuous exposure to PI animals until approximately midgestation. Although BVDV can have potentially devastating reproductive effects, timing of infection is a critical determinant in the outcome of a BVDV infection. A controlled breeding season with introduction of herd additions at less critical reproductive time points can mitigate the negative reproductive health consequences of BVDV.

  20. Structural and Functional Characterization of a Single-chain Peptide-MHC Molecule that Modulates both Naive and Activated CD8plus T Cells

    SciTech Connect

    D Samanta; G Mukherjee; U Ramagopal; R Chaparro; S Nathenson; T DiLorenzo; S Almo

    2011-12-31

    Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8{sup +} T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8{sup +} T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK{sup d}.IGRP) by using the class I MHC molecule H-2K{sup d} and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP{sub 206-214}), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK{sup d}.IGRP tetramers bound specifically to cognate CD8{sup +} T cells. Tetramer binding induced death of naive T cells and in vitro- and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-{gamma} response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8{sup +} T cells makes them a potential intervention strategy in early and late stages of disease.

  1. Support vector inductive logic programming outperforms the naive Bayes classifier and inductive logic programming for the classification of bioactive chemical compounds.

    PubMed

    Cannon, Edward O; Amini, Ata; Bender, Andreas; Sternberg, Michael J E; Muggleton, Stephen H; Glen, Robert C; Mitchell, John B O

    2007-05-01

    We investigate the classification performance of circular fingerprints in combination with the Naive Bayes Classifier (MP2D), Inductive Logic Programming (ILP) and Support Vector Inductive Logic Programming (SVILP) on a standard molecular benchmark dataset comprising 11 activity classes and about 102,000 structures. The Naive Bayes Classifier treats features independently while ILP combines structural fragments, and then creates new features with higher predictive power. SVILP is a very recently presented method which adds a support vector machine after common ILP procedures. The performance of the methods is evaluated via a number of statistical measures, namely recall, specificity, precision, F-measure, Matthews Correlation Coefficient, area under the Receiver Operating Characteristic (ROC) curve and enrichment factor (EF). According to the F-measure, which takes both recall and precision into account, SVILP is for seven out of the 11 classes the superior method. The results show that the Bayes Classifier gives the best recall performance for eight of the 11 targets, but has a much lower precision, specificity and F-measure. The SVILP model on the other hand has the highest recall for only three of the 11 classes, but generally far superior specificity and precision. To evaluate the statistical significance of the SVILP superiority, we employ McNemar's test which shows that SVILP performs significantly (p < 5%) better than both other methods for six out of 11 activity classes, while being superior with less significance for three of the remaining classes. While previously the Bayes Classifier was shown to perform very well in molecular classification studies, these results suggest that SVILP is able to extract additional knowledge from the data, thus improving classification results further.

  2. Increased Putamen and Callosal Motor Subregion in Treatment-Naive Boys with Tourette Syndrome Indicates Changes in the Bihemispheric Motor Network

    ERIC Educational Resources Information Center

    Roessner, Veit; Overlack, Sebastian; Schmidt-Samoa, Carsten; Baudewig, Jurgen; Dechent, Peter; Rothenberger, Aribert; Helms, Gunther

    2011-01-01

    Background: Despite an increasing number of studies, findings of structural brain alterations in patients with Tourette syndrome are still inconsistent. Several confounders (comorbid conditions, medication, gender, age, IQ) might explain these discrepancies. In the present study, these confounders were excluded to identify differences in basal…

  3. Relationship between a BDNF gene polymorphism and the brain volume in treatment-naive patients with major depressive disorder: A VBM analysis of brain MRI.

    PubMed

    Ide, Satoru; Kakeda, Shingo; Watanabe, Keita; Yoshimura, Reiji; Abe, Osamu; Hayashi, Kenji; Ueda, Issei; Kishi, Taro; Katsuki, Asuka; Umene-Nakano, Wakako; Iwata, Nakao; Nakamura, Jun; Korogi, Yukunori

    2015-08-30

    The brain-derived neurotrophic factor (BDNF) relates to basic neuronal functions, such as cell survival, axonal outgrowth, and dendritic growth. The Val66Met polymorphism of the BDNF gene may affect genetic susceptibility to major depressive disorder (MDD). We prospectively investigated the relationship between the Val66Met BDNF genotype and voxel-based morphometry (VBM) findings for first episode and drug-naïve MDD patients and healthy subjects (HS). Participants comprised 38 MDD patients and 42 age- and sex-matched HS were divided into groups based on their BDNF genotype. The effects of diagnosis and genotype, as well as the genotype-diagnosis interaction, in relation to brain morphology were evaluated using a voxel-by-voxel statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Among the Met-carriers, the volume of the left middle frontal gyrus (composition of the prefrontal cortex [PFC]) was significantly smaller for MDD patients than for the HS, i.e., there was a significant genotype-diagnosis interaction effect on brain morphology noted in the left PFC. The BDNF polymorphism was associated with atrophy of the PFC in MDD patients, which suggests that the BDNF Val66Met polymorphism may play an important role in the pathogenesis of early stages of MDD.

  4. Elevated Linoleic Acid (A Pro-Inflammatory PUFA) and Liver Injury in a Treatment Naive HIV-HCV Co-Infected Alcohol Dependent Patient

    PubMed Central

    Vatsalya, Vatsalya; Barve, Shirish S.; McClain, Craig J.; Ramchandani, Vijay A.

    2016-01-01

    HIV and HCV co-infection is a unique disease condition, and medical management of such condition is difficult due to severity and systemic complications. Added with heavy alcohol drinking, risk of liver injury increases due to several pro-inflammatory responses that subsequently get involved with alcohol metabolism. Elevated levels of fatty acids have been reported both in viral infections as well as alcoholic liver disease though such investigations have not addressed the adverse events with dual viral infection of HIV and HCV along with heavy drinking. This case report is of a patient with excessive alcohol drinking and first time diagnosis of HIV and HCV dual infection, elaborating concurrent alteration in Linoleic Acid (LA) levels and pro-inflammatory shift in ω-6/ω-3 ratio along with the elevations in liver injury markers. Elevated LA has been recently studied extensively for its role in alcoholic liver disease; and in the present case, we also found it to be clinically relevant to liver injury. PMID:27489857

  5. TGF-beta1 enhances SDF-1alpha-induced chemotaxis and homing of naive T cells by up-regulating CXCR4 expression and downstream cytoskeletal effector molecules.

    PubMed

    Franitza, Susanne; Kollet, Orit; Brill, Alexander; Vaday, Gayle G; Petit, Isabelle; Lapidot, Tsvee; Alon, Ronen; Lider, Ofer

    2002-01-01

    The migration of immunocytes within the extracellular matrix (ECM) is influenced by the activation state of the incoming cell and its responses to the presence of chemokines and cytokines. We studied the regulatory role of TGF-beta1 on T cell homing to secondary lymphatic organs, such as the spleen, and chemotaxis within an ECM-like environment in using an ECM-like 3-dimensional gel system designed to follow the migration of individual leukocytes along chemokine gradients in real time. The numbers of migrating naive, but not memory T cells toward SDF-1alpha markedly increased after pre-incubating the cells with TGF-beta1 (0.25 ng/ml) for 24 h. The mechanisms underlying TGFbeta1-modulated migration involve the up-regulation of the expression of the SDF-1alpha receptor CXCR4, the enhancement of the SDF-1alpha-induced actin polymerization, and increased phosphorylation of Pyk2, a focal adhesion kinase involved in integrin-mediated lymphocyte migration, adhesion and interactions with ECM. Interestingly, priming of naive human T cells with TGF-beta1 increased homing of these cells to the spleen of NOD/SCID mice in a CXCR4-dependent manner. We propose that the effect of TGF-beta1 on the chemotaxis of naive T cells may be important in the locomotion of naive T cells toward SDF-1alpha-rich niches. PMID:11754360

  6. The DRD3 Ser9Gly Polymorphism Predicted Metabolic Change in Drug-Naive Patients With Bipolar II Disorder

    PubMed Central

    Chang, Ting-Ting; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po-See; Chu, Chun-Hsien; Chen, Shih-Heng; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Wang, Tzu-Yun; Li, Chia-Ling; Chung, Yi-Lun; Hsieh, Tsai-Hsin; Lee, I-Hui; Chen, Kao-Ching; Yang, Yen-Kuang; Hong, Jau-Shyong; Lu, Ru-Band; Lee, Sheng-Yu

    2016-01-01

    Abstract Patients with bipolar II disorder (BDII) have a higher prevalence rate of metabolic disturbance. Whether BDII itself, in addition to its current standard treatment, is a risk factor for metabolic syndrome warrants additional study. The dopamine receptor D3 (DRD3) gene, one of the candidate genes for BDII, is also involved in the dopaminergic system. We investigated whether it is related to changes in the metabolic indices of patients with BDII given 12 weeks of standard treatment. Patients with a first diagnosis of BDII (n = 117) were recruited. Metabolic profiles (cholesterol, triglycerides, fasting serum glucose, body mass index) were measured at baseline and at 2, 8, and 12 weeks. The genotype of the DRD3 Ser9Gly polymorphism (rs6280) was determined. Multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the 12-week intervention. Significant differences in triglyceride change were associated with the DRD3 Ser9Gly genotype (P = 0.03). Patients with the Ser/Ser genotype had significantly smaller triglyceride increases and a lower risk of developing metabolic syndrome than did those with the Ser/Gly+Gly/Gly genotype. However, the associations between the DRD3 Ser9Gly polymorphism with changes in triglyceride level become nonsignificant after correcting for multiple comparisons. We conclude that the DRD3 Ser9Gly polymorphism is nominally associated with changes in triglycerides and metabolic syndrome after 12 weeks of standard BDII treatment. PMID:27310943

  7. Developmental exposure to a complex PAH mixture causes persistent behavioral effects in naive Fundulus heteroclitus (killifish) but not in a population of PAH-adapted killifish.

    PubMed

    Brown, D R; Bailey, J M; Oliveri, A N; Levin, E D; Di Giulio, R T

    2016-01-01

    Acute exposures to some individual polycyclic aromatic hydrocarbons (PAHs) and complex PAH mixtures are known to cause cardiac malformations and edema in the developing fish embryo. However, the heart is not the only organ impacted by developmental PAH exposure. The developing brain is also affected, resulting in lasting behavioral dysfunction. While acute exposures to some PAHs are teratogenically lethal in fish, little is known about the later life consequences of early life, lower dose subteratogenic PAH exposures. We sought to determine and characterize the long-term behavioral consequences of subteratogenic developmental PAH mixture exposure in both naive killifish and PAH-adapted killifish using sediment pore water derived from the Atlantic Wood Industries Superfund Site. Killifish offspring were embryonically treated with two low-level PAH mixture dilutions of Elizabeth River sediment extract (ERSE) (TPAH 5.04 μg/L and 50.4 μg/L) at 24h post fertilization. Following exposure, killifish were raised to larval, juvenile, and adult life stages and subjected to a series of behavioral tests including: a locomotor activity test (4 days post-hatch), a sensorimotor response tap/habituation test (3 months post hatch), and a novel tank diving and exploration test (3months post hatch). Killifish were also monitored for survival at 1, 2, and 5 months over 5-month rearing period. Developmental PAH exposure caused short-term as well as persistent behavioral impairments in naive killifish. In contrast, the PAH-adapted killifish did not show behavioral alterations following PAH exposure. PAH mixture exposure caused increased mortality in reference killifish over time; yet, the PAH-adapted killifish, while demonstrating long-term rearing mortality, had no significant changes in mortality associated with ERSE exposure. This study demonstrated that early embryonic exposure to PAH-contaminated sediment pore water caused long-term locomotor and behavioral alterations in

  8. Lack of correlation between membrane CD30 expression and cytokine secretion pattern in allergen-primed naive cord blood T-cell lines and clones.

    PubMed

    Spinozzi, F; Agea, E; Piattoni, S; Falini, B; Grignani, F; Bertotto, A

    1997-04-01

    Various surface molecules are expressed by activated T cells. Among them, the CD30 antigen has been proposed as a reproducible marker that identifies a subset of differentiated and/or activated T lymphocytes that produce T helper (Th)-2-type cytokines, i.e. interleukin (IL)-4 and IL-5. However, because CD30 has mainly been detected on established T-cell clones, it is still unclear whether a priming allergen and/or cytokine can induce its membrane expression on naive T cells, perhaps in parallel with the up-regulation of other relevant activation markers, such as CD25, HLA-DR and L-selectin. It is also unknown whether proper allergen stimulation affects the cytokine secretion pattern by CD30+ T-cell clones derived from antigen-unprimed (naive) T lymphocytes. More information on these questions was sought by adopting a model that used cord blood as a source of virgin T cells and exposing them to native cypress allergen or cytokine (IL-2 or IL-4) stimulation, as well as to conventional polyclonal activators such as PHA or anti-CD3. Peripheral blood MC from four adult cypress-sensitive patients was also assayed and used as controls for all culture experiments. Freshly isolated cord and adult T cells did not express the CD30 antigen on their membrane. Many of the stimulating agents tested were able to up-regulate the expression of CD30. However, despite high expression of this molecule, cloned allergen-specific cord CD4+ T lymphocytes were unable to produce IFN-gamma and/or IL-4. In contrast, they retained the capability to produce IL-2. Thus, expression of the CD30 antigen on virgin T cells does not correlate with a polarized model of T helper (Th)-1 or Th-2 cytokine-producing cells, suggesting that these types of lymphokine-secreting lymphocytes are not a paradigmatic example of T-cell subpopulations that display stable phenotypical features. PMID:9105430

  9. Patients with solid tumors treated with high-temperature whole body hyperthermia show a redistribution of naive/memory T-cell subtypes.

    PubMed

    Atanackovic, Djordje; Pollok, Kristina; Faltz, Christiane; Boeters, Ina; Jung, Roman; Nierhaus, Alexander; Braumann, Klaus-Michael; Hossfeld, Dieter Kurt; Hegewisch-Becker, Susanna

    2006-03-01

    An activation of the immune system might contribute to the therapeutic effect of whole body hyperthermia (WBH) in cancer patients. We explored immune and endocrine responses in patients undergoing high-temperature WBH. Identical parameters were investigated in a separate group of healthy volunteers undergoing physical exercise to rule out effects of sympathetic activation. Lymphocyte subpopulations, lymphocytic expression of a range of adhesion molecules, and serum concentrations of a variety of hormones and cytokines were assessed in cancer patients undergoing high-temperature (60 min at 41.0-41.8 degrees C) WBH (n = 25) and in a separate group of healthy volunteers (n = 10) performing strenuous physical exercise. WBH induced an increase in human growth hormone (hGH), ACTH, and cortisol as well as in TNF-alpha, IL-6, IL-8, and IL-12R. We observed an increase in natural killer (NK) cells and CD56+ NK T cells shortly after initiation of WBH. In contrast, we found a decrease in T cells expressing L-selectin (CD62L) or alpha4beta7 integrin adhesion molecules mediating homing to lymphatic tissues. Accordingly, we observed a decrease in CD45RA+CCR7+ naive and CD45RA-CCR7+ central memory T cells. Numbers of CD45RA-CCR7- memory effector and CD45RA+CCR7 terminally differentiated T cells, on the other hand, remained unchanged. No comparable changes were observed in the group of healthy volunteers. In conclusion, patients with solid tumors treated with WBH show an increase in NK and NK T cells. In a later phase, plasma concentrations of IL-8, hGH, and cortisol increase, correlated with an influx of neutrophils into the peripheral blood. The alterations in T-cell populations suggest that WBH may induce naive and central-memory T cells to enter lymphatic tissue to await antigen exposure and effector T cells to migrate into peripheral tissues to exert their effector function. Although the exercise group may not be an appropriate control to proof the effect of WBH, these changes

  10. Experiences of Power and Violence in Mexican Men Attending Mutual-Aid Residential Centers for Addiction Treatment.

    PubMed

    Lozano-Verduzco, Ignacio; Marín-Navarrete, Rodrigo; Romero-Mendoza, Martha; Tena-Suck, Antonio

    2016-05-01

    Fundamental elements of hegemonic masculinity such as power and violence are analyzed through characteristics of 12-step programs and philosophy immersed in Mutual-Aid Residential Centers for Addiction Treatment (CRAMAAs). CRAMAAs are a culturally specific form of substance abuse treatment in Mexico that are characterized by control and violence. Fifteen interviews were carried out with men of varied sociodemographic characteristics, and who resided in at least two of these centers. Results identify that power is expressed through drug abuse and leads them to subsequent biopsychosocial degradation. Residency in CRAMAAs is motivated by women, but men do not seek the residency and are usually admitted unwillingly. Power through violence is carried out inside CRAMAAs where men are victims of abuse. From a 12-step philosophy, this violence is believed to lead them to a path of recovery but instead produces feelings of anger and frustration. The implications of these centers on Mexican public health are discussed.

  11. Investigate-and-redesign tasks as a context for learning and doing science and technology: A study of naive, novice and expert high school and adult designers doing product comparisons and redesign tasks

    NASA Astrophysics Data System (ADS)

    Crismond, David Paul

    This thesis studied high school students and adults with varying degrees of design experience doing two technology investigate-and-redesign (I&R) tasks. Each involved subjects investigating products, designing experiments to compare them fairly, and then redesigning the devices. A total of 25 pairs of subjects participated in this investigation and included naive and novice high school designers, as well as naive, novice, and expert adult designers. Subjects of similar age and design experience worked in same-gender teams and met for two 2-hour sessions. The essential research question of this thesis was: "What process skills and concepts do naive, novice and expert designers use and learn when investigating devices, designing experiments, and redesigning the devices?" Three methodologies were used to gather and analyze the data: clinical interviewing (Piaget, 1929/1960), protocol analysis (Ericsson & Simon, 1984) and interaction analysis (Jordan and Henderson, 1995). The thesis provides composite case-studies of 10 of the 50 test sessions, buttressed by descriptions of performance trends for all subjects. Given the small sample sizes involved, the findings are by necessity tentative and not supported by statistical analysis: (1) I&R activities are engaging, less time-intensive complements to design-and-build tasks, which involve simple mechanical devices and carry with them a host of potential "alternative understandings" in science and technology. Much gets learned during these tasks, more involving "device knowledge" and "device inquiry skills" than "big ideas" in science and technology. (2) Redesign tasks scaffold naive and novice designers to improved performance in the multidimensional and context-specific activity of design. The performances of naive and novice designers were more like that of expert designers when redesigning existing devices than when doing start-from-scratch designing. (3) Conceptual redesign involved more analysis- than synthesis

  12. Either main or accessory olfactory system signaling can mediate the rewarding effects of estrous female chemosignals in sexually naive male mice.

    PubMed

    Korzan, Wayne J; Freamat, Mihael; Johnson, Adam G; Cherry, James A; Baum, Michael J

    2013-10-01

    A long-held view has been that interest of male mice in female body odors reflects an activation of reward circuits in the male brain following their detection by the vomeronasal organ (VNO) and processing via the accessory olfactory system. We found that adult, sexually naive male mice acquired a conditioned place preference (CPP) after repeatedly receiving estrous female urine on the nose and being placed in an initially nonpreferred chamber with soiled estrous bedding on the floor. CPP was not acquired in control mice that received saline on the nose before being placed in a nonpreferred chamber with clean bedding. Robust acquisition of a CPP using estrous female odors as the reward persisted in separate groups of mice in which VNO-accessory olfactory function was disrupted by bilateral lesioning of the accessory olfactory bulb (AOB) or in which main olfactory function was disrupted by zinc sulfate lesions of the main olfactory epithelium (MOE). By contrast, no CPP was acquired for estrous odors in males that received combined AOB and MOE lesions. Either the main or the accessory olfactory system suffices to mediate the rewarding effects of estrous female odors in the male mouse, even in the absence of prior mating experience. The main olfactory system is part of the circuitry that responds to chemosignals involved in motivated behavior, a role that may be particularly important for humans who lack a functional accessory olfactory system.

  13. Antibody-Mediated and Cellular Immune Responses Induced in Naive Volunteers by Vaccination with Long Synthetic Peptides Derived from the Plasmodium vivax Circumsporozoite Protein

    PubMed Central

    Arévalo-Herrera, Myriam; Soto, Liliana; Perlaza, Blanca Liliana; Céspedes, Nora; Vera, Omaira; Lenis, Ana Milena; Bonelo, Anilza; Corradin, Giampietro; Herrera, Sócrates

    2011-01-01

    Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell-mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-γ production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-γ production induced by these vaccine candidates warrants further testing in a phase II clinical trial. PMID:21292876

  14. HIV Type 1 Molecular Epidemiology in pol and gp41 Genes Among Naive Patients from Mato Grosso do Sul State, Central Western Brazil

    PubMed Central

    da Silveira, Alexsander Augusto; Cardoso, Ludimila Paula Vaz; Francisco, Roberta Barbosa Lopes

    2012-01-01

    Abstract Antiretroviral naive patients (n=49) were recruited in central western Brazil (Campo Grande City/Mato Grosso do Sul State, located across the Bolivia and Paraguay borders). HIV-1 protease (PR), reverse transcriptase (RT), and env gp41 HR1 fragments were sequenced. Genetic diversity was analyzed by REGA/phylogenetic analyses. Intersubtype recombinants were identified by SimPlot/phylogenetic trees. PR/RT resistance was analyzed by Calibrated Population Resistance/Stanford databases. T-20 resistance in gp41 was assessed by Stanford, Los Alamos, and other sources. Of HIV-1 subtypes 65.3% were BPRBRT, 10.2% were CPRCRT, and 8.2% were F1PRF1RT. Intersubtype recombinants were 16.3%: four B/F1 and four B/C (two were “CRF31_BC-like”). The Pol-RT V75M mutation was detected in two homosexual partners; one patient had the T215S revertant mutation. T-20/gp41 resistance mutations were L44M (n=2) and V38A (n=1). The high percentage of non-B isolates (∼35%) highlights the importance of molecular surveillance studies in settings distant from the origin of the epidemic. Our data help elaborate the molecular epidemiological map of HIV-1 in Brazil. PMID:21790471

  15. Detection of drug resistance-associated mutations in human immunodeficiency virus type 1 integrase derived from drug-naive individuals in Surabaya, Indonesia.

    PubMed

    Kotaki, Tomohiro; Khairunisa, Siti Qamariyah; Sukartiningrum, Septhia Dwi; Witaningrum, Adiana Mutamsari; Rusli, Musofa; Diansyah, M Noor; Arfijanto, M Vitanata; Rahayu, Retno Pudji; Nasronudin; Kameoka, Masanori

    2014-05-01

    Although human immunodeficiency virus type 1 (HIV-1) infection causes serious health problems in Indonesia, information in regard to drug resistance is limited. We performed a genotypic study on HIV-1 integrase derived from drug-naive individuals in Surabaya, Indonesia. Sequencing analysis revealed that no primary mutations associated with drug resistance to integrase inhibitors were detected; however, secondary mutations, V72I, L74I/M, V165I, V201I, I203M, and S230N, were detected in more than 5% of samples. In addition, V201I was conserved among all samples. Most integrase genes were classified into CRF01_AE genes. Interestingly, 40% of the CRF01_AE genes had an unusual insertion in the C-terminus of integrase. These mutations and insertions were considered natural polymorphisms since these mutations coincided with previous reports, and integrase inhibitors have not been used in Indonesia. Our results indicated that further studies may be required to assess the impact of these mutations on integrase inhibitors prior to their introduction into Indonesia.

  16. HIV type 1 molecular epidemiology in pol and gp41 genes among naive patients from Mato Grosso do Sul State, central western Brazil.

    PubMed

    da Silveira, Alexsander Augusto; Cardoso, Ludimila Paula Vaz; Francisco, Roberta Barbosa Lopes; de Araújo Stefani, Mariane Martins

    2012-03-01

    Antiretroviral naive patients (n=49) were recruited in central western Brazil (Campo Grande City/Mato Grosso do Sul State, located across the Bolivia and Paraguay borders). HIV-1 protease (PR), reverse transcriptase (RT), and env gp41 HR1 fragments were sequenced. Genetic diversity was analyzed by REGA/phylogenetic analyses. Intersubtype recombinants were identified by SimPlot/phylogenetic trees. PR/RT resistance was analyzed by Calibrated Population Resistance/Stanford databases. T-20 resistance in gp41 was assessed by Stanford, Los Alamos, and other sources. Of HIV-1 subtypes 65.3% were B(PR)B(RT), 10.2% were C(PR)C(RT), and 8.2% were F1(PR)F1(RT). Intersubtype recombinants were 16.3%: four B/F1 and four B/C (two were "CRF31_BC-like"). The Pol-RT V75M mutation was detected in two homosexual partners; one patient had the T215S revertant mutation. T-20/gp41 resistance mutations were L44M (n=2) and V38A (n=1). The high percentage of non-B isolates (∼35%) highlights the importance of molecular surveillance studies in settings distant from the origin of the epidemic. Our data help elaborate the molecular epidemiological map of HIV-1 in Brazil.

  17. Recursion-based depletion of human immunodeficiency virus-specific naive CD4(+) T cells may facilitate persistent viral replication and chronic viraemia leading to acquired immunodeficiency syndrome.

    PubMed

    Tsukamoto, Tetsuo; Yamamoto, Hiroyuki; Okada, Seiji; Matano, Tetsuro

    2016-09-01

    Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in individuals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection.

  18. CD8+ T-cell Responses in Flavivirus-Naive Individuals Following Immunization with a Live-Attenuated Tetravalent Dengue Vaccine Candidate.

    PubMed

    Chu, Haiyan; George, Sarah L; Stinchcomb, Dan T; Osorio, Jorge E; Partidos, Charalambos D

    2015-11-15

    We are developing a live-attenuated tetravalent dengue vaccine (TDV) candidate based on an attenuated dengue 2 virus (TDV-2) and 3 chimeric viruses containing the premembrane and envelope genes of dengue viruses (DENVs) -1, -3, and -4 expressed in the context of the attenuated TDV-2 genome (TDV-1, TDV-3, and TDV-4, respectively). In this study, we analyzed and characterized the CD8(+) T-cell response in flavivirus-naive human volunteers vaccinated with 2 doses of TDV 90 days apart via the subcutaneous or intradermal routes. Using peptide arrays and intracellular cytokine staining, we demonstrated that TDV elicits CD8(+) T cells targeting the nonstructural NS1, NS3, and NS5 proteins of TDV-2. The cells were characterized by the production of interferon-γ, tumor necrosis factor-α, and to a lesser extent interleukin-2. Responses were highest on day 90 after the first dose and were still detectable on 180 days after the second dose. In addition, CD8(+) T cells were multifunctional, producing ≥2 cytokines simultaneously, and cross-reactive to NS proteins of the other 3 DENV serotypes. Overall, these findings describe the capacity of our candidate dengue vaccine to elicit cellular immune responses and support the further evaluation of T-cell responses in samples from future TDV clinical trials. PMID:25943203

  19. Female sexual dysfunction: A comparative study in drug naive 1st episode of depression in a general hospital of South Asia

    PubMed Central

    Roy, Payel; Manohar, Shivananda; Raman, Rajesh; Sathyanarayana Rao, T. S.; Darshan, M. S.

    2015-01-01

    Background: Women's sexual dysfunction is found to be highly prevalent in western and Indian literature. Limited studies are available on drug naive depression in western literature and in Indian population. Aim: To determine the prevalence rate and symptom profile of female sexual dysfunctions in patients with untreated depression. Design: A cross-sectional study in the psychiatry out-patient department of general hospital in South India. Materials and Methods: Following written informed consent female sexual functioning index (FSFI) and Arizona Sexual Experience Scale (ASEX) – female version and Hamilton Depression Rating Scale (HAMD - 17 item) on 30 cases and 30 controls was administered. Sociodemographic data, pattern and type of sexual dysfunctions were enquired. Data were analyzed using descriptive statistics, contingency co-efficient analysis and stepwise multiple regression. Results: The mean score of HAMD 17 item in study group was 19.13. The study showed that female sexual dysfunction was 70.3% in study group compared to 43.3% in control FSFI scores above 16 in HAMD had dysfunction of 76% with FSFI in study group. With ASEX-F sexual dysfunction was 73.3% in study compared to 20% in control. Scores above 16 in HAMD had 80% of sexual dysfunction with ASEX-F in study group. Conclusion: The study found that ASEX-F co-related better with HAMD 17 item. Following the onset of depression, the incidence of sexual dysfunction started at an early age in women. PMID:26600576

  20. Selection and characterisation of recombinant single-chain antibodies to the hapten Aflatoxin-B1 from naive recombinant antibody libraries.

    PubMed

    Moghaddam, A; Løbersli, I; Gebhardt, K; Braunagel, M; Marvik, O J

    2001-08-01

    Selection of antibodies from large repertoire phage display libraries has become a common technique for isolation of specific antibodies to antigens. Many of these libraries are shown to contain antibodies specific to haptens, but only when these haptens are derivatised or conjugated to an immobilising molecule, such as bovine serum albumin (BSA). There has been little demonstration of the suitability of naive recombinant antibody libraries for isolating antibodies that bind low molecular weight haptens in the absence of a carrier molecule and few have addressed the problems associated with selecting antibodies that only recognize the combination of hapten and the carrier molecule. We have panned two-phage antibody libraries against AflatoxinB1-BSA and screened single-chain antibody fragments for binding to AflatoxinB1-BSA and Aflatoxin-B1. Many of the antibodies isolated specifically bound AflatoxinB1-BSA, but not soluble Aflatoxin-B1 or BSA. Modification of the protocol led to isolation of single-chain fragment variable antibody domain (scFv) antibodies that specifically bound soluble Aflatoxin-B1 with an affinity of 6x10(-9) M. PMID:11406162

  1. Recursion-based depletion of human immunodeficiency virus-specific naive CD4(+) T cells may facilitate persistent viral replication and chronic viraemia leading to acquired immunodeficiency syndrome.

    PubMed

    Tsukamoto, Tetsuo; Yamamoto, Hiroyuki; Okada, Seiji; Matano, Tetsuro

    2016-09-01

    Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in individuals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection. PMID:27515208

  2. Nevirapine and Efavirenz Elicit Different Changes in Lipid Profiles in Antiretroviral- Therapy-Naive Patients Infected with HIV-1

    PubMed Central

    2004-01-01

    ABSTRACT Background Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). Methods and Findings Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. Conclusion NVP-containing ART shows larger increases in

  3. Comparison of plasma MicroRNA levels in drug naive, first episode depressed patients and healthy controls.

    PubMed

    Camkurt, Mehmet Akif; Acar, Şenel; Coşkun, Salih; Güneş, Mehmet; Güneş, Serkan; Yılmaz, Mehmet Fatih; Görür, Ayşegül; Tamer, Lülüfer

    2015-10-01

    Major depression is the most common psychiatric disorder. The diagnosis of depression depends on a patient's subjective complaints, and the nature of the heterogeneous disorder. Thus, there is no known biomarker for depression to date. Previous research has indicated that microRNAs are dysregulated in bipolar disorder and schizophrenia. We aimed to investigate microRNA dysregulation in plasma samples of patients with major depression. Venous blood samples of 50 depressed patients and 41 healthy controls were collected and the quantification of microRNAs was established using qRT-PCR. We found miR-320a significantly downregulated and miR-451a significantly upregulated in depressed patients. We also found miR-17-5p and miR-223-3p upregulated, but not as significantly as miR-451a. Merging our results with previous published data shows that the blood miR-320 family may be a potential microRNA family dysregulated in major depression. Research should be performed on miR-320-related pathways and their relationship to depression. Additionally, miR-451a could serve as a candidate biomarker for depression based on the acting mechanism of ketamine. Studies targeting miR-451a levels before and after treatment could be helpful. PMID:26343596

  4. Disrupted causal connectivity anchored on the anterior cingulate cortex in first-episode medication-naive major depressive disorder.

    PubMed

    Feng, Zhan; Xu, Shunliang; Huang, Manli; Shi, Yushu; Xiong, Bing; Yang, Hong

    2016-01-01

    In recent years, major depressive disorder (MDD) has been demonstrated to be associated with abnormalities in neural networks, particularly the prefrontal-limbic network (PLN). However, there are few current studies that have examined information flow in the PLN. In this study, Granger causality analysis (GCA), based on signed regression coefficient, was used to explore changes in causal connectivity in resting-state PLNs of MDD patients. A total of 23 first-episode medication-naïve MDD patients and 20 normal control participants were subjected to resting-state functional magnetic resonance imaging (RS-fMRI) scans. Increased causal effects of the right insular cortex, right putamen and right caudate on the rostral anterior cingulate cortex (rACC) and reduced causal effects of bilateral dorsolateral prefrontal cortex (DLPFC) and left orbitofrontal cortex (OFC) on the rACC were found in MDD patients compared to normal controls. The extensive reduction in the causal effect of the prefrontal cortex (PFC) demonstrates impaired top-down cognitive control in MDD patients. Changes in the causal relationship between the right insula and rACC suggest problems in coordination of the default mode network by the right anterior insular cortex (rAI). These findings provide valuable insight into MDD-related neural network disorders reported in previous RS-fMRI studies and may potentially guide clinical treatment of MDD in the future. PMID:26234517

  5. Response to Therapy in Antiretroviral Therapy–Naive Patients With Isolated Nonnucleoside Reverse Transcriptase Inhibitor–Associated Transmitted Drug Resistance

    PubMed Central

    Fessel, W. Jeffrey; Rhee, Soo-Yon; Hurley, Leo B.; Klein, Daniel B.; Ioannidis, John P. A.; Silverberg, Michael J.; Shafer, Robert W.

    2016-01-01

    Background: Nonnucleoside reverse transcriptase inhibitor (NNRTI)–associated transmitted drug resistance (TDR) is the most common type of TDR. Few data guide the selection of antiretroviral therapy (ART) for patients with such resistance. Methods: We reviewed treatment outcomes in a cohort of HIV-1–infected patients with isolated NNRTI TDR who initiated ART between April 2002 and May 2014. In an as-treated analysis, virological failure (VF) was defined as not reaching undetectable virus levels within 24 weeks, virological rebound, or switching regimens during viremia. In an intention-to-treat analysis, failure was defined more broadly as VF, loss to follow-up, and switching during virological suppression. Results: Of 3245 patients, 131 (4.0%) had isolated NNRTI TDR; 122 received a standard regimen comprising 2 NRTIs plus a boosted protease inhibitor (bPI; n = 54), an integrase strand transfer inhibitor (INSTI; n = 52), or an NNRTI (n = 16). The median follow-up was 100 weeks. In the as-treated analysis, VF occurred in 15% (n = 8), 2% (n = 1), and 25% (n = 4) of patients in the bPI, INSTI, and NNRTI groups, respectively. In multivariate regression, there was a trend toward a lower risk of VF with INSTIs than with bPIs (hazard ratio: 0.14; 95% confidence interval: 0.02 to 1.1; P = 0.07). In intention-to-treat multivariate regression, INSTIs had a lower risk of failure than bPIs (hazard ratio: 0.38; 95% confidence interval: 0.18 to 0.82; P = 0.01). Conclusions: Patients with isolated NNRTI TDR experienced low VF rates with INSTIs and bPIs. INSTIs were noninferior to bPIs in an analysis of VF but superior to bPIs when frequency of switching and loss to follow-up were also considered. PMID:26855248

  6. Metronomic cyclophosphamide therapy in hormone-naive patients with non-metastatic biochemical recurrent prostate cancer: a phase II trial.

    PubMed

    Calcagno, Fabien; Mouillet, Guillaume; Adotevi, Olivier; Maurina, Tristan; Nguyen, Thierry; Montcuquet, Philippe; Curtit, E; Kleinclauss, F; Pivot, Xavier; Borg, Christophe; Thiery-Vuillemin, Antoine

    2016-08-01

    After curative local therapy, biochemical recurrence is a mode of relapse among patient with prostate cancer (PC). Deferring androgen deprivation therapy (ADT) or offering non-hormonal therapies may be an appropriate option for these non-symptomatic patients with no proven metastases. Metronomic cyclophosphamide (MC) has shown activity in metastatic PC setting and was chosen to be assessed in biochemical relapse. This prospective single-arm open-label phase II study was conducted to evaluate MC regimen in patients with biochemical recurrent PC. MC was planned to be administered orally at a daily dose of 50 mg for 6 months. Primary endpoint was PSA response. Thirty-eight patients were included and treated. Median follow-up was 45.5 months (range 17-100). Among them, 14 patients (37 %) achieved PSA stabilisation and 22 patients (58 %) experienced PSA progression. Response rate was 5 % with one complete response (2.6 %), and 1 partial response with PSA decrease >50 % (2.6 %). The median time until androgen deprivation therapy initiation was around 15 months. The treatment was well tolerated. Neither grade 3-4 toxicity nor serious adverse events were observed. This first prospective clinical trial with MC therapy in patients with non-metastatic biochemical recurrence of PC displayed modest efficacy when measured with PSA response rate, without significant toxicity. It might offer a new safe and non-expensive option to delay initiation of ADT. These results would need to be confirmed with larger prospective randomised trials. PMID:27400698

  7. Prevention of GVHD by modulation of rat bone marrow with UV-B irradiation. II. Kinetics of migration of UV-B-irradiated bone marrow cells in naive and lethally irradiated rats

    SciTech Connect

    Oluwole, S.F.; Engelstad, K.; Hardy, M.A. )

    1990-06-01

    UV-B irradiation (700 J/m2) of bone marrow (BM) cells prior to transplantation into lethally gamma-irradiated (1050 rad) allogeneic rats prevents the development of GVHD and results in a stable mixed lymphohematopoietic chimerism. To better understand the underlying mechanisms of the development of stable radiation chimeras in this model, this study was designed to examine whether the dose (700 J/m2) of UV-B irradiation used for the modulation of the BM inoculum would affect the homing pattern of radiolabeled BM cells compared to that of thoracic duct lymphocytes (TDL) in the naive and lethally irradiated recipients. The results showed that intravenously administered, 111Indium-oxine-labeled, unmodified TDL home specifically to the spleen, lymph nodes, and BM compartments with a subsequent recirculation of a large number of cells from the spleen to the lymph nodes. In contrast, radiolabeled, unmodified BM cells migrate specifically to the spleen, liver, and BM with the lymph nodes, thymus, and nonlymphoid organs containing very little amounts of radioactivity. The stable concentrations of radioactivity in the lymphoid and nonlymphoid compartments between 3 and 72 hr after injection suggest that BM cells, unlike TDL, do not recirculate. The migration pattern of BM cells in the naive recipient was not significantly different from that seen in lethally irradiated animals except for the higher concentration of radioactivity in the spleen and BM of irradiated animals compared to that seen in naive recipients. The similarity of tissue localization of BM cells in naive or in irradiated syngeneic recipients to that of allogeneic recipients suggests that the homing of BM cells is not MHC restricted.

  8. Participation in specific treatment components predicts alcohol-specific and general coping skills.

    PubMed

    Forys, Kelly; McKellar, John; Moos, Rudolf

    2007-08-01

    This study identified which aspects of substance abuse treatment in community residential facilities (CRFs) were correlated with patients' post-treatment coping. A total of 2376 patients supplied demographic information and completed measures at baseline (coping and abstinence self-efficacy) and one year after treatment (coping, level of drug and alcohol use, and substance-related problems). Staff provided information about treatment orientation and patients' participation in treatment (e.g., life skills training, vocational counseling). The data were used to predict coping 1 year after treatment. As expected, higher levels of general approach coping and alcohol-specific coping and lower levels of general avoidance coping were associated with less 1-year alcohol and drug use and fewer drinking problems. Patients' greater level of participation in life skills counseling predicted more approach coping at 1 year. In addition, positive social relationships and participation in 12-step self-help groups predicted less general avoidance coping and more alcohol-specific coping at 1 year post-treatment. Life skills training, 12-step self-help groups, and enhancement of supportive relationships during CRF treatment for substance abuse are related to healthy coping. Future research should examine the effect of these components in less intensive programs and with women. PMID:17182195

  9. Effects of rolipram and zaprinast on learning and memory in the Morris water maze and radial arm maze tests in naive mice.

    PubMed

    Akar, F; Mutlu, O; Celikyurt, I K; Ulak, G; Erden, F; Bektas, E; Tanyeri, P

    2015-02-01

    Inhibition of phosphodiesterase 5 (PDE) improved recognition memory and counteracted spatial learning impairment induced by nitric oxide synthase (NOS) inhibition in recent studies. Aim of this study was to investigate effects of rolipram, a PDE4 inhibitor and zaprinast, a PDE5 inhibitor, on learning and memory in Morris water maze (MWM) and radial arm maze (RAM) tests in naive mice. Male Balb-c mice were treated subchronically with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) for 6 days in the MWM test and acutely before the retention trial of radial arm maze test. Rolipram (0.05 and 0.1 mg/kg) significantly decreased escape latency between 2(nd) and 5(th) sessions, while zaprinast (10 mg/kg) significantly decreased escape latency only in 2(nd) session. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly increased time spent in escape platform's quadrant in probe trial of MWM test; only rolipram decreased mean distance to platform, while zaprinast had no effect on mean distance to platform. Zaprinast (3 and 10 mg/kg) significantly decreased number of errors compared to control group, while rolipram (0.05 and 0.1mg/kg) had no effect on number of errors in retention trial of RAM test. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly decreased time spent to complete retention trial (latency) compared to control group. Our study revealed that both zaprinast and rolipram enhanced spatial memory in MWM, while zaprinast seems to have more memory enhancing effects compared to rolipram in radial arm maze test. PMID:24764251

  10. Live cell imaging of the nascent inactive X chromosome during the early differentiation process of naive ES cells towards epiblast stem cells.

    PubMed

    Guyochin, Aurélia; Maenner, Sylvain; Chu, Erin Tsi-Jia; Hentati, Asma; Attia, Mikael; Avner, Philip; Clerc, Philippe

    2014-01-01

    Random X-chromosome inactivation ensures dosage compensation in mammals through the transcriptional silencing of one of the two X chromosomes present in each female cell. Silencing is initiated in the differentiating epiblast of the mouse female embryos through coating of the nascent inactive X chromosome by the non-coding RNA Xist, which subsequently recruits the Polycomb Complex PRC2 leading to histone H3-K27 methylation. Here we examined in mouse ES cells the early steps of the transition from naive ES cells towards epiblast stem cells as a model for inducing X chromosome inactivation in vitro. We show that these conditions efficiently induce random XCI. Importantly, in a transient phase of this differentiation pathway, both X chromosomes are coated with Xist RNA in up to 15% of the XX cells. In an attempt to determine the dynamics of this process, we designed a strategy aimed at visualizing the nascent inactive X-chromosome in live cells. We generated transgenic female XX ES cells expressing the PRC2 component Ezh2 fused to the fluorescent protein Venus. The fluorescent fusion protein was expressed at sub-physiological levels and located in nuclei of ES cells. Upon differentiation of ES cell towards epiblast stem cell fate, Venus-fluorescent territories appearing in interphase nuclei were identified as nascent inactive X chromosomes by their association with Xist RNA. Imaging of Ezh2-Venus for up to 24 hours during the differentiation process showed survival of some cells with two fluorescent domains and a surprising dynamics of the fluorescent territories across cell division and in the course of the differentiation process. Our data reveal a strategy for visualizing the nascent inactive X chromosome and suggests the possibility for a large plasticity of the nascent inactive X chromosome.

  11. Live Cell Imaging of the Nascent Inactive X Chromosome during the Early Differentiation Process of Naive ES Cells towards Epiblast Stem Cells

    PubMed Central

    Guyochin, Aurélia; Maenner, Sylvain; Chu, Erin Tsi-Jia; Hentati, Asma; Attia, Mikael; Avner, Philip; Clerc, Philippe

    2014-01-01

    Random X-chromosome inactivation ensures dosage compensation in mammals through the transcriptional silencing of one of the two X chromosomes present in each female cell. Silencing is initiated in the differentiating epiblast of the mouse female embryos through coating of the nascent inactive X chromosome by the non-coding RNA Xist, which subsequently recruits the Polycomb Complex PRC2 leading to histone H3-K27 methylation. Here we examined in mouse ES cells the early steps of the transition from naive ES cells towards epiblast stem cells as a model for inducing X chromosome inactivation in vitro. We show that these conditions efficiently induce random XCI. Importantly, in a transient phase of this differentiation pathway, both X chromosomes are coated with Xist RNA in up to 15% of the XX cells. In an attempt to determine the dynamics of this process, we designed a strategy aimed at visualizing the nascent inactive X-chromosome in live cells. We generated transgenic female XX ES cells expressing the PRC2 component Ezh2 fused to the fluorescent protein Venus. The fluorescent fusion protein was expressed at sub-physiological levels and located in nuclei of ES cells. Upon differentiation of ES cell towards epiblast stem cell fate, Venus-fluorescent territories appearing in interphase nuclei were identified as nascent inactive X chromosomes by their association with Xist RNA. Imaging of Ezh2-Venus for up to 24 hours during the differentiation process showed survival of some cells with two fluorescent domains and a surprising dynamics of the fluorescent territories across cell division and in the course of the differentiation process. Our data reveal a strategy for visualizing the nascent inactive X chromosome and suggests the possibility for a large plasticity of the nascent inactive X chromosome. PMID:25546018

  12. Chemical Compounds Related to the Predation Risk Posed by Malacophagous Ground Beetles Alter Self-Maintenance Behavior of Naive Slugs (Deroceras reticulatum)

    PubMed Central

    Bursztyka, Piotr; Saffray, Dominique; Lafont-Lecuelle, Céline; Brin, Antoine; Pageat, Patrick

    2013-01-01

    Evidence that terrestrial gastropods are able to detect chemical cues from their predators is obvious yet scarce, despite the scientific relevance of the topic to enhancing our knowledge in this area. This study examines the influence of cuticular extracts from predacious ground beetles (Carabus auratus, Carabus hispanus, Carabus nemoralis and Carabus coriaceus), and a neutral insect species (Musca domestica) on the shelter-seeking behavior of naive slugs (Deroceras reticulatum). Slugs, known to have a negative phototactic response, were exposed to light, prompting them to make a choice between either a shelter treated with a cuticular extract or a control shelter treated with pure ethyl alcohol. Their behavioral responses were recorded for one hour in order to determine their first shelter choice, their final position, and to compare the percentage of time spent in the control shelters with the time spent in the treated shelters.The test proved to be very effective: slugs spent most of the experiment in a shelter. They spent significantly more time in the control shelter than in the shelter treated with either C. nemoralis (Z = 2.43; p = 0.0151; Wilcoxon matched-pairs signed-ranks test) or C. coriaceus cuticular extracts (Z = 3.31; p<0.01; Wilcoxon matched-pairs signed-ranks test), with a seemingly stronger avoidance effect when presented with C. coriaceus extracts. The other cuticular extracts had no significant effect on any of the behavioral items measured. Although it cannot be entirely excluded that the differences observed, are partly due to the intrinsic properties of the vehicle employed to build the cuticular extracts, the results suggest that slugs can innately discriminate amongst different potential predators and adjust their behavioral response according to the relevance of the threat conveyed by their predator’s chemical cues. PMID:24244487

  13. Relationship of Hemoglobin A1c with β Cell Function and Insulin Resistance in Newly Diagnosed and Drug Naive Type 2 Diabetes Patients

    PubMed Central

    Hou, Xinguo; Liu, Jinbo; Song, Jun; Wang, Chuan; Liang, Kai; Sun, Yu; Ma, Zeqiang; Yang, Weifang; Li, Chengqiao; Zhang, Xiuping; Lin, Peng; Gong, Lei; Wang, Meijian; Liu, Fuqiang; Li, Wenjuan; Yan, Fei; Qin, Jun; Wang, Lingshu; Liu, Jidong; Zhao, Ruxing; Chen, Shihong; Chen, Li

    2016-01-01

    Objective. To investigate changes in the glycated hemoglobin A1c (A1c) level and those in β cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. Design and Methods. A total of 818 newly diagnosed diabetic individuals who were ≥40 years of age were recruited. The subjects were grouped by A1c values (<6.5%, 6.5–7%, 7-8%, 8-9%, and ≥9%). The homeostasis model assessment (HOMA) was used to evaluate pancreatic β cell function (HOMA-β) and insulin resistance (HOMA-IR). ANOVA, t-tests, and binary logistic regression analysis were used for data analysis. Results. Compared with subjects with A1c values <6.5%, individuals with an A1c of 6.5–7% exhibited an increased HOMA-β index. However, the HOMA-β index was significantly decreased at A1c values ≥7% and further decreased by 9.3% and by 23.7%, respectively, at A1c values of 7-8% and 8-9%. As A1c increased to ≥9%, a 62% reduction in β cell function was observed, independently of age, gender, body mass index (BMI), blood pressure (BP), blood lipids, and hepatic enzyme levels. Meanwhile, insulin resistance was significantly increased with an increase in A1c values. Conclusions. Elevated A1c values (≥7%) were associated with substantial reductions in β cell function. PMID:26640807

  14. Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder.

    PubMed

    Won, E; Choi, S; Kang, J; Kim, A; Han, K-M; Chang, H S; Tae, W S; Son, K R; Joe, S-H; Lee, M-S; Ham, B-J

    2016-08-09

    Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearson's correlation: r=-0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=-0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD.

  15. Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder.

    PubMed

    Won, E; Choi, S; Kang, J; Kim, A; Han, K-M; Chang, H S; Tae, W S; Son, K R; Joe, S-H; Lee, M-S; Ham, B-J

    2016-01-01

    Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearson's correlation: r=-0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=-0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD. PMID:27505229

  16. Effects of rolipram and zaprinast on learning and memory in the Morris water maze and radial arm maze tests in naive mice.

    PubMed

    Akar, F; Mutlu, O; Celikyurt, I K; Ulak, G; Erden, F; Bektas, E; Tanyeri, P

    2015-02-01

    Inhibition of phosphodiesterase 5 (PDE) improved recognition memory and counteracted spatial learning impairment induced by nitric oxide synthase (NOS) inhibition in recent studies. Aim of this study was to investigate effects of rolipram, a PDE4 inhibitor and zaprinast, a PDE5 inhibitor, on learning and memory in Morris water maze (MWM) and radial arm maze (RAM) tests in naive mice. Male Balb-c mice were treated subchronically with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) for 6 days in the MWM test and acutely before the retention trial of radial arm maze test. Rolipram (0.05 and 0.1 mg/kg) significantly decreased escape latency between 2(nd) and 5(th) sessions, while zaprinast (10 mg/kg) significantly decreased escape latency only in 2(nd) session. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly increased time spent in escape platform's quadrant in probe trial of MWM test; only rolipram decreased mean distance to platform, while zaprinast had no effect on mean distance to platform. Zaprinast (3 and 10 mg/kg) significantly decreased number of errors compared to control group, while rolipram (0.05 and 0.1mg/kg) had no effect on number of errors in retention trial of RAM test. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly decreased time spent to complete retention trial (latency) compared to control group. Our study revealed that both zaprinast and rolipram enhanced spatial memory in MWM, while zaprinast seems to have more memory enhancing effects compared to rolipram in radial arm maze test.

  17. MyD88- and TRIF-independent induction of type I interferon drives naive B cell accumulation but not loss of lymph node architecture in Lyme disease.

    PubMed

    Hastey, Christine J; Ochoa, Jennine; Olsen, Kimberley J; Barthold, Stephen W; Baumgarth, Nicole

    2014-04-01

    Rapidly after infection, live Borrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robust Borrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated that B. burgdorferi infection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88- and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus, B. burgdorferi infection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robust Borrelia-specific immunity.

  18. Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder

    PubMed Central

    Won, E; Choi, S; Kang, J; Kim, A; Han, K-M; Chang, H S; Tae, W S; Son, K R; Joe, S-H; Lee, M-S; Ham, B-J

    2016-01-01

    Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearson's correlation: r=−0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=−0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD. PMID:27505229

  19. Apoptotic markers in cultured fibroblasts correlate with brain metabolites and regional brain volume in antipsychotic-naive first-episode schizophrenia and healthy controls.

    PubMed

    Batalla, A; Bargalló, N; Gassó, P; Molina, O; Pareto, D; Mas, S; Roca, J M; Bernardo, M; Lafuente, A; Parellada, E

    2015-08-25

    Cultured fibroblasts from first-episode schizophrenia patients (FES) have shown increased susceptibility to apoptosis, which may be related to glutamate dysfunction and progressive neuroanatomical changes. Here we determine whether apoptotic markers obtained from cultured fibroblasts in FES and controls correlate with changes in brain glutamate and N-acetylaspartate (NAA) and regional brain volumes. Eleven antipsychotic-naive FES and seven age- and gender-matched controls underwent 3-Tesla magnetic resonance imaging scanning. Glutamate plus glutamine (Glx) and NAA levels were measured in the anterior cingulate (AC) and the left thalamus (LT). Hallmarks of apoptotic susceptibility (caspase-3-baseline activity, phosphatidylserine externalization and chromatin condensation) were measured in fibroblast cultures obtained from skin biopsies after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 μM. Apoptotic biomarkers were correlated to brain metabolites and regional brain volume. FES and controls showed a negative correlation in the AC between Glx levels and percentages of cells with condensed chromatin (CC) after both apoptosis inductions (STS 0.5 μM: r = -0.90; P = 0.001; STS 0.25 μM: r = -0.73; P = 0.003), and between NAA and cells with CC (STS 0.5 μM induction r = -0.76; P = 0.002; STS 0.25 μM r = -0.62; P = 0.01). In addition, we found a negative correlation between percentages of cells with CC and regional brain volume in the right supratemporal cortex and post-central region (STS 0.25 and 0.5 μM; P < 0.05 family-wise error corrected (FWEc)). We reveal for the first time that peripheral markers of apoptotic susceptibility may correlate with brain metabolites, Glx and NAA, and regional brain volume in FES and controls, which is consistent with the neuroprogressive theories around the onset of the schizophrenia illness.

  20. Avoiding Pedagogically Naive "Captive" Software.

    ERIC Educational Resources Information Center

    Walbert, Mark S.

    An increasing number of non-statistical software packages are being written as supplementary instructional materials provided free or at low cost for economics principles textbooks. This paper reviews the software programs currently available as ancillary material to several major texts and compares what is available as a group against what should…

  1. Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Botrel, Tobias Engel Ayer; Clark, Otávio; Lima Pompeo, Antônio Carlos; Horta Bretas, Francisco Flávio; Sadi, Marcus Vinicius; Ferreira, Ubirajara; Borges dos Reis, Rodolfo

    2016-01-01

    Objective Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). Results The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group

  2. [Costs of a guideline-based treatment of patients with chronic hepatitis C in the era of interferon-free treatment].

    PubMed

    Stahmeyer, J T; Rossol, S; Bert, F; Liersch, S; Krauth, C

    2016-08-01

    The treatment of chronic hepatitis C has considerably changed with the introduction of recent direct acting antivirals. These antivirals have sustained virologic response (SVR) rates above 90 % as well as reduced toxicity and treatment duration. Therefore, current German guidelines recommend these interferon-free regimens as first-choice treatment. Nevertheless, recent developments were accompanied by a significant increase in treatment costs, which led to extensive discussions on reasonable pharmaceutical prices. The aim of the current study was to analyze the average treatment costs and costs per patient cured for guideline treatment recommendations. Analyses were stratified according to genotype, treatment status (naive/experienced), and presence/absence of cirrhosis. Costs were separated in (1.) basic diagnostic procedures, (2.) monitoring, and (3.) pharmaceuticals. The calculation is based on a remuneration scheme in the statutory health insurance system. In treatment-naïve non-cirrhotic patients, the average cost is 41 766 €/SVR for the treatment with SOF/LDV calculated (PTV/r/OMV+DSV: 53 129 €/SVR). In treatment-naive cirrhotic patients, costs were 60 323 €/SVR (SOF/LDV+RBV) and 80 604 €/SVR (PTV/r/OMV+DSV+RBV). Treatment-experienced genotype 1 patients had average costs of 60 366 €/SVR for SOF/LDV treatment as well as 53 134 €/SVR for PTV/r/OMV+DSV±RBV treatment (cirrhotic patients: 62 208 €/SVR for SOF/LDV+RBV; 80 824 €/SVR for PTV/r/OMV+DSV+RBV). The average treatment costs per SVR in treatment-naive genotype 1 patients are comparable to previous standard of care treatments and lower in treatment-experienced patients. In other genotypes, treatment costs and costs per cure are significantly higher compared to previous standard of care. However, long-term modelling studies show that new regimens are cost-effective. PMID:27529526

  3. Prevalence of Metabolic Syndrome and Its Clinical and Angiographic Profile in Patients With Naive Acute Coronary Syndrome in North Indian Population

    PubMed Central

    Sinha, Santosh Kumar; Goel, Amit; Madaan, Amit; Thakur, Ramesh; Krishna, Vinay; Singh, Karandeep; Sachan, Mohit; Pandey, Umeshwar; Varma, Chandra Mohan

    2016-01-01

    Background Data of isolated metabolic syndrome as risk factor in patients presenting with acute coronary syndrome (ACS) especially in context to Indian subcontinent are sparse. Therefore, we studied the prevalence of metabolic syndrome (MetS), and its clinical and angiographic profile in naive ACS patients in North Indian population. Methods A single-center, prospective, observational study of 324 patients was conducted at LPS Institute of Cardiology, G.S.V.M. Medical College, Kanpur, India with newly diagnosed ACS patients with MetS, as per modified NCEP-ATP III criteria. They were divided into two groups with and without MetS, and their clinical and angiographic profiles were studied. Results Prevalence of MetS in our study was 37.65%. Patients with MetS were significantly older than without MetS (60.3 ± 8.4 vs. 57.6 ± 7.9), and had females preponderance (35.24% vs. 24.25%), less tobacco abuse (30.32% vs. 42.57%), more non-ST-segment elevation ACS (58.19% vs. 36.14%), less ST-segment elevation myocardial infarction (STEMI) (41.80% vs. 63.86%), more cardiogenic shock (27.04% vs. 17.32%), recurrent ischemia (14.75% vs. 7.42%) and on angiogram, lesser single vessel disease (21.13% vs. 53.96%), more double vessel disease (39.34 vs. 24.26%), triple vessel disease (19.67% vs. 10.39%), left main (13.11% vs. 4.45%) and complex coronary lesions (tubular 40.98% vs. 31.68%; diffuse 26.23% vs. 18.32%). However, there was a trend of lower but insignificant mortality with MetS (5.44% vs. 6.55%). Conclusion There was high prevalence of MetS among patients with ACS in North Indian population with more advanced coronary artery disease. To the best of our knowledge, this is the first study from North India documenting clinical and angiographic profile of patients with MetS and ACS. PMID:27540441

  4. Distribution of radiolabeled L-glutamate and D-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection

    SciTech Connect

    Klin, Yael; Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram; Teichberg, Vivian I.

    2010-09-03

    Research highlights: {yields} Blood glutamate has a half-life time of 2-3 min. {yields} Blood glutamate is submitted to rapid decarboxylation. {yields} Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. {yields} The skeletal muscle and liver are now targets for potential drugs affording brain neuroprotection. -- Abstract: Excess L-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either L-[1-{sup 14}C] Glutamic acid (L-[1-{sup 14}C] Glu), L-[G-{sup 3}H] Glutamic acid (L-[G-{sup 3}H] Glu) or D-[2,3-{sup 3}H] Aspartic acid (D-[2,3-{sup 3}H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with L-[1-{sup 14}C] Glu and L-[G-{sup 3}H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3-{sup 3}H] Asp. L-[1-{sup 14}C] Glu was subjected in blood to a rapid decarboxylation with the loss of {sup 14}CO{sub 2}. The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total L-[U-{sup 14}C] Glu or D-[2,3-{sup 3}H] Asp radioactivity capture. L-[U-{sup 14}C] Glu and D-[2,3-{sup 3}H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues

  5. Cellular HIV type 1 DNA levels are equivalent among drug-sensitive and drug-resistant strains in newly diagnosed and antiretroviral naive patients.

    PubMed

    Antoniadou, Zoi-Anna; Hezka, Johana; Kousiappa, Ioanna; Mamais, Ioannis; Skoura, Lemonia; Pilalas, Dimitris; Metallidis, Simeon; Nicolaidis, Pavlos; Malisiovas, Nicolaos; Kostrikis, Leondios G

    2014-03-01

    The emergence of resistance against current antiretroviral drugs to human immunodeficiency virus type 1 (HIV-1) is an increasingly important concern to the continuous success of antiretroviral therapy to HIV-1-infected patients. In the past decade, a number of studies reported that the prevalence of transmitted drug resistance among newly diagnosed patients has reached an overall 9% prevalence worldwide. Also, a number of studies using longitudinal HIV-1 patient study cohorts demonstrated that the cellular HIV-1 DNA level in peripheral blood mononuclear cells (PBMCs) has a prognostic value for the progression of HIV-1 disease independently of plasma HIV-1 RNA load and CD4 count. Using a previously established molecular-beacon-based real-time PCR methodology, cellular HIV-1 DNA levels were quantified in newly diagnosed and antiretroviral-naive patients in Northern Greece recruited between 2009 and 2010 using a predefined enrolling strategy, in an effort to investigate whether there is any relationship between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. As part of the same study, DNA sequences encoding the env (C2-C5 region of gp120) were also amplified from PBMC-extracted DNA in order to determine the genotypic coreceptor tropism and genetic subtype. Cellular HIV-1 DNA levels had a median of 3.309 log10 HIV-1 copies per 10(6) PBMCs and demonstrated no correlation between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. An absence of association between cellular HIV-1 DNA levels with plasma viral HIV-1 RNA load and CD4 levels was also found reconfirming the previously published study. Genotypic analysis of coreceptor tropism indicated that 96% of samples, independently of the presence or not of genotypic drug resistance, were CCR5-tropic. Overall, the findings reconfirmed the previously proposed proposition that transmitted drug resistance does not have an impact on disease progression in HIV-1-infected individuals. Also, CCR5

  6. Apoptotic markers in cultured fibroblasts correlate with brain metabolites and regional brain volume in antipsychotic-naive first-episode schizophrenia and healthy controls

    PubMed Central

    Batalla, A; Bargalló, N; Gassó, P; Molina, O; Pareto, D; Mas, S; Roca, J M; Bernardo, M; Lafuente, A; Parellada, E

    2015-01-01

    Cultured fibroblasts from first-episode schizophrenia patients (FES) have shown increased susceptibility to apoptosis, which may be related to glutamate dysfunction and progressive neuroanatomical changes. Here we determine whether apoptotic markers obtained from cultured fibroblasts in FES and controls correlate with changes in brain glutamate and N-acetylaspartate (NAA) and regional brain volumes. Eleven antipsychotic-naive FES and seven age- and gender-matched controls underwent 3-Tesla magnetic resonance imaging scanning. Glutamate plus glutamine (Glx) and NAA levels were measured in the anterior cingulate (AC) and the left thalamus (LT). Hallmarks of apoptotic susceptibility (caspase-3-baseline activity, phosphatidylserine externalization and chromatin condensation) were measured in fibroblast cultures obtained from skin biopsies after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 μM. Apoptotic biomarkers were correlated to brain metabolites and regional brain volume. FES and controls showed a negative correlation in the AC between Glx levels and percentages of cells with condensed chromatin (CC) after both apoptosis inductions (STS 0.5 μM: r=−0.90; P=0.001; STS 0.25 μM: r=−0.73; P=0.003), and between NAA and cells with CC (STS 0.5 μM induction r=−0.76; P=0.002; STS 0.25 μM r=−0.62; P=0.01). In addition, we found a negative correlation between percentages of cells with CC and regional brain volume in the right supratemporal cortex and post-central region (STS 0.25 and 0.5 μM; P<0.05 family-wise error corrected (FWEc)). We reveal for the first time that peripheral markers of apoptotic susceptibility may correlate with brain metabolites, Glx and NAA, and regional brain volume in FES and controls, which is consistent with the neuroprogressive theories around the onset of the schizophrenia illness. PMID:26305477

  7. Does age at first treatment episode make a difference in outcomes over 11 years?

    PubMed

    Chi, Felicia W; Weisner, Constance; Grella, Christine E; Hser, Yih-Ing; Moore, Charles; Mertens, Jennifer

    2014-04-01

    This study examines the associations between age at first substance use treatment entry and trajectory of outcomes over 11 years. We found significant differences in individual and treatment characteristics between adult intakes first treated during young adulthood (25 years or younger) and those first treated at an older age. Compared to their first treated older age counterparts matched on demographics and dependence type, those who entered first treatment during young adulthood had on average an earlier onset for substance use but a shorter duration between first substance use and first treatment entry; they also had worse alcohol and other drug outcomes 11 years post treatment entry. While subsequent substance use treatment and 12-step meeting attendance are important for both age groups in maintaining positive outcomes, relationships varied by age group. Findings underline the importance of different continuing care management strategies for those entering first treatment at different developmental stages. PMID:24462221

  8. Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo).

    PubMed

    Joly, Véronique; Fagard, Catherine; Grondin, Carine; Descamps, Diane; Yazdanpanah, Yazdan; Charpentier, Charlotte; Colin de Verdiere, Nathalie; Tabuteau, Sophie; Raffi, François; Cabie, André; Chene, Geneviève; Yeni, Patrick

    2013-02-01

    We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm(3) or stage B/C disease with CD4 counts of <200/mm(3). Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥ 200/mm(3) at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm(3), and the median HIV-1 RNA load was 5.4 log(10) copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥ 200/mm(3) at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression. PMID:23165467

  9. Transient Surface CCR5 Expression by Naive CD8+ T Cells within Inflamed Lymph Nodes Is Dependent on High Endothelial Venule Interaction and Augments Th Cell-Dependent Memory Response.

    PubMed

    Askew, David; Su, Charles A; Barkauskas, Deborah S; Dorand, R Dixon; Myers, Jay; Liou, Rachel; Nthale, Joseph; Huang, Alex Y

    2016-05-01

    In inflamed lymph nodes, Ag-specific CD4(+) and CD8(+) T cells encounter Ag-bearing dendritic cells and, together, this complex enhances the release of CCL3 and CCL4, which facilitate additional interaction with naive CD8(+) T cells. Although blocking CCL3 and CCL4 has no effect on primary CD8(+) T cell responses, it dramatically impairs the development of memory CD8(+) T cells upon Ag rechallenge. Despite the absence of detectable surface CCR5 expression on circulating native CD8(+) T cells, these data imply that naive CD8(+) T cells are capable of expressing surface CCR5 prior to cognate Ag-induced TCR signaling in inflamed lymph nodes; however, the molecular mechanisms have not been characterized to date. In this study, we show that CCR5, the receptor for CCL3 and CCL4, can be transiently upregulated on a subset of naive CD8(+) T cells and that this upregulation is dependent on direct contact with the high endothelial venule in inflamed lymph node. Binding of CD62L and CD11a on T cells to their ligands CD34 and CD54 on the high endothelial venule can be enhanced during inflammation. This enhanced binding and subsequent signaling promote the translocation of CCR5 molecules from intracellular vesicles to the surface of the CD8(+) T cell. The upregulation of CCR5 on the surface of the CD8(+) T cells increases the number of contacts with Ag-bearing dendritic cells, which ultimately results in increased CD8(+) T cell response to Ag rechallenge.

  10. Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo).

    PubMed

    Joly, Véronique; Fagard, Catherine; Grondin, Carine; Descamps, Diane; Yazdanpanah, Yazdan; Charpentier, Charlotte; Colin de Verdiere, Nathalie; Tabuteau, Sophie; Raffi, François; Cabie, André; Chene, Geneviève; Yeni, Patrick

    2013-02-01

    We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm(3) or stage B/C disease with CD4 counts of <200/mm(3). Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥ 200/mm(3) at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm(3), and the median HIV-1 RNA load was 5.4 log(10) copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥ 200/mm(3) at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

  11. [ERPs changes during neuroleptic treatment in schizophrenia--a vulnerability marker in schizophrenia].

    PubMed

    Asato, N; Hirayasu, Y; Hiramatsu, K; Ohta, H

    1999-01-01

    P300 amplitude reduction and P300 latency prolongation are consistent findings in schizophrenia, but it is unclear if these abnormalities were the effect of current or past neuroleptic treatment or were present at the onset of illness. We previously recorded ERPs in drug free schizophrenic patients (45 neuroleptic-naive and 56 previously treated with neuroleptics). In that study, P300 amplitude reduction was observed in both the neuroleptic-naive and the previously treated patients. However, both N200 and P300 latencies were prolonged only in the previously treated schizophrenic patients. In this study, we investigated ERPs in 60 drug free schizophrenic patients before and after neuroleptic treatment was begun. According to DSM-IV, schizophrenia subtype classification, 26 cases were paranoid type, 14 were disorganized, 2 catatonic and 18 undifferentiated. Twenty six of the patients were neuroleptic-naive and 34 had been previously treated. Sixty gender- and age-matched healthy controls were also investigated. ERPs were recorded during an auditory oddball task. The scalp EEGs were recorded from AgAgCl electrodes at 16 sites according to the international 10-20 system. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Before treatment, all schizophrenic patients displayed larger N200 amplitudes than the controls; however, increases in N200 amplitudes were not observed after neuroleptic treatment was begun. Both N200 and P300 latencies in the patients before treatment were prolonged only in those previously treated. Neuroleptic-naive patients demonstrated prolongation of both N200 and P300 latencies only after treatment. P300 amplitudes in patients were increased by neuroleptic treatment; but patients had smaller P300 amplitudes than the controls even after treatment. The change in P300 amplitudes (Pz) and the change in total BPRS scores by neuroleptic treatment were positively correlated in the patients whose duration of illness was six

  12. Residual effects of prolonged cannabis treatment on shuttle-box avoidance in the rat.

    PubMed

    Stiglick, A; Llewellyn, M E; Kalant, H

    1984-01-01

    Chronic oral administration of cannabis extract to rats was examined for its residual effects on shuttle-box avoidance learning. In experiment 1 avoidance learning was assessed in rats that had been tested previously on other behavioral tests. Chronic treatment (3 months) facilitated the learning of shuttle-box avoidance in cannabis-treated animals relative to vehicle controls. In experiment 2 very similar results were obtained in naive rats. These and other residual effects of chronic cannabis treatment are similar to the effects of hippocampal lesions.

  13. All Might Have Won, But Not All Have the Prize: Optimal Treatment for Substance Abuse Among Adolescents with Conduct Problems

    PubMed Central

    Spas, Jayson; Ramsey, Susan; Paiva, Andrea L.; Stein, L.A.R.

    2012-01-01

    Considerable evidence from the literature on treatment outcomes indicates that substance abuse treatment among adolescents with conduct problems varies widely. Treatments commonly used among this population are cognitive-behavioral therapy (CBT), 12-step facilitation, multisystemic therapy (MST), psychoeducation (PE), and motivational interviewing (MI). This manuscript thoroughly and systematically reviews the available literature to determine which treatment is optimal for substance-abusing adolescents with conduct problems. Results suggest that although there are several evidence-based and empirically supported treatments, those that incorporate family-based intervention consistently provide the most positive treatment outcomes. In particular, this review further reveals that although many interventions have gained empirical support over the years, only one holds the prize as being the optimal treatment of choice for substance abuse treatment among adolescents with conduct problems. PMID:23170066

  14. Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study

    PubMed Central

    Osorio, Jorge E; Velez, Ivan D; Thomson, Cynthia; Lopez, Liliana; Jimenez, Alejandra; Haller, Aurelia A; Silengo, Shawn; Scott, Jaclyn; Boroughs, Karen L; Stovall, Janae L; Luy, Betty E; Arguello, John; Beatty, Mark E; Santangelo, Joseph; Gordon, Gilad S; Huang, Claire Y-H; Stinchcomb, Dan T

    2015-01-01

    %) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group. Interpretation Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted. Funding Takeda Vaccines. PMID:25087476

  15. Incorporating 12-Step Group Attendance in Addictions Courses: A Cross-Cultural Experience

    ERIC Educational Resources Information Center

    MacMaster, Samuel A.; Holleran, Lori K.

    2005-01-01

    The development of cultural competency skills is important for a clinician in any cross-cultural setting where a working knowledge of the client's culture is important to the delivery of services. This paper suggests that incorporating attendance at Twelve Step recovery programs may begin to facilitate cultural competency for students, or at the…

  16. What Do Adolescents Exposed to Alcoholic Anonymous Think about 12-Step Groups?

    ERIC Educational Resources Information Center

    Kelly, John F.; Myers, Mark G.; Rodolico, John

    2008-01-01

    Objectives: Referral to Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) is a common continuing care recommendation. Evidence suggests some youth benefit, yet, despite referrals, youth participation is low. Little is known about adolescents' experiences of AA/NA. Greater knowledge would inform and help tailor aftercare recommendations.…

  17. Reframing Spirituality: AA, the 12 Steps, and the Mental Health Counselor.

    ERIC Educational Resources Information Center

    Hanna, Fred J.

    1992-01-01

    Surveys literature and explores ways to understand spirituality in Alcoholics Anonymous (AA). Topics explored range from Jungian and Jamesian psychology, to Stoicism, the work of Bateson, and transpersonal psychology and therapy. Speculates that difficulty some mental health counselors have in accepting AA as therapy could be a result of…

  18. Sofosbuvir for the treatment of chronic hepatitis C virus infection.

    PubMed

    Temesgen, Z; Talwani, R; Rizza, S A

    2014-06-01

    Sofosbuvir is a nucleotide analogue selective inhibitor of the RNA-directed RNA polymerase (NS5B) enzyme of the hepatitis C virus (HCV) genome. It has shown potent antiviral activity across all HCV genotypes and in a variety of patient populations, including treatment-naive patients; treatment-experienced patients who had failed previous standard therapy; patients with decompensated liver disease, including cirrhosis; and HIV co-infected patients. It is administered as a single, once-daily 400-mg tablet, has no food restrictions, has low potential for drug interactions, and requires no dose adjustment in mild to moderate kidney or liver impairment. When sofosbuvir is combined with pegylated interferon and/or ribavirin, its clinical and laboratory safety profile is similar to that which is expected from pegylated interferon or ribavirin alone. Rates of treatment discontinuation and dose reduction with sofosbuvir-containing regimens were lower than those commonly observed with pegylated interferon and ribavirin.

  19. The current situation of treatment systems for alcoholism in Korea.

    PubMed

    Kim, Jee Wook; Lee, Boung Chul; Kang, Tae-Cheon; Choi, Ihn-Geun

    2013-02-01

    Alcoholism is becoming one of the most serious issues in Korea. The purpose of this review article was to understand the present status of the treatment system for alcoholism in Korea compared to the United States and to suggest its developmental direction in Korea. Current modalities of alcoholism treatment in Korea including withdrawal treatment, pharmacotherapy, and psychosocial treatment are available according to Korean evidence-based treatment guidelines. Benzodiazepines and supportive care including vitamin and nutritional support are mainly used to treat alcohol withdrawal in Korea. Naltrexone and acamprosate are the drugs of first choice to treat chronic alcoholism. Psychosocial treatment methods such as individual psychotherapy, group psychotherapy, family therapy, cognitive behavior therapy, cue exposure therapy, 12-step facilitation therapy, self-help group therapy, and community-based treatment have been carried out to treat chronic alcoholism in Korea. However, current alcohol treatment system in Korea is not integrative compared to that in the United States. To establish the treatment system, it is important to set up an independent governmental administration on alcohol abuse, to secure experts on alcoholism, and to conduct outpatient alcoholism treatment programs and facilities in an open system including some form of continuing care.

  20. Incontinence Treatment: Surgical Treatments

    MedlinePlus

    ... Incontinence Managing Incontinence: A Survey The Patient's Perspective Barriers on Diagnosis and Treatment Personal Stories Contact Us ... Incontinence Managing Incontinence: A Survey The Patient's Perspective Barriers on Diagnosis and Treatment Personal Stories Contact Us ...

  1. First Detection of TR46/Y121F/T289A and TR34/L98H Alterations in Aspergillus fumigatus Isolates from Azole-Naive Patients in Denmark despite Negative Findings in the Environment

    PubMed Central

    Astvad, K. M. T.; Jensen, R. H.; Hassan, T. M.; Mathiasen, E. G.; Thomsen, G. M.; Pedersen, U. G.; Christensen, M.; Hilberg, O.

    2014-01-01

    Azole-resistant Aspergillus fumigatus harboring the TR34/L98H or TR46/Y121F/T289A alterations is increasingly found in Europe and Asia. Here, we present the first clinical cases of TR46/Y121/T289A and three cases of TR34/L98H outside the cystic fibrosis (CF) population in Denmark and the results of environmental surveys. Four patients (2012 to 2014) with 11 A. fumigatus and 4 Rhizomucor pusillus isolates and 239 soil samples (spring 2010 and autumn 2013, respectively) with a total of 113 A. fumigatus isolates were examined. Aspergillus isolates were screened for azole resistance using azole-containing agar. Confirmatory susceptibility testing was done using the EUCAST microbroth dilution EDEF 9.1 reference method. For relevant A. fumigatus isolates, CYP51A sequencing and microsatellite genotyping were performed. Three patients harbored TR34/L98H isolates. Two were azole naive at the time of acquisition and two were coinfected with wild-type A. fumigatus or R. pusillus isolates, complicating and delaying diagnosis. The TR46/Y121F/T289A strain was isolated in 2014 from a lung transplant patient. Genotyping indicated that susceptible and resistant Aspergillus isolates were unrelated and that no transmission between patients occurred. Azole resistance was not detected in any of the 113 soil isolates. TR34/L98H and TR46/Y121F/T289A alterations appear to be emerging in the clinical setting in Denmark and now involve azole-naive patients. Two recent soil-sampling surveys in Denmark were unable to indicate any increased prevalence of azole-resistant A. fumigatus in the environment. These findings further support the demand for real-time susceptibility testing of all clinically relevant isolates and for studies investigating the seasonal variation and ecological niches for azole-resistant environmental A. fumigatus. PMID:24936595

  2. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study

    PubMed Central

    2011-01-01

    Background It is unclear whether antiretroviral (ART) naive HIV-positive individuals with high CD4 counts have a raised mortality risk compared with the general population, but this is relevant for considering earlier initiation of antiretroviral therapy. Methods Pooling data from 23 European and North American cohorts, we calculated country-, age-, sex-, and year-standardised mortality ratios (SMRs), stratifying by risk group. Included patients had at least one pre-ART CD4 count above 350 cells/mm3. The association between CD4 count and death rate was evaluated using Poisson regression methods. Findings Of 40,830 patients contributing 80,682 person-years of follow up with CD4 count above 350 cells/mm3, 419 (1.0%) died. The SMRs (95% confidence interval) were 1.30 (1.06-1.58) in homosexual men, and 2.94 (2.28-3.73) and 9.37 (8.13-10.75) in the heterosexual and IDU risk groups respectively. CD4 count above 500 cells/mm3 was associated with a lower death rate than 350-499 cells/mm3: adjusted rate ratios (95% confidence intervals) for 500-699 cells/mm3 and above 700 cells/mm3 were 0.77 (0.61-0.95) and 0.66 (0.52-0.85) respectively. Interpretation In HIV-infected ART-naive patients with high CD4 counts, death rates were raised compared with the general population. In homosexual men this was modest, suggesting that a proportion of the increased risk in other groups is due to confounding by other factors. Even in this high CD4 count range, lower CD4 count was associated with raised mortality. PMID:20638118

  3. First detection of TR46/Y121F/T289A and TR34/L98H alterations in Aspergillus fumigatus isolates from azole-naive patients in Denmark despite negative findings in the environment.

    PubMed

    Astvad, K M T; Jensen, R H; Hassan, T M; Mathiasen, E G; Thomsen, G M; Pedersen, U G; Christensen, M; Hilberg, O; Arendrup, M C

    2014-09-01

    Azole-resistant Aspergillus fumigatus harboring the TR34/L98H or TR46/Y121F/T289A alterations is increasingly found in Europe and Asia. Here, we present the first clinical cases of TR46/Y121/T289A and three cases of TR34/L98H outside the cystic fibrosis (CF) population in Denmark and the results of environmental surveys. Four patients (2012 to 2014) with 11 A. fumigatus and 4 Rhizomucor pusillus isolates and 239 soil samples (spring 2010 and autumn 2013, respectively) with a total of 113 A. fumigatus isolates were examined. Aspergillus isolates were screened for azole resistance using azole-containing agar. Confirmatory susceptibility testing was done using the EUCAST microbroth dilution EDEF 9.1 reference method. For relevant A. fumigatus isolates, CYP51A sequencing and microsatellite genotyping were performed. Three patients harbored TR34/L98H isolates. Two were azole naive at the time of acquisition and two were coinfected with wild-type A. fumigatus or R. pusillus isolates, complicating and delaying diagnosis. The TR46/Y121F/T289A strain was isolated in 2014 from a lung transplant patient. Genotyping indicated that susceptible and resistant Aspergillus isolates were unrelated and that no transmission between patients occurred. Azole resistance was not detected in any of the 113 soil isolates. TR34/L98H and TR46/Y121F/T289A alterations appear to be emerging in the clinical setting in Denmark and now involve azole-naive patients. Two recent soil-sampling surveys in Denmark were unable to indicate any increased prevalence of azole-resistant A. fumigatus in the environment. These findings further support the demand for real-time susceptibility testing of all clinically relevant isolates and for studies investigating the seasonal variation and ecological niches for azole-resistant environmental A. fumigatus. PMID:24936595

  4. Methadone maintenance in the treatment of opioid dependence. A current perspective.

    PubMed

    Zweben, J E; Payte, J T

    1990-05-01

    We describe the historical underpinnings of negative attitudes towards methadone and how these affect medical decisions. Current developments have increased the understanding of the origins of opioid addiction, such as how receptor system dysfunction may affect the ability to remain abstinent once out of treatment. Specialized topics include the pregnant addict, the role of methadone maintenance in limiting the spread of the acquired immunodeficiency syndrome, and patients with a dual diagnosis. We also describe issues that arise when methadone is used in conjunction with prescribed or abused drugs, noting pharmacologic alternatives and adjuncts to methadone treatment. Finally, we comment on treatment issues such as methadone patients in 12-step programs and the growing legitimacy of this treatment method.

  5. Peripheral retinal non-perfusion and treatment response in branch retinal vein occlusion

    PubMed Central

    Abri Aghdam, Kaveh; Reznicek, Lukas; Soltan Sanjari, Mostafa; Framme, Carsten; Bajor, Anna; Klingenstein, Annemarie; Kernt, Marcus; Seidensticker, Florian

    2016-01-01

    AIM To evaluate the association between the size of peripheral retinal non-perfusion and the number of intravitreal ranibizumab injections in patients with treatment-naive branch retinal vein occlusion (BRVO) and macular edema. METHODS A total of 53 patients with treatment-naive BRVO and macular edema were included. Each patient underwent a full ophthalmologic examination including optical coherence tomography (OCT) imaging and ultra wide-field fluorescein angiography (UWFA). Monthly intravitreal ranibizumab injections were applied according to the recommendations of the German Ophthalmological Society. Two independent, masked graders quantified the areas of peripheral retinal non-perfusion. RESULTS Intravitreal injections improved best-corrected visual acuity (BCVA) significantly from 22.23±16.33 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters to 36.23±15.19 letters (P<0.001), and mean central subfield thickness significantly reduced from 387±115 µm to 321±115 µm (P=0.01). Mean number of intravitreal ranibizumab injections was 3.61±1.56. The size of retinal non-perfusion correlated significantly with the number of intravitreal ranibizumab injections (R=0.724, P<0.001). CONCLUSION Peripheral retinal non-perfusion in patients with BRVO associates significantly with intravitreal ranibizumab injections in patients with BRVO and macular edema. PMID:27366688

  6. Intestinal Parasitosis in Relation to CD4+T Cells Levels and Anemia among HAART Initiated and HAART Naive Pediatric HIV Patients in a Model ART Center in Addis Ababa, Ethiopia

    PubMed Central

    Mengist, Hylemariam Mihiretie; Taye, Bineyam; Tsegaye, Aster

    2015-01-01

    Background Intestinal parasites (IPs) are major concerns in most developing countries where HIV/AIDS cases are concentrated and almost 80% of AIDS patients die of AIDS-related infections. In the absence of highly active antiretroviral therapy (HAART), HIV/AIDS patients in developing countries unfortunately continue to suffer from the consequences of opportunistic and other intestinal parasites. The aim of the study was to determine the prevalence of intestinal parasites in relation to CD4+ T cells levels and anemia among HAART initiated and HAART naïve pediatric HIV patients in a Model ART center in Addis Ababa, Ethiopia. Methods A prospective comparative cross-sectional study was conducted among HAART initiated and HAART naive pediatric HIV/AIDS patients attending a model ART center at Zewditu Memorial Hospital between August 05, 2013 and November 25, 2013. A total of 180 (79 HAART initiated and 101 HAART naïve) children were included by using consecutive sampling. Stool specimen was collected and processed using direct wet mount, formol-ether concentration and modified Ziehl-Neelsen staining techniques. A structured questionnaire was used to collect data on socio-demographic and associated risk factors. CD4+ T cells and complete blood counts were performed using BD FACScalibur and Cell-Dyn 1800, respectively. The data was analyzed by SPSS version 16 software. Logistic regressions were applied to assess any association between explanatory factors and outcome variables. P values < 0.05 were taken as statistically significant. Results The overall prevalence of IPs was 37.8% where 27.8% of HAART initiated and 45.5% of HAART naive pediatric HIV/AIDS patients were infected (p < 0.05). Cryptosporidium species, E. histolytica/dispar, Hook worm and Taenia species were IPs associated with CD4+ T cell counts <350 cells/μμL in HAART naive patients. The overall prevalence of anemia was 10% in HAART and 31.7% in non-HAART groups. Hook worm, S. stercoralis and H. nana were

  7. The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults

    PubMed Central

    Dinges, Warren; Girard, Pierre-Marie; Podzamczer, Daniel; Brockmeyer, Norbert H.; García, Felipe.; Harrer, Thomas; Lelievre, Jean-Daniel; Frank, Ian; Colin De Verdière, Nathalie; Yeni, Guy-Patrick; Ortega Gonzalez, Enrique; Rubio, Rafael; Clotet Sala, Bonaventura; DeJesus, Edwin; Pérez-Elias, Maria Jesus; Launay, Odile; Pialoux, Gilles; Slim, Jihad; Weiss, Laurence; Bouchaud, Olivier; Felizarta, Franco; Meurer, Anja; Raffi, François; Esser, Stefan; Katlama, Christine; Koletar, Susan L.; Mounzer, Karam; Swindells, Susan; Baxter, John D.; Schneider, Stefan; Chas, Julie; Molina, Jean-Michel; Koutsoukos, Marguerite; Collard, Alix; Bourguignon, Patricia; Roman, François

    2016-01-01

    Abstract The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults. This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4+ T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks. At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): −0.088; 0.235]), or F4/AS01B_3 and control group (−0.096 log10 copies/mL [97.5% CI: −0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4+ T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4+ T-cells, but had no significant impact on F4-specific CD8+ T-cell and anti-F4 antibody levels. F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4+ T-cell responses, but did not reduce HIV-1 VL, impact CD4+ T-cells count, delay ART initiation, or prevent HIV-1 related clinical events. PMID:26871794

  8. The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial.

    PubMed

    Dinges, Warren; Girard, Pierre-Marie; Podzamczer, Daniel; Brockmeyer, Norbert H; García, Felipe; Harrer, Thomas; Lelievre, Jean-Daniel; Frank, Ian; Colin De Verdière, Nathalie; Yeni, Guy-Patrick; Ortega Gonzalez, Enrique; Rubio, Rafael; Clotet Sala, Bonaventura; DeJesus, Edwin; Pérez-Elias, Maria Jesus; Launay, Odile; Pialoux, Gilles; Slim, Jihad; Weiss, Laurence; Bouchaud, Olivier; Felizarta, Franco; Meurer, Anja; Raffi, François; Esser, Stefan; Katlama, Christine; Koletar, Susan L; Mounzer, Karam; Swindells, Susan; Baxter, John D; Schneider, Stefan; Chas, Julie; Molina, Jean-Michel; Koutsoukos, Marguerite; Collard, Alix; Bourguignon, Patricia; Roman, François

    2016-02-01

    The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10 copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.

  9. The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial.

    PubMed

    Dinges, Warren; Girard, Pierre-Marie; Podzamczer, Daniel; Brockmeyer, Norbert H; García, Felipe; Harrer, Thomas; Lelievre, Jean-Daniel; Frank, Ian; Colin De Verdière, Nathalie; Yeni, Guy-Patrick; Ortega Gonzalez, Enrique; Rubio, Rafael; Clotet Sala, Bonaventura; DeJesus, Edwin; Pérez-Elias, Maria Jesus; Launay, Odile; Pialoux, Gilles; Slim, Jihad; Weiss, Laurence; Bouchaud, Olivier; Felizarta, Franco; Meurer, Anja; Raffi, François; Esser, Stefan; Katlama, Christine; Koletar, Susan L; Mounzer, Karam; Swindells, Susan; Baxter, John D; Schneider, Stefan; Chas, Julie; Molina, Jean-Michel; Koutsoukos, Marguerite; Collard, Alix; Bourguignon, Patricia; Roman, François

    2016-02-01

    The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10 copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events. PMID:26871794

  10. Hyperbaric treatment

    NASA Technical Reports Server (NTRS)

    Amoroso, Michael T.

    1990-01-01

    Viewgraphs on hyperbaric treatment are presented. Topics covered include: hyperbaric treatment - purpose; decompression sickness; sources of decompression sickness; physical description; forms of decompression sickness; hyperbaric treatment of decompression sickness; and duration of treatment.

  11. Aggressive experience affects the sensitivity of neurons towards pharmacological treatment in the hypothalamic attack area.

    PubMed

    Haller, J; Abrahám, I; Zelena, D; Juhász, G; Makara, G B; Kruk, M R

    1998-09-01

    Early investigators of brain stimulation-evoked complex behaviours (attack, escape, feeding, self-grooming, sexual behaviour) reported that experience may affect the behavioural outcome of brain stimulation. This intriguing example of functional neuronal plasticity was later totally neglected. The present experiment investigated the behavioural outcome of in vivo microdialysis perfusion of the glutamate agonist kainate and/or the GABAA antagonist bicuculline into the hypothalamic attack area (HAA) of (1) animals naive to dyadic encounters; (2) animals with a recent aggressive experience (the probe being implanted 6-24 h after the last of a series of dyadic encounters); and (3) animals with an earlier aggressive experience (probe being implanted 2 weeks after the last aggressive experience). On the experimental day, rats received two 5-min infusions during a dyadic encounter lasting 35 min with an unknown opponent. Flow rate was 1.5-2 microliters/min, drug concentrations were 1.8 x 10(-5) and 1.5 x 10(-5) M for kainate and bicuculline, respectively. Behaviour was analysed before, during and after perfusions. Only the combined kainate + bicuculline treatment had significant effects on behaviour at the doses studied. A significant increase in aggressive behaviour was elicited only in animals with a recent aggressive experience, while naive animals and with an earlier experience responded to the treatments by grooming. These results appear to support early observations indicating that one important aspect of brain stimulation effects is previous experience. PMID:9832932

  12. Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial

    PubMed Central

    Saxena, Deepti; Spino, Michael; Tricta, Fernando; Connelly, John; Cracchiolo, Bernadette M.; Hanauske, Axel-Rainer; D’Alliessi Gandolfi, Darlene; Mathews, Michael B.; Karn, Jonathan; Holland, Bart; Park, Myung Hee; Pe’ery, Tsafi; Palumbo, Paul E.; Hanauske-Abel, Hartmut M.

    2016-01-01

    Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug’s half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster (‘polyproline’)-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound. Trial Registration: ClinicalTrial.gov NCT02191657 PMID:27191165

  13. HIV-1 pol mutation frequency by subtype and treatment experience

    PubMed Central

    Rhee, Soo-Yon; Kantor, Rami; Katzenstein, David A.; Camacho, Ricardo; Morris, Lynn; Sirivichayakul, Sunee; Jorgensen, Louise; Brigido, Luis F.; Schapiro, Jonathan M.; Shafer, Robert W.

    2008-01-01

    Objective HIVseq was developed in 2000 to make published data on the frequency of HIV-1 group M protease and reverse transcriptase (RT) mutations available in real time to laboratories and researchers sequencing these genes. Because most published protease and RT sequences belonged to subtype B, the initial version of HIVseq was based on this subtype. As additional non-B sequences from persons with well-characterized antiretroviral treatment histories have become available, the program has been extended to subtypes A, C, D, F, G, CRF01, and CRF02. Methods The latest frequency of each protease and RT mutation according to subtype and drug-class exposure was calculated using published sequences in the Stanford HIV RT and Protease Sequence Database. Each mutation was hyperlinked to published reports of viruses containing the mutation. Results As of September 2005, the mean number of protease sequences per non-B subtype was 534 from protease inhibitor-naive persons and 133 from protease inhibitor-treated persons, representing 13.2% and 2.3%, respectively, of the data available for subtype B. The mean number of RT sequences per non-B subtype was 373 from RT inhibitor-naive persons and 288 from RT inhibitor-treated persons, representing 17.9% and 3.8%, respectively, of the data available for subtype B. Conclusions HIVseq allows users to examine protease and RT mutations within the context of previously published sequences of these genes. The publication of additional non-B protease and RT sequences from persons with well-characterized treatment histories, however, will be required to perform the same types of analysis possible with the much larger number of subtype B sequences. PMID:16514293

  14. Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial

    PubMed Central

    Overton, Edgar Turner; Stapleton, Jack; Frank, Ian; Hassler, Shawn; Goepfert, Paul A.; Barker, David; Wagner, Eva; von Krempelhuber, Alfred; Virgin, Garth; Meyer, Thomas Peter; Müller, Jutta; Bädeker, Nicole; Grünert, Robert; Young, Philip; Rösch, Siegfried; Maclennan, Jane; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

    2015-01-01

    Background. First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods. An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results. Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions. Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations. PMID:26380340

  15. β-Tubulin genotypes in six species of cyathostomins from anthelmintic-naive Przewalski and benzimidazole-resistant brood horses in Ukraine.

    PubMed

    Blackhall, William J; Kuzmina, Tetyana; von Samson-Himmelstjerna, Georg

    2011-10-01

    Resistance to benzimidazoles (BZ) in the gastrointestinal nematodes of livestock is characterised by the presence of specific polymorphisms in the β-tubulin isotype 1 protein, a component of microtubules. The most prevalent polymorphism associated with resistance in nematodes infecting cattle, sheep, and goats is found at codon 200, with minor occurrences of polymorphisms at codons 167 and 198. In the cyathostomins that infect horses, however, a polymorphism at codon 167 appears to be more common than the codon 200 polymorphism. In the present study, a focussed analysis of PCR-amplified β-tubulin fragments incorporating the above-mentioned three polymorphic sites in isotype 1 and 2 genes in worms of six species of cyathostomins, Cylicocyclus nassatus, Cylicocyclus ashworthi, Cyathostomum catinatum, Cylicostephanus goldi, Cylicostephanus longibursatus, and Coronocyclus coronatus, was performed. Worms were collected from two distinct horse populations, i.e. they were collected from Przewalski horses of the Askania-Nova Biosphere Reserve that had never received any anthelmintic treatment and from brood horses of the Dubrovsky farm where benzimidazole resistance had become established. DNA was extracted and sequenced from three worms of each species and population as well as from pools of 50 male C. nassatus and C. catinatum from both populations. The vast majority of putatively BZ resistance-associated TAC alleles were found at codon 167, compared to codon 200. The former allele occurred in isotype 1 in all six species of the supposedly benzimidazole-resistant cyathostomins from Dubrovsky horses. None of the polymorphisms associated with resistance was found in the corresponding isotype 2 codons nor at codon 198 in any of the six species of cyathostomins (neither single nor pooled worm DNA) from either of the two populations. These findings further support the predominant association of β-tubulin isotype 1 and therein codon 167 with BZ resistance in cyathostomins.

  16. Manualized treatment for substance abusers with personality disorders: dual focus schema therapy.

    PubMed

    Ball, S A

    1998-01-01

    The presence of an untreated personality disorder may be associated with worse compliance and outcome in substance abuse treatment. Therapeutic attention to the symptoms of personality disorder may reduce the severity of substance abuse and other Axis I symptoms which potentially contribute to relapse. A 24-week manual-guided individual cognitive-behavioral therapy approach has been developed that integrates relapse prevention with targeted intervention for early maladaptive schemas (enduring negative beliefs about oneself, others, and events) and coping styles. This Dual Focus Schema Therapy is being compared to 12-Step Drug Counseling for opioid-dependent individuals with personality disorders in an ongoing study funded by the National Institute on Drug Abuse. This article reviews Young's (1994) schema-focused theory and approach and summarizes the treatment manual, which integrates relapse prevention for substance abuse.

  17. Effectiveness and safety of vedolizumab for treatment of Crohn's disease: a systematic review and meta-analysis

    PubMed Central

    Moćko, Paweł; Smela-Lipińska, Beata; Pilc, Andrzej

    2016-01-01

    Introduction The aim of this systematic review (SR) and meta-analysis was to assess the efficacy and safety of vedolizumab in the treatment of Crohn's disease (CD). Material and methods A systematic literature search was conducted in Medline/PubMed, Embase and Cochrane Library until 25 January, 2015. Included studies were critically appraised according to the PRISMA protocol. Assessment in specified subgroups of CD patients and meta-analysis with Revman software were performed. Results Two randomized controlled trial (RCTs) were included in a meta-analysis for the induction phase of therapy: GEMINI II and GEMINI III. The clinical response was significantly higher for patients who received vedolizumab compared to placebo in the general population (risk benefit (RB) = 1.48; p = 0.0006) and in both analyzed subgroups: patients with previous failure of anti-TNFs treatment (RB = 1.51; p = 0.006) and patients naive to earlier anti-TNFs (RB = 1.41; p = 0.001). The clinical remission in the general population and subpopulation of TNF-antagonist naive patients was significantly higher for patients who received vedolizumab compared to placebo (RB = 1.77; p = 0.003; RB = 2.29; p = 0.0004; respectively). Meta-analysis for adverse events, serious adverse events (SAEs) and serious infections, revealed that vedolizumab was as safe as placebo in the induction phase of therapy. Conclusions The clinical response was significantly higher for patients who received vedolizumab in the general population and in both analyzed subgroups of patients. The clinical remission in the general population and subpopulation of TNF-antagonist naive patients was significantly higher for vedolizumab, but no significant differences were revealed in the subgroup of patients with previous TNF antagonist failure. PMID:27695501

  18. Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level

    PubMed Central

    1996-01-01

    The development of CD4+ T helper (Th) type 1 and 2 cells is essential for the eradication of pathogens, but can also be responsible for various pathological disorders. Therefore, modulation of Th cell differentiation may have clinical utility in the treatment of human disease. Here, we show that interleukin (IL) 12 and IL-4 directly induce human neonatal CD4- T cells, activated via CD3 and CD28, to differentiate into Th1 and Th2 subsets. In contrast, IL-13, which shares many biological activities with IL-4, failed to induce T cell differentiation, consistent with the observation that human T cells do not express IL-13 receptors. Both the IL-12-induced Th1 subset and the IL-4-induced Th2 subset produce large quantities of IL-10, confirming that human IL-10 is not a typical human Th2 cytokine. Interestingly, IL- 4-driven Th2 cell differentiation was completely prevented by an IL-4 mutant protein (IL-4.Y124D), indicating that this molecule acts as a strong IL-4 receptor antagonist. Analysis of single T cells producing interferon gamma or IL-4 revealed that induction of Th1 cell differentiation occurred rapidly and required only 4 d of priming of the neonatal CD4+ T cells in the presence of IL-12. The IL-12-induced Th1 cell phenotype was stable and was not significantly affected when repeatedly stimulated in the presence of recombinant IL-4. In contrast, the differentiation of Th2 cells occurred slowly and required not only 6 d of priming, but also additional restimulation of the primed CD4+ T cells in the presence of IL-4. Moreover, IL-4-induced Th2 cell phenotypes were not stable and could rapidly be reverted into a population predominantly containing Th0 and Th1 cells, after a single restimulation in the presence of IL-12. The observed differences in stability of IL-12- and IL-4-induced human Th1 and Th2 subsets, respectively, may have implications for cytokine-based therapies of chronic disease. PMID:8760801

  19. A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer.

    PubMed

    Elias, A D; Richardson, P; Avigan, D; Ibrahim, J; Joyce, R; Demetri, G; Levine, J; Warren, D; Arthur, T; Reich, E; Wheele, C; Frei, E; Ayash, L

    2001-02-01

    receptor blockade. This particular toxicity was not observed again. No toxic deaths occurred and dose-limiting toxicity was not encountered. Three patients were removed from study prior to transplant: one for insurance refusal and two for disease progression. All others completed both cycles of transplant. Complete and near complete response (CR/nCR) after completion of therapy was achieved in 23 (72%) of 32 patients. The median EFS is 26 months. The median overall survival has not yet been reached. At a median follow-up of 58 months, EFS and overall survival are 41% and 53%, respectively. This double transplant approach is feasible, safe, and tolerable. Treatment duration is only 14 weeks and eliminates lengthy induction chemotherapy. The observed event-free and overall survivals are promising and are better than expected following a single transplant. Whilst selection biases may in part contribute to this effect, a much larger phase II double transplant trial is warranted in preparation for a potential randomized comparison of standard therapy vs single vs double transplant. PMID:11277174

  20. Immunologic Effects Of Peritoneal Photodynamic Treatment

    NASA Astrophysics Data System (ADS)

    Lynch, David H.; Haddad, Sandra; Jolles, Christopher J.; King, Vernon J.; Ott, Mark J.; Robertson, Bekkie; Straight, Richard C.

    1989-06-01

    One of the side effects of peritoneal photodynamic treatment (PDT) of mice is a systemic suppression of contact hypersensitivity (CH) responses. Treatment with either laser alone or the photosensitizer, Photofrin II (PFII), alone does not cause suppression of CH responses. Immunosuppression of CH responses is an active process that is adoptively transferable using viable cells, but not serum, from PDT-treated mice. The induction of adoptively transferable suppressor cells in PDT-treated mice requires exposure to an antigenic stimulus, yet the suppressor cells are antigen non-specific in their function. T cell function in PDT-treated mice, as measured by the ability of splenic lymphoid cells to generate allogeneic cytotoxic T lymphocyte responses, is comparable to that detected in normal mice. However, the ability of spleen cells from PDT-treated mice to act as stimulators in a mixed lymhocyte reaction is dramatically impaired, suggesting that the major cell type affected by peritoneal PDT is of the macrophage lineage. Support for this concept is provided by experiments in which spleen cells from PDT-treated mice were chromatographically separated into populations of T cells, B cells and macrophages prior to adoptive transfer into naive recipients. The results indicate that the cell type mediating adoptively transferable suppression of CH responsiveness is of the macrophage lineage. Analysis of hematologic parameters revealed that induction of suppression by PDT-treatment was associated with a marked neutrophilia and lymphocytosis, and was also accompanied by a 5-fold increase in concentration of the acute phase protein, Serum Amyloid P. Finally, attempts to ameliorate PDT-induced immunosuppression by pharmacologic intervention have proved successful using implants of pellets that release indomethacin at a rate of 1.25µg/day. Thus, the data suggest that PDT-treatment induces macrophages to produce factors (e.g., prostaglandins) that are known to be potently

  1. Eosinophils elicit proliferation of naive and fungal-specific cells in vivo so enhancing a T helper type 1 cytokine profile in favour of a protective immune response against Cryptococcus neoformans infection.

    PubMed

    Garro, Ana P; Chiapello, Laura S; Baronetti, Jose L; Masih, Diana T

    2011-10-01

    Experimental Cryptococcus neoformans infection in rats has been shown to have similarities with human cryptococcosis, because as in healthy humans, rats can effectively contain cryptococcal infection. Moreover, it has been shown that eosinophils are components of the immune response to C. neoformans infections. In a previous in vitro study, we demonstrated that rat peritoneal eosinophils phagocytose opsonized live yeasts of C. neoformans, thereby triggering their activation, as indicated by the up-regulation of MHC and co-stimulatory molecules and the increase in interleukin-12, tumour necrosis factor-α and interferon-γ production. Furthermore, this work demonstrated that C. neoformans-specific CD4(+) and CD8(+) T lymphocytes cultured with these activated C. neoformans-pulsed eosinophils proliferated, and produced important amounts of T helper type 1 (Th1) cytokines in the absence of Th2 cytokine synthesis. In the present in vivo study, we have shown that C. neoformans-pulsed eosinophils are also able to migrate into lymphoid organs to present C. neoformans antigens, thereby priming naive and re-stimulating infected rats to induce T-cell and B-cell responses against infection with the fungus. Furthermore, the antigen-specific immune response induced by C. neoformans-pulsed eosinophils, which is characterized by the development of a Th1 microenvironment with increased levels of NO synthesis and C. neoformans-specific immunoglobulin production, was demonstrated to be able to protect rats against subsequent infection with fungus. In summary, the present work demonstrates that eosinophils act as antigen-presenting cells for the fungal antigen, hence initiating and modulating a C. neoformans-specific immune response. Finally, we suggest that C. neoformans-loaded eosinophils might participate in the protective immune response against these fungi.

  2. Lipopolysaccharide modulation of dendritic cells is insufficient to mature dendritic cells to generate CTLs from naive polyclonal CD8+ T cells in vitro, whereas CD40 ligation is essential.

    PubMed

    Kelleher, M; Beverley, P C

    2001-12-01

    Many cytotoxic CD8+ T cell responses are dependent on the interactions between CD40 ligand on the helper CD4+ T cell and CD40 on the APC. Although CD40 triggering of dendritic cells (DC) has been shown to mature the DC by increasing the level of expression of costimulatory molecules and inducing IL-12 secretion, the precise mechanisms by which CD40-CD40 ligand interactions allow DC to drive CTL responses remain unknown. We have used an in vitro model in which naive polyclonal CD8+ T cells can be activated by bone marrow-derived DC to investigate factor(s) that are responsible for this CD40-dependent generation of CTLs. DC modulated with agonistic anti-CD40 mAb (aCD40) are able to generate Ag-specific CTL responses while DC modulated with the microbial stimulus LPS alone do not. We compared the Ag-presenting capacity, levels of costimulatory molecules, and release of cytokines and chemokines of DC modulated with aCD40 to that of DC modulated by LPS. None of the factors assayed account for the unique capacity of anti-CD40-matured DC to drive CTL but this model provides a simplified system for further investigation. Although we attempted to use an LPS-free system for these studies, we are unable to rule out the possibility that very low levels of endotoxin (<20 pg/ml) may synergize with CD40 ligation in the generation of CTLs. PMID:11714787

  3. A new model of corneal transplantation in the miniature pig: efficacy of immunosuppressive treatment.

    PubMed

    Tavandzi, Urania; Procházka, Radek; Usvald, Dusan; Hlucílová, Jana; Vitásková, Martina; Motlík, Jan; Vítová, Andrea; Filipec, Martin; Forrester, John V; Holán, Vladimír

    2007-05-27

    Corneal allograft rejection is frequently studied in small rodent or rabbit models. To study mechanisms of rejection in a model that more closely mimics transplantation in humans, we performed orthotopic corneal transplantation in the miniature pig using a 7-mm diameter donor graft. Four groups of recipients were studied: 1) untreated naive, 2) untreated vascularized (high risk), 3) high-risk grafts treated by topical application of prednisolone, or 4) high-risk grafts treated with a combined systemic immunosuppression regime of oral prednisone, cyclosporine A, and mycophenolate mofetil. Both the clinical features and histological assessment of corneal graft rejection showed close similarities to graft rejection in humans. Interestingly, preliminary results indicated that topical steroid treatment was superior to systemic immunosuppression in significantly promoting graft survival. Thus, corneal transplantation in the pig represents an animal model most closely resembling corneal grafting in humans, and offers possibilities for testing various clinically applicable immunosuppressive treatments.

  4. Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

    PubMed Central

    Chang, Xiubao; Zhu, Yuanxiao; Shi, Changxin; Stewart, A. Keith

    2014-01-01

    Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields. PMID:24374776

  5. Development of macitentan for the treatment of pulmonary arterial hypertension.

    PubMed

    Selej, Mona; Romero, Alain J; Channick, Richard N; Clozel, Martine

    2015-11-01

    Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event-driven morbidity and mortality study of treatment-naive and background PAH therapy-treated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class II and III PAH patients. Macitentan reduced the incidence of the composite end point of PAH-related hospitalizations and mortality and improved WHO FC and exercise capacity (6-min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.

  6. Archaean tectonic systems: a naive geochemist's view

    NASA Astrophysics Data System (ADS)

    Moyen, Jean-François

    2013-04-01

    On a global scale, the geochemistry of common igneous rocks reflects the dominant processes operating on Earth. Therefore, any change in global tectonic patterns should reflect on global geochemical patterns. This work examines the global distribution of Archaean and modern igneous rock's compositions, without relying on preconceptions about the link between rock compositions and tectonic sites (as in "geotectonic" diagrams). Rather, geochemical patterns are interpreted in terms of source and melting conditions; Archaean and modern patterns are compared. The dataset used is extracted from web databases (georoc and petDB), supplemented with the author's own compilation (for granitoids). The igneous rock record for both Archaean and Phanerozoic systems is bimodal, with mafic/ultramafic rocks on one hand (mantle source) and granitic rocks on the other hand (crustal recycling). Ultramafic rocks are rare in modern systems, but common in the Archaean - this is classically interpreted as reflecting a higher degree of melting in a hotter Archaean mantle. Mafic rocks on the modern Earth show a clear separation between "arc" and "non-arc" rocks, depicting for instance two clearly separated, parallel arrays in a Th/Yb vs. Nb/Yb diagram. This points to the first order difference between "wet" (arc) and "dry" (mid-ocean ridges and hotspots) melting of the mantle. Dry melts are further separated in depleted (MORB, high Zr/Nb) and enriched (OIB, low Zr/Nb) sources. This three-fold pattern is a clear image of the ridge/subduction/plume system that dominates modern tectonics. In contrast, Archaean mafic and ultramafic rocks are clustered in an "intermediate" position, between "arc" and non "arc" and between "enriched" and "depleted" components. The distribution is unimodal; Archaean rocks depict a single, oblique array in Th/Yb vs. Nb/Yb, and cluster between the three main modern types in e.g. Zr/Nb vs. Nb/Th. This suggests that the Archaean mantle had lesser amounts of clearly depleted or enriched portions; that true subductions were rare; and that the distinction between oceanic plateaux and ridges may have been less significant. Modern granitic rocks are essentially metaluminous (subduction-related), plotting together with mafic "arc" rocks; or peraluminous (collision, plotting near the average continental crust), with rare "mantle-like" rocks plotting near MORBs or OIBs. Again, the Archaean granites show a different picture, with the near absence of peraluminous rocks; a group of low HFSE and HREE granites (the "high pressure" TTGs) that have no modern match; and the near-absence of "within plate" or "oceanic ridge" granites. This points to the absence of large sedimentary accumulations, and the presence of uniquely Archaean petrogenetic processes (high pressure melting of basalts). Collectively, the geochemical evidence suggests an Archaean Earth with somewhat different tectonic systems. In particular, the familiar distinction between collision, arcs, ridges and hotspots seems to blur in the Archaean, where "hybrid" tectonic sites may have existed.

  7. Impossibility of naively generalizing squeezed coherent states

    NASA Astrophysics Data System (ADS)

    Fisher, Robert A.; Nieto, Michael Martin; Sandberg, Vernon D.

    1984-03-01

    Pertinent properties of the unitary operators that create coherent states and squeezed coherent states are discussed. We show that certain generalizations of squeezed coherent states do not exist. This is accomplished by demonstrating that for the generalized squeeze operators Uk=exp(iAk)=exp[zk(a†)k+ihk-1-(zk)*ak], <0|Uk|0> diverges, k>2. This implies that |0> is not an analytic vector of Ak for all k>2, where hk-1 is a Hermitian polynomial in a and a† up to powers of (k-1).

  8. The Value of Pooling "Naive" Expertise: Comment

    ERIC Educational Resources Information Center

    Schulz, Marc S.; Waldinger, Robert J.

    2005-01-01

    This article presents comments on the article by D. Westen and J. Weinberger, which explored the benefits and limitations of clinical observation and judgment. Westen and Weinberger identify two categories of informants--clinicians and participants--but these categories could be expanded to include other observers who might have particular…

  9. The use of art and music therapy in substance abuse treatment programs.

    PubMed

    Aletraris, Lydia; Paino, Maria; Edmond, Mary Bond; Roman, Paul M; Bride, Brian E

    2014-01-01

    Although the implementation of evidence-based practices in the treatment of substance use disorders has attracted substantial research attention, little consideration has been given to parallel implementation of complementary and alternative medical (CAM) practices. Using data from a nationally representative sample (N = 299) of U.S. substance abuse treatment programs, this study modeled organizational factors falling in the domains of patient characteristics, treatment ideologies, and structural characteristics, associated with the use of art therapy and music therapy. We found that 36.8% of treatment programs offered art therapy and 14.7% of programs offered music therapy. Programs with a greater proportion of women were more likely to use both therapies, and programs with larger proportions of adolescents were more likely to offer music therapy. In terms of other treatment ideologies, programs' use of Motivational Enhancement Therapy was positively related to offering art therapy, whereas use of contingency management was positively associated with offering music therapy. Finally, our findings showed a significant relationship between requiring 12-step meetings and the use of both art therapy and music therapy. With increasing use of CAM in a diverse range of medical settings and recent federal legislation likely to reduce barriers in accessing CAM, the inclusion of CAM in addiction treatment is growing in importance. Our findings suggest treatment programs may be utilizing art and music therapies to address unique patient needs of women and adolescents. PMID:25514689

  10. Theory-based active ingredients of effective treatments for substance use disorders.

    PubMed

    Moos, Rudolf H

    2007-05-11

    This paper describes four related theories that specify common social processes that protect individuals from developing substance use disorders and may underlie effective psychosocial treatments for these disorders: social control theory, behavioral economics and behavioral choice theory, social learning theory, and stress and coping theory. It then provides an overview of the rationale and evidence for four effective psychosocial treatments for substance use disorders: motivational interviewing and motivational enhancement therapy, 12-step facilitation treatment, cognitive-behavioral treatment and behavioral family counseling, and contingency management and community reinforcement approaches. The presumed active ingredients of these treatments are described in terms of how they exemplify the social processes highlighted by the four theories. The identified common components of effective treatment include support, goal direction, and structure; an emphasis on rewards that compete with substance use, a focus on abstinence-oriented norms and models, and attempts to develop self-efficacy and coping skills. Several issues that need to be addressed to enhance our understanding of the active ingredients involved in effective treatment are discussed, including how to develop measures of these ingredients, how well the ingredients predict outcomes and influence conceptually comparable aspects of clients' life contexts, and how much their influence varies depending upon clients' demographic and personal characteristics.

  11. The use of art and music therapy in substance abuse treatment programs.

    PubMed

    Aletraris, Lydia; Paino, Maria; Edmond, Mary Bond; Roman, Paul M; Bride, Brian E

    2014-01-01

    Although the implementation of evidence-based practices in the treatment of substance use disorders has attracted substantial research attention, little consideration has been given to parallel implementation of complementary and alternative medical (CAM) practices. Using data from a nationally representative sample (N = 299) of U.S. substance abuse treatment programs, this study modeled organizational factors falling in the domains of patient characteristics, treatment ideologies, and structural characteristics, associated with the use of art therapy and music therapy. We found that 36.8% of treatment programs offered art therapy and 14.7% of programs offered music therapy. Programs with a greater proportion of women were more likely to use both therapies, and programs with larger proportions of adolescents were more likely to offer music therapy. In terms of other treatment ideologies, programs' use of Motivational Enhancement Therapy was positively related to offering art therapy, whereas use of contingency management was positively associated with offering music therapy. Finally, our findings showed a significant relationship between requiring 12-step meetings and the use of both art therapy and music therapy. With increasing use of CAM in a diverse range of medical settings and recent federal legislation likely to reduce barriers in accessing CAM, the inclusion of CAM in addiction treatment is growing in importance. Our findings suggest treatment programs may be utilizing art and music therapies to address unique patient needs of women and adolescents.

  12. The Use of Art and Music Therapy in Substance Abuse Treatment Programs

    PubMed Central

    Aletraris, Lydia; Paino, Maria; Edmond, Mary Bond; Roman, Paul M.; Bride, Brian E.

    2014-01-01

    While the implementation of evidence-based practices (EBPs) in the treatment of substance use disorders (SUD) has attracted substantial research attention, little consideration has been given to parallel implementation of complementary and alternative medical (CAM) practices. Using data from a nationally representative sample (N = 299) of U.S. substance abuse treatment programs, this study modeled organizational factors falling in the domains of patient characteristics, treatment ideologies, and structural characteristics, associated with the use of art therapy and music therapy. We found that 36.8% of treatment programs offered art therapy and 14.7% of programs offered music therapy. Programs with a greater proportion of women were more likely to use both therapies, and programs with larger proportions of adolescents were more likely to offer music therapy. In terms of other treatment ideologies, programs’ use of Motivational Enhancement Therapy (MET) was positively related to offering art therapy, while use of Contingency Management (CM) was positively associated with offering music therapy. Finally, our findings showed a significant relationship between requiring 12-step meetings and the use of both art therapy and music therapy. With increasing use of CAM in a diverse range of medical settings, and recent federal legislation likely to reduce barriers in accessing CAM, the inclusion of CAM in addiction treatment is growing in importance. Our findings suggest treatment programs may be utilizing art and music therapies to address unique patient needs of women and adolescents. PMID:25514689

  13. Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-α treatment and comparison to other guidelines.

    PubMed

    Hur, Jin-Wuk; Choe, Jung-Yoon; Kim, Dong-Wook; Kim, Hyun Ah; Kim, Sang-Hyon; Kim, Wan-Uk; Kim, Yun Sung; Lee, Hye-Soon; Lee, Sang-Heon; Park, Sung-Hwan; Park, Won; Park, Yong-Beom; Suh, Chang-Hee; Shim, Seung-Cheol; Song, Yeong-Wook; Yoon, Bo Young; Yu, Dae Young; Yoo, Dae Hyun

    2015-11-01

    The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % (n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA.

  14. A 12-step user guide for analyzing voxel-wise gray matter asymmetries in statistical parametric mapping (SPM).

    PubMed

    Kurth, Florian; Gaser, Christian; Luders, Eileen

    2015-02-01

    Voxel-based morphometry (VBM) has been proven capable of capturing cerebral gray matter asymmetries with a high (voxel-wise) regional specificity. However, a standardized reference on how to conduct voxel-wise asymmetry analyses is missing. This protocol provides the scientific community with a carefully developed guide describing, in 12 distinct steps, how to take structural images from data pre-processing, via statistical analysis, to the final interpretation of the significance maps. Key adaptations compared with the standard VBM workflow involve establishing a voxel-wise hemispheric correspondence, capturing the direction and degree of asymmetry and preventing a blurring of information across hemispheres. The workflow incorporates the most recent methodological developments, including high-dimensional spatial normalization and partial volume estimations. Although the protocol is primarily designed to enable relatively inexperienced users to conduct a voxel-based asymmetry analysis on their own, it may also be useful to experienced users who wish to efficiently adapt their existing scripts or pipelines.

  15. The impact of transient combination antiretroviral treatment in early HIV infection on viral suppression and immunologic response in later treatment

    PubMed Central

    Pantazis, Nikos; Touloumi, Giota; Meyer, Laurence; Olson, Ashley; Costagliola, Dominique; Kelleher, Anthony D.; Lutsar, Irja; Chaix, Marie-Laure; Fisher, Martin; Moreno, Santiago; Porter, Kholoud

    2016-01-01

    Objective: Effects of transient combination antiretroviral treatment (cART) initiated during early HIV infection (EHI) remain unclear. We investigate whether this intervention affects viral suppression and CD4+ cell count increase following its reinitiation in chronic infection (CHI). Design: Longitudinal observational study. Methods: We identified adult patients from Concerted Action of Seroconversion to AIDS and Death in Europe who seroconverted after 1/1/2000, had a 12 months or less HIV test interval and initiated cART from naive. We classified individuals as ‘pretreated in EHI’ if treated within 6 months of seroconversion, interrupted for at least 12 weeks, and reinitiated during CHI. Statistical analysis was performed using survival analysis methods and mixed models. Results: Pretreated and initiated in CHI groups comprised 202 and 4263 individuals, with median follow-up after CHI treatment 4.5 and 3 years, respectively. Both groups had similar virologic response and relapse rates (P = 0.585 and P = 0.206) but pretreated individuals restarted treatment with higher baseline CD4+ cell count (∼80 cells/μl; P < 0.001) and retained significantly higher CD4+ cell count for more than 3 years after treatment (re)initiation. Assuming common baseline CD4+ cell count, differences in CD4+ cell count slopes were nonsignificant. Immunovirologic response to CHI treatment was not associated with timing or duration of the transient treatment. Conclusion: Although treatment interruptions are not recommended, stopping cART initiated in EHI does not seem to reduce the chance of a successful outcome of treatment in CHI. PMID:26636925

  16. Incontinence Treatment: Newer Treatment Options

    MedlinePlus

    ... Incontinence Managing Incontinence: A Survey The Patient's Perspective Barriers on Diagnosis and Treatment Personal Stories Contact Us ... Incontinence Managing Incontinence: A Survey The Patient's Perspective Barriers on Diagnosis and Treatment Personal Stories Contact Us ...

  17. 'A violent thunderstorm': Cardiazol treatment in British mental hospitals.

    PubMed

    McCrae, Niall

    2006-03-01

    In the annals of psychiatric treatment, the advent of Cardiazol therapy has been afforded merely passing mention as a stepping-stone to the development of electroconvulsive therapy. Yet in the 1930s it was the most widely used of the major somatic treatment innovations in Britain's public mental hospitals, where its relative simplicity and safety gave it preference over the elaborate and hazardous insulin coma procedure. Devised on a dubious hypothesis of biological antagonism, Cardiazol armed psychiatry with an immediately effective weapon in the battle against schizophrenia, an enduring and debilitating condition responsible for over half of the mental hospital population. What made Cardiazol work - or appear to work? This account shows how evaluation of convulsive therapy was skewed by naive outcome measurement and diagnostic discrepancies, and how its therapeutic indication evolved from schizophrenia to affective disorders. Psychological mechanisms are considered, with the suggestion that the intense fear experienced during treatment--the major reason for abandoning Cardiazol in favour of electroshock--was therapeutically advantageous. PMID:17153475

  18. 'A violent thunderstorm': Cardiazol treatment in British mental hospitals.

    PubMed

    McCrae, Niall

    2006-03-01

    In the annals of psychiatric treatment, the advent of Cardiazol therapy has been afforded merely passing mention as a stepping-stone to the development of electroconvulsive therapy. Yet in the 1930s it was the most widely used of the major somatic treatment innovations in Britain's public mental hospitals, where its relative simplicity and safety gave it preference over the elaborate and hazardous insulin coma procedure. Devised on a dubious hypothesis of biological antagonism, Cardiazol armed psychiatry with an immediately effective weapon in the battle against schizophrenia, an enduring and debilitating condition responsible for over half of the mental hospital population. What made Cardiazol work - or appear to work? This account shows how evaluation of convulsive therapy was skewed by naive outcome measurement and diagnostic discrepancies, and how its therapeutic indication evolved from schizophrenia to affective disorders. Psychological mechanisms are considered, with the suggestion that the intense fear experienced during treatment--the major reason for abandoning Cardiazol in favour of electroshock--was therapeutically advantageous.

  19. Gender differences in predictors of initiation, retention, and completion in an HMO-based substance abuse treatment program.

    PubMed

    Green, Carla A; Polen, Michael R; Dickinson, Daniel M; Lynch, Frances L; Bennett, Marjorie D

    2002-12-01

    We studied gender differences in treatment process indicators among 293 HMO members recommended for substance abuse treatment. Treatment initiation, completion, and time spent in treatment did not differ by gender, but factors predicting these outcomes differed markedly. Initiation was predicted in women by alcohol diagnoses; in men, by being employed or married. Failure to initiate treatment was predicted in women by mental health diagnoses; in men, by less education. Treatment completion was predicted in women by higher income and legal/agency referral; in men, by older age. Failure to complete was predicted in women by more dependence diagnoses and higher Addiction Severity Index Employment scores; in men, by worse psychiatric status, receiving Medicaid, and motivation for entering treatment. More time spent in treatment was predicted, in women, by alcohol or opiate diagnoses and legal/agency referral; in men, by fewer mental health diagnoses, higher education, domestic violence victim status, and prior 12-step attendance. Clinical implications of results are discussed. PMID:12495790

  20. Treatment Modifications and Treatment-Limiting Toxicities or Side Effects: Risk Factors and Temporal Trends.

    PubMed

    Pantazis, Nikos; Psichogiou, Mina; Paparizos, Vassilios; Gargalianos, Panagiotis; Chini, Maria; Protopapas, Konstantinos; Sipsas, Nikolaos V; Panos, George; Chrysos, George; Sambatakou, Helen; Katsarou, Olga; Touloumi, Giota

    2015-07-01

    Combined antiretroviral treatment (cART) modifications are often required due to treatment failure or side effects. We investigate cART regimens' durability, frequency of treatment-limiting adverse events, and potential risk factors and temporal trends. Data were derived from the Athens Multicenter AIDS Cohort Study (AMACS). Statistical analyses were based on survival techniques, allowing for multiple contributions per individual. Overall, 2,756 individuals, aged >15 years, initiated cART. cART regimens were grouped by their initiation date into four calendar periods (1995-1998, 1999-2002, 2003-2006, and 2007+). Median [95% confidence interval (CI)] time to first treatment modification was 2.11 (1.95-2.33) years; cumulative probabilities at 1 year were 31.6%, 29.0%, 33.1%, and 29.6% for the four periods, respectively. cART modifications were less frequent in more recent years (adjusted HR=0.96 per year; p<0.001). Longer treatment duration was associated with lower HIV-RNA, higher CD4 counts, and being previously ART naive. cART modifications due to treatment failure became less frequent in recent years (adjusted HR=0.91 per year; p<0.001). Estimated (95% CI) 1 year cumulative probabilities of treatment-limiting side effects were 16.4% (12.0-21.3%), 19.3% (15.6-23.3%), 24.9% (20.3-29.7%), and 21.1% (13.4-29.9%) for the four periods, respectively, with no significant temporal trends. Risk of side effects was lower in nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens or triple nucleoside reverse transcriptase inhibitor (NRTI)-based cART regimens. Treatment modifications have become less frequent in more recent years. This could be partly attributed to the lower risk for side effects of NNRTI-based cART regimens and mainly to the improved efficacy of newer drugs. However, the rate of drugs substitutions due to adverse events remains substantially high. PMID:25950848

  1. Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.

    PubMed

    Lori, F; Rosenberg, E; Lieberman, J; Foli, A; Maserati, R; Seminari, E; Alberici, F; Walker, B; Lisziewicz, J

    1999-10-10

    Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

  2. Protection of pigs with cysticercosis from further infections after treatment with oxfendazole.

    PubMed

    Gonzalez, A E; Gavidia, C; Falcon, N; Bernal, T; Verastegui, M; Garcia, H H; Gilman, R H; Tsang, V C

    2001-07-01

    Cysticercosis, the infection by the larvae of Taenia solium, is a major cause of acquired epilepsy in the world; it also causes significant economic loss because of contaminated pork. This disease is endemic in most developing countries and no control strategy has yet been proven efficient and sustainable. To further evaluate the full potential of single-dose oxfendazole treatment for pigs as a control measure, 20 pigs with cysticercosis were treated with oxfendazole and later matched with 41 naive pigs and exposed to a natural challenge in a hyperendemic area. New infections were found by serologic testing in 15 of the 32 controls (47%), and by the presence of cysts at necropsy in 12 of them (37%). Only minute residual scars were detected in the carcasses of oxfendazole-treated pigs. Pigs with cysticercosis, once treated with oxfendazole, are protected from new infections for at least three months.

  3. Gefitinib in the treatment of nonsmall cell lung cancer with activating epidermal growth factor receptor mutation

    PubMed Central

    Nurwidya, Fariz; Takahashi, Fumiyuki; Takahashi, Kazuhisa

    2016-01-01

    Lung cancer is still the main cause of cancer-related deaths worldwide, with most patients present with advanced disease and poor long-term prognosis. The aim of lung cancer treatment is to slow down the progression of the disease, to relieve the patients from the lung cancer symptoms and whenever possible, to increase the overall survival. The discovery of small molecule targeting tyrosine kinase of epidermal growth factor receptor opens a new way in the management of advanced nonsmall cell lung cancer (NSCLC). This review will discuss several Phase II and III trials evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemotherapy-naive patients. PMID:27433059

  4. Predictors of addiction treatment providers' beliefs in the disease and choice models of addiction.

    PubMed

    Russell, Christopher; Davies, John B; Hunter, Simon C

    2011-03-01

    Addiction treatment providers working in the United States (n = 219) and the United Kingdom (n = 372) were surveyed about their beliefs in the disease and choice models of addiction, as assessed by the 18-item Addiction Belief Scale of J. Schaler (1992). Factor analysis of item scores revealed a three-factor structure, labeled "addiction is a disease," "addiction is a choice," and "addiction is a way of coping with life," and factor scores were analyzed in separate hierarchical multiple regression analyses. Controlling for demographic and addiction history variables, treatment providers working in the United States more strongly believe addiction is a disease, whereas U.K.-based providers more strongly believe that addiction is a choice and a way of coping with life. Beliefs that addiction is a disease were stronger among those who provide for-profit treatment, have stronger spiritual beliefs, have had a past addiction problem, are older, are members of a group of addiction professionals, and have been treating addiction longer. Conversely, those who viewed addiction as a choice were more likely to provide public/not-for-profit treatment, be younger, not belong to a group of addiction professionals, and have weaker spiritual beliefs. Additionally, treatment providers who have had a personal addiction problem in the past were significantly more likely to believe addiction is a disease the longer they attend a 12-step-based group and if they are presently abstinent. PMID:21036516

  5. Text message content preferences to improve buprenorphine maintenance treatment in primary care.

    PubMed

    Tofighi, Babak; Grossman, Ellie; Bereket, Sewit; D Lee, Joshua

    2016-01-01

    Few studies have evaluated text message content preferences to support evidence-based treatment approaches for opioid use disorders, and none in primary care office-based buprenorphine treatment settings. This study assessed the acceptability and preferences for a tailored text message intervention in support of core office-based buprenorphine treatment medical management components (e.g., treatment adherence, encouraging abstinence, 12-step group participation, motivational interviewing, and patient-provider communication as needed). There were 97 patients enrolled in a safety net office-based buprenorphine treatment program who completed a 24-item survey instrument that consisted of multiple-choice responses, 7-point Likert-type scales, binomial "Yes/No" questions, and open-ended responses. The sample was predominately male (81%), had an average age of 46 years, and was diverse (64% ethnic/racial minorities); 56% lacked stable employment. Respondents were interested in receiving text message appointment reminders (90%), information pertaining to their buprenorphine treatment (76%), supportive content (70%), and messages to reduce the risk of relapse (88%). Participants preferred to receive relapse prevention text messages during all phases of treatment: immediately after induction into buprenorphine treatment (81%), a "few months" into treatment (57%), and after discontinuing buprenorphine treatment (72%). Respondents also expressed interest in text message content enhancing self-efficacy, social support, and frequent provider communication to facilitate unobserved "home" induction with buprenorphine. Older participants were significantly less receptive to receiving text message appointment reminders; however, they were as interested in receiving supportive, informational, and relapse prevention components compared to younger respondents. Implications for integrating a text message support system in office-based buprenorphine treatment are discussed.

  6. Sewage Treatment

    NASA Technical Reports Server (NTRS)

    1976-01-01

    A million gallon-a-day sewage treatment plant in Huntington Beach, CA converts solid sewage to activated carbon which then treats incoming waste water. The plant is scaled up 100 times from a mobile unit NASA installed a year ago; another 100-fold scale-up will be required if technique is employed for widespread urban sewage treatment. This unique sewage-plant employed a serendipitous outgrowth of a need to manufacture activated carbon for rocket engine insulation. The process already exceeds new Environmental Protection Agency Standards Capital costs by 25% compared with conventional secondary treatment plants.

  7. Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats.

    PubMed

    Uzbay, Tayfun; Kayir, Hakan; Celik, Turgay; Yüksel, Nevzat

    2006-05-01

    Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

  8. Wastewater Treatment.

    ERIC Educational Resources Information Center

    Zoltek, J., Jr.; Melear, E. L.

    1978-01-01

    Presents the 1978 literature review of wastewater treatment. This review covers: (1) process application; (2) coagulation and solids separation; (3) adsorption; (4) ion exchange; (5) membrane processes; and (6) oxidation processes. A list of 123 references is also presented. (HM)

  9. Treatment & Coping

    MedlinePlus

    ... Patient gender Curve worsening Associated symptoms such as back pain or shortness of breath What are treatment options ... problems in addition to your scoliosis (such as back pain), your doctor may prescribe physical therapy to address ...

  10. [Home Treatment].

    PubMed

    Widmann, F; Bachhuber, G; Riedelsheimer, A; Schiele, A; Ullrich, S; Kilian, R; Becker, T; Frasch, K

    2016-01-01

    Home Treatment (HT) means acute psychiatric treatment in the patient's usual environment. Conceptually, HT is to be differentiated from other home-based services: It is limited with regard to duration and multiprofessional (e. g. psychiatrist plus psychiatric nursing staff plus social worker); the "24/7"-accessibility is frequently provided by the corresponding background hospital infrastructure. Target group are acutely mentally ill persons with an indication to inpatient treatment, who are willing to cooperate, and absence of endangerment to self and others. In contrast to the Scandinavian and many Anglophone countries where nationwide HT services are delivered, there are not many HT sites in Germany so far. Consequently, empirical data concerning HT in Germany is scarce. In summary, international studies show equivalent effects on psychopathological measures compared to inpatient treatment, reductions with regard to inpatient days, higher patient satisfaction and a trend towards cost-effectivity. PMID:26878432

  11. Stroke Treatments

    MedlinePlus

    ... weakened blood vessels that also cause hemorrhagic stroke: aneurysms and arteriovenous malformations (AVMs). Treatment differs depending on ... the leg or arm, then guided to the aneurysm or AVM ; it then deposits a mechanical agent, ...

  12. Hepatitis C: Treatment of difficult to treat patients

    PubMed Central

    Hilgenfeldt, Eric G; Schlachterman, Alex; Firpi, Roberto J

    2015-01-01

    Over the past several years, more so recently, treatment options for hepatitis C virus (HCV) have seemed to exponentially grow. Up until recently, the regimen of pegylated interferon (peg-IFN) and ribavirin (RBV) stood as the standard of care. Direct acting antivirals, which target nonstructural proteins involved in replication and infection of HCV were first approved in 2011 as an addition to the peg-IFN and RBV regimen and with them have come increased sustained virological response rates (SVR). The previously reported 50%-70% SVR rates using the combination of peg-IFN and RBV are no longer the standard of care with direct acting antiviral (DAA) based regimens now achieving SVR of 70%-90%. Peg-IFN free as well as “all oral” regimens are also available. The current randomized controlled trials available show favorable SVRs in patients who are naive to treatment, non-cirrhotic, and not human immunodeficiency virus (HIV)-co-infected. What about patients who do not fit into these categories? In this review, we aim to discuss the currently approved and soon to be approved DAAs while focusing on their roles in patients that are treatment experienced, cirrhotic, or co-infected with HIV. In this discussion, review of the clinical trials leading to recent consensus guidelines as well as discussion of barriers to treatment will occur. A case will attempt will be made that social services, including financial support and drug/alcohol treatment, should be provided to all HCV infected patients to improve chances of cure and thus prevention of late stage sequela. PMID:26244069

  13. [Lopinavir/ritonavir in new initial antiretroviral treatment strategies].

    PubMed

    Rolón, María José; Figueroa, María Inés; Sued, Omar; Cahn, Pedro

    2014-11-01

    According to evidence from randomized controlled trials and epidemiological data, the antiretroviral treatment (ART) of choice has consisted of the combination of 2 nucleoside analog reverse-transcriptase inhibitors (NRTI) plus 1 non-nucleoside analog reverse-transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) for more than 17 years. There are several unresolved issues, notably the toxocity associated with NRTI, especially thymidine analogs, and the possibility of cross resistance, which may affect subsequent treatment. The development of new antiretroviral drugs with simpler dosing regimens and lower toxicity has led to evaluation of innovative strategies such as dual therapy for initial ART in treatment-naive, with the aim of preventing long-term toxicity and increasing treatment adherence. Despite encouraging results, some combinations have proven unsatisfactory. The strategies with favorable results to date consist of twice-daily lopinavir/ritonavir (LPV/r)-based regimens, those in the PROGRESS (LPV/r + raltegravir) and GARDEL (LPV/r + lamivudine) trials, and the combination of darunavir and raltegravir (NEAT 001 trial), although the latter observed a higher tendency (statistically nonsignificant) to virological failure in the dual combination arm. These trials were based on the use of NRTI-sparing regimens consisting of 2-3 fully- active agents for highly-active ART in treatment-naïve HIV-positive patients. Recent studies provide evidence supporting the use of NRTI-sparing regimens in HIV-infected patients with failure to an initial NNRTI-based ART regimen. The present review will discuss only LPV/r-based innovative strategies in initial ART regimens.

  14. Social Anxiety and Peer Helping in Adolescent Addiction Treatment

    PubMed Central

    Pagano, Maria E.; Wang, Alexandra R.; Rowles, Brieana M.; Lee, Matthew T.; Johnson, Byron R.

    2015-01-01

    Background The developmental need to fit in may lead to higher alcohol and other drug use among socially anxious youths which exacerbates the drink/trouble cycle. In treatment, youths with social anxiety disorder (SAD) may avoid participating in therapeutic activities with risk of negative peer appraisal. Peer-helping is a low-intensity, social activity in the 12-step program associated with greater abstinence among treatment-seeking adults. This study examined the influence of SAD on clinical severity at intake, peer-helping during treatment, and outcomes in a large sample of adolescents court-referred to residential treatment. Methods Adolescents (N = 195; 52% female, 30% Black) aged 14 to 18 were prospectively assessed at treatment admission, treatment discharge, and 6 months after treatment discharge. Data were collected using rater-administered assessments, youth reports, clinician reports, medical charts, and electronic court records. The influence of SAD on peer-helping and outcomes was examined using hierarchical linear regression and event history methods. Results Forty-two percent of youths reported a persistent fear of being humiliated or scrutinized in social situations, and 15% met current diagnostic criteria for SAD. SAD onset preceded initial use for two-thirds of youths with SAD and substance dependency. SAD youths presented for treatment with greater clinical severity in terms of earlier age of first use (p < 0.01), greater lifetime use of heroin and polysubstance use (p < 0.05), incarceration history (p < 0.01), and lifetime trauma (p < 0.001). Twelve-step participation patterns during treatment did not differ between youths with and without SAD except for peer-helping, which was associated with reduced risk of relapse (p < 0.01) and incarceration (p < 0.05) in the 6 months posttreatment. Conclusions This study found evidence of an association between SAD and earlier age of first use, greater lifetime use of heroin, incarceration history, and

  15. Study of Lurasidone in Treating Antipsychotic Naive or Quasi-Naive Children and Adolescents

    ClinicalTrials.gov

    2014-08-24

    Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder; Psychosis NOS; Autistic Disorder; Asperger Syndrome; Child Development Disorders, Pervasive; Bipolar I Disorder; Bipolar II Disorder; Mood Disorder NOS; Severe Major Depression With Psychotic Features; Single Episode Major Depression Without Psychotic Symptoms; Severe Mood Disorder With Psychotic Features

  16. What works in addiction treatment and what doesn't: is the best therapy no therapy?

    PubMed

    Peele, S

    The current trend toward treating drug and alcohol (and other) addictions in disease-oriented, 12-step programs has had less success than most people believe. Treatments that teach coping skills, mobilize community forces, and instill values toward prosocial behavior have had success rates far superior to therapies that instruct individuals that they take drugs or drink excessively because they have a disease or because drugs are inherently addictive. Successful treatments instead deal with addicts' interactions with their environments and help them develop beliefs in their self-efficacy. Nonetheless, even addiction treatments which have demonstrated success face limitations in their ability to confront individual intentions and values, community standards, and environmental pressures and opportunities. At the same time, more individuals have quit addictions on their own than have been successfully treated by even the best therapies. Put simply, no therapy will ever be able in itself to make a substantial impact on our drug and alcohol or other addictive problems. In the meantime, addiction treatment is becoming more pervasive and coercive, and today holds out the possibility of corrupting our society and the self-conceptions of its members.

  17. Sewage Treatment

    NASA Technical Reports Server (NTRS)

    1991-01-01

    Stennis Space Center's aquaculture research program has led to an attractive wastewater treatment for private homes. The system consists of a septic tank or tanks for initial sewage processing and a natural secondary treatment facility for further processing of septic tanks' effluent, consisting of a narrow trench, which contains marsh plants and rocks, providing a place for microorganisms. Plants and microorganisms absorb and digest, thus cleansing partially processed wastewater. No odors are evident and cleaned effluent may be discharged into streams or drainage canals. The system is useful in rural areas, costs about $1,900, and requires less maintenance than mechanical systems.

  18. WATER TREATMENT

    DOEpatents

    Pitman, R.W.; Conley, W.R. Jr.

    1962-12-01

    An automated system for adding clarifying chemicals to water in a water treatment plant is described. To a sample of the floc suspension polyacrylamide or similar filter aid chemicals are added, and the sample is then put through a fast filter. The resulting filtrate has the requisite properties for monitoring in an optical turbidimeter to control the automated system. (AEC)

  19. PARACOCCIDIOIDOMYCOSIS TREATMENT

    PubMed Central

    SHIKANAI-YASUDA, Maria Aparecida

    2015-01-01

    SUMMARY Considered to be an emerging endemic mycosis in Latin America, paracoccidioidomycosis is characterized by a chronic course and involvement of multiple organs in immunocompromised hosts. Infection sequelae are mainly related to pulmonary and adrenal insufficiency. The host-parasite interaction results in different expressions of the immune response depending on parasite pathogenicity, fungal load and genetic characteristics of the host. A few controlled and case series reports have shown that azoles and fast-acting sulfa derivatives are useful treatment alternatives in milder forms of the disease. For moderate/severe cases, more prolonged treatments or even parenteral routes are required especially when there is involvement of the digestive tract mucosa, resulting in poor drug absorption. Although comparative studies have reported that shorter treatment regimens with itraconazole are able to induce cure in chronically-infected patients, there are still treatment challenges such as the need for more controlled studies involving acute cases, the search for new drugs and combinations, and the search for compounds capable of modulating the immune response in severe cases as well as the paradoxical reactions. PMID:26465367

  20. Surface Treatment

    NASA Technical Reports Server (NTRS)

    Park, Cheol (Inventor); Lowther, Sharon E. (Inventor); St.Clair, Terry L. (Inventor)

    2003-01-01

    A simple surface treatment process is provided which offers a high performance surface for a variety of applications at low cost. This novel surface treatment, which is particularly useful for Ti-6Al-4V alloys, is achieved by forming oxides on the surface with a two-step chemical process and without mechanical abrasion. First, after solvent degreasing, sulfuric acid is used to generate a fresh titanium surface. Next, an alkaline perborate solution is used to form an oxide on the surface. This acid-followed-by-base treatment is cost effective and relatively safe to use in commercial applications. In addition, it is chromium-free, and has been successfully used with a sol-gel coating to afford a strong adhesive bond that exhibits excellent durability after the bonded specimens have been subjected to a harsh 72 hour water boil immersion. Phenylethynyl containing adhesives were used to evaluate this surface treatment with a novel coupling agent containing both trialkoxysilane and phenylethynyl groups. 8 Claims, 16 Drawing Sheets

  1. Rotavirus Treatment

    MedlinePlus

    ... Rotavirus Vaccine Program American Academy of Pediatrics Treatment Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir ... PATH's Rotavirus Vaccine Program American Academy of Pediatrics Language: English Español (Spanish) File Formats Help: How do I ...

  2. Myelodysplastic/ Myeloproliferative Neoplasms Treatment

    MedlinePlus

    ... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

  3. Chronic Myeloproliferative Neoplasms Treatment

    MedlinePlus

    ... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Chronic Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Chronic ...

  4. Antimicrobials Treatment

    NASA Astrophysics Data System (ADS)

    Drosinos, Eleftherios H.; Skandamis, Panagiotis N.; Mataragas, Marios

    The use of antimicrobials is a common practice for preservation of foods. Incorporation, in a food recipe, of chemical antimicrobials towards inhibition of spoilage and pathogenic micro-organisms results in the compositional modification of food. This treatment is nowadays undesirable for the consumer, who likes natural products. Scientific community reflecting consumers demand for natural antimicrobials has made efforts to investigate the possibility to use natural antimicrobials such us bacteriocins and essential oils of plant origin to inhibit microbial growth.

  5. Patient Violence Towards Counselors in Substance Use Disorder Treatment Programs: Prevalence, Predictors, and Responses

    PubMed Central

    Bride, Brian E.; Choi, Y. Joon; Olin, Ilana W.; Roman, Paul M.

    2015-01-01

    Workplace violence disproportionately impacts healthcare and social service providers. Given that substance use and abuse are documented risk factors for the perpetration of violence, SUD treatment personnel are at risk for patient-initiated violence. However, little research has addressed SUD treatment settings. Using data nationally representative of the U. S., the present study explores SUD counselors’ experiences of violent behaviors perpetrated by patients. More than half (53%) of counselors personally experienced violence, 44% witnessed violence, and 61% had knowledge of violence directed at a colleague. Counselors reported that exposure to violence led to an increased concern for personal safety (29%), impacted their treatment of patients (15%), and impaired job performance (12%). In terms of organizational responses to patient violence, 70% of organizations increased training on de-escalation of violent situations and 58% increased security measures. Exposure to verbal assault was associated with age, minority, tenure, recovery status, 12-step philosophy, training in MI/MET, and higher caseloads of patients with co-occurring disorders. Exposure to physical threats was associated with age gender, minority, tenure, recovery status, and higher caseloads of patients with co-occurring disorders. Exposure to physical assault was associated with age, gender, and sample. Implications of these findings for organizations and individuals are discussed. PMID:26025921

  6. Patient Violence Towards Counselors in Substance Use Disorder Treatment Programs: Prevalence, Predictors, and Responses.

    PubMed

    Bride, Brian E; Choi, Y Joon; Olin, Ilana W; Roman, Paul M

    2015-10-01

    Workplace violence disproportionately impacts healthcare and social service providers. Given that substance use and abuse are documented risk factors for the perpetration of violence, SUD treatment personnel are at risk for patient-initiated violence. However, little research has addressed SUD treatment settings. Using data nationally representative of the U. S., the present study explores SUD counselors' experiences of violent behaviors perpetrated by patients. More than half (53%) of counselors personally experienced violence, 44% witnessed violence, and 61% had knowledge of violence directed at a colleague. Counselors reported that exposure to violence led to an increased concern for personal safety (29%), impacted their treatment of patients (15%), and impaired job performance (12%). In terms of organizational responses to patient violence, 70% of organizations increased training on de-escalation of violent situations, and 58% increased security measures. Exposure to verbal assault was associated with age, minority, tenure, recovery status, 12-step philosophy, training in MI/MET, and higher caseloads of patients with co-occurring disorders. Exposure to physical threats was associated with age gender, minority, tenure, recovery status, and higher caseloads of patients with co-occurring disorders. Exposure to physical assault was associated with age, gender, and sample. Implications of these findings for organizations and individuals are discussed. PMID:26025921

  7. Massive release of extracellular vesicles from cancer cells after photodynamic treatment or chemotherapy

    PubMed Central

    Aubertin, Kelly; Silva, Amanda K. A.; Luciani, Nathalie; Espinosa, Ana; Djemat, Aurélie; Charue, Dominique; Gallet, François; Blanc-Brude, Olivier; Wilhelm, Claire

    2016-01-01

    Photodynamic therapy is an emerging cancer treatment that is particularly adapted for localized malignant tumor. The phototherapeutic agent is generally injected in the bloodstream and circulates in the whole organism as a chemotherapeutic agent, but needs light triggering to induce localized therapeutic effects. We found that one of the responses of in vitro and in vivo cancer cells to photodynamic therapy was a massive production and emission of extracellular vesicles (EVs): only 1 hour after the photo-activation, thousands of vesicles per cell were emitted in the extracellular medium. A similar effect has been found after treatment with Doxorubicin (chemotherapy), but far less EVs were produced, even 24 hours after the treatment. Furthermore, we found that the released EVs could transfer extracellular membrane components, drugs and even large intracellular objects to naive target cells. In vivo, photodynamic treatment and chemotherapy increased the levels of circulating EVs several fold, confirming the vast induction of cancer cell vesiculation triggered by anti-cancer therapies. PMID:27752092

  8. In vivo immune responses to Candida albicans modified by treatment with recombinant murine gamma interferon.

    PubMed

    Garner, R E; Kuruganti, U; Czarniecki, C W; Chiu, H H; Domer, J E

    1989-06-01

    The immunologic effects of in vivo administration of recombinant murine gamma interferon (rMuIFN-gamma) were determined in a murine model of candidiasis. Naive mice were given graded doses of rMuIFN-gamma and then challenged intravenously with Candida albicans. Increased morbidity and mortality were noted in four different strains of mice, viz., BALB/c, A/J, Swiss Webster, and CBA/J, providing the mice had not been immunized with C. albicans before challenge. Quantitative culture of selected organs of Swiss Webster and CBA/J mice surviving treatment with rMuIFN-gamma revealed elevated numbers of C. albicans cells, particularly in the kidneys, but also in the liver, lungs, and spleen. The lungs, livers, and spleen of female CBA/J mice were more protected from increased multiplication of the fungus than were those of males of the same species or female Swiss Webster mice. On the basis of these initial findings, the effect of treatment with 5,000 U of rMuIFN-gamma on immune responses in a gastrointestinal model of candidiasis was determined. CBA/J mice that had been colonized with C. albicans as infants were boosted with a cutaneous inoculation of the fungus when 6 to 10 weeks old; development of delayed hypersensitivity (DH), antibodies, and protective responses was assayed at intervals thereafter. Daily treatment with rMuIFN-gamma (beginning 1 day before cutaneous inoculation) suppressed weak immune responses but had little effect on responses which were strong. For example, DH and anti-C. albicans antibody production were suppressed in animals colonized with C. albicans but not boosted by cutaneous inoculation, and DH was suppressed in uncolonized animals that had been inoculated once cutaneously with the fungus as well. There was no rMuIFN-gamma-induced suppressive effect of DH in mice which had been stimulated maximally with C. albicans, i.e., colonized animals that had been boosted cutaneously with the organisms. Collectively, these data indicate that naive mice

  9. In vivo immune responses to Candida albicans modified by treatment with recombinant murine gamma interferon.

    PubMed Central

    Garner, R. E.; Kuruganti, U.; Czarniecki, C. W.; Chiu, H. H.; Domer, J. E.

    1989-01-01

    The immunologic effects of in vivo administration of recombinant murine gamma interferon (rMuIFN-gamma) were determined in a murine model of candidiasis. Naive mice were given graded doses of rMuIFN-gamma and then challenged intravenously with Candida albicans. Increased morbidity and mortality were noted in four different strains of mice, viz., BALB/c, A/J, Swiss Webster, and CBA/J, providing the mice had not been immunized with C. albicans before challenge. Quantitative culture of selected organs of Swiss Webster and CBA/J mice surviving treatment with rMuIFN-gamma revealed elevated numbers of C. albicans cells, particularly in the kidneys, but also in the liver, lungs, and spleen. The lungs, livers, and spleen of female CBA/J mice were more protected from increased multiplication of the fungus than were those of males of the same species or female Swiss Webster mice. On the basis of these initial findings, the effect of treatment with 5,000 U of rMuIFN-gamma on immune responses in a gastrointestinal model of candidiasis was determined. CBA/J mice that had been colonized with C. albicans as infants were boosted with a cutaneous inoculation of the fungus when 6 to 10 weeks old; development of delayed hypersensitivity (DH), antibodies, and protective responses was assayed at intervals thereafter. Daily treatment with rMuIFN-gamma (beginning 1 day before cutaneous inoculation) suppressed weak immune responses but had little effect on responses which were strong. For example, DH and anti-C. albicans antibody production were suppressed in animals colonized with C. albicans but not boosted by cutaneous inoculation, and DH was suppressed in uncolonized animals that had been inoculated once cutaneously with the fungus as well. There was no rMuIFN-gamma-induced suppressive effect of DH in mice which had been stimulated maximally with C. albicans, i.e., colonized animals that had been boosted cutaneously with the organisms. Collectively, these data indicate that naive mice

  10. Sewage Treatment

    NASA Technical Reports Server (NTRS)

    1984-01-01

    In the early 1970's, National Space Technology Laboratories discovered that water hyacinths literally thrive on sewage; they absorb and digest nutrients and minerals from wastewater, converting sewage effluents to clean water. They offer a means of purifying water at a fraction of the cost of a conventional sewage treatment plant, and provide a bonus value in byproducts. Hyacinths must be harvested at intervals; the harvested plants are used as fertilizers, high-protein animal feed and a source of energy. Already serving a number of small towns, the "aquaculture" technique has significantly advanced with its adoption by a major U.S. city.

  11. Is residential treatment effective for opioid use disorders? A longitudinal comparison of treatment outcomes among opioid dependent, opioid misusing, and non-opioid using emerging adults with substance use disorder

    PubMed Central

    Schuman-Olivier, Zev; Greene, M. Claire; Bergman, Brandon G.; Kelly, John F.

    2014-01-01

    Background Opioid misuse and dependence rates among emerging adults have increased substantially. While office-based opioid treatments (e.g., buprenorphine/naloxone) have shown overall efficacy, discontinuation rates among emerging adults are high. Abstinence-based residential treatment may serve as a viable alternative, but has seldom been investigated in this age group. Methods Emerging adults attending 12-step-oriented residential treatment (N=292; 18–24yrs, 74% Male, 95% White) were classified into opioid dependent (OD; 25%), opioid misuse (OM; 20%), and no opiate use (NO; 55%) groups. Paired t-tests and ANOVAs tested baseline differences and whether groups differed in their during-treatment response. Longitudinal multilevel models tested whether groups differed on substance use outcomes and treatment utilization during the year following the index treatment episode. Results Despite a more severe clinical profile at baseline among OD, all groups experienced similar during-treatment increases on therapeutic targets (e.g., abstinence self-efficacy), while OD showed a greater decline in psychiatric symptoms. During follow-up relative to OM, both NO and OD had significantly greater Percent Days Abstinent, and significantly less cannabis use. OD attended significantly more outpatient treatment sessions than OM or NO; 29% of OD was completely abstinent at 12-month follow-up. Conclusions Findings here suggest residential treatment may be helpful for emerging adults with opioid dependence. This benefit may be less prominent, though, among non-dependent opioid misusers. Randomized trials are needed to compare more directly the relative benefits of outpatient agonist-based treatment to abstinence-based, residential care in this vulnerable age-group, and to examine the feasibility of an integrated model. PMID:25267606

  12. Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3

    PubMed Central

    Marciano, Sebastián; Borzi, Silvia M; Dirchwolf, Melisa; Ridruejo, Ezequiel; Mendizabal, Manuel; Bessone, Fernando; Sirotinsky, María E; Giunta, Diego H; Trinks, Julieta; Olivera, Pablo A; Galdame, Omar A; Silva, Marcelo O; Fainboim, Hugo A; Gadano, Adrián C

    2015-01-01

    AIM: To evaluate pre-treatment factors associated with sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 3 treated with peginterferon and ribavirin (RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index, steatosis, INFL3 polymorphism, pre-treatment HCV-RNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1 (± 1.8) wk. Overall, 58% (62/107) of the patients achieved an SVR and 42% (45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/mL (OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis (OR = 0.278, 95%CI: 0.113-0.684, P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥ 600000 UI/mL and advanced fibrosis, the probability of achieving an SVR was 29% (95%CI: 13.1-45.2). In patients with pre-treatment HCV-RNA < 600000 UI/mL and mild to moderate fibrosis, the probability of achieving an SVR was 81% (95%CI: 68.8-93.4). CONCLUSION: In patients with HCV genotype 3 infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agents-based regimes. PMID:25866607

  13. Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment

    PubMed Central

    Stellbrink, Hans-Jürgen; Le Fevre, Eric; Carr, Andrew; Saag, Michael S.; Mukwaya, Geoffrey; Nozza, Silvia; Valluri, Srinivas Rao; Vourvahis, Manoli; Rinehart, Alex R.; McFadyen, Lynn; Fichtenbaum, Carl; Clark, Andrew; Craig, Charles; Fang, Annie F.; Heera, Jayvant

    2016-01-01

    Objective: The aim of this study was to evaluate the efficacy of maraviroc along with darunavir/ritonavir, all once daily, for the treatment of antiretroviral-naive HIV-1 infected individuals. Design: MODERN was a multicentre, double-blind, noninferiority, phase III study in HIV-1 infected, antiretroviral-naive adults with plasma HIV-1 RNA at least 1000 copies/ml and no evidence of reduced susceptibility to study drugs. Methods: At screening, participants were randomized 1 : 1 to undergo either genotypic or phenotypic tropism testing. Participants with CCR5-tropic HIV-1 were randomized 1 : 1 to receive maraviroc 150 mg once daily or tenofovir/emtricitabine once daily each with darunavir/ritonavir once daily for 96 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml (Food and Drug Administration snapshot algorithm) at Week 48. A substudy evaluated bone mineral density, body fat distribution and serum bone turnover markers. Results: Seven hundred and ninety-seven participants were dosed (maraviroc, n = 396; tenofovir/emtricitabine, n = 401). The Data Monitoring Committee recommended early study termination due to inferior efficacy in the maraviroc group. At Week 48, the proportion of participants with HIV-1 RNA less than 50 copies/ml was 77.3% for maraviroc and 86.8% for tenofovir/emtricitabine [difference of −9.54% (95% confidence interval: −14.83 to −4.24)]. More maraviroc participants discontinued for lack of efficacy, which was not associated with non-R5 tropism or resistance. Discontinuations for adverse events, Category C events, Grade 3/4 adverse events and laboratory abnormalities were similar between groups. Conclusion: A once-daily nucleos(t)ide-sparing two-drug regimen of maraviroc and darunavir/ritonavir was inferior to a three-drug regimen of tenofovir/emtricitabine and darunavir/ritonavir in antiretroviral-naive adults. PMID:26854810

  14. Anaerobic treatment

    SciTech Connect

    Witt, E.R.; Humphrey, W.J.; Cave, J.P.

    1982-12-28

    This invention provides for the anaerobic treatment of acidic petrochemical wastes in an anaerobic filter at high loadings and high recycle rates. The effluent from the top of the filter passes into a gas-disengaging/solids-settling zone containing a quiescent body of the effluent liquid. The settled solids are withdrawn and recycled to the base of the filter together with fresh acidic waste and an inorganic alkaline material (preferably magnesium oxide or carbonate) to maintain a neutral pH. The liquid portion of the effluent is sent to an aerobic digester to remove the rest of the organic material, which is used to support the growth of bacteria and fed back to the anaerobic system.

  15. Psychological treatments.

    PubMed

    Barlow, David H

    2004-12-01

    Psychology has recently identified itself as a health care profession and codified this change in the bylaws of the American Psychological Association. Although psychologists make a number of contributions to the nation's health--and mental health--the most identifiable activity focuses on treating physical or psychological pathology with psychological interventions. Recently, health care policymakers have established that evidence supporting the efficacy of these interventions is more than sufficient for their inclusion in health care systems around the world. To promote faster and more widespread dissemination of these interventions specifically targeting problems severe enough to be included in health care systems and to solidify the identification of psychology as a health care profession, perhaps it is time for a change in terminology. It is proposed that psychologists label these procedures psychological treatments so as to differentiate them from more generic psychotherapy, which is often used outside of the scope of health care systems.

  16. Elevated on-treatment levels of serum IFN-gamma is associated with treatment failure of peginterferon plus ribavirin therapy for chronic hepatitis C

    PubMed Central

    Lu, Ming-Ying; Huang, Ching-I; Dai, Chia-Yen; Wang, Shu-Chi; Hsieh, Ming-Yen; Hsieh, Meng-Hsuan; Liang, Po-Cheng; Lin, Yi-Hung; Hou, Nai-Jen; Yeh, Ming-Lun; Huang, Chung-Feng; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Chuang, Wan-Long; Yu, Ming-Lung

    2016-01-01

    Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1β, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response. PMID:26965318

  17. Impact of Research Network Participation on the Adoption of Buprenorphine for Substance Abuse Treatment

    PubMed Central

    Rieckmann, Traci R.; Abraham, Amanda J.; Kovas, Anne E.; McFarland, Bentson H.; Roman, Paul M.

    2014-01-01

    There is a growing body of research supporting the use of buprenorphine and other medication assisted treatments (MATs) for the rapidly accelerating opioid epidemic in the United States. Despite numerous advantages of buprenorphine (accessible in primary care, no daily dosing required, minimal stigma), implementation has been slow. As the field progresses, there is a need to understand the impact of participation in practitioner-scientist research networks on acceptance and uptake of buprenorphine. This paper examines the impact of research network participation on counselor attitudes toward buprenorphine addressing both counselor-level characteristics and program-level variables using hierarchical linear modeling (HLM) to account for nesting of counselors within treatment programs. Using data from the National Treatment Center Study, this project compares privately funded treatment programs (n=345) versus programs affiliated with the National Institute on Drug Abuse Clinical Trials Network (CTN) (n=198). Models included 922 counselors in 172 CTN programs and 1,203 counselors in 251 private programs. Results of two-level HLM logistic (Bernoulli) models revealed that counselors with higher levels of education, larger caseloads, more buprenorphine-specific training, and less preference for 12-step treatment models were more likely to perceive buprenorphine as acceptable and effective. Furthermore, buprenorphine was 50% more likely to be perceived as effective among counselors working in CTN-affiliated programs as compared to private programs. This study suggests that research network affiliation positively impacts counselors’ acceptance and perceptions of buprenorphine. Thus, research network participation can be utilized as a means to promote positive attitudes toward the implementation of innovations including medication assisted treatment. PMID:24594902

  18. Predicting the duration of antiviral treatment needed to suppress plasma HIV-1 RNA

    PubMed Central

    Rizzardi, G. Paolo; De Boer, Rob J.; Hoover, Shelley; Tambussi, Giuseppe; Chapuis, Aude; Halkic, Nermin; Bart, Pierre-Alexandre; Miller, Veronica; Staszewski, Schlomo; Notermans, Daan W.; Perrin, Luc; Fox, Cecil H.; Lange, Joep M.A.; Lazzarin, Adriano; Pantaleo, Giuseppe

    2000-01-01

    Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1–infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure. PMID:10727446

  19. A Study to Evaluate Lipid Profile in Treatment Naïve HIV Positive Patients.

    PubMed

    Devanath, Anitha; Ray, Somdattaa; Kumar, Ravi; Prarthana, B S

    2014-01-01

    HIV infection is associated with lipid abnormalities in treatment naïve patients. CD4 count is used for monitoring the HIV infection. Primary objective was to evaluate and correlate lipid profile and CD4 counts in HIV infection. Secondary objective was to evaluate the feasibility of using Lipid profile to monitor the HIV infected treatment naïve patients instead of CD4 counts. 112 patients were selected based on a criteria from ART center in tertiary care center. CD4 counts were assessed and Lipid profile was evaluated enzymatically. A correlation study was done between the lipid profile and the CD4 count and clinical stages of infection. Cholesterol showed no significant correlation in any stage. HDL-C showed significant correlation (p < 0.05) with stage 2 and 4 disease. LDL-C showed no significant correlation in any stage. TGL showed significant correlation (p < 0.05) at stage 4 disease. Hence, HDL-C and TGL can be used as indicators of lipid status and for infection progression in treatment naive HIV patients, while Cholesterol and LDL-C has no role to play.

  20. Transcriptional Adaptation of Drug-tolerant Mycobacterium tuberculosis During Treatment of Human Tuberculosis

    PubMed Central

    Walter, Nicholas D.; Dolganov, Gregory M.; Garcia, Benjamin J.; Worodria, William; Andama, Alfred; Musisi, Emmanuel; Ayakaka, Irene; Van, Tran T.; Voskuil, Martin I.; de Jong, Bouke C.; Davidson, Rebecca M.; Fingerlin, Tasha E.; Kechris, Katerina; Palmer, Claire; Nahid, Payam; Daley, Charles L.; Geraci, Mark; Huang, Laurence; Cattamanchi, Adithya; Strong, Michael; Schoolnik, Gary K.; Davis, John Lucian

    2015-01-01

    Background. Treatment initiation rapidly kills most drug-susceptible Mycobacterium tuberculosis, but a bacterial subpopulation tolerates prolonged drug exposure. We evaluated drug-tolerant bacilli in human sputum by comparing messenger RNA (mRNA) expression of drug-tolerant bacilli that survive the early bactericidal phase with treatment-naive bacilli. Methods. M. tuberculosis gene expression was quantified via reverse-transcription polymerase chain reaction in serial sputa from 17 Ugandans treated for drug-susceptible pulmonary tuberculosis. Results. Within 4 days, bacterial mRNA abundance declined >98%, indicating rapid killing. Thereafter, the rate of decline slowed >94%, indicating drug tolerance. After 14 days, 16S ribosomal RNA transcripts/genome declined 96%, indicating slow growth. Drug-tolerant bacilli displayed marked downregulation of genes associated with growth, metabolism, and lipid synthesis and upregulation in stress responses and key regulatory categories—including stress-associated sigma factors, transcription factors, and toxin-antitoxin genes. Drug efflux pumps were upregulated. The isoniazid stress signature was induced by initial drug exposure, then disappeared after 4 days. Conclusions. Transcriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically downregulated state. Absence of the isoniazid stress signature in drug-tolerant bacilli indicates that physiological state influences drug responsiveness in vivo. These results identify novel drug targets that should aid in development of novel shorter tuberculosis treatment regimens. PMID:25762787

  1. PERCEIVED BARRIERS TO TREATMENT FOR ALCOHOL PROBLEMS: A LATENT CLASS ANALYSIS

    PubMed Central

    Schuler, Megan S.; Puttaiah, Savitha; Mojtabai, Ramin; Crum, Rosa M.

    2015-01-01

    Objective Low rates of alcohol treatment seeking has been shown to be associated with perceived barriers to treatment, yet heterogeneity in patterns of perceived barriers have not been explored. We used data from a population-based sample of adults with alcohol abuse and dependence to: describe latent classes of perceived barriers to seeking alcohol treatment and identify characteristics associated with class membership. Methods Data are from the National Epidemiologic Survey on Alcohol and Related Conditions (2001-02). Analyses were restricted to treatment-naive adults with alcohol abuse or dependence with a perceived treatment need (N=1,053). Latent class analysis was performed to identify subgroups with respect to barriers to treatment; latent class regression was performed to identify variables associated with each subgroup. Results Two subgroups emerged: the low barriers class (87%), characterized primarily by attitudinal barriers, and the high barriers class (13%), characterized by significant attitudinal, financial, stigma and readiness for change barriers. In both classes, the most frequently endorsed barrier was the attitudinal belief that they should be “strong enough” to handle it on their own. Univariate analyses showed strong associations between membership in the high barriers class and comorbid psychiatric disorders, alcohol dependence (relative to abuse), and family history of alcohol problems; multivariate analyses found significant associations with lifetime anxiety disorder and education level. Conclusions Findings show that attitudinal barriers are most prevalent, and highlight the existence of a notable subgroup with multiple barriers, including financial and stigma-related barriers, who may require additional resources and support in order to enter treatment. PMID:26234326

  2. Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study)

    PubMed Central

    Hilbe, Wolfgang; Pall, Georg; Kocher, Florian; Pircher, Andreas; Zabernigg, August; Schmid, Thomas; Schumacher, Michael; Jamnig, Herbert; Fiegl, Michael; Gächter, Anne; Freund, Martin; Kendler, Dorota; Manzl, Claudia; Zelger, Bettina; Popper, Helmut; Wöll, Ewald

    2015-01-01

    Background Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles. Methods Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2) and docetaxel (75 mg/m2 d1) q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly). The primary endpoint was radiological response according to RECIST. Results 40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95%) underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months. Conclusions Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected. Trial Registration EU Clinical Trials Register; Eudract-Nr: 2006-004639-31 PMID:26020783

  3. Factors Associated with Interest in Initiating Treatment for Hepatitis C Virus (HCV) Infection among Young HCV-Infected Injection Drug Users

    PubMed Central

    Strathdee, Steffanie A.; Latka, M.; Campbell, J.; O’Driscoll, P. T.; Golub, E. T.; Kapadia, F.; Pollini, R. A.; Garfein, R. S.; Thomas, D. L.; Hagan, H.

    2007-01-01

    Objective We sought to identify factors associated with interest in receiving therapy for hepatitis C virus (HCV) infection among HCV-infected injection drug users (IDUs) in 3 United States cities. Methods IDUs aged 18–35 years who were HCV-infected and seronegative for human immunodeficiency virus underwent surveys on behaviors, experience, and interest in treatment for HCV infection and readiness to quit drug use. Results Among treatment-naive IDUs (n = 216), 81.5% were interested in treatment for HCV infection, but only 27.3% had seen a health-care provider since receiving a diagnosis of HCV infection. Interest in treatment for HCV infection was greater among IDUs with a high perceived threat of progressive liver disease, those with a usual source of care, those without evidence of alcohol dependence, and those with higher readiness scores for quitting drug use. Interest in treatment for HCV infection was 7-fold higher among IDUs who were told by their health-care provider that they were at risk for cirrhosis or liver cancer. Conclusions Improving provider-patient communication and integrating treatments for substance abuse and HCV may increase the proportion of IDUs who initiate treatment for HCV infection. PMID:15768339

  4. Lanreotide autogel(®): a review of its use in the treatment of patients with acromegaly.

    PubMed

    Burness, Celeste B; Dhillon, Sohita; Keam, Susan J

    2014-09-01

    Lanreotide Autogel(®) (ATG) [Somatuline(®) Autogel(®), Somatuline(®) Depot(®)] is a prolonged-release, supersaturated aqueous gel formulation of the somatostatin analogue lanreotide acetate that acts via somatostatin receptors to reduce both growth hormone and insulin-like growth factor-I levels. It is indicated for the treatment of patients with acromegaly who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. This article reviews the clinical efficacy and tolerability of lanreotide ATG in the treatment of acromegaly, as well as summarizing its pharmacological properties. Results of clinical trials and extension studies of up to 4 years duration showed that deep subcutaneous lanreotide ATG was a generally effective treatment in treatment-naive and treatment-experienced adults with acromegaly. Lanreotide ATG provided hormonal control and improved both health-related quality of life and acromegaly symptoms in most patients; it also reduced tumour volume to a clinically significant extent in studies of primary therapy. Moreover, lanreotide ATG was generally no less effective than intramuscular lanreotide long-acting microparticles and was as effective as intramuscular octreotide long-acting release in switching or crossover studies, including those with standard or extended dosing intervals. Lanreotide ATG is generally well tolerated; the most frequently reported adverse events were mild or moderate transient gastrointestinal symptoms. Lanreotide ATG also has the advantage of being available in a convenient pre-filled syringe and is given subcutaneously rather than intramuscularly. Thus, lanreotide ATG continues to be a valuable option in the treatment of acromegaly, with potential advantages being ease of administration and longer dosing intervals in patients who have an adequate response to initial therapy.

  5. The RADAR Study: Week 48 Safety and Efficacy of RAltegravir Combined with Boosted DARunavir Compared to Tenofovir/Emtricitabine Combined with Boosted Darunavir in Antiretroviral-Naive Patients. Impact on Bone Health

    PubMed Central

    Bedimo, Roger J.; Drechsler, Henning; Jain, Mamta; Cutrell, James; Zhang, Song; Li, Xilong; Farukhi, Irfan; Castanon, Rosinda; Tebas, Pablo; Maalouf, Naim M.

    2014-01-01

    Background NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression. Methods In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48. Results Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP). Conclusion The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health. Trial Registration ClinicalTrials.gov NCT 00677300 PMID:25170938

  6. Non-Invasive Vagus Nerve Stimulation as Treatment for Trigeminal Allodynia

    PubMed Central

    Oshinsky, Michael L.; Murphy, Angela L.; Hekierski, Hugh; Cooper, Marnie; Simon, Bruce J.

    2014-01-01

    Implanted vagus nerve stimulation (VNS) has been used to treat seizures and depression. In this study, we explore the mechanism of action of non-invasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which leads to chronic trigeminal allodynia. nVNS for 2min decreases periorbital sensitivity in rats with periorbital trigeminal allodynia for up to 3.5hr after stimulation. Using microdialysis, we quantified levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC). Allodynic rats showed a 7.7±0.9 fold increase in extracellular glutamate in the TNC following i.p. administration of the chemical headache trigger, glyceryl trinitrate (GTN; 0.1mg/kg). Allodynic rats, which received nVNS, had only a 2.3±0.4 fold increase in extracellular glutamate following GTN similar to the response in control naive rats. When nVNS was delayed until 120min after GTN treatment, the high levels of glutamate in the TNC were reversed following nVNS. The nVNS stimulation parameters used in this study did not produce significant changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat trigeminal allodynia. PMID:24530613

  7. Phasic Treatment with Interferon Gamma Stimulates Release of Exosomes that Protect Against Spreading Depression.

    PubMed

    Pusic, Aya D; Kraig, Richard P

    2015-10-01

    The detrimental effects of T-cell-secreted interferon gamma (IFNγ) on oxidative stress (OS) and demyelination in multiple sclerosis (MS) are well recognized. Recently, we demonstrated that IFNγ-mediated damage to myelin also increases susceptibility to spreading depression (SD; the likely basis of migraine with aura). However, before onset of MS, induction of physiological levels of IFNγ, like that produced by environmental enrichment (EE), protects against demyelination and OS. Accordingly, we focused on the potential for physiological levels of IFNγ to protect against SD. EE, which occurs with a moderate and phasic increase in proinflammatory cytokines, reduces migraine frequency. Thus, we applied phasic or pulsed IFNγ to brain slice cultures to emulate EE. This treatment reduced OS, increased myelin basic protein, a marker for myelin, and reduced susceptibility to SD. Building on our research on exosomes in EE-based neuroprotection, we found that IFNγ stimulation of slice cultures induced release of exosomes, likely from the microglia that produce the same protective effects as IFNγ treatment when applied to naive cultures. Finally, nasal administration of IFNγ to rats recapitulated in vitro effects, reducing OS, increasing myelin, and reducing SD. These results support phasic IFNγ signaling as a therapeutic target for prevention of SD and, by extension, migraine.

  8. Three-Year Chemical Dependency and Mental Health Treatment Outcomes Among Adolescents: The Role of Continuing Care

    PubMed Central

    Sterling, Stacy; Chi, Felicia; Campbell, Cynthia; Weisner, Constance

    2010-01-01

    Background Few studies have examined the effects of treatment factors, including the types of services [chemical dependency (CD), psychiatric, or both], on long-term outcomes among adolescents following CD treatment, and whether receiving continuing care may contribute to better outcomes. This study examines the effect of the index CD and ongoing CD and psychiatric treatment episodes, 12-step participation, and individual characteristics such as CD and mental health (MH) severity and gender, age, and ethnicity, on 3-year CD and MH outcomes. Methods Participants were 296 adolescents aged 13 to 18 seeking treatment at 4 CD programs of a nonprofit, managed care, integrated health system. We surveyed participants at intake, 1 year, and 3 years, and examined survey and administrative data, and CD and psychiatric utilization. Results At 3 years, 29.7% of the sample reported total abstinence from both alcohol and drugs (excluding tobacco). Compared with girls, boys had only half the odds of being abstinent (OR = 0.46, p = 0.0204). Gender also predicted Externalizing severity at 3 years (coefficients 18.42 vs. 14.77, p < 0.01). CD treatment readmission in the second and third follow-up years was related to abstinence at 3 years (OR = 0.24, p = 0.0066 and OR = 3.33, p = 0.0207, respectively). Abstinence at 1 year predicted abstinence at 3 years (OR = 4.11, p < 0.0001). Those who were abstinent at 1 year also had better MH outcomes (both lower Internalizing and Externalizing scores) than those who were not (11.75 vs. 15.55, p = 0.0012 and 15.13 vs. 18.06, p = 0.0179, respectively). Conclusions A CD treatment episode resulting in good 1-year CD outcomes may contribute significantly to both CD and MH outcomes 3 years later. The findings also point to the value of providing a continuing care model of treatment for adolescents. PMID:19413644

  9. New approaches in the treatment of hepatitis C

    PubMed Central

    González-Grande, Rocío; Jiménez-Pérez, Miguel; González Arjona, Carolina; Mostazo Torres, José

    2016-01-01

    About 130-170 million people, is estimated to be infected with the hepatitis C virus (HCV). Chronic HCV infection is one of the leading causes of liver-related death and in many countries it is the primary reason for having a liver transplant. The main aim of antiviral treatment is to eradicate the virus. Until a few years ago the only treatment strategy was based on the combination of pegylated interferon and ribavirin (PEG/RBV). However, in genotypes 1 and 4 the rates of viral response did not surpass 50%, reaching up to 80% in the rest. In 2011 approval was given for the first direct acting antiviral agents (DAA), boceprevir and telaprevir, for treatment of genotype 1, in combination with traditional dual therapy. This strategy managed to increase the rates of sustained viral response (SVR) in both naive patients and in retreated patients, but with greater toxicity, interactions and cost, as well as being less safe in patients with advanced disease, in whom this treatment can trigger decompensation or even death. The recent, accelerated incorporation since 2013 of new more effective DAA, with pan-genomic properties and excellent tolerance, besides increasing the rates of SVR (even up to 100%), has also created a new scenario: shorter therapies, less toxicity and regimens free of PEG/RBV. This has enabled their almost generalised applicability in all patients. However, it should be noted that most of the scientific evidence available is based on expert opinion, case-control series, cohort studies and phase 2 and 3 trials, some with a reduced number of patients and select groups. Few data are currently available about the use of these drugs in daily clinical practice, particularly in relation to the appearance of side effects and interactions with other drugs, or their use in special populations or persons with the less common genotypes. This situation suggests the need for the generalised implementation of registries of patients receiving antiviral therapy. The

  10. Hepatitis C: Treatment

    MedlinePlus

    ... Public Home » Hepatitis C » Hepatitis C Treatment Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis C Treatment for Veterans and the Public Treatment ...

  11. Treatment of acute gout.

    PubMed

    Schlesinger, Naomi

    2014-05-01

    This article presents an overview of the treatment of acute gout. Nonpharmacologic and pharmacologic treatments, monotherapy versus combination therapy, suggested recommendations, guidelines for treatment, and drugs under development are discussed.

  12. Hyperprolactinemia Diagnosis and Treatment

    MedlinePlus

    ... may receive treatment with estrogen (for women) or testosterone (for men). Hypothyroidism. An underactive thyroid most often needs treatment with synthetic (laboratory- made) thyroid hormone. Most often this treatment ...

  13. Symptoms, Diagnosis & Treatment

    MedlinePlus

    ... three types of standard treatment for leukemia: chemotherapy, radiation, and stem cell transplant. Chemotherapy uses drugs to stop the growth ... three types of standard treatment for leukemia: chemotherapy, radiation, and stem cell transplant. Latest Treatment Over the past 10 years, ...

  14. Body Lice Treatment

    MedlinePlus

    ... Treatment FAQs Malathion FAQs Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ... Frequently Asked Questions (FAQs) Epidemiology & Risk Factors Disease Biology Diagnosis Treatment Prevention & Control Resources for Health Professionals ...

  15. Assertive Community Treatment (ACT)

    MedlinePlus

    ... community treatment? Assertive community treatment (ACT) is a model of psychiatric care that can be very effective ... it the most. Similar to the “treatment team” model of an inpatient psychiatric unit, which includes nurses, ...

  16. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase

    PubMed Central

    Hughes, T P; Saglio, G; Quintás-Cardama, A; Mauro, M J; Kim, D-W; Lipton, J H; Bradley-Garelik, M B; Ukropec, J; Hochhaus, A

    2015-01-01

    BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247. PMID:26118315

  17. Engaging HIV-HCV co-infected patients in HCV treatment: the roles played by the prescribing physician and patients' beliefs (ANRS CO13 HEPAVIH cohort, France)

    PubMed Central

    2012-01-01

    Background Treatment for the hepatitis C virus (HCV) may be delayed significantly in HIV/HCV co-infected patients. Our study aims at identifying the correlates of access to HCV treatment in this population. Methods We used 3-year follow-up data from the HEPAVIH ANRS-CO13 nationwide French cohort which enrolled patients living with HIV and HCV. We included pegylated interferon and ribavirin-naive patients (N = 600) at enrolment. Clinical/biological data were retrieved from medical records. Self-administered questionnaires were used for both physicians and their patients to collect data about experience and behaviors, respectively. Results Median [IQR] follow-up was 12[12-24] months and 124 patients (20.7%) had started HCV treatment. After multiple adjustment including patients' negative beliefs about HCV treatment, those followed up by a general practitioner working in a hospital setting were more likely to receive HCV treatment (OR[95%CI]: 1.71 [1.06-2.75]). Patients followed by general practitioners also reported significantly higher levels of alcohol use, severe depressive symptoms and poor social conditions than those followed up by other physicians. Conclusions Hospital-general practitioner networks can play a crucial role in engaging patients who are the most vulnerable and in reducing existing inequities in access to HCV care. Further operational research is needed to assess to what extent these models can be implemented in other settings and for patients who bear the burden of multiple co-morbidities. PMID:22409788

  18. Therapeutic Efficacy and Macrofilaricidal Activity of Doxycycline for the Treatment of River Blindness

    PubMed Central

    Walker, Martin; Specht, Sabine; Churcher, Thomas S.; Hoerauf, Achim; Taylor, Mark J.; Basáñez, María-Gloria

    2015-01-01

    Background. Onchocerca volvulus and lymphatic filariae, causing river blindness and elephantiasis, depend on endosymbiotic Wolbachia bacteria for growth, development, fertility, and survival. Clinical trials have shown that doxycycline treatment eliminates Wolbachia, causing long-term sterilization of adult female filariae and effecting potent macrofilaricidal activity. The continual reinfection by drug-naive worms that occurs in these trial settings dilutes observable anti-Wolbachia and antifilarial effects, making it difficult to estimate therapeutic efficacy and compare different doxycycline regimens, evaluated at different times after treatment. Methods. A meta-analytical modeling framework is developed to link all usable data collected from clinical trials measuring the Wolbachia status and viability of individual female adult worms collected at various times after treatment with 4, 5, or 6 weeks of daily 100 or 200 mg oral doxycycline. The framework is used to estimate efficacy parameters that are not directly measurable as trial outcomes. Results. The estimated efficacy of doxycycline (the maximum proportional reduction in the percentage of adult female O. volvulus positive for Wolbachia) is 91%–94% on average, irrespective of the treatment regimen. Efficacy is >95% in the majority of trial participants. The life span of Wolbachia-depleted worms is reduced by 70%–80%, from approximately 10 years to 2–3 years. Conclusions. The efficacy parameters are pertinent to the prospects of using doxycycline on a “test and treat” basis for onchocerciasis control and confirm doxycycline as a potent macrofilaricidal therapy. The modeling approach is more generally relevant to the design and evaluation of clinical trials for antifilarial drugs condu