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Sample records for cns relapse prediction

  1. CNS Genes Implicated in Relapse

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    Willard M. Freeman

    2008-01-01

    Full Text Available Drug abuse is a condition that impacts not only the individual drug user, but society as a whole. Although prevention of initial drug use is the most effective way to prevent addiction, avoiding relapse is a crucial component of drug addiction recovery. Recent studies suggest that there is a set of genes whose expression is robustly and stably altered following drug use and ensuing abstinence. Such stable changes in gene expression correlate with ultrastructural changes in brain as well as alterations in behavior. As persistent molecular changes, these genes may provide targets for the development of therapeutics. Developing a list of well-characterized candidate genes and examining the effect of manipulating these genes will contribute to the ultimate goal of developing effective treatments to prevent relapse to drug use.

  2. Secondary CNS relapse in diffuse large B-cell lymphoma: defining high-risk patients and optimization of prophylaxis strategies.

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    Savage, Kerry J

    2017-12-08

    Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. A number of studies have evaluated clinical risk factors in an attempt to identify high-risk patients to direct CNS staging investigations and consider prophylaxis strategies. The CNS International Prognostic Index is a robust and reproducible risk model that can identity patients at high risk of CNS relapse, but its specificity remains limited. Studies are emerging of biomarkers that predict CNS relapse that can be integrated with clinical risk models to better identify high-risk patients for CNS-directed prophylaxis strategies. Because CNS parenchymal disease is the predominant compartment, prophylaxis should include deeply penetrant drugs such as high-dose methotrexate. However, this has been associated with toxicity and has limited use in older patients. Novel therapies are being tested in primary CNS lymphoma with encouraging results and may represent rational strategies to be further explored in the prophylaxis setting. © 2016 by The American Society of Hematology. All rights reserved.

  3. CNS relapse in a low risk acute promyelocytic leukemia patient treated with ATRA-based regimen: is there a role for prophylactic CNS therapy in acute promyelocytic leukemia?

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    Gangadharan, K. V.; Prabhu, Raghuveer; Mampilly, Neena

    2009-01-01

    Though the incidence of CNS relapse in acute promyelocytic leukemia (AML-M3 FAB classification) has increased following the advent of all-trans retinoic acid (ATRA), still CNS relapse accounts for only 2–3% of all relapses in AML-M3 trated with standard ATRA plus chemotherapy regimen. We report a case of low risk AML-M3 treated with standard therapy, developing CNS relapse while on maintenance therapy with ATRA + 6-mercaptopurine (6-MP) + methotrexate (MTX).

  4. Impact of TCF3 rearrangement on CNS relapse in egyptian pediatric acute lymphoblastic leukemia.

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    ElGendi, Hoda M; Abdelmaksoud, Abeer A; Eissa, Doaa G; Abusikkien, Samy A

    2014-10-01

    TCF3 rearrangement mostly t(1;19) (q23;p13)/ TCF3-PBX1 gene is associated with favorable outcome in acute lymphoblastic leukemia (ALL) upon treatment with intensification protocols; however, it is associated with higher incidence of central nervous system (CNS) relapse which may affect outcome of patients. We aimed to assess TCF3 rearrangement in newly diagnosed pediatric ALL patients in relation to clinical and laboratory parameters, CNS relapse, and clinical outcome. Eighty newly diagnosed pediatric ALL patients following at Pediatric Hematology Oncology Clinic, Ain Shams University Hospitals were included in this study. Their ages ranged from 0.75 to 16 years. Seventy six (95%) patients had B-lineage ALL and four (5%) had T-lineage ALL. Data recorded included; age, sex, extramedullary manifestations, CNS, and testes infiltrations, risk stratification, response to treatment, and CBC and BM findings. TCF3 rearrangement was assessed by FISH technique using dual color break-apart probe. TCF3 rearrangement [t(1;19) (q23;p13)] was detected in 16 (20%) out of the 80 studied patients, and it was significantly associated with splenomegaly, lymphadenopathy, CNS infiltration at presentation, high total leucocytic count, low platelet count, high-risk group, and isolated CNS relapse. These results identify a group of high-risk ALL patients with high incidence of CNS relapse and poor response to standard therapeutic regimen. Analysis of TCF3 rearrangement [t(1;19) (q23;p13)] at diagnosis may provide a valuable target for modified and intensified CNS-directed chemotherapeutic protocol aiming to improve the patients' outcome.

  5. Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial

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    Pestalozzi, B.C.; Francis, P.; Quinaux, E.

    2008-01-01

    for these patients. RESULTS: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence...... of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3......%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. CONCLUSION: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse Udgivelsesdato: 2008/11...

  6. Attentional bias predicts heroin relapse following treatment

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    Marissen, Marlies A. E.; Franken, Ingmar H. A.; Waters, Andrew J.; Blanken, Peter; van den Brink, Wim; Hendriks, Vincent M.

    2006-01-01

    AIMS: Previous studies have shown that abstinent heroin addicts exhibit an attentional bias to heroin-related stimuli. It has been suggested that attentional bias may represent a vulnerability to relapse into drug use. In the present study, the predictive value of pre-treatment attentional bias on

  7. Lenalidomide and temozolomide combination in a very elderly patient with CNS relapse of diffuse large b-cell lymphoma.

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    Emanuele Cencini

    2017-06-01

    Full Text Available A 83 years old woman with CNS relapse occurred 6 months after chemoimmunoitherapy. The patient was defined ineligible for radiotherapy (RT and started oral temozolomide 250mg daily for 5 consecutive days without any improvement after 1st cycle. We administer lenalidomide 25mg daily for 21 days every 28 days together with temozolomide 250mg daily for 5 days every 28 days. The patient experienced a rapid improvement of general and cognitive conditions; Gadolinium-enhnaced brain MRI showed a wide reduction of neoplastic tissue. The patients maintained good clinical conditions with mild treatment toxicity until the end of 6th cycle, when brain MRI showed disease progression and the patient died 1 month later. We suggest lenalidomide could be a feasible option for CNS relapse in elderly DLBCL patients and it could be associated in future studies with other cytotoxic agents such as temozolomide

  8. Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era.

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    Kridel, Robert; Telio, David; Villa, Diego; Sehn, Laurie H; Gerrie, Alina S; Shenkier, Tamara; Klasa, Richard; Slack, Graham W; Tan, King; Gascoyne, Randy D; Connors, Joseph M; Savage, Kerry J

    2017-01-01

    The addition of rituximab has improved outcomes in diffuse large B-cell lymphoma (DLBCL), however, there remains limited information on the impact of rituximab in those with testicular involvement. All patients with diffuse large cell lymphoma and testicular involvement treated with curative intent were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. In total, 134 patients diagnosed between 1982 and 2015 with diffuse large cell lymphoma involving the testis were identified: 61 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like chemotherapy and 73 received CHOP plus rituximab (R-CHOP). A greater proportion of R-CHOP treated patients had higher International Prognostic Index (IPI, P = 0·005). In multivariate analysis, the protective effect of rituximab on progression-free survival (hazard ratio (HR) 0·42, P survival (HR 0·39, P < 0·001) and cumulative incidence of progression (HR 0·46, P = 0·014) were independent of the IPI. However, in a competing risk multivariate analysis including central nervous system (CNS) prophylaxis and the CNS-IPI, rituximab was not associated with a decreased risk of CNS relapse. The addition of rituximab has reduced the risk of lymphoma recurrence in testicular DLBCL, presumably through improved eradication of systemic disease. However, CNS relapse risk remains high and further studies evaluating effective prophylactic strategies are needed. © 2016 John Wiley & Sons Ltd.

  9. A classification framework for drug relapse prediction | Salleh ...

    African Journals Online (AJOL)

    mining algorithms, Artificial Intelligence Neural Network (ANN) is one of the best algorithms to predict relapse among drug addicts. This may help the rehabilitation center to predict relapse individually and the prediction result is hoped to prevent drug addicts from relapse. Keywords: classification; artificial neural network; ...

  10. LATE-BREAKING ABSTRACT: Early relapse of non-small cell lung cancer (NSCLC) found after CNS-symptoms

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    Hansen, Niels-Chr. G.; Laursen, Christian B.; Jeppesen, Stefan S.

    2016-01-01

    Background: Danish guidelines have since February 2014 recommended MR of the brain prior to curative radiotherapy in patients with NSCLC and N2-disease. More recently O'Dowd et al. [Lung Cancer 86 (2014) 185–189] have suggested MR of the brain prior to surgery no matter the stage.Aim: To study...... after symptoms within 24 months decreased in the 3½ years after the introduction of CT-based follow-up, p < 0,001 (table), but the total fraction presenting with CNS-symptoms did not change, p = 0.296. Relapses after stage I cancer decreased (p = 0.025), while no differences or changes for stages II...

  11. Acute disseminated encephalomyelitis mimicking late CNS relapse of acute lymphoblastic leukaemia: case report

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    Kumar Ram

    2007-02-01

    Full Text Available Abstract Background Acute encephalomyelopathy occurring after an allogeneic bone marrow transplant for leukaemia is a diagnostic emergency. The diagnosis can be challenging since there is a wide set of alternative diagnoses, including opportunistic infections and relapse of the leukaemia. Case presentation A 13-year old girl presented with a severe acute myelopathy and encephalopathy. She was in prolonged remission from a central nervous system and bone marrow relapse of an acute lymphoblastic leukaemia, treated with allogeneic bone marrow transplantation. Neuroimaging showed multifocal grey and white matter lesions of demyelinating appearance in the brain and entire spine. Immunophenotyping and cytogenetic investigations of the girl's cerebrospinal fluid lymphocytosis excluded a late central nervous system relapse of her leukaemia. The diagnosis was acute disseminated encephalomyelitis. With standard immunosuppressive therapy, the girl had early cerebral recovery but a prolonged period of recovery from her myelopathy. Conclusion Acute disseminated encephalomyelitis should be considered in the differential diagnosis of acute encephalomyelopathy after bone marrow transplantation for leukaemia. Demyelinating syndromes such as acute disseminated encephalomyelitis may be late sequelae of bone marrow transplantation.

  12. Acute disseminated encephalomyelitis mimicking late CNS relapse of acute lymphoblastic leukaemia: case report

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    Kumar, Ram; Nijalingappa, Shobha; Grainger, John; Ismayl, Omar

    2007-01-01

    Background Acute encephalomyelopathy occurring after an allogeneic bone marrow transplant for leukaemia is a diagnostic emergency. The diagnosis can be challenging since there is a wide set of alternative diagnoses, including opportunistic infections and relapse of the leukaemia. Case presentation A 13-year old girl presented with a severe acute myelopathy and encephalopathy. She was in prolonged remission from a central nervous system and bone marrow relapse of an acute lymphoblastic leukaemia, treated with allogeneic bone marrow transplantation. Neuroimaging showed multifocal grey and white matter lesions of demyelinating appearance in the brain and entire spine. Immunophenotyping and cytogenetic investigations of the girl's cerebrospinal fluid lymphocytosis excluded a late central nervous system relapse of her leukaemia. The diagnosis was acute disseminated encephalomyelitis. With standard immunosuppressive therapy, the girl had early cerebral recovery but a prolonged period of recovery from her myelopathy. Conclusion Acute disseminated encephalomyelitis should be considered in the differential diagnosis of acute encephalomyelopathy after bone marrow transplantation for leukaemia. Demyelinating syndromes such as acute disseminated encephalomyelitis may be late sequelae of bone marrow transplantation. PMID:17411447

  13. Models to predict relapse in psychosis: A systematic review.

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    Sarah Sullivan

    Full Text Available There is little evidence on the accuracy of psychosis relapse prediction models. Our objective was to undertake a systematic review of relapse prediction models in psychosis.We conducted a literature search including studies that developed and/or validated psychosis relapse prediction models, with or without external model validation. Models had to target people with psychosis and predict relapse. The key databases searched were; Embase, Medline, Medline In-Process Citations & Daily Update, PsychINFO, BIOSIS Citation Index, CINAHL, and Science Citation Index, from inception to September 2016. Prediction modelling studies were assessed for risk of bias and applicability using the PROBAST tool.There were two eligible studies, which included 33,088 participants. One developed a model using prodromal symptoms and illness-related variables, which explained 14% of relapse variance but was at high risk of bias. The second developed a model using administrative data which was moderately discriminative (C = 0.631 and associated with relapse (OR 1.11 95% CI 1.10, 1.12 and achieved moderately discriminative capacity when validated (C = 0.630. The risk of bias was low.Due to a lack of high quality evidence it is not possible to make any specific recommendations about the predictors that should be included in a prognostic model for relapse. For instance, it is unclear whether prodromal symptoms are useful for predicting relapse. The use of routine data to develop prediction models may be a more promising approach, although we could not empirically compare the two included studies.

  14. Reactivity to laboratory stress provocation predicts relapse to cocaine.

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    Back, Sudie E; Hartwell, Karen; DeSantis, Stacia M; Saladin, Michael; McRae-Clark, Aimee L; Price, Kimber L; Moran-Santa Maria, Megan M; Baker, Nathaniel L; Spratt, Eve; Kreek, Mary Jeanne; Brady, Kathleen T

    2010-01-01

    Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood. The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1 microg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocortico-trophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants' cocaine use was monitored for approximately 1 month following testing. The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use. The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention. Published by Elsevier Ireland Ltd.

  15. Relapse prediction: A meteorology-inspired mobile model

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    F Michler Bishop

    2016-08-01

    Full Text Available Predicting relapses to binge drinking in non-dependent drinkers may now be possible with smartphones. Smartphones have been shown to help individuals reduce their drinking and may help binge drinkers accelerate that process. Predicting the weather has improved greatly over the past 50 years, but predicting a binge drinking episode may be less difficult. It is hypothesized that the number of factors with high predictive value for any particular individual may not be large. Collecting data over time, a smartphone should be able to learn which combination of factors has a high probability of leading to an episode of binge drinking.

  16. Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial.

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    Tabouret, Emeline; Houillier, Caroline; Martin-Duverneuil, Nadine; Blonski, Marie; Soussain, Carole; Ghesquières, Herve; Houot, Roch; Larrieu, Delphine; Soubeyran, Pierre; Gressin, Remy; Gyan, Emmanuel; Chinot, Olivier; Taillandier, Luc; Choquet, Sylvain; Alentorn, Agusti; Leclercq, Delphine; Omuro, Antonio; Tanguy, Marie-Laure; Hoang-Xuan, Khe

    2017-03-01

    Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities. Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that objective response at 2 months (P 11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions. Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.

  17. Decreased dopamine activity predicts relapse in methamphetamine abusers

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    Wang G. J.; Wang, G.-J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

    2011-01-20

    Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

  18. Mood Linked Responses in Medial Prefrontal Cortex Predict Relapse in Patients with Recurrent Unipolar Depression

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    Farb, Norman A. S.; Anderson, Adam K.; Bloch, Richard T.; Segal, Zindel V.

    2011-01-01

    Background Altered cognitive processing following mood challenge is associated with elevated relapse risk in remitted unipolar depressed patients, but little is known about the neural basis of this reactivity and its link to depressive relapse and prophylaxis. Methods Remitted unipolar depressed participants (n = 16) and healthy controls (n = 16) underwent functional magnetic resonance imaging (fMRI) while viewing sad and neutral film clips. Correlations were determined between emotional reactivity (neural responses to sad vs. neutral films) in remitted patients and subsequent relapse status over an 18 month follow-up period. An ROC analysis was used to determine signal cutoffs for predicting relapse. Emotional reactivity in relapse prognostic areas was compared between groups. Results Within the remitted group, relapse was predicted by medial prefrontal cortical activity (MPFC, BA 32), and contraindicated by visual cortical activity (BA 17). MPFC reactivity predicted rumination, whereas visual cortical reactivity predicted distress tolerance (acceptance). Compared to control participants, remitted depressed patients who sustained remission demonstrated a more pronounced tradeoff between MPFC and visual cortex reactivity. The difference score between MPFC and visual reactivity yielded excellent prediction of depressive relapse. Conclusions Medial prefrontal cortical reactivity to mood provocation in remitted unipolar depressed patients serves as a marker of relapse risk rather than successful emotion regulation. Enduring remission is characterized by a normalization of the MPFC to the level of healthy controls. Further, visual cortex reactivity predicts resilience against depressive relapse, indicating a prophylactic role for sensory rather than ruminative cognitive reactivity in the processing of negative emotion. PMID:21531382

  19. Predictive factors for relapse in patients on buprenorphine maintenance.

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    Ferri, Michael; Finlayson, Alistair J Reid; Wang, Li; Martin, Peter R

    2014-01-01

    Despite the dramatic increase in the use of buprenorphine for the treatment of opioid dependence, clinical outcomes of this treatment approach continue to need evaluation. This study examines factors associated with relapse and retention during buprenorphine treatment in a sample of opioid dependent outpatients. In a retrospective chart review of 62 patients with opioid dependence, relapse was determined by self-report, urine toxicology screens, and by checking the state controlled substance monitoring database. Data was analyzed using two-way tests of association and logistic regression. Patients with comorbid anxiety disorders, active benzodiazepine use (contrary to clinic policy), or active alcohol abuse, were significantly more likely to relapse. Patients who relapsed were also more likely to be on a higher buprenorphine maintenance dose. This study identifies relapse risk factors during buprenorphine treatment for opioid dependence. Future research is needed to determine whether modifying these factors may lead to improved treatment outcomes. © American Academy of Addiction Psychiatry.

  20. Exercise identity and attribution properties predict negative self-conscious emotions for exercise relapse.

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    Flora, Parminder K; Strachan, Shaelyn M; Brawley, Lawrence R; Spink, Kevin S

    2012-10-01

    Research on exercise identity (EXID) indicates that it is related to negative affect when exercisers are inconsistent or relapse. Although identity theory suggests that causal attributions about this inconsistency elicit negative self-conscious emotions of shame and guilt, no EXID studies have examined this for exercise relapse. Weiner's attribution-based theory of interpersonal motivation (2010) offers a means of testing the attribution-emotion link. Using both frameworks, we examined whether EXID and attributional properties predicted negative emotions for exercise relapse. Participants (n = 224) read an exercise relapse vignette, and then completed EXID, attributions, and emotion measures. Hierarchical multiple regression models using EXID and the attributional property of controllability significantly predicted each of shame and guilt, R² adjusted = .09, ps ≤ .001. Results support identity theory suggestions and Weiner's specific attribution-emotion hypothesis. This first demonstration of an interlinking of EXID, controllability, and negative self-conscious emotions offers more predictive utility using complementary theories than either theory alone.

  1. Mindfulness predicts relapse/recurrence in major depressive disorder after mindfulness-based cognitive therapy.

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    Michalak, Johannes; Heidenreich, Thomas; Meibert, Petra; Schulte, Dietmar

    2008-08-01

    Empirical evidence for the effectiveness of mindfulness-based cognitive therapy (MBCT) is encouraging. However, data concerning the role of mindfulness in its relapse preventive effect are lacking. In our study, 25 formerly depressed patients received MBCT. Mindfulness was assessed before and immediately after MBCT using the Mindful Attention and Awareness Scale. Mindfulness significantly increased during MBCT, and posttreatment levels of mindfulness predicted the risk of relapse/recurrence to major depressive disorder in the 12-month follow-up period. Mindfulness predicted the risk of relapse/recurrence after controlling for numbers of previous episodes and residual depressive symptoms. The results provide preliminary evidence for the notion that mindfulness is an important factor in relapse prevention in major depression.

  2. Comparing early signs and basic symptoms as methods for predicting psychotic relapse in clinical practice.

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    Eisner, Emily; Drake, Richard; Lobban, Fiona; Bucci, Sandra; Emsley, Richard; Barrowclough, Christine

    2017-05-09

    Early signs interventions show promise but could be further developed. A recent review suggested that 'basic symptoms' should be added to conventional early signs to improve relapse prediction. This study builds on preliminary evidence that basic symptoms predict relapse and aimed to: 1. examine which phenomena participants report prior to relapse and how they describe them; 2. determine the best way of identifying pre-relapse basic symptoms; 3. assess current practice by comparing self- and casenote-reported pre-relapse experiences. Participants with non-affective psychosis were recruited from UK mental health services. In-depth interviews (n=23), verbal checklists of basic symptoms (n=23) and casenote extracts (n=208) were analysed using directed content analysis and non-parametric statistical tests. Three-quarters of interviewees reported basic symptoms and all reported conventional early signs and 'other' pre-relapse experiences. Interviewees provided rich descriptions of basic symptoms. Verbal checklist interviews asking specifically about basic symptoms identified these experiences more readily than open questions during in-depth interviews. Only 5% of casenotes recorded basic symptoms; interviewees were 16 times more likely to report basic symptoms than their casenotes did. The majority of interviewees self-reported pre-relapse basic symptoms when asked specifically about these experiences but very few casenotes reported these symptoms. Basic symptoms may be potent predictors of relapse that clinicians miss. A self-report measure would aid monitoring of basic symptoms in routine clinical practice and would facilitate a prospective investigation comparing basic symptoms and conventional early signs as predictors of relapse. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer.

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    Garcia-Murillas, Isaac; Schiavon, Gaia; Weigelt, Britta; Ng, Charlotte; Hrebien, Sarah; Cutts, Rosalind J; Cheang, Maggie; Osin, Peter; Nerurkar, Ashutosh; Kozarewa, Iwanka; Garrido, Javier Armisen; Dowsett, Mitch; Reis-Filho, Jorge S; Smith, Ian E; Turner, Nicholas C

    2015-08-26

    The identification of early-stage breast cancer patients at high risk of relapse would allow tailoring of adjuvant therapy approaches. We assessed whether analysis of circulating tumor DNA (ctDNA) in plasma can be used to monitor for minimal residual disease (MRD) in breast cancer. In a prospective cohort of 55 early breast cancer patients receiving neoadjuvant chemotherapy, detection of ctDNA in plasma after completion of apparently curative treatment-either at a single postsurgical time point or with serial follow-up plasma samples-predicted metastatic relapse with high accuracy [hazard ratio, 25.1 (confidence interval, 4.08 to 130.5; log-rank P Mutation tracking in serial samples increased sensitivity for the prediction of relapse, with a median lead time of 7.9 months over clinical relapse. We further demonstrated that targeted capture sequencing analysis of ctDNA could define the genetic events of MRD, and that MRD sequencing predicted the genetic events of the subsequent metastatic relapse more accurately than sequencing of the primary cancer. Mutation tracking can therefore identify early breast cancer patients at high risk of relapse. Subsequent adjuvant therapeutic interventions could be tailored to the genetic events present in the MRD, a therapeutic approach that could in part combat the challenge posed by intratumor genetic heterogeneity. Copyright © 2015, American Association for the Advancement of Science.

  4. The Value of Fecal Markers in Predicting Relapse in Inflammatory Bowel Diseases

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    Bianca J. Galgut

    2018-01-01

    Full Text Available The inflammatory bowel diseases (IBDs are lifelong chronic illnesses that place an immense burden on patients. The primary aim of therapy is to reduce disease burden and prevent relapse. However, the occurrence of relapses is often unpredictable. Current disease monitoring is primarily by way of clinical indices, with relapses often only recognized once the inflammatory episode is established with subsequent symptoms and gut damage. The window between initial upregulation of the inflammatory response and the recognition of symptoms may provide an opportunity to prevent the relapse and associated morbidity. This review will describe the existing literature surrounding predictive indicators of relapse of IBD with a specific focus on fecal biomarkers. Fecal biomarkers offer promise as a convenient, non-invasive, low cost option for disease monitoring that is predictive of subsequent relapse. To exploit the potential of fecal biomarkers in this role, further research is now required. This research needs to assess multiple fecal markers in context with demographics, disease phenotype, genetics, and intestinal microbiome composition, to build disease behavior models that can provide the clinician with sufficient confidence to intervene and change the long-term disease course.

  5. PREDICTION OF RELAPSE FROM HYPERTHYROIDISM FOLLOWING ANTITHYROID MEDICATION WITHDRAWAL USING TECHNETIUM THYROID UPTAKE SCANNING.

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    Nakhjavani, Manouchehr; Abdollahi, Soraya; Farzanefar, Saeed; Abousaidi, Mohammadtagi; Esteghamati, Alireza; Naseri, Maryam; Eftekhari, Mohamad; Abbasi, Mehrshad

    2017-04-02

    Technetium thyroid uptake (TTU) is not inhibited by antithyroid drugs (ATD) and reflects the degree of thyroid stimulation. We intended to predict the relapse rate from hyperthyroidism based on TTU measurement. Out of 44 initially enrolled subjects, 38 patients aged 41.6 ± 14.6 with Graves disease (duration: 84 ± 78 months) completed the study. TTU was performed with 40-second imaging of the neck and mediastinum 20 minutes after injection of 1 mCi technetium-99m pertechnetate. TTU was measured as the percentage of the count of activity accumulated in the thyroidal region minus the mediastinal background uptake to the count of 1 mCi technetium-99m under the same acquisition conditions. Then methimazole was stopped and patients were followed. The optimal TTU cutoff value for Graves relapse prediction was calculated using Youden's J statistic. Hyperthyroidism relapsed in 11 (28.9%) patients 122 ± 96 (range: 15-290) days post-ATD withdrawal. The subjects in remission were followed for 209 ± 81 days (range: 88-390). TTU was significantly higher in patients with forthcoming relapse (12.0 ± 8.0 vs. 3.9 ± 2.0, P = .007). The difference was significant after adjustment for age, sex, history of previous relapse, disease duration, and thyroid-stimulating hormone (TSH) levels before withdrawal. The area under the receiver operative characteristic (ROC) curve was 0.87. The optimal TTU cutoff value for classification of subjects with relapse and remission was 8.7 with sensitivity, specificity, and positive and negative predictive value of 73%, 100%, 100%, and 90%, respectively (odds ratio [OR] = 10.0; 95% confidence interval [CI]: 3.4-29.3). TTU evaluation in hyperthyroid patients receiving antithyroid medication is an accurate and practical method for predicting relapse after ATD withdrawal. ATD = antithyroid drugs RIU = radio-iodine uptake TSH = thyroid-stimulating hormone TSI = thyroid-stimulating immunoglobulin TTU = technetium thyroid uptake.

  6. Cognitive reactivity versus dysfunctional cognitions and the prediction of relapse in recurrent major depressive disorder.

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    Figueroa, Caroline A; Ruhé, Henricus G; Koeter, Maarten W; Spinhoven, Philip; Van der Does, Willem; Bockting, Claudi L; Schene, Aart H

    2015-10-01

    Major depressive disorder (MDD) is a burdensome disease that has a high risk of relapse/recurrence. Cognitive reactivity appears to be a risk factor for relapse. It remains unclear, however, whether dysfunctional cognitions alone or the reactivity of such cognitions to mild states of sadness (ie, cognitive reactivity) is the crucial factor that increases relapse risk. We aimed to assess the long-term predictive value of cognitive reactivity versus dysfunctional cognitions and other risk factors for depressive relapse. In a prospective cohort of outpatients (N = 116; studied between 2000-2005) who had experienced ≥ 2 previous major depressive episodes (MDEs) and were in remission (DSM-IV) at the start of follow-up, we measured cognitive reactivity, with the Leiden Index of Depression Sensitivity (LEIDS), and dysfunctional cognitions, with the Dysfunctional Attitudes Scale, simultaneously. Course of illness (with the primary outcome of MDE assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders Patient Edition) and time to relapse were monitored prospectively for 3.5 years. Cognitive reactivity scores were associated with time to relapse over the 3.5-year follow-up and also when corrected for the number of previous MDEs and concurrent depressive symptoms (hazard ratio for 1 standard deviation [(HR(SD)); 20 points of the LEIDS, measuring cognitive reactivity] = 1.47; 95% CI, 1.04-2.09; P = .031). Rumination appeared to be a particularly strong predictor of relapse (HR(SD) = 1.60; 95% CI, 1.13-2.26; P = .007). Dysfunctional cognitions did not predict relapse over 3.5 years (HR(SD) = 1.00; 95% CI, 0.74-1.37; P = .93). Every 20-point increase on the cognitive reactivity scale resulted in a 10% to 15% increase in risk of relapse (corrected for previous MDEs and concurrent depressive symptoms). Cognitive reactivity--and particularly rumination--is a long-term predictor of relapse. Future research should address whether psychological interventions can

  7. Do Alcohol Relapse Episodes During Treatment Predict Long-Term Outcomes? Investigating the Validity of Existing Definitions of Alcohol Use Disorder Relapse.

    Science.gov (United States)

    Maisto, Stephen A; Roos, Corey R; Hallgren, Kevin A; Moskal, Dezarie; Wilson, Adam D; Witkiewitz, Katie

    2016-10-01

    The construct of relapse is used widely in clinical research and practice of alcohol use disorder (AUD) treatment. The purpose of this study was to test the predictive validity of commonly appearing definitions of AUD relapse in the empirical literature. Secondary analyses of data from Project MATCH and COMBINE were conducted using 7 definitions of "relapse" based on drinking quantity within a single drinking episode: any drinking; at least 4/5 drinks for women/men; at least 4.3/7.1 drinks for women/men; at least 6/7 drinks for women/men; at least 6 drinks; at least 7/9 drinks for women/men; and at least 8/10 drinks for women/men. Relapse was used to predict alcohol consumption, related consequences, and nonconsumption outcomes (quality of life, psychosocial functioning) at the end of treatment and up to 1 year posttreatment. Regression analyses indicated within-treatment relapse definitions significantly predicted end-of-treatment alcohol consumption and alcohol-related consequences. Heavy drinking definitions were generally more predictive than the any drinking definition, but no single heavy drinking definition was consistently a better predictor of outcomes. Relapse definitions were less predictive of longer-term alcohol-related outcomes and both shorter- and longer-term nonconsumption outcomes, including health and psychosocial functioning. One particular definition of relapse did not consistently stand out as the best predictor. Advances in AUD research may require reconceptualization of relapse as a multifaceted dynamic process and may consider a wider range of relevant behaviors (e.g., health and psychosocial functioning) when examining the change process in individuals with AUD. Copyright © 2016 by the Research Society on Alcoholism.

  8. Prediction of acute multiple sclerosis relapses by transcription levels of peripheral blood cells

    Directory of Open Access Journals (Sweden)

    Or-Bach Rotem

    2009-07-01

    Full Text Available Abstract Background The ability to predict the spatial frequency of relapses in multiple sclerosis (MS would enable physicians to decide when to intervene more aggressively and to plan clinical trials more accurately. Methods In the current study our objective was to determine if subsets of genes can predict the time to the next acute relapse in patients with MS. Data-mining and predictive modeling tools were utilized to analyze a gene-expression dataset of 94 non-treated patients; 62 patients with definite MS and 32 patients with clinically isolated syndrome (CIS. The dataset included the expression levels of 10,594 genes and annotated sequences corresponding to 22,215 gene-transcripts that appear in the microarray. Results We designed a two stage predictor. The first stage predictor was based on the expression level of 10 genes, and predicted the time to next relapse with a resolution of 500 days (error rate 0.079, p Conclusion We conclude that gene expression analysis is a valuable tool that can be used in clinical practice to predict future MS disease activity. Similar approach can be also useful for dealing with other autoimmune diseases that characterized by relapsing-remitting nature.

  9. Fecal Calprotectin Predicts Relapse and Histological Mucosal Healing in Ulcerative Colitis

    DEFF Research Database (Denmark)

    Theede, Klaus; Holck, Susanne; Ibsen, Per

    2016-01-01

    endoscopy, and the need for a reliable noninvasive biomarker to predict disease relapse is obvious. METHODS: Seventy patients were included and followed up for 12 months. Inclusion criteria were a total Mayo score ≤1 and a Mayo endoscopic score = 0. The patients underwent sigmoidoscopy with rectal biopsies...

  10. Prediction of immunophenotype, treatment response, and relapse in childhood acute lymphoblastic leukemia using DNA microarrays

    DEFF Research Database (Denmark)

    Willenbrock, Hanni; Juncker, Agnieszka; Schmiegelow, K.

    2004-01-01

    Gene expression profiling is a promising tool for classification of pediatric acute lymphoblastic leukemia ( ALL). We analyzed the gene expression at the time of diagnosis for 45 Danish children with ALL. The prediction of 5-year event-free survival or relapse after treatment by NOPHO-ALL92 or 2000...

  11. Identification of blood-based molecular signatures for prediction of response and relapse in schizophrenia patients

    NARCIS (Netherlands)

    E. Schwarz (Emanuel); P.C. Guest (Paul); J. Steiner (Johann); B. Bogerts (Bernhard); S. Bahn (Sabine)

    2012-01-01

    textabstractThe current inability of psychiatric medicine to objectively select the most appropriate treatment or to predict imminent relapse are major factors contributing to the severity and clinical burden of schizophrenia. We have previously used multiplexed immunoassays to show that

  12. Barkhof Magnetic Resonance Imaging Criteria Predict Early Relapse in Pediatric Multiple Sclerosis

    NARCIS (Netherlands)

    Neuteboom, Rinze F.; Ketelslegers, Immy A.; Boon, Maartje; Catsman-Berrevoets, Coriene E.; Hintzen, Rogier Q.

    We sought to identify clinical and radiologic features predicting early relapse after a diagnosis of multiple sclerosis in children. In this nationwide retrospective multicenter study in The Netherlands, we included 28 children with multiple sclerosis with onset before age 16 years. Magnetic

  13. Barkhof magnetic resonance imaging criteria predict early relapse in pediatric multiple sclerosis.

    NARCIS (Netherlands)

    Neuteboom, R.F.; Ketelslegers, I.A.; Boon, M.; Catsman-Berrevoets, C.E.; Hintzen, R.Q.

    2010-01-01

    We sought to identify clinical and radiologic features predicting early relapse after a diagnosis of multiple sclerosis in children. In this nationwide retrospective multicenter study in The Netherlands, we included 28 children with multiple sclerosis with onset before age 16 years. Magnetic

  14. Descriptive and predictive validity of a high-risk alcoholism relapse model.

    Science.gov (United States)

    Yates, W R; Booth, B M; Reed, D A; Brown, K; Masterson, B J

    1993-11-01

    A major problem with alcoholism treatment is the high rate of early recidivism to drinking and re-admission for alcoholism treatment. The objective of this study was to retest a model or predict early (within 6 months) re-admission to alcoholism treatment using a second independent sample. Additionally, we compared a high-risk alcoholism relapse (HAR) model (defined by chronicity of heavy drinking, daily alcohol consumption and previous treatment history) with three previously defined alcoholism typologies for descriptive and predictive validity. Male alcoholics (N = 299) admitted for treatment at a Veterans Affairs inpatient treatment program were interviewed and then followed for 6 months after discharge. The HAR model identified 107 (35.8%) alcoholics at high-risk for relapse prior to discharge. Of the HAR group 61% were re-admitted within 6 months compared to 28% of the low-risk alcoholism relapse (LAR) group (OR = 4.0, 95% CI = 2.4-6.8). The HAR group was older with a lower socioeconomic status, fewer legal problems, more physical and mental health problems and decreased evidence of social support. The HAR model was more successful than were the typologies for predicting early relapse. The HAR model demonstrates descriptive and predictive validity and compares favorably to existing typology models.

  15. Expression changes in the stroma of prostate cancer predict subsequent relapse.

    Directory of Open Access Journals (Sweden)

    Zhenyu Jia

    Full Text Available Biomarkers are needed to address overtreatment that occurs for the majority of prostate cancer patients that would not die of the disease but receive radical treatment. A possible barrier to biomarker discovery may be the polyclonal/multifocal nature of prostate tumors as well as cell-type heterogeneity between patient samples. Tumor-adjacent stroma (tumor microenvironment is less affected by genetic alteration and might therefore yield more consistent biomarkers in response to tumor aggressiveness. To this end we compared Affymetrix gene expression profiles in stroma near tumor and identified a set of 115 probe sets for which the expression levels were significantly correlated with time-to-relapse. We also compared patients that chemically relapsed shortly after prostatectomy (<1 year, and patients that did not relapse in the first four years after prostatectomy. We identified 131 differentially expressed microarray probe sets between these two categories. 19 probe sets (15 genes overlapped between the two gene lists with p<0.0001. We developed a PAM-based classifier by training on samples containing stroma near tumor: 9 rapid relapse patient samples and 9 indolent patient samples. We then tested the classifier on 47 different samples, containing 90% or more stroma. The classifier predicted the risk status of patients with an average accuracy of 87%. This is the first general tumor microenvironment-based prognostic classifier. These results indicate that the prostate cancer microenvironment exhibits reproducible changes useful for predicting outcomes for patients.

  16. Predicting relapsing-remitting dynamics in multiple sclerosis using discrete distribution models: a population approach.

    Directory of Open Access Journals (Sweden)

    Nieves Velez de Mendizabal

    Full Text Available Relapsing-remitting dynamics are a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. A clinical relapse in MS reflects an acute focal inflammatory event in the central nervous system that affects signal conduction by damaging myelinated axons. Those events are evident in T1-weighted post-contrast magnetic resonance imaging (MRI as contrast enhancing lesions (CEL. CEL dynamics are considered unpredictable and are characterized by high intra- and inter-patient variability. Here, a population approach (nonlinear mixed-effects models was applied to analyse of CEL progression, aiming to propose a model that adequately captures CEL dynamics.We explored several discrete distribution models to CEL counts observed in nine MS patients undergoing a monthly MRI for 48 months. All patients were enrolled in the study free of immunosuppressive drugs, except for intravenous methylprednisolone or oral prednisone taper for a clinical relapse. Analyses were performed with the nonlinear mixed-effect modelling software NONMEM 7.2. Although several models were able to adequately characterize the observed CEL dynamics, the negative binomial distribution model had the best predictive ability. Significant improvements in fitting were observed when the CEL counts from previous months were incorporated to predict the current month's CEL count. The predictive capacity of the model was validated using a second cohort of fourteen patients who underwent monthly MRIs during 6-months. This analysis also identified and quantified the effect of steroids for the relapse treatment.The model was able to characterize the observed relapsing-remitting CEL dynamic and to quantify the inter-patient variability. Moreover, the nature of the effect of steroid treatment suggested that this therapy helps resolve older CELs yet does not affect newly appearing active lesions in that month. This model could be used for design of future longitudinal studies and clinical trials, as

  17. The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    El-Galaly, Tarec Christoffer; Villa, Diego; Michaelsen, Thomas Yssing

    2017-01-01

    independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2–21.2%) compared with 2.6% (95% CI 1.7–3.5) among......Purpose Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown....... Methods We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We...

  18. Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease.

    Science.gov (United States)

    Stebbing, Justin; Adams, Caroline; Sanitt, Adam; Mletzko, Salvinia; Nelson, Mark; Gazzard, Brian; Newsom-Davis, Tom; Bower, Mark

    2011-07-14

    HIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals.

  19. Usefulness of a rapid faecal calprotectin test to predict relapse in Crohn's disease patients on maintenance treatment with adalimumab.

    Science.gov (United States)

    Ferreiro-Iglesias, Rocio; Barreiro-de Acosta, Manuel; Lorenzo-Gonzalez, Aurelio; Dominguez-Muñoz, Juan Enrique

    2016-01-01

    Predicting relapse in Crohn's disease (CD) patients by measuring non-invasive biomarkers could allow for early changes of treatment. Data are scarce regarding the utility of monitoring calprotectin to predict relapse. The aim of the study was to evaluate the predictive value of a rapid test of faecal calprotectin (FC) to predict for flares in CD patients on maintenance treatment with adalimumab (ADA). A prospective, observational cohort study was designed. Inclusion criteria were CD patients in clinical remission on a standard dose of ADA therapy. Fresh FC was measured using a rapid test. Thirty patients were included (median age 38 years, 56.7% female). After the 4 months follow-up, 70.0% patients remained in clinical remission and 30.0% had a relapse. FC concentration at inclusion was significantly higher in those patients who relapsed during the follow-up (625 μg/g) compared to those who stayed in remission (45 μg/g). The optimal cut-off for FC to predict relapse was 204 μg/g. The area under the receiver-operating characteristic curve was 0.968. Sensitivity, specificity, positive, and negative predictive value of FC to predict relapse were 100%, 85.7%, 74.1%, and 100%, respectively. In CD patients on ADA maintenance therapy, FC levels measured with a rapid test allow relapse over the following months to be predicted with high accuracy. Low FC levels exclude relapse within at least 4 months after testing, whereas high levels are associated with relapse in three out of every four patients.

  20. Role of fecal calprotectin testing to predict relapse in teenagers with inflammatory bowel disease who report full disease control.

    Science.gov (United States)

    van Rheenen, Patrick F

    2012-11-01

    Teenagers with inflammatory bowel disease undergo regular follow-up visits to watch for symptoms that may indicate relapse. Current disease activity is frequently estimated with the use of the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohn's Disease Activity Index (PCDAI). We examined the capacity of fecal calprotectin and C-reactive protein (CRP) to predict relapse in teenagers who report no symptoms. Second, we examined whether calprotectin and CRP as an "add-on test" improve the specificity of PUCAI or PCDAI to predict relapse. We collected data of 62 consecutive teenagers (31 with Crohn's disease and 31 with ulcerative colitis) who scored their degree of disease control between 90 and 100% on two successive outpatient clinic visits. Calprotectin, PUCAI or PCDAI, and CRP were measured at baseline. Primary outcome was symptomatic relapse within 3 months of baseline, necessitating the introduction of steroids, exclusive enteral nutrition, or an aminosalicylate dose escalation. Fifteen teenagers (24%) developed symptomatic relapse within 3 months of baseline. Based on the receiver operating characteristic curve, the optimum calprotectin cutpoint to differentiate high from low risk patients was 500 μg/g. The PUCAI or PCDAI predicted relapse in 42% (11/26) of teenagers with a positive result (score ≥ 10 points), while a negative PUCAI or PCDAI result reduced the risk of relapse to 11% (4/36). Teenagers with a positive calprotectin test had a 53% (10/19) risk of progressing to symptomatic relapse within 3 months, whereas a negative calprotectin result gave a 12% (5/43) risk of symptomatic relapse. A positive CRP result (cutoff 10 mg/L) gave a 50% (4/8) risk of relapse, whereas a negative CRP result hardly reduced the risk compared with the pretest probability (from 24% to 21% (11/53)). As an add-on test after PUCAI or PCDAI, the calprotectin test limited the number of false positives and thus increased the specificity to detect

  1. Impulsive choice predicts short-term relapse in substance-dependent individuals attending an in-patient detoxification programme.

    Science.gov (United States)

    Stevens, L; Goudriaan, A E; Verdejo-Garcia, A; Dom, G; Roeyers, H; Vanderplasschen, W

    2015-07-01

    Impulsivity is a hallmark characteristic of substance use disorders. Recently, studies have begun to explore whether increased impulsivity in substance-dependent individuals (SDIs) is associated with a greater propensity to relapse following treatment. Despite growing recognition of its multidimensional nature, however, most studies have treated impulsivity unilaterally. Accordingly, it remains unclear whether certain facets of impulsivity are more relevant to relapse than others. The aim of the current study was to examine the relationship between multiple facets of impulsivity and short-term relapse in SDIs. As a secondary aim, we explored the role of treatment retention in this relationship. A personality-based impulsivity questionnaire (UPPS) and three neurocognitive tasks of impulsivity [stop-signal task (SST), delay discounting task (DDT) and Iowa gambling task (IGT)] were administered in a heterogeneous sample of 70 SDIs shortly following their entry in an in-patient detoxification programme. Mediation analyses were performed to explore whether the effects of impulsivity on relapse were mediated by treatment retention. Performance on two neurocognitive indices of impulsive choice (i.e. delay discounting and impulsive decision-making) significantly predicted short-term relapse. The effects of delay discounting and impulsive decision-making on relapse propensity were mediated by treatment retention. Neurocognitive indices of impulsivity may be more sensitive to the prediction of relapse than trait-based self-report questionnaires. Post-treatment relapse in SDIs may be reduced by targeting the processes involved in impulsive choice and by improving treatment retention in SDIs with inflated impulsivity.

  2. Trait impulsive choice predicts resistance to extinction and propensity to relapse to cocaine seeking: a bidirectional investigation.

    Science.gov (United States)

    Broos, Nienke; Diergaarde, Leontien; Schoffelmeer, Anton Nm; Pattij, Tommy; De Vries, Taco J

    2012-05-01

    Despite the strong association between impulsivity and addiction in humans, it is still a matter of debate whether impulsive choice predisposes to, or results from, drug dependence. Furthermore, it is unknown whether treating impulsivity can protect against relapse propensity. Therefore, this study explored the bidirectional relationship between impulsive choice and cocaine taking and seeking in rat behavioral models. In experiment 1, to determine whether impulsive choice predisposes to cocaine taking or seeking, rats were selected based on trait impulsivity in a delayed reward task and subsequently compared on various stages of cocaine self-administration (SA). To examine the consequence of cocaine intake on impulsive choice, impulsivity was monitored once a week throughout various stages of cocaine SA. To determine whether treating impulsive choice can protect against relapse propensity, in experiment 2, impulsive choice was manipulated by pharmacological interventions and cocaine-associated contextual cues. Trait impulsive choice as determined in experiment 1 predicted high extinction resistance and enhanced propensity to context-induced relapse in the cocaine SA model, whereas cocaine intake did not alter impulsive choice. Furthermore, acute changes in impulsive choice were not related to rates of context-induced relapse. Taken together, the current data indicate that trait impulsive choice predicts persistent cocaine seeking during extinction and enhanced propensity to relapse, whereas acute manipulations of impulsive choice had no favorable outcomes on relapse measures. These observations suggest that trait impulsivity can be used as a predictive factor for addiction liability, but treating this impulsivity does not necessarily protect against relapse.

  3. Trait Impulsive Choice Predicts Resistance to Extinction and Propensity to Relapse to Cocaine Seeking: A Bidirectional Investigation

    Science.gov (United States)

    Broos, Nienke; Diergaarde, Leontien; Schoffelmeer, Anton NM; Pattij, Tommy; De Vries, Taco J

    2012-01-01

    Despite the strong association between impulsivity and addiction in humans, it is still a matter of debate whether impulsive choice predisposes to, or results from, drug dependence. Furthermore, it is unknown whether treating impulsivity can protect against relapse propensity. Therefore, this study explored the bidirectional relationship between impulsive choice and cocaine taking and seeking in rat behavioral models. In experiment 1, to determine whether impulsive choice predisposes to cocaine taking or seeking, rats were selected based on trait impulsivity in a delayed reward task and subsequently compared on various stages of cocaine self-administration (SA). To examine the consequence of cocaine intake on impulsive choice, impulsivity was monitored once a week throughout various stages of cocaine SA. To determine whether treating impulsive choice can protect against relapse propensity, in experiment 2, impulsive choice was manipulated by pharmacological interventions and cocaine-associated contextual cues. Trait impulsive choice as determined in experiment 1 predicted high extinction resistance and enhanced propensity to context-induced relapse in the cocaine SA model, whereas cocaine intake did not alter impulsive choice. Furthermore, acute changes in impulsive choice were not related to rates of context-induced relapse. Taken together, the current data indicate that trait impulsive choice predicts persistent cocaine seeking during extinction and enhanced propensity to relapse, whereas acute manipulations of impulsive choice had no favorable outcomes on relapse measures. These observations suggest that trait impulsivity can be used as a predictive factor for addiction liability, but treating this impulsivity does not necessarily protect against relapse. PMID:22318198

  4. Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease

    Directory of Open Access Journals (Sweden)

    Hyemi Kwon

    2016-06-01

    Full Text Available BackgroundHyperthyroidism relapse in Graves disease after antithyroid drug (ATD withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb and thyrotropin-binding inhibitory immunoglobulin (TBII at ATD withdrawal to predict relapse.MethodsThis retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35 or TBII (TBII group; n=39 every 3 to 6 months for 2 years after ATD withdrawal.ResultsTwenty-eight patients (38% relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67% than patients with negative TSAb (17%; P=0.007. Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%.ConclusionTSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.

  5. Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease.

    Science.gov (United States)

    Kwon, Hyemi; Kim, Won Gu; Jang, Eun Kyung; Kim, Mijin; Park, Suyeon; Jeon, Min Ji; Kim, Tae Yong; Ryu, Jin Sook; Shong, Young Kee; Kim, Won Bae

    2016-06-01

    Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.

  6. Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study.

    Science.gov (United States)

    Wang, Xuexia; Sun, Can-Lan; Hageman, Lindsey; Smith, Kandice; Singh, Purnima; Desai, Sunil; Hawkins, Douglas S; Hudson, Melissa M; Mascarenhas, Leo; Neglia, Joseph P; Oeffinger, Kevin C; Ritchey, A Kim; Robison, Leslie L; Villaluna, Doojduen; Landier, Wendy; Bhatia, Smita

    2017-10-04

    Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.

  7. Investigating associations between cortisol and cognitive reactivity to sad mood provocation and the prediction of relapse in remitted major depression.

    Science.gov (United States)

    Chopra, K K; Segal, Z V; Buis, T; Kennedy, S H; Levitan, R D

    2008-12-01

    In remitted depressed patients, an increase in dysfunctional thoughts following a sad mood induction can predict relapse over 18 months. The current analysis examined whether salivary cortisol levels could also predict relapse in these same individuals. 99 subjects with major depression were first treated to full remission using either antidepressant medication or cognitive behavioural therapy. While in the remitted state, subjects were exposed to sad music to trigger dysfunctional thoughts. In a subset of 55 subjects, salivary cortisol levels taken before and after the mood challenge were also obtained. Unexpectedly, cortisol levels tended to decrease rather than increase following the mood challenge, suggesting that anticipation of the mood challenge was more stressful than the challenge itself. We thus used pre-challenge cortisol levels as the main grouping variable. Based on Kaplan-Meier survival curves, among subjects with low pre-challenge cortisol levels, those with a history of three or more prior episodes had significantly higher rates of relapse than did subjects with two or less prior episodes. In subjects with high pre-challenge cortisol levels, there was no significant difference in rates of relapse based on the number of prior episodes. In depressed patients with few prior episodes, assessing risk of relapse and thus establishing the duration for treatment can be a difficult clinical problem. Pending replication, the current results suggest that high anticipatory cortisol levels may have utility in predicting relapse even in patients with few prior episodes. Copyright © 2008 Elsevier B.V. All rights reserved.

  8. Neural correlates of graphic cigarette warning labels predict smoking cessation relapse.

    Science.gov (United States)

    Owens, Max M; MacKillop, James; Gray, Joshua C; Hawkshead, Brittany E; Murphy, Cara M; Sweet, Lawrence H

    2017-04-30

    Exposure to graphic warning labels (GWLs) on cigarette packaging has been found to produce heightened activity in brain regions central to emotional processing and higher-order cognitive processes. The current study extends this literature by using functional magnetic resonance imaging (fMRI) to investigate neural activation in response to GWLs and use it to predict relapse in an evidence-based smoking cessation treatment program. Participants were 48 treatment-seeking nicotine-dependent smokers who completed an fMRI paradigm in which they were exposed to GWLs, text-only warning labels (TOLs), and matched control stimuli. Subsequently, they enrolled in smoking cessation treatment and their smoking behavior was monitored. Activation in bilateral amygdala, right dorsolateral prefrontal cortex, right inferior frontal gyrus, left medial temporal gyrus, bilateral occipital lobe, and bilateral fusiform gyrus was greater during GWLs than TOLs. Neural response in the ventromedial prefrontal cortex (vmPFC) during exposure to GWLs (relative to a visual control image) predicted relapse during treatment beyond baseline demographic and dependence severity, but response in the amygdala to GWLs did not. These findings suggest that neurocognitive processes in the vmPFC may be critical to understanding how GWL's induce behavior change and may be useful as a predictor of smoking cessation treatment prognosis. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  9. SOX9 Expression Predicts Relapse of Stage II Colon Cancer Patients

    DEFF Research Database (Denmark)

    Espersen, Maiken Lise Marcker; Linnemann, Dorte; Christensen, Ib Jarle

    2016-01-01

    The aim of this study was to investigate if the protein expression of Sex-determining region y-box 9 (SOX9) in primary tumors could predict relapse of stage II colon cancer patients.144 patients with stage II primary colon cancer were retrospectively enrolledin the study. SOX9 expression was eval......The aim of this study was to investigate if the protein expression of Sex-determining region y-box 9 (SOX9) in primary tumors could predict relapse of stage II colon cancer patients.144 patients with stage II primary colon cancer were retrospectively enrolledin the study. SOX9 expression...... low to high expression) in univariate (HR: 0.73; 95% CI: 0.56-0.94; p=0.01) and multivariate cox proportional hazards analysis (HR: 0.75; 95% CI: 0.58-0.96; p=0.02) adjusting for mismatch repair deficiency and histopathological risk factors. Conversely, low SOX9 expression at the invasive front...

  10. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... been affected—or may be affected—by a hurricane, wildfire, or other natural disaster, we can help. ... attacks of inflammation (relapses) in the CNS, progressive forms of MS involve much less of this type ...

  11. Targeted intervention: Computational approaches to elucidate and predict relapse in alcoholism.

    Science.gov (United States)

    Heinz, Andreas; Deserno, Lorenz; Zimmermann, Ulrich S; Smolka, Michael N; Beck, Anne; Schlagenhauf, Florian

    2017-05-01

    Alcohol use disorder (AUD) and addiction in general is characterized by failures of choice resulting in repeated drug intake despite severe negative consequences. Behavioral change is hard to accomplish and relapse after detoxification is common and can be promoted by consumption of small amounts of alcohol as well as exposure to alcohol-associated cues or stress. While those environmental factors contributing to relapse have long been identified, the underlying psychological and neurobiological mechanism on which those factors act are to date incompletely understood. Based on the reinforcing effects of drugs of abuse, animal experiments showed that drug, cue and stress exposure affect Pavlovian and instrumental learning processes, which can increase salience of drug cues and promote habitual drug intake. In humans, computational approaches can help to quantify changes in key learning mechanisms during the development and maintenance of alcohol dependence, e.g. by using sequential decision making in combination with computational modeling to elucidate individual differences in model-free versus more complex, model-based learning strategies and their neurobiological correlates such as prediction error signaling in fronto-striatal circuits. Computational models can also help to explain how alcohol-associated cues trigger relapse: mechanisms such as Pavlovian-to-Instrumental Transfer can quantify to which degree Pavlovian conditioned stimuli can facilitate approach behavior including alcohol seeking and intake. By using generative models of behavioral and neural data, computational approaches can help to quantify individual differences in psychophysiological mechanisms that underlie the development and maintenance of AUD and thus promote targeted intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. MALDI mass spectrometry based molecular phenotyping of CNS glial cells for prediction in mammalian brain tissue

    DEFF Research Database (Denmark)

    Hanrieder, Jørg; Wicher, Grzegorz; Bergquist, Jonas

    2011-01-01

    tracers for prediction of oligodendroglial and astroglial localization in brain tissue. The different cell type specific protein distributions in tissue were validated using immunohistochemistry. ICMS of intact neuroglia is a simple and straightforward approach for characterization and discrimination...

  13. A decrease in the plasma DHEA to cortisol ratio during smoking abstinence may predict relapse: a preliminary study.

    Science.gov (United States)

    Rasmusson, Ann M; Wu, Ran; Paliwal, Prashni; Anderson, George M; Krishnan-Sarin, Suchitra

    2006-06-01

    Increases in depressive symptoms during smoking cessation have been associated with risk for relapse. Several studies have linked plasma levels of cortisol and dehydroepiandrosterone (DHEA) or DHEA-sulfate (DHEAS) to depressive symptoms. To determine whether changes in plasma cortisol, DHEA, or DHEAS levels and emergence of depressive symptoms during smoking cessation are associated with smoking relapse. Subjects were healthy non-medicated men and women, aged 39+/-12 years, who smoked, on average, 22 cigarettes per day. Depressive symptoms, smoking withdrawal symptoms, and plasma steroid levels were measured before and after 8 days of verified smoking abstinence. Relapse status at day 15 was then determined. In the full sample (n=63), there was a trend for changes in depressive symptoms to be associated with relapse. In the subset of 25 subjects with plasma neuroactive steroid data, there was a significant interaction between the change in the plasma DHEA/cortisol ratio from day 0 to day 8 and relapse status at day 15. This ratio was similar before abstinence, but lower at day 8 in relapsed, compared to abstinent, subjects. Changes in the DHEA/cortisol ratio tended to predict changes in depressive symptoms in the women only. A decrease in the plasma DHEA/cortisol ratio during 8 days of smoking abstinence was associated with relapse over the following week. Further research is needed to fully characterize sex-specific relationships between abstinence-induced changes in neuroactive steroid levels, depressive or withdrawal symptoms, and relapse. Such research may lead to new interventions for refractory smoking dependence.

  14. Fluctuations of spontaneous EEG topographies predict disease state in relapsing-remitting multiple sclerosis.

    Science.gov (United States)

    Gschwind, Markus; Hardmeier, Martin; Van De Ville, Dimitri; Tomescu, Miralena I; Penner, Iris-Katharina; Naegelin, Yvonne; Fuhr, Peter; Michel, Christoph M; Seeck, Margitta

    2016-01-01

    Spontaneous fluctuations of neuronal activity in large-scale distributed networks are a hallmark of the resting brain. In relapsing-remitting multiple sclerosis (RRMS) several fMRI studies have suggested altered resting-state connectivity patterns. Topographical EEG analysis reveals much faster temporal fluctuations in the tens of milliseconds time range (termed "microstates"), which showed altered properties in a number of neuropsychiatric conditions. We investigated whether these microstates were altered in patients with RRMS, and if the microstates' temporal properties reflected a link to the patients' clinical features. We acquired 256-channel EEG in 53 patients (mean age 37.6 years, 45 females, mean disease duration 9.99 years, Expanded Disability Status Scale ≤ 4, mean 2.2) and 49 healthy controls (mean age 36.4 years, 33 females). We analyzed segments of a total of 5 min of EEG during resting wakefulness and determined for both groups the four predominant microstates using established clustering methods. We found significant differences in the temporal dynamics of two of the four microstates between healthy controls and patients with RRMS in terms of increased appearance and prolonged duration. Using stepwise multiple linear regression models with 8-fold cross-validation, we found evidence that these electrophysiological measures predicted a patient's total disease duration, annual relapse rate, disability score, as well as depression score, and cognitive fatigue measure. In RRMS patients, microstate analysis captured altered fluctuations of EEG topographies in the sub-second range. This measure of high temporal resolution provided potentially powerful markers of disease activity and neuropsychiatric co-morbidities in RRMS.

  15. Can a one-item mood scale do the trick? Predicting relapse over 5.5-years in recurrent depression

    NARCIS (Netherlands)

    van Rijsbergen, Gerard D.; Bockting, Claudi L. H.; Berking, Matthias; Koeter, Maarten W.J.; Schene, Aart H.

    2012-01-01

    BACKGROUND: To examine whether a simple Visual Analogue Mood Scale (VAMS) is able to predict time to relapse over 5.5-years. METHODOLOGY/PRINCIPAL FINDINGS: 187 remitted recurrently depressed out-patients were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)

  16. Prediction of Relapse After Cognitive-Behavioral Treatment of Gambling Disorder in Individuals With Chronic Schizophrenia: A Survival Analysis.

    Science.gov (United States)

    Echeburúa, Enrique; Gómez, Montserrat; Freixa, Montserrat

    2017-01-01

    Gambling disorder (GD) in individuals with chronic schizophrenia is relevant because there are higher rates of GD in schizophrenic populations (10%) than in the nonschizophrenic population (1%-5%). In addition, these patients have more severe alcohol use disorder (i.e., meeting at least 6 of the DSM-5 11 criteria for diagnosis of this disorder), higher depression scores, a poor adherence to treatment, and more frequent use of outpatient mental health care. One of the main problems in GD is therapeutic failure (defined as three or more lapse episodes during treatment) or relapse (three or more lapse episodes in the follow-up period). Predicting a relapse of GD in individuals with chronic schizophrenia can be useful in targeting the patients for aftercare services. The main aim of this study was to estimate the time to a GD relapse (survival rate) and to evaluate some of the qualitative and quantitative variables related to a GD relapse by a survival analysis. The sample consisted of 35 patients with chronic schizophrenia and GD who were treated with pharmacological and cognitive-behavioral therapy. The therapeutic failure rate in the treatment period was 43%, and it was associated with the number of episodes of schizophrenia, the age of gambling onset, and the age of the patients. The relapse rate in the follow-up period was 32%, and it was associated with the patients' age, educational level, and weekly allowance. The implications of this study for future research are discussed. Copyright © 2016. Published by Elsevier Ltd.

  17. Cognitive reactivity versus dysfunctional cognitions and the prediction of relapse in recurrent major depressive disorder

    NARCIS (Netherlands)

    Figueroa, Caroline A.; Ruhe, Henricus G.; Koeter, Maarten W.; Spinhoven, Philip; Van der Does, Willem; Bockting, Claudi L.; Schene, Aart H.

    2015-01-01

    Objective: Major depressive disorder (MDD) is a burdensome disease that has a high risk of relapse/recurrence. Cognitive reactivity appears to be a risk factor for relapse. It remains unclear, however, whether dysfunctional cognitions alone or the reactivity of such cognitions to mild states of

  18. Co-morbid anxiety disorders predict early relapse after inpatient alcohol treatment

    NARCIS (Netherlands)

    Schellekens, A.F.A.; Jong, C.A.J. de; Buitelaar, J.K.; Verkes, R.J.

    2015-01-01

    Introduction Alcohol dependence and anxiety disorders often co-occur. Yet, the effect of co-morbid anxiety disorders on the alcohol relapse-risk after treatment is under debate. This study investigated the effect of co-morbid anxiety disorders on relapse rates in alcohol dependence. We hypothesized

  19. Prediction of Driving Ability in People with Relapsing-Remitting Multiple Sclerosis Using the Stroke Driver Screening Assessment

    OpenAIRE

    AKINWUNTAN, Abiodun Emmanuel; O'Connor, Christina; McGonegal, Erin; Turchi, Kristen; Smith, Suzanne; Williams, Mitzi; Wachtel, Jerry

    2012-01-01

    The ability to drive is often affected in individuals with multiple sclerosis (MS) because of the motor, visual, or cognitive deficits commonly associated with the condition. In this study, we investigated the accuracy with which the Stroke Driver Screening Assessment (SDSA), an established battery for the prediction of driving performance of stroke survivors, would predict driving performance of individuals with MS. Driving performance of 44 individuals with relapsing-remitting MS (mean ± SD...

  20. Neurophysiological correlates of response inhibition predict relapse in detoxified alcoholic patients: some preliminary evidence from event-related potentials

    Directory of Open Access Journals (Sweden)

    Petit G

    2014-06-01

    response-inhibition skills that demand greater neural resources. We propose that event-related potentials can be used in conjunction with behavioral data to predict relapse; this would identify patients that need a higher level of neural resources when suppressing a response is requested.Keywords: alcoholism, relapse, response inhibition, go/no-go task, ERPs, P3d 

  1. Cell proliferation index predicts relapse of brain metastases in non-irradiated patients

    DEFF Research Database (Denmark)

    Peev, N A; Tonchev, A B; Penkowa, M

    2008-01-01

    of diagnosis of brain metastasis as compared to the primary cancer diagnosis, and the perifocal brain oedema. RESULTS: Statistical evaluation of the indexes in the patients with brain metastases relapsing within 2 months after the first craniotomy (n = 13) revealed significantly higher values as compared...... to the patients with lesions which had not relapsed or which had relapsed more than 2 months after first craniotomy (n = 12). The synchronous brain metastasis (that is, those occurring before or within 2 months of the primary cancer diagnosis) had a significantly higher proliferation index than the metachronous...... lesions (those occurring more than 2 months after primary cancer diagnosis). CONCLUSIONS: The synchronous brain metastasis relapses within 2 months of primary resection and have a significantly higher proliferation index than the metachronous lesions which did not recur within 2 months. These results...

  2. Relapse in pathological gamblers: A pilot study on the predictive value of different impulsivity measures

    NARCIS (Netherlands)

    Wilde, B. de; Goudriaan, A.E.; Sabbe, B.G.C.; Hulstijn, W.; Dom, G.

    2013-01-01

    Backgrounds and aims: Pathological gambling, a common psychiatric disorder, has many similarities with substance use disorders. Relapse, an important element in addictive disorders, however, has seldom been studied in pathological gambling. Hence, in analogy with previous research studies examining

  3. Tumour markers and FDG PET/CT for prediction of disease relapse in patients with breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Evangelista, Laura [Istituto Oncologico Veneto IOV - IRCCS, Radiotherapy and Nuclear Medicine Unit, Padova (Italy); University of Naples ' ' Federico II' ' , Departments of Biomorphological and Functional Imaging, Naples (Italy); Baretta, Zora; Ghiotto, Cristina [Istituto Oncologico Veneto IOV - IRCCS, Oncology Unit, Padova (Italy); Vinante, Lorenzo; Cervino, Anna Rita; Gregianin, Michele; Saladini, Giorgio; Sotti, Guido [Istituto Oncologico Veneto IOV - IRCCS, Radiotherapy and Nuclear Medicine Unit, Padova (Italy)

    2011-02-15

    The aim of the study was to assess the role of CA 15.3, CT and positron emission tomography (PET)/CT in patients with breast cancer and suspected disease relapse after primary treatment. We studied 111 consecutive patients (mean age 61 {+-} 12 years) with previous breast cancer, already treated and with clinical or biochemical suspicion of disease relapse. All patients underwent CT and {sup 18}F-fluorodeoxyglucose (FDG) PET/CT. In all patients, the value of CA 15.3 was compared to PET/CT and CT. The final diagnosis of relapse was established by invasive and noninvasive follow-up and was compared with CA 15.3, CT and PET/CT results. Univariate and multivariate analyses were used to identify the independent predictors of disease relapse and receiver-operating characteristic (ROC) curve for the identification of optimal CA 15.3 cutoff. Of all patients, 40 (36%) showed an increased CA 15.3 value, CT was positive in 73 (66%), whereas at PET/CT imaging 64 (58%) showed positive findings for disease relapse. Of 40 patients with increased marker levels, 22 patients had positive CT and 30 positive PET/CT (55 vs 75%, p < 0.001). At the end of follow-up, recurrence occurred in 32 (29%) patients, 16 (50%) of whom showed high levels of CA 15.3. PET/CT predicted relapse in 26 (81%) patients, whereas CT correctly identified 23 (72%). At univariate analysis, recurrence was significantly associated with high CA 15.3 values (p < 0.05) and positive PET/CT (p < 0.005). At multivariable analysis only positive PET/CT remained an independent predictor of disease relapse (p < 0.05). ROC analysis showed an optimal cutoff point for CA 15.3 of 19.1 U/ml (AUC 0.65, p < 0.01) to individuate positive PET/CT. FDG PET/CT is more sensitive than CT and CA 15.3 in the evaluation of disease relapse. PET/CT might be considered a complementary imaging technique during follow-up in patients with breast cancer. (orig.)

  4. A nomogram to predict brain metastasis as the first relapse in curatively resected non-small cell lung cancer patients.

    Science.gov (United States)

    Won, Young-Woong; Joo, Jungnam; Yun, Tak; Lee, Geon-Kook; Han, Ji-Youn; Kim, Heung Tae; Lee, Jin Soo; Kim, Moon Soo; Lee, Jong Mog; Lee, Hyun-Sung; Zo, Jae Ill; Kim, Sohee

    2015-05-01

    Development of brain metastasis results in a significant reduction in overall survival. However, there is no an effective tool to predict brain metastasis in non-small cell lung cancer (NSCLC) patients. We conducted this study to develop a feasible nomogram that can predict metastasis to the brain as the first relapse site in patients with curatively resected NSCLC. A retrospective review of NSCLC patients who had received curative surgery at National Cancer Center (Goyang, South Korea) between 2001 and 2008 was performed. We chose metastasis to the brain as the first relapse site after curative surgery as the primary endpoint of the study. A nomogram was modeled using logistic regression. Among 1218 patients, brain metastasis as the first relapse developed in 87 patients (7.14%) during the median follow-up of 43.6 months. Occurrence rates of brain metastasis were higher in patients with adenocarcinoma or those with a high pT and pN stage. Younger age appeared to be associated with brain metastasis, but this result was not statistically significant. The final prediction model included histology, smoking status, pT stage, and the interaction between adenocarcinoma and pN stage. The model showed fairly good discriminatory ability with a C-statistic of 69.3% and 69.8% for predicting brain metastasis within 2 years and 5 years, respectively. Internal validation using 2000 bootstrap samples resulted in C-statistics of 67.0% and 67.4% which still indicated good discriminatory performances. The nomogram presented here provides the individual risk estimate of developing metastasis to the brain as the first relapse site in patients with NSCLC who have undergone curative surgery. Surveillance programs or preventive treatment strategies for brain metastasis could be established based on this nomogram. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Cingulate cortex functional connectivity predicts future relapse in alcohol dependent individuals.

    Science.gov (United States)

    Zakiniaeiz, Yasmin; Scheinost, Dustin; Seo, Dongju; Sinha, Rajita; Constable, R Todd

    2017-01-01

    Alcohol dependence is a chronic relapsing illness. Alcohol and stress cues have consistently been shown to increase craving and relapse risk in recovering alcohol dependent (AUD) patients. However, differences in functional connectivity in response to these cues have not been studied using data-driven approaches. Here, voxel-wise connectivity is used in a whole-brain investigation of functional connectivity differences associated with alcohol and stress cues and to examine whether these differences are related to subsequent relapse. In Study 1, 45, 4- to 8-week abstinent, recovering AUD patients underwent functional magnetic resonance imaging during individualized imagery of alcohol, stress, and neutral cues. Relapse measures were collected prospectively for 90 days post-discharge from inpatient treatment. AUD patients showed blunted anterior (ACC), mid (MCC) and posterior cingulate cortex (PCC), voxel-wise connectivity responses to stress compared to neutral cues and blunted PCC response to alcohol compared to neutral cues. Using Cox proportional hazard regression, weaker connectivity in ACC and MCC during neutral exposure was associated with longer time to relapse (better recovery outcome). Similarly, greater connectivity in PCC during alcohol-cue compared to stress cue was associated with longer time to relapse. In Study 2, a sub-group of 30 AUD patients were demographically-matched to 30 healthy control (HC) participants for group comparisons. AUD compared to HC participants showed reduced cingulate connectivity during alcohol and stress cues. Using novel data-driven approaches, the cingulate cortex emerged as a key region in the disruption of functional connectivity during alcohol and stress-cue processing in AUD patients and as a marker of subsequent alcohol relapse.

  6. Cingulate cortex functional connectivity predicts future relapse in alcohol dependent individuals

    Directory of Open Access Journals (Sweden)

    Yasmin Zakiniaeiz

    2017-01-01

    Full Text Available Alcohol dependence is a chronic relapsing illness. Alcohol and stress cues have consistently been shown to increase craving and relapse risk in recovering alcohol dependent (AUD patients. However, differences in functional connectivity in response to these cues have not been studied using data-driven approaches. Here, voxel-wise connectivity is used in a whole-brain investigation of functional connectivity differences associated with alcohol and stress cues and to examine whether these differences are related to subsequent relapse. In Study 1, 45, 4- to 8-week abstinent, recovering AUD patients underwent functional magnetic resonance imaging during individualized imagery of alcohol, stress, and neutral cues. Relapse measures were collected prospectively for 90 days post-discharge from inpatient treatment. AUD patients showed blunted anterior (ACC, mid (MCC and posterior cingulate cortex (PCC, voxel-wise connectivity responses to stress compared to neutral cues and blunted PCC response to alcohol compared to neutral cues. Using Cox proportional hazard regression, weaker connectivity in ACC and MCC during neutral exposure was associated with longer time to relapse (better recovery outcome. Similarly, greater connectivity in PCC during alcohol-cue compared to stress cue was associated with longer time to relapse. In Study 2, a sub-group of 30 AUD patients were demographically-matched to 30 healthy control (HC participants for group comparisons. AUD compared to HC participants showed reduced cingulate connectivity during alcohol and stress cues. Using novel data-driven approaches, the cingulate cortex emerged as a key region in the disruption of functional connectivity during alcohol and stress-cue processing in AUD patients and as a marker of subsequent alcohol relapse.

  7. Prediction of driving ability in people with relapsing-remitting multiple sclerosis using the stroke driver screening assessment.

    Science.gov (United States)

    Akinwuntan, Abiodun Emmanuel; O'Connor, Christina; McGonegal, Erin; Turchi, Kristen; Smith, Suzanne; Williams, Mitzi; Wachtel, Jerry

    2012-01-01

    The ability to drive is often affected in individuals with multiple sclerosis (MS) because of the motor, visual, or cognitive deficits commonly associated with the condition. In this study, we investigated the accuracy with which the Stroke Driver Screening Assessment (SDSA), an established battery for the prediction of driving performance of stroke survivors, would predict driving performance of individuals with MS. Driving performance of 44 individuals with relapsing-remitting MS (mean ± SD age, 46 ± 11 years; 37 females and 7 males) who were currently driving at least once a month was predicted using their performance on the SDSA. Outcomes of a road test and the Useful Field of View (UFOV) test were used as measures of driving ability. Participants' performance on both the road and UFOV tests was predicted with more than 80% accuracy. The SDSA was more accurate in predicting who would pass the two tests than who would fail the tests. The SDSA battery appears to be a good predictor of driving performance of individuals with relapsing-remitting MS, especially those who have sufficient cognitive skills to continue driving. Larger studies are needed to definitively establish its predictive accuracy and confirm the validity of the predictions.

  8. Does deterioration in mental health after smoking cessation predict relapse to smoking?

    Science.gov (United States)

    Taylor, Gemma; McNeill, Ann; Aveyard, Paul

    2015-11-20

    It is possible that some people who quit smoking experience improved mental health after cessation and therefore remain abstinent, whereas other people who quit may experience worse mental health after cessation and therefore be more likely to relapse to smoking. Thus, in this study we aimed to examine the association between an enduring change in mental health following the cessation period and future risk of relapse. A secondary analysis of prospective data pooled from five placebo-controlled randomised trials for smoking reduction conducted in Europe, USA and Australia. Change in mental health (SF-36, scored 0-100) was measured from baseline to four months for those who were biologically-validated as point-prevalence abstainers at four month follow-up. Thereafter we assessed whether relapse to smoking by 12 months was more likely in those whose mental health had worsened between baseline and four months compared with those who saw no change or an improvement. After adjustment for baseline mental health and other major covariates, there was no greater tendency to relapse at 12 months for those whose mental health worsened after cessation compared with those who had no change or an improvement. The odds ratio and 95% confidence interval was 1.01 (0.97 to 1.05). People whose mental health worsens after smoking cessation are at no greater risk of subsequent relapse to smoking than those whose mental health stays the same or improves.

  9. Large fragment pre-S deletion and high viral load independently predict hepatitis B relapse after liver transplantation.

    Directory of Open Access Journals (Sweden)

    Ting-Jung Wu

    Full Text Available Hepatitis B virus (HBV associated end-stage liver diseases are the leading causes of liver transplantation (LT in Taiwan. Relapse of hepatitis B occurs after LT, raising the risk of graft failure and reducing patient survival. Although several oral antiviral agents have been approved for anti-HBV treatment, lamivudine (LAM remained to be the most widely used preventive regimen in Taiwan. While several clinical predictors have been identified for hepatitis B relapse, the predictive roles of the histopathological characteristics in liver explants as well as the genotypic features of the viruses in pre-LT serum samples have not been assessed. Between September 2002 and August 2009, 150 consecutive hepatitis B surface antigen (HBsAg positive patients undergoing LT were included for outcome analysis following assessment of the clinicopathological and virological factors prior to LT. Kaplan-Meier analyses discovered that pre-operative LAM treatment ≤3 months; membranous distribution and higher expression of tissue HBsAg in liver explants; preoperative viral load ≥10(6 copies/ml; and presence of large fragment (>100 base pairs pre-S deletion (LFpreSDel correlated significantly with hepatitis B relapse. Multivariate Cox regression analysis showed that the presence of LFpreSDel (P = 0.001 and viral load ≥10(6 copies/mL (P = 0.023 were independent predictors for hepatitis B relapse. In conclusion, besides high viral load, LFpreSDel mutation is an important independent predictor for hepatitis B relapse after LT. More aggressive preventive strategies should be applied for patients carrying these risk factors.

  10. When Habits Are Dangerous: Alcohol Expectancies and Habitual Decision Making Predict Relapse in Alcohol Dependence.

    Science.gov (United States)

    Sebold, Miriam; Nebe, Stephan; Garbusow, Maria; Guggenmos, Matthias; Schad, Daniel J; Beck, Anne; Kuitunen-Paul, Soeren; Sommer, Christian; Frank, Robin; Neu, Peter; Zimmermann, Ulrich S; Rapp, Michael A; Smolka, Michael N; Huys, Quentin J M; Schlagenhauf, Florian; Heinz, Andreas

    2017-12-01

    Addiction is supposedly characterized by a shift from goal-directed to habitual decision making, thus facilitating automatic drug intake. The two-step task allows distinguishing between these mechanisms by computationally modeling goal-directed and habitual behavior as model-based and model-free control. In addicted patients, decision making may also strongly depend upon drug-associated expectations. Therefore, we investigated model-based versus model-free decision making and its neural correlates as well as alcohol expectancies in alcohol-dependent patients and healthy controls and assessed treatment outcome in patients. Ninety detoxified, medication-free, alcohol-dependent patients and 96 age- and gender-matched control subjects underwent functional magnetic resonance imaging during the two-step task. Alcohol expectancies were measured with the Alcohol Expectancy Questionnaire. Over a follow-up period of 48 weeks, 37 patients remained abstinent and 53 patients relapsed as indicated by the Alcohol Timeline Followback method. Patients who relapsed displayed reduced medial prefrontal cortex activation during model-based decision making. Furthermore, high alcohol expectancies were associated with low model-based control in relapsers, while the opposite was observed in abstainers and healthy control subjects. However, reduced model-based control per se was not associated with subsequent relapse. These findings suggest that poor treatment outcome in alcohol dependence does not simply result from a shift from model-based to model-free control but is instead dependent on the interaction between high drug expectancies and low model-based decision making. Reduced model-based medial prefrontal cortex signatures in those who relapse point to a neural correlate of relapse risk. These observations suggest that therapeutic interventions should target subjective alcohol expectancies. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights

  11. Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone.

    Science.gov (United States)

    Couder, Florence; Massardier, Jérôme; You, Benoît; Abbas, Fatima; Hajri, Touria; Lotz, Jean-Pierre; Schott, Anne-Marie; Golfier, François

    2016-07-01

    Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86-8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR = 5.96; 95% CI, 1.40-25.4, P = .016), a number of methotrexate courses superior to 5 courses (5-8 courses vs 1-4: HR = 6.19; 95% CI, 1.43-26.8, P = .015; 9 courses and more vs 1-4: HR = 6.80; 95% CI, 1.32-35.1, P = .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR = 1.27; 95% CI, 1.09-1.49, P = .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia

  12. Psychosocial characteristics of drunk drivers assessed by the Addiction Severity Index, prediction of relapse.

    Science.gov (United States)

    Hubicka, Beata; Laurell, Hans; Bergman, Hans

    2010-02-01

    To investigate psychosocial characteristics and problems of a representative sample of Swedish drunk drivers with special consideration of the gender of the driver; analyze criminal records of the drivers before and after enrollment in the study; identify psychosocial predictors of relapse to drunk driving. Psychosocial characteristics were assessed by the Addiction Severity Index (ASI). Alcohol problems were additionally assessed by the Alcohol Use Disorders Identification Test (AUDIT). Criminal records were collected for the five year period before the enrollment, and for the subsequent two years, from Sweden's official crime statistics. About half of the investigated drivers had other psychosocial problems besides the drink driving offence. Female drivers had more alcohol, drug, psychiatric and relational problems, including with parents when growing up, than male drivers, but less previous and subsequent criminality. Heavily drunk drivers (blood alcohol concentration > or = 0.1%) had more problems with alcohol, legal status and employment and support than the other drunk drivers. Problems with legal status, family and social relations and alcohol use increased the risk of relapse in drunk driving, while medical problems seemed to be a protective factor. Different ASI risk factors were identified for relapse in either traffic offences or other crimes. As well as the drunk driving offence, drunk drivers often have other psychosocial problems, female drivers in particular. Already the blood alcohol concentration per se gives some indication of the psychosocial problem profile of a drunk driver and the ASI profile has some prognostic value for relapse in drunk driving.

  13. Transverse Diffusivity of Cerebral Parenchyma Predicts Visual Tracking Performance in Relapsing-Remitting Multiple Sclerosis

    Science.gov (United States)

    Warlop, Nele P.; Achten, Eric; Fieremans, Els; Debruyne, Jan; Vingerhoets, Guy

    2009-01-01

    This study investigated the relation between cerebral damage related to multiple sclerosis (MS) and cognitive decline as determined by two classical mental tracking tests. Cerebral damage in 15 relapsing-remitting MS patients was measured by diffusion tensor imaging (DTI). Fractional anisotropy, longitudinal and transverse diffusivity were defined…

  14. Accuracy of Consecutive Fecal Calprotectin Measurements to Predict Relapse in Inflammatory Bowel Disease Patients Under Maintenance With Anti-TNF Therapy: A Prospective Longitudinal Cohort Study.

    Science.gov (United States)

    Ferreiro-Iglesias, Rocio; Barreiro-de Acosta, Manuel; Lorenzo-Gonzalez, Aurelio; Dominguez-Muñoz, Juan E

    2016-12-14

    Predicting relapse in inflammatory bowel disease (IBD) patients could allow early changes in therapy. We aimed at evaluating the accuracy of consecutive fecal calprotectin (FC) measurements to predict flares in IBD patients under maintenance treatment with anti-tumor necrosis factor (TNF) drugs. A prospective longitudinal cohort study with 16-month follow-up period was designed. IBD patients in clinical remission for at least 6 months under anti-TNF therapy were included. FC was quantified at 4-month intervals for 1 year, and patients were clinically evaluated for relapse at 2-month intervals. Diagnostic accuracy of FC for predicting relapse was evaluated by receiver-operating characteristic curve analysis. In total, 95 of 106 included patients finalized the study and were analyzed (median age 44 y, 50.5% female, 75% with Crohn's disease). A total of 30 patients (31.6%) had a relapse over follow-up. FC concentration was significantly higher in patients who relapsed (477 μg/g) than in patients who maintained in remission (65 μg/g) (Ppredict remission was 130 μg/g (negative predictive value of 100%), and 300 μg/g to predict relapse (positive predictive value of 78.3%). FC is a good predictor of clinical relapse and a particularly good predictor of remission over the following 4 months in patients with IBD on maintenance therapy with anti-TNF drugs. FC levels 300 μg/g allow predicting relapse with a high probability at any time over the following 4 months.

  15. External validation of the GREAT score to predict relapse risk in Graves' disease: results from a multicenter, retrospective study with 741 patients.

    Science.gov (United States)

    Struja, Tristan; Kaeslin, Marina; Boesiger, Fabienne; Jutzi, Rebecca; Imahorn, Noemi; Kutz, Alexander; Bernasconi, Luca; Mundwiler, Esther; Mueller, Beat; Christ-Crain, Mirjam; Meienberg, Fabian; Ebrahimi, Fahim; Henzen, Christoph; Fischli, Stefan; Kraenzlin, Marius; Meier, Christian; Schuetz, Philipp

    2017-04-01

    First-line treatment in Graves' disease is often done with antithyroid agents (ATD), but relapse rates remain high making definite treatment necessary. Predictors for relapse risk help guiding initial treatment decisions. We aimed to externally validate the prognostic accuracy of the recently proposed Graves' Recurrent Events After Therapy (GREAT) score to predict relapse risk in Graves' disease. We retrospectively analyzed data (2004-2014) of patients with a first episode of Graves' hyperthyroidism from four Swiss endocrine outpatient clinics. Relapse of hyperthyroidism analyzed by multivariate Cox regression. Of the 741 included patients, 371 experienced a relapse (50.1%) after a mean follow-up of 25.6 months after ATD start. In univariate regression analysis, higher serum free T4, higher thyrotropin-binding inhibitor immunoglobulin (TBII), younger age and larger goiter were associated with higher relapse risk. We found a strong increase in relapse risk with more points in the GREAT score from 33.8% in patients with GREAT class I (0-1 points), 59.4% in class II (2-3 points) with a hazard ratio of 1.79 (95% CI: 1.42-2.27, P GREAT score shows good external validity and can be used for assessing the risk for relapse in Graves' disease, which influence the initial treatment decisions. © 2017 European Society of Endocrinology.

  16. The role of self-reported impulsivity and reward sensitivity versus neurocognitive measures of disinhibition and decision-making in the prediction of relapse in pathological gamblers.

    Science.gov (United States)

    Goudriaan, A E; Oosterlaan, J; De Beurs, E; Van Den Brink, W

    2008-01-01

    Disinhibition and decision-making skills play an important role in theories on the cause and outcome of addictive behaviors such as substance use disorders and pathological gambling. In recent studies, both disinhibition and disadvantageous decision-making strategies, as measured by neurocognitive tests, have been found to influence the course of substance use disorders. Research on factors affecting relapse in pathological gambling is scarce. This study investigated the effect of both self-reported impulsivity and reward sensitivity, and neurocognitively assessed disinhibition and decision-making under conflicting contingencies, on relapse in a group of 46 pathological gamblers. Logistic regression analysis indicated that longer duration of the disorder and neurocognitive indicators of disinhibition (Stop Signal Reaction Time) and decision-making (Card Playing Task) were significant predictors of relapse (explaining 53% of the variance in relapse), whereas self-reported impulsivity and reward sensitivity did not significantly predict relapse. Overall classification accuracy was 76%, with a positive classification accuracy of 76% and a negative classification accuracy of 75%. Duration of the disorder and neurocognitive measures of disinhibition and decision-making are powerful predictors of relapse in pathological gambling. The results suggest that endophenotypical neurocognitive characteristics are more promising in the prediction of relapse in pathological gambling than phenotypical personality characteristics. Neurocognitive predictors may be useful to guide treatment planning of follow-up contacts and booster sessions.

  17. A comparison of peripheral blood and buffy coat smear examination for the prediction of bone marrow relapse of acute lymphoblastic leukaemia in childhood.

    Science.gov (United States)

    Franklin, I M

    1983-02-01

    In an attempt to see if buffy coat smear examination might be an alternative to bone marrow aspiration for predicting relapse, 98 consecutive bone marrow aspirates from 96 children with acute lymphoblastic leukaemia were examined blind with buffy coat and peripheral blood from the same patients. The 28 bone marrow aspirates from children no longer on treatment were all normal, and routine aspirates would appear unjustified in these patients. Eight of the remaining marrows showed relapse, but only three were not predicted from the peripheral blood and buffy coat. In no case was buffy coat superior to peripheral blood in the detection of bone marrow relapse. Routine bone marrow aspirates are an inefficient way of diagnosing relapse in acute lymphoblastic leukaemia in childhood, despite their precision, and a prospective study is needed to determine their value.

  18. A comparison of peripheral blood and buffy coat smear examination for the prediction of bone marrow relapse of acute lymphoblastic leukaemia in childhood.

    OpenAIRE

    Franklin, I M

    1983-01-01

    In an attempt to see if buffy coat smear examination might be an alternative to bone marrow aspiration for predicting relapse, 98 consecutive bone marrow aspirates from 96 children with acute lymphoblastic leukaemia were examined blind with buffy coat and peripheral blood from the same patients. The 28 bone marrow aspirates from children no longer on treatment were all normal, and routine aspirates would appear unjustified in these patients. Eight of the remaining marrows showed relapse, but ...

  19. PET/CT before autologous stem cell transplantation predicts outcome in refractory/relapsed follicular lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Alcantara, Marion; Tilly, Herve [Universite de Rouen, Service d' Hematologie, Centre Henri Becquerel, Rouen (France); Dupuis, Jehan; Haioun, Corinne [CHU Henri Mondor et Universite Paris-Est, Assistance Publique - Hopitaux de Paris, Unite Hemopathies Lymphoides, Marechal de Lattre de Tassigny (France); Mareschal, Sylvain; Dubois, Sydney [Centre Henri Becquerel, IRIB, Unite Inserm U918, Rouen (France); Julian, Anne [CHU Purpan, Service de Medecine Nucleaire, Toulouse (France); Cottereau, Anne Segolene; Becker, Stephanie [Centre Henri Becquerel, Service de Medecine Nucleaire, Rouen (France); Oberic, Lucie; Huynh, Anne; Laurent, Guy; Ysebaert, Loic [IUCT-Oncopole, Departement d' Hematologie, Toulouse (France); Meignan, Michel [CHU Henri-Mondor, Service de Medecine Nucleaire, Paris (France)

    2014-09-20

    Salvage of young patients with follicular lymphoma (FL) after R-CHOP includes salvage immunochemotherapy followed by autologous stem cell transplantation (ASCT). Previous studies dealing with relapsed Hodgkin lymphoma have shown the prognostic value of PET/CT prior to ASCT. We retrospectively analysed 59 patients with refractory/relapsed FL after first-line R-CHOP who were chemosensitive (as evaluated by CT) to the salvage treatment and who proceeded to ASCT. The role of PET/CT in this setting to define chemosensitivity is not definitely established. So we focused on the prognostic value of PET/CT performed after salvage treatment, before ASCT. The estimated 3-year progression-free survival (PFS) and overall survival were 63.1 % (50.9-78.3 %) and 90.5 % (82.8 - 98.8 %), respectively, and did not differ significantly according to their Follicular Lymphoma International Prognostic Index at relapse, conditioning regimen, or type of salvage. PFS was significantly lower in PET/CT-positive patients, according to the International Harmonization Project revised response criteria, with a 3-year PFS of 45.5 % (26.6 - 77.8 %) versus 72.6 % (58.5 - 90.0 %; p = 0.039). To better refine prognosis, we applied two types of thresholds: a Deauville five-point scale positive threshold of ≥3 (3-year PFS of 74.9 %, range 61.0 - 92.1 % %, versus 42.8 %, range 24.7 - 74.4 %; p = 0.02), and a ≥70 % ∇SUV{sub max} threshold between presalvage and pre-ASCT PET/CT (3-year PFS of 72.4 %, range 57.5 - 91.3 % versus 13.3 %, 2.2 - 81.7 %; p < 10{sup -3}). The PET/CT findings before ASCT were independently correlated with PFS in our series. PET/CT negativity before ASCT is a desirable and achievable goal in the management of chemosensitive FL relapsing after first-line R-CHOP. (orig.)

  20. New patterns of relapse in multiple myeloma: a case of "light chain escape" in which FLC predicted relapse earlier than urine and serum immunofixation.

    Science.gov (United States)

    Caldini, Anna; Nozzoli, Chiara; Terreni, Alessandro; Staderini, Michela; Berardi, Margherita; Biagioli, Tiziana; Brogi, Marco; Bosi, Alberto

    2016-06-01

    Multiple myeloma (MM) is characterized, in about 80% of cases, by the production of monoclonal intact immunoglobulin and more than 95% of them have elevated concentrations of involved (i.e. of the same class of intact immunoglobulin) free light chain (FLC). The introduction of novel therapeutic strategies has changed the natural history of the disease, leading to new manifestations of relapse. Light chain escape (LCE) is a pattern of relapse in which the FLC increase is not accompanied by a concomitant raise of the original monoclonal component (MC). Here we present a case of a 55-year-old man with an IgG kappa MM stage III diagnosed in September 2007. At presentation an IgG kappa MC and urine Bence Jones protein (BJP) kappa were present. Bone marrow biopsy (BMB) showed the presence of 80% monotypic kappa plasma cells (PCs). The patient received bortezomib, thalidomide, dexamethasone before undergoing a double autologous stem cell transplantation (ASCT) in October 2008 and April 2009. In May 2011 he relapsed showing the same pattern of presentation and treatment with lenalidomide and dexamethasone was started. ln May 2013 serum and urine immunofixation and FLC became negative. In September 2014, an increase of kappa FLC was observed, while serum and urine immunofixations remained negative until January 2015, when urine immunofixation became positive. Eventually, in February 2015, serum immunofixation revealed the presence of a free kappa MC. After a new BMB showing 80% of monotypic kappa PCs, a LCE relapse was diagnosed and the patient started the treatment with bendamustine, bortezomib and dexamethasone. In the present case, the increase of kappa FLC has indicated relapse 4 and 5 months earlier than urine and serum IFE, respectively. Our observation confirms that it is advisable to routinely perform FLC or BJP during follow up of MM patients undergoing ASCT and/or treatment with biological drugs to ensure that LCE is not missed.

  1. What Do You Say Before You Relapse? How Language Use in a Peer-to-peer Online Discussion Forum Predicts Risky Drinking among Those in Recovery.

    Science.gov (United States)

    Kornfield, Rachel; Toma, Catalina L; Shah, Dhavan V; Moon, Tae Joon; Gustafson, David H

    2017-08-09

    Increasingly, individuals with alcohol use disorder (AUD) seek and provide support for relapse prevention in text-based online environments such as discussion forums. This paper investigates whether language use within a peer-to-peer discussion forum can predict future relapse among individuals treated for AUD. A total of 104 AUD sufferers who had completed residential treatment participated in a mobile phone-based relapse-prevention program, where they communicated via an online forum over the course of a year. We extracted patterns of language use on the forum within the first four months on study using Linguistic Inquiry and Word Count (LIWC), a dictionary-based text analysis program. Participants reported their incidence of risky drinking via a survey at 4, 8, and 12 months. A logistic regression model was built to predict the likelihood that individuals would engage in risky drinking within a year based on their language use, while controlling for baseline characteristics and rates of utilizing the mobile system. Results show that all baseline characteristics and system use factors explained just 13% of the variance in relapse, whereas a small number of linguistic cues, including swearing and cognitive mechanism words, accounted for an additional 32% of the total 45% of variance in relapse explained by the model. Effective models for predicting relapse are needed. Messages exchanged on AUD forums could provide an unobtrusive and cost-effective window into the future health outcomes of AUD sufferers, and their psychological underpinnings. As online communication expands, models that leverage user-submitted text toward predicting relapse will be increasingly scalable and actionable.

  2. Central diabetes insipidus as a very late relapse limited to the pituitary stalk in Langerhans cell histiocytosis.

    Science.gov (United States)

    Nakagawa, Shunsuke; Shinkoda, Yuichi; Hazeki, Daisuke; Imamura, Mari; Okamoto, Yasuhiro; Kawakami, Kiyoshi; Kawano, Yoshifumi

    2016-07-01

    Central diabetes insipidus (CDI) and relapse are frequently seen in multifocal Langerhans cell histiocytosis (LCH). We present two females with multifocal LCH who developed CDI 9 and 5 years after the initial diagnosis, respectively, as a relapse limited to the pituitary stalk. Combination chemotherapy with cytarabine reduced the mass in the pituitary stalk. Although CDI did not improve, there has been no anterior pituitary hormone deficiency (APHD), neurodegenerative disease in the central nervous system (ND-CNS) or additional relapse for 2 years after therapy. It was difficult to predict the development of CDI in these cases. CDI might develop very late in patients with multifocal LCH, and therefore strict follow-up is necessary, especially with regard to symptoms of CDI such as polydipsia and polyuria. For new-onset CDI with LCH, chemotherapy with cytarabine might be useful for preventing APHD and ND-CNS.

  3. microRNAs in CNS disorders

    DEFF Research Database (Denmark)

    Kocerha, Jannet; Kauppinen, Sakari; Wahlestedt, Claes

    2009-01-01

    RNAs (miRNAs) have been identified in the mammalian central nervous system (CNS) and are reported to mediate pivotal roles in many aspects of neuronal functions. Disruption of miRNA-based post-transcriptional regulation has been implicated in a range of CNS disorders as one miRNA is predicted to impact...... of miRNAs in Alzheimer's disease and schizophrenia, including the characterization of their downstream CNS mRNA targets, such as beta-secretase (BACE1) and calmodulin-dependent protein kinase II (CaMKII). Here, we present an overview of the current progress in miRNA research related to CNS disorders...

  4. Stratification according to HGG-IMMUNO RPA model predicts outcome in a large group of patients with relapsed malignant glioma treated by adjuvant postoperative dendritic cell vaccination.

    Science.gov (United States)

    De Vleeschouwer, Steven; Ardon, Hilko; Van Calenbergh, Frank; Sciot, Raf; Wilms, Guido; van Loon, Johannes; Goffin, Jan; Van Gool, Stefaan

    2012-11-01

    Adult patients with relapsed high-grade glioma are a very heterogenous group with, however, an invariably dismal prognosis. We stratified patients with relapsed high-grade glioma treated with re-operation and postoperative dendritic cell (DC) vaccination according to a simple recursive partitioning analysis (RPA) model to predict outcome. Based on age, pathology, Karnofsky performance score, and mental status, 117 adult patients with relapsed malignant glioma, undergoing re-operation, and postoperative adjuvant dendritic cell (DC) vaccination were stratified into 4 classes. Kaplan-Meier survival estimates were generated for each class of this HGG-IMMUNO RPA model. Extent of resection was documented but not included in the prognostic model. Kaplan-Meier overall survival estimates revealed significant (p < 0.0001) differences among the 4 HGG-IMMUNO RPA classes. Long-term survivors, surviving more than 24 months after the re-operation and vaccination, are seen in 54.5, 26.7, 11.5, and 0 % for the classes I, II, III, and IV respectively. This HGG-IMMUNO RPA classification is able to predict overall survival in a large group of adult patients with a relapsed malignant glioma, treated with re-operation and postoperative adjuvant DC vaccination in the HGG-IMMUNO-2003 cohort comparison trial. The model appears useful for prognostic patient counseling for patients participating in DC vaccination trials. A substantial number of long-term survivors after relapse are seen in class I to III, but not in class IV patients.

  5. Hepatitis B surface antigen quantification at hepatitis B e antigen seroconversion predicts virological relapse after the cessation of entecavir treatment in hepatitis B e antigen-positive patients

    Directory of Open Access Journals (Sweden)

    Yuan-wang Qiu

    2016-02-01

    Conclusions: HBsAg levels can help guide the timing of cessation of ETV treatment. HBsAg levels of 2.5 log10 IU/ml at HBeAg seroconversion may be a useful marker to predict virological relapse after the cessation of ETV treatment in HBeAg-positive CHB patients.

  6. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.

    Science.gov (United States)

    Yamamoto, Yumi; Välitalo, Pyry A; van den Berg, Dirk-Jan; Hartman, Robin; van den Brink, Willem; Wong, Yin Cheong; Huntjens, Dymphy R; Proost, Johannes H; Vermeulen, An; Krauwinkel, Walter; Bakshi, Suruchi; Aranzana-Climent, Vincent; Marchand, Sandrine; Dahyot-Fizelier, Claire; Couet, William; Danhof, Meindert; van Hasselt, Johan G C; de Lange, Elizabeth C M

    2017-02-01

    Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model. A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.

  7. Chimerism Analysis of Cell-Free DNA in Patients Treated with Hematopoietic Stem Cell Transplantation May Predict Early Relapse in Patients with Hematologic Malignancies

    Directory of Open Access Journals (Sweden)

    Mahmoud Aljurf

    2016-01-01

    Full Text Available Background. We studied DNA chimerism in cell-free DNA (cfDNA in patients treated with HSCT. Methods. Chimerism analysis was performed on CD3+ cells, polymorphonuclear (PMN cells, and cfDNA using 16 small tandem repeat loci. The resulting labeled PCR-products were size-fractionated and quantified. Results. Analyzing samples from 191 patients treated with HSCT for nonneoplastic hematologic disorders demonstrated that the cfDNA chimerism is comparable to that seen in PMN cells. Analyzing leukemia patients (N = 126 showed that, of 84 patients with 100% donor DNA in PMN, 16 (19% had evidence of clinical relapse and >10% recipient DNA in the plasma. Additional 16 patients of the 84 (19% showed >10% recipient DNA in plasma, but without evidence of relapse. Eight patients had mixed chimerism in granulocytes, lymphocytes, and plasma, but three of these patients had >10% recipient DNA in plasma compared to PMN cells and these three patients had clinical evidence of relapse. The remaining 34 patients showed 100% donor DNA in both PMN and lymphocytes, but cfDNA showed various levels of chimerism. Of these patients 14 (41% showed laboratory or clinical evidence of relapse and all had >10% recipient DNA in cfDNA. Conclusion. Monitoring patients after HSCT using cfDNA might be more reliable than cellular DNA in predicting early relapse.

  8. Tumour Relapse Prediction Using Multiparametric MR Data Recorded during Follow-Up of GBM Patients

    Directory of Open Access Journals (Sweden)

    Adrian Ion-Margineanu

    2015-01-01

    Full Text Available Purpose. We have focused on finding a classifier that best discriminates between tumour progression and regression based on multiparametric MR data retrieved from follow-up GBM patients. Materials and Methods. Multiparametric MR data consisting of conventional and advanced MRI (perfusion, diffusion, and spectroscopy were acquired from 29 GBM patients treated with adjuvant therapy after surgery over a period of several months. A 27-feature vector was built for each time point, although not all features could be obtained at all time points due to missing data or quality issues. We tested classifiers using LOPO method on complete and imputed data. We measure the performance by computing BER for each time point and wBER for all time points. Results. If we train random forests, LogitBoost, or RobustBoost on data with complete features, we can differentiate between tumour progression and regression with 100% accuracy, one time point (i.e., about 1 month earlier than the date when doctors had put a label (progressive or responsive according to established radiological criteria. We obtain the same result when training the same classifiers solely on complete perfusion data. Conclusions. Our findings suggest that ensemble classifiers (i.e., random forests and boost classifiers show promising results in predicting tumour progression earlier than established radiological criteria and should be further investigated.

  9. [Central nervous system relapse in diffuse large B cell lymphoma: Risk factors].

    Science.gov (United States)

    Sancho, Juan-Manuel; Ribera, Josep-Maria

    2016-01-15

    Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  10. CSF and clinical data are useful in differentiating CNS inflammatory demyelinating disease from CNS lymphoma.

    Science.gov (United States)

    Ikeguchi, Ryotaro; Shimizu, Yuko; Shimizu, Satoru; Kitagawa, Kazuo

    2017-06-01

    It is often difficult to diagnose central nervous system (CNS) inflammatory demyelinating diseases (IDDs) because they are similar to CNS lymphoma and glioma. To evaluate whether cerebrospinal fluid (CSF) analysis can differentiate CNS IDDs from CNS lymphoma and glioma. We measured CSF cell counts; concentrations of proteins, glucose, interleukin (IL)-6, IL-10, soluble IL-2 receptor (sIL-2R), and myelin basic protein; and IgG index in patients with multiple sclerosis (MS, n = 64), neuromyelitis optica spectrum disorder (NMOSD, n = 35), tumefactive demyelinating lesion (TDL, n = 17), CNS lymphoma ( n = 12), or glioma ( n = 10). We detected diagnostic markers using logistic regression and receiver operating characteristic (ROC) analyses. Median CSF IL-10 and sIL-2R levels were higher in CNS lymphoma patients than in MS, NMOSD, or TDL patients. Logistic regression revealed that CSF sIL-2R levels predicted CNS lymphoma. In the ROC analysis of CSF sIL-2R levels, the area under the curve was 0.867, and the sensitivity and specificity were 83.3% and 90.0%, respectively. CSF sIL-2R levels can be used to differentiate CNS lymphoma from CNS IDDs. Further studies may identify other applications of CSF as a diagnostic biomarker.

  11. Technetium uptake predicts remission and relapse in Grave's disease patients on antithyroid drugs for at least 1 year in South Indian subjects

    Directory of Open Access Journals (Sweden)

    Neha Singhal

    2016-01-01

    Full Text Available Context: Most of the information on remission related factors in Grave's disease are derived from Western literature. It is likely that there may be additional prognostic factors and differences in the postdrug treatment course of Grave's disease in India. Aim: To study factors which predict remission/relapse in Grave's disease patients from South India. Also to establish if technetium (Tc uptake has a role in predicting remission. Subjects and Methods: Records of 174 patients with clinical, biochemical, and scintigraphic criteria consistent with Grave's disease, seen in our Institution between January 2006 and 2014 were analyzed. Patient factors, drug-related factors, Tc-99m uptake and other clinical factors were compared between the remission and nonremission groups. Statistical Analysis Used: Mann–Whitney U-test and Chi-square tests were used when appropriate to compare the groups. Results: Fifty-seven (32.7% patients attained remission after at least 1 year of thionamide therapy. Of these, 11 (19.2% patients relapsed within 1 year. Age, gender, goiter, and presence of extrathyroidal manifestations were not associated with remission. Higher values of Tc uptake were positively associated with remission (P- 0.02. Time to achievement of normal thyroid function and composite dose: Time scores were significantly associated with remission (P - 0.05 and P - 0.01, respectively. Patients with lower FT4 at presentation had a higher chance of remission (P - 0.01. The relapse rates were lower than previously reported in the literature. A higher Tc uptake was found to be significantly associated with relapse also (P - 0.009. Conclusion: The prognostic factors associated with remission in Graves's disease in this South Indian study are not the same as that reported in Western literature. Tc scintigraphy may have an additional role in identifying people who are likely to undergo remission and thus predict the outcome of Grave's disease.

  12. Role of fecal calprotectin testing to predict relapse in teenagers with inflammatory bowel disease who report full disease control

    NARCIS (Netherlands)

    van Rheenen, Patrick F.

    2012-01-01

    Background: Teenagers with inflammatory bowel disease undergo regular follow-up visits to watch for symptoms that may indicate relapse. Current disease activity is frequently estimated with the use of the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohn's Disease Activity

  13. Trait Impulsive Choice Predicts Resistance to Extinction and Propensity to Relapse to Cocaine Seeking: A Bidirectional Investigation

    NARCIS (Netherlands)

    Broos, N.; Diergaarde, L.; Schoffelmeer, A.N.M.; Pattij, T.; de Vries, T.J.

    2012-01-01

    Despite the strong association between impulsivity and addiction in humans, it is still a matter of debate whether impulsive choice predisposes to, or results from, drug dependence. Furthermore, it is unknown whether treating impulsivity can protect against relapse propensity. Therefore, this study

  14. Impact of Social Cognition on Alcohol Dependence Treatment Outcome: Poorer Facial Emotion Recognition Predicts Relapse/Dropout.

    Science.gov (United States)

    Rupp, Claudia I; Derntl, Birgit; Osthaus, Friederike; Kemmler, Georg; Fleischhacker, W Wolfgang

    2017-12-01

    Despite growing evidence for neurobehavioral deficits in social cognition in alcohol use disorder (AUD), the clinical relevance remains unclear, and little is known about its impact on treatment outcome. This study prospectively investigated the impact of neurocognitive social abilities at treatment onset on treatment completion. Fifty-nine alcohol-dependent patients were assessed with measures of social cognition including 3 core components of empathy via paradigms measuring: (i) emotion recognition (the ability to recognize emotions via facial expression), (ii) emotional perspective taking, and (iii) affective responsiveness at the beginning of inpatient treatment for alcohol dependence. Subjective measures were also obtained, including estimates of task performance and a self-report measure of empathic abilities (Interpersonal Reactivity Index). According to treatment outcomes, patients were divided into a patient group with a regular treatment course (e.g., with planned discharge and without relapse during treatment) or an irregular treatment course (e.g., relapse and/or premature and unplanned termination of treatment, "dropout"). Compared with patients completing treatment in a regular fashion, patients with relapse and/or dropout of treatment had significantly poorer facial emotion recognition ability at treatment onset. Additional logistic regression analyses confirmed these results and identified poor emotion recognition performance as a significant predictor for relapse/dropout. Self-report (subjective) measures did not correspond with neurobehavioral social cognition measures, respectively objective task performance. Analyses of individual subtypes of facial emotions revealed poorer recognition particularly of disgust, anger, and no (neutral faces) emotion in patients with relapse/dropout. Social cognition in AUD is clinically relevant. Less successful treatment outcome was associated with poorer facial emotion recognition ability at the beginning of

  15. Predicting relapse in major depressive disorder using patient-reported outcomes of depressive symptom severity, functioning, and quality of life in the Individual Burden of Illness Index for Depression (IBI-D).

    Science.gov (United States)

    Ishak, Waguih William; Greenberg, Jared M; Cohen, Robert M

    2013-10-01

    Patients with Major Depressive Disorder (MDD) often experience unexpected relapses, despite achieving remission. This study examines the utility of a single multidimensional measure that captures variance in patient-reported Depressive Symptom Severity, Functioning, and Quality of Life (QOL), in predicting MDD relapse. Complete data from remitted patients at the completion of 12 weeks of citalopram in the STAR*D study were used to calculate the Individual Burden of Illness index for Depression (IBI-D), and predict subsequent relapse at six (n=956), nine (n=778), and twelve months (n=479) using generalized linear models. Depressive Symptom Severity, Functioning, and QOL were all predictors of subsequent relapse. Using Akaike information criteria (AIC), the IBI-D provided a good model for relapse even when Depressive Symptom Severity, Functioning, and QOL were combined in a single model. Specifically, an increase of one in the IBI-D increased the odds ratio of relapse by 2.5 at 6 months (β=0.921 ± 0.194, z=4.76, pDepressive Symptom Severity in the IBI-D is useful in assessing the full burden of illness and in adequately predicting relapse, in MDD. © 2013 Elsevier B.V. All rights reserved.

  16. CNS infections in Greenland

    DEFF Research Database (Denmark)

    Nordholm, Anne Christine; Søborg, Bolette; Andersson, Mikael

    2017-01-01

    ), but equally high among Inuits in Greenland and Denmark (38.2 and 35.4, respectively). Mortality from CNS infections was 2 fold higher among Inuits (10.5%) than among non-Inuits (4.8%) with a fivefold higher case fatality rate in Inuit toddlers. CONCLUSION: Overall, Inuits living in Greenland and Denmark...... suffer from twice the rate of CNS infections compared with non-Inuits, and Inuit toddlers carried the highest risk of mortality. Further studies regarding risk factors such as genetic susceptibility, life style and socioeconomic factors are warranted....

  17. The Effectiveness of Motivational Council (MI Model on Prediction of the Relapse in Women Addicted to Narcotic Drugs

    Directory of Open Access Journals (Sweden)

    S Dehghani Firozabadi

    2014-11-01

    Full Text Available Objective: The aim of present research was to study of the effectiveness of motivational council on preventing of relapse in women addicted to narcotic drugs. Method: This research was carried on by semi experimental method with the pretest-posttest with witness group. Population included all addicted women referring to Ayandeh Roshan recovery addiction camp of Isfahan during summer 1391. Sample was 30 women who were selected of addicted women of recovery camp, and randomly divided to two groups. The aware of returning to use of narcotic drugs questionnaire administered among two groups two times as pretest and posttest. The motivational counsel training administered for 8 sessions in experimental group. Results: The results showed that motivational counsel training was affected on experimental group. Conclusion: It could be said that motivational council was useful and effective in reducing the relapse of using narcotic drugs.

  18. CNS and inflammation

    African Journals Online (AJOL)

    EL-HAKIM

    Synthesis of inflammatory mediators – e.g. cytokines, free radicals, prostaglandins. Expression of adhesion molecules. Invasion of immune cells. Leukocytes have the ability to infiltrate the. CNS and cytokines are produced by resident cells, especially during injuries and diseases. Although the cellular source and role of ...

  19. CNS Tumors in Neurofibromatosis.

    Science.gov (United States)

    Campian, Jian; Gutmann, David H

    2017-07-20

    Neurofibromatosis (NF) encompasses a group of distinct genetic disorders in which affected children and adults are prone to the development of benign and malignant tumors of the nervous system. The purpose of this review is to discuss the spectrum of CNS tumors arising in individuals with NF type 1 (NF1) and NF type 2 (NF2), their pathogenic etiologies, and the rational treatment options for people with these neoplasms. This article is a review of preclinical and clinical data focused on the treatment of the most common CNS tumors encountered in children and adults with NF1 and NF2. Although children with NF1 are at risk for developing low-grade gliomas of the optic pathway and brainstem, individuals with NF2 typically manifest low-grade tumors affecting the cranial nerves (vestibular schwannomas), meninges (meningiomas), and spinal cord (ependymomas). With the identification of the NF1 and NF2 genes, molecularly targeted therapies are beginning to emerge, as a result of a deeper understanding of the mechanisms underlying NF1 and NF2 protein function. As we enter into an era of precision oncology, a more comprehensive awareness of the factors that increase the risk of developing CNS cancers in affected individuals, coupled with a greater appreciation of the cellular and molecular determinants that maintain tumor growth, will undoubtedly yield more effective therapies for these cancer predisposition syndromes.

  20. Antiphospholipid antibodies, steroid dose, arterial hypertension, relapses, and late-onset predict organ damage in a population of Colombian patients with systemic lupus erythematosus.

    Science.gov (United States)

    Pinto-Peñaranda, Luis F; Muñoz-Grajales, C; Echeverri Garcia, A F; Velásquez-Franco, C J; Mesa-Navas, M A; Zuluaga Quintero, M; Herrera-Uribe, S; Márquez-Hernández, J D

    2017-12-04

    Organ damage predicts mortality, increased accrual of detriment, and poor quality of life in systemic lupus erythematosus patients. The objective of this study is to determine the damage-free survival and its predictive factors in a population of Colombian subjects. The method used in this study is the retrospective follow-up of a cohort; damage was measured with SLICC/ACR index. Predictors of impairment were assessed by logistic regression and survival analysis. One hundred sixty-one individuals were included; 28.9% suffered damage, primarily neuropsychiatric, renal, and vascular. Arterial hypertension, antiphospholipid antibodies, prednisone dose, and number of relapses were all predictors of detriment. Onset after age 50 and daily prednisone dose higher than 7.5 mg determined earlier occurrence of damage.

  1. Ambroxol: a CNS drug?

    Science.gov (United States)

    Weiser, Thomas

    2008-01-01

    For almost three decades ambroxol has been used in the therapy of airway diseases. In 2002, ambroxol lozenges were marketed for the treatment of sore throat making use of its local anesthetic effect. Detailed investigations of ambroxol with modern pharmacological methods yielded additional interesting results: ambroxol has been found to have profound effects on neuronal voltage-gated Na(+), as well as Ca(2+) channels, and to effectively reduce chronic inflammatory and neuropathic pain in rodents. The question was raised whether ambroxol affects the central nervous system (CNS) directly, or whether its effects can be explained solely by a peripheral action. This issue was addressed by re-examining pharmacokinetics, as well as toxicology of ambroxol. It has been concluded that even at the highest clinically used doses ambroxol does not have significant direct effects on the CNS. At clinically relevant plasma concentrations ambroxol either does not penetrate blood-brain barrier, or its brain levels are too low to cause relevant effects. The analgesic effects of ambroxol by either systemic administration to animals, or by topical application in humans can be explained by ambroxol-induced blockade of ion channels in peripheral neurons.

  2. Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage therapy.

    Science.gov (United States)

    Devillier, Raynier; Coso, Diane; Castagna, Luca; Brenot Rossi, Isabelle; Anastasia, Antonella; Chiti, Arturo; Ivanov, Vadim; Schiano, Jean Marc; Santoro, Armando; Chabannon, Christian; Balzarotti, Monica; Blaise, Didier; Bouabdallah, Reda

    2012-07-01

    High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin's lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin's lymphoma. We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin's lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed

  3. Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy

    Science.gov (United States)

    Devillier, Raynier; Coso, Diane; Castagna, Luca; Brenot Rossi, Isabelle; Anastasia, Antonella; Chiti, Arturo; Ivanov, Vadim; Schiano, Jean Marc; Santoro, Armando; Chabannon, Christian; Balzarotti, Monica; Blaise, Didier; Bouabdallah, Reda

    2012-01-01

    Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to

  4. Flavonoids and the CNS

    DEFF Research Database (Denmark)

    Jäger, Anna Katharina; Saaby, Lasse

    2011-01-01

    Flavonoids are present in almost all terrestrial plants, where they provide UV-protection and colour. Flavonoids have a fused ring system consisting of an aromatic ring and a benzopyran ring with a phenyl substituent. The flavonoids can be divided into several classes depending on their structure....... Flavonoids are present in food and medicinal plants and are thus consumed by humans. They are found in plants as glycosides. Before oral absorption, flavonoids undergo deglycosylation either by lactase phloridzin hydrolase or cytosolic ß-glucocidase. The absorbed aglycone is then conjugated by methylation......, sulphatation or glucuronidation. Both the aglycones and the conjugates can pass the blood-brain barrier. In the CNS several flavones bind to the benzodiazepine site on the GABA(A)-receptor resulting in sedation, anxiolytic or anti-convulsive effects. Flavonoids of several classes are inhibitors of monoamine...

  5. Risk of relapse phenotype recurrence in multiple sclerosis.

    Science.gov (United States)

    Kalincik, Tomas; Buzzard, Katherine; Jokubaitis, Vilija; Trojano, Maria; Duquette, Pierre; Izquierdo, Guillermo; Girard, Marc; Lugaresi, Alessandra; Grammond, Pierre; Grand'Maison, Francois; Oreja-Guevara, Celia; Boz, Cavit; Hupperts, Raymond; Petersen, Thor; Giuliani, Giorgio; Iuliano, Gerardo; Lechner-Scott, Jeannette; Barnett, Michael; Bergamaschi, Roberto; Van Pesch, Vincent; Amato, Maria Pia; van Munster, Erik; Fernandez-Bolanos, Ricardo; Verheul, Freek; Fiol, Marcela; Cristiano, Edgardo; Slee, Mark; Rio, Maria Edite; Spitaleri, Daniele; Alroughani, Raed; Gray, Orla; Saladino, Maria Laura; Flechter, Sholmo; Herbert, Joseph; Cabrera-Gomez, Jose Antonio; Vella, Norbert; Paine, Mark; Shaw, Cameron; Moore, Fraser; Vucic, Steve; Savino, Aldo; Singhal, Bhim; Petkovska-Boskova, Tatjana; Parratt, John; Sirbu, Carmen-Adella; Rozsa, Csilla; Liew, Danny; Butzkueven, Helmut

    2014-10-01

    The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance. © The Author(s), 2014.

  6. The predictive value of fluctuations in IgM and IgG class anti-dsDNA antibodies for relapses in systemic lupus erythematosus. A prospective long term observation

    NARCIS (Netherlands)

    Bootsma, H.; SPRONK, P.E.; TERBORG, E.J.; HUMMEL, E.J.; deBoer, G.; Limburg, Piet; Kallenberg, Cees

    1997-01-01

    Objective-This study investigated the predictive value of rises in IgM class antibodies against double stranded DNA (anti-dsDNA) for ensuing relapses in systemic lupus erythematosus (SLE) in comparison with rises in IgG class antibodies. In addition, it was analysed whether rises in IgM class

  7. Comparison of the performance of log-logistic regression and artificial neural networks for predicting breast cancer relapse.

    Science.gov (United States)

    Faradmal, Javad; Soltanian, Ali Reza; Roshanaei, Ghodratollah; Khodabakhshi, Reza; Kasaeian, Amir

    2014-01-01

    Breast cancer is the most common cancers in female populations. The exact cause is not known, but is most likely to be a combination of genetic and environmental factors. Log-logistic model (LLM) is applied as a statistical method for predicting survival and it influencing factors. In recent decades, artificial neural network (ANN) models have been increasingly applied to predict survival data. The present research was conducted to compare log-logistic regression and artificial neural network models in prediction of breast cancer (BC) survival. A historical cohort study was established with 104 patients suffering from BC from 1997 to 2005. To compare the ANN and LLM in our setting, we used the estimated areas under the receiver-operating characteristic (ROC) curve (AUC) and integrated AUC (iAUC). The data were analyzed using R statistical software. The AUC for the first, second and third years after diagnosis are 0.918, 0.780 and 0.800 in ANN, and 0.834, 0.733 and 0.616 in LLM, respectively. The mean AUC for ANN was statistically higher than that of the LLM (0.845 vs. 0.744). Hence, this study showed a significant difference between the performance in terms of prediction by ANN and LLM. This study demonstrated that the ability of prediction with ANN was higher than with the LLM model. Thus, the use of ANN method for prediction of survival in field of breast cancer is suggested.

  8. Innate Interferons Regulate CNS Inflammation

    DEFF Research Database (Denmark)

    Dieu, Ruthe; Khorooshi, Reza M. H.; Mariboe, Anne

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathology is characterised by demyelination and axonal damage. This results from interplay between CNS-resident glia, infiltrating leukocytes and a plethora of cytokines and chemokines. Currently, ...

  9. HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status.

    Science.gov (United States)

    Weitsman, Gregory; Barber, Paul R; Nguyen, Lan K; Lawler, Katherine; Patel, Gargi; Woodman, Natalie; Kelleher, Muireann T; Pinder, Sarah E; Rowley, Mark; Ellis, Paul A; Purushotham, Anand D; Coolen, Anthonius C; Kholodenko, Boris N; Vojnovic, Borivoj; Gillett, Cheryl; Ng, Tony

    2016-08-09

    Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker.FFPE tissues were obtained from patients included in the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. HER2-HER3 dimerisation was quantified using an improved fluorescence lifetime imaging microscopy (FLIM) histology-based analysis. Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Förster Resonance Energy Transfer (FRET) determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery (hazard ratio 3.91 (1.61-9.5), p = 0.003) independently of HER2 expression, in a multivariate model. Interestingly there was no correlation between the level of HER2 protein expressed and HER2-HER3 heterodimer formation. We used a mathematical model that takes into account the complex interactions in a network of all four HER proteins to explain this counterintuitive finding.Future utility of this technique may highlight a group of patients who do not overexpress HER2 protein but are nevertheless dependent on the HER2-HER3 heterodimer as driver of proliferation. This assay could, if validated in a group of patients treated with, for instance pertuzumab, be used as a predictive biomarker to predict for response to such targeted therapies.

  10. Flavonoids and the CNS

    Directory of Open Access Journals (Sweden)

    Anna K. Jäger

    2011-02-01

    Full Text Available Flavonoids are present in almost all terrestrial plants, where they provide UV-protection and colour. Flavonoids have a fused ring system consisting of an aromatic ring and a benzopyran ring with a phenyl substituent. The flavonoids can be divided into several classes depending on their structure. Flavonoids are present in food and medicinal plants and are thus consumed by humans. They are found in plants as glycosides. Before oral absorption, flavonoids undergo deglycosylation either by lactase phloridzin hydrolase or cytosolic β-glucocidase. The absorbed aglycone is then conjugated by methylation, sulphatation or glucuronidation. Both the aglycones and the conjugates can pass the blood-brain barrier. In the CNS several flavones bind to the benzodiazepine site on the GABAA-receptor resulting in sedation, anxiolytic or anti-convulsive effects. Flavonoids of several classes are inhibitors of monoamine oxidase A or B, thereby working as anti-depressants or to improve the conditions of Parkinson’s patients. Flavanols, flavanones and anthocyanidins have protective effects preventing inflammatory processes leading to nerve injury. Flavonoids seem capable of influencing health and mood.

  11. Depression relapse and ethological measures

    NARCIS (Netherlands)

    Hale, WWH; Jansen, JHC; Bouhuys, AL; vandenHoofdakker, RH

    1997-01-01

    Within the framework of interactional theories on depression, the question is raised whether depression relapse can be predicted by observable behavior of remitted patients and their interviewer during an interaction (i.e. discharge interview). Thirty-four patients were interviewed at hospital

  12. Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture

    Directory of Open Access Journals (Sweden)

    Zartaj Ahmed

    2014-01-01

    Full Text Available Primary CNS lymphoma (PCNSL is a rare non-Hodgkin’s lymphoma confined to the CNS. Local relapse of this disease is common, but extracranial or subcutaneous metastasis is rare with only a few cases being reported in literature. We report a 63-year-old male patient, who responded well to treatment for PCNSL but relapsed two and half years later with a lumbosacral nodule at the site of a previous lumbar puncture due to microscopic tumor seeding. Clinicians treating patients with PCNSL must remain alert to the possibility of extracranial solitary relapse even after the resolution of initial disease because prompt treatment can result in a good outcome.

  13. Are Fusion Transcripts in Relapsed/Metastatic Head and Neck Cancer Patients Predictive of Response to Anti-EGFR Therapies?

    Directory of Open Access Journals (Sweden)

    Paolo Bossi

    2017-01-01

    Full Text Available Prediction of benefit from combined chemotherapy and the antiepidermal growth factor receptor cetuximab is a not yet solved question in head and neck squamous cell carcinoma (HNSCC. In a selected series of 14 long progression-free survival (PFS and 26 short PFS patients by whole gene and microRNA expression analysis, we developed a model potentially predictive of cetuximab sensitivity. To better decipher the “omics” profile of our patients, we detected transcript fusions by RNA-seq through a Pan-Cancer panel targeting 1385 cancer genes. Twenty-seven different fusion transcripts, involving mRNA and long noncoding RNA (lncRNA, were identified. The majority of fusions (81% were intrachromosomal, and 24 patients (60% harbor at least one of them. The presence/absence of fusions and the presence of more than one fusion were not related to outcome, while the lncRNA-containing fusions resulted enriched in long PFS patients (P=0.0027. The CD274-PDCD1LG2 fusion was present in 7/14 short PFS patients harboring fusions and was absent in long PFS patients (P=0.0188. Among the short PFS patients, those harboring this fusion had the worst outcome (P=0.0172 and increased K-RAS activation (P=0.00147. The associations between HNSCC patient’s outcome following cetuximab treatment and lncRNA-containing fusions or the CD274-PDCD1LG2 fusion deserve validation in prospective clinical trials.

  14. An invertebrate model for CNS drug discovery

    DEFF Research Database (Denmark)

    Al-Qadi, Sonia; Schiøtt, Morten; Hansen, Steen Honoré

    2015-01-01

    and is considered the most vital efflux pump. Functionally, this model showed transport kinetic behaviors comparable to those obtained from in vitro models. Particularly, substrate affinity of the putative P-gp was observed as in P-gp expressing cells lines, used for predicting drug penetration across biological......BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple...... was performed. Subsequently, identified transcripts were matched with their counterparts in human, rat, mouse and Drosophila melanogaster, based on amino acid sequence similarity, and phylogenetic trees were constructed to reveal the most likely evolutionary history of the proteins. Further, functional...

  15. Usefulness of desmopressin testing to predict relapse during long-term follow-up in patients in remission from Cushing’s disease

    Directory of Open Access Journals (Sweden)

    Alberto Giacinto Ambrogio

    2017-11-01

    Full Text Available Recurrence of Cushing’s disease after successful transsphenoidal surgery occurs in some 30% of the patients and the response to desmopressin shortly after surgery has been proposed as a marker for disease recurrence. The aim of the present study was to evaluate the response to desmopressin over time after surgery. We tested 56 patients with Cushing’s disease in remission after transsphenoidal surgery with desmopressin for up to 20 years after surgery. The ACTH and cortisol response to desmopressin over time was evaluated in patients on long-term remission or undergoing relapse; an increase by at least 27 pg/mL in ACTH levels identified responders. The vast majority of patients who underwent successful adenomectomy failed to respond to desmopressin after surgery and this response pattern was maintained over time in patients on long-term remission. Conversely, a response to desmopressin reappeared in patients who subsequently developed a recurrence of Cushing’s disease, even years prior to frank hypercortisolism. It appears therefore that a change in the response pattern to desmopressin proves predictive of recurrence of Cushing’s disease and may indicate which patients require close monitoring.

  16. Levels of Neural Progenitors in the Hippocampus Predict Memory Impairment and Relapse to Drug Seeking as a Function of Excessive Methamphetamine Self-Administration

    Science.gov (United States)

    Recinto, Patrick; Samant, Anjali Rose H; Chavez, Gustavo; Kim, Airee; Yuan, Clara J; Soleiman, Matthew; Grant, Yanabel; Edwards, Scott; Wee, Sunmee; Koob, George F; George, Olivier; Mandyam, Chitra D

    2012-01-01

    Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2′-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended

  17. Coordinated Noninvasive Studies (CNS) Project

    Science.gov (United States)

    1988-11-01

    made by Neuroscience , and offers a variety of testing options, including evoked-potential testing sampling several levels of the CNS via several...designing the qEEG test series to be included in the CNS Project. Testing for this project will be conducted using the Dept of Neurology’s Neuroscience Brain...Discrimination of Multisyllabic Sequences by Young Infants (Roanne Karzon, Ph.D. Dissertation, 1982) Hypnosis and Its Relationship to Right Hemisphere

  18. Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease.

    Science.gov (United States)

    Garvey, L; Winston, A; Walsh, J; Post, F; Porter, K; Gazzard, B; Fisher, M; Leen, C; Pillay, D; Hill, T; Johnson, M; Gilson, R; Anderson, J; Easterbrook, P; Bansi, L; Orkin, C; Ainsworth, J; Palfreeman, A; Gompels, M; Phillips, A N; Sabin, C A

    2011-02-22

    The impact of different antiretroviral agents on the risk of developing or surviving CNS disease remains unknown. The aim of this study was to investigate whether using antiretroviral regimens with higher CNS penetration effectiveness (CPE) scores was associated with reduced incidence of CNS disease and improved survival in the UK Collaborative HIV Cohort (CHIC) Study. Adults without previous CNS disease, who commenced combination antiretroviral therapy (cART) between 1996 and 2008, were included (n = 22,356). Initial and most recent cART CPE scores were calculated. CNS diseases were HIV encephalopathy (HIVe), progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis (TOXO), and cryptococcal meningitis (CRYPTO). Incidence rates and overall survival were stratified by CPE score. A multivariable Poisson regression model was used to identify independent associations. The median (interquartile range) CPE score for initial cART regimen increased from 7 (5-8) in 1996-1997 to 9 (8-10) in 2000-2001 and subsequently declined to 6 (7-8) in 2006-2008. Differences in gender, HIV acquisition risk group, and ethnicity existed between CPE score strata. A total of 251 subjects were diagnosed with a CNS disease (HIVe 80; TOXO 59; CRYPTO 56; PML 54). CNS diseases occurred more frequently in subjects prescribed regimens with CPE scores ≤ 4, and less frequently in those with scores ≥ 10; however, these differences were nonsignificant. Initial and most recent cART CPE scores ≤ 4 were independently associated with increased risk of death. Clinical status at time of commencing cART influences antiretroviral selection and CPE score. This information should be considered when utilizing CPE scores for retrospective analyses.

  19. Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Navikas, V; Schaub, M

    1998-01-01

    We studied the kinetics of expression of costimulatory molecules and cytokines in the central nervous system (CNS) in murine relapsing experimental autoimmune encephalomyelitis (EAE). During the natural course of EAE, B7-2 expression in the CNS correlated with clinical signs, while B7-1 was exclu...

  20. Pro-Inflammatory Cytokines Predict Relapse-Free Survival after One Month of Interferon-α but Not Observation in Intermediate Risk Melanoma Patients.

    Directory of Open Access Journals (Sweden)

    Ahmad A Tarhini

    Full Text Available E1697 was a phase III trial of adjuvant interferon (IFN-α2b for one month (Arm B versus observation (Arm A in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS in Arm A and Arm B among 268 patients with banked biospecimens.ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected CTLA4 and FOXP3 Single nucleotide polymorphisms (SNPs and microsatellites were tested for by polymerase chain reaction (PCR. Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV was used to avoid over-fitting of the data.In the multi-marker modeling analysis conducted in Arm B, one month serum IL2Rα, IL-12p40 and IFNα levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2Rα and IFNα were the most stable (selected in all the cross validation cycles. The risk score (linear combination of the 3 markers separated the RFS curves of low and high risk groups well (p = 0.05. This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy.Early on-treatment proinflammatory serum markers (IL2Rα, IL-12p40, IFNα significantly predict RFS in our cohort of patients treated with adjuvant IFN-α2b and warrant further study.

  1. Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients

    DEFF Research Database (Denmark)

    Wesolowska, Agata; Borst, L.; Dalgaard, Marlene Danner

    2015-01-01

    associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups......Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10–15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant singlenucleotide polymorphisms (SNPs) to identify host...... genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin–Frankfurt–Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly...

  2. MRI patterns in recurrence of primary CNS lymphoma in immunocompetent patients

    Energy Technology Data Exchange (ETDEWEB)

    Schulte-Altedorneburg, Gernot, E-mail: Gernot.Schulte-Altedorneburg@klinikum-muenchen.de [Institute of Radiology, Neuroradiology and Nuclear Medicine, University of Bochum, Knappschaftskrankenhaus, In der Schornau 23-25, 44892 Bochum (Germany); Heuser, Lothar [Institute of Radiology, Neuroradiology and Nuclear Medicine, University of Bochum, Knappschaftskrankenhaus, In der Schornau 23-25, 44892 Bochum (Germany); Pels, Hendrik [Department of Neurology, Knappschaftskrankenhaus, University of Bochum, In der Schornau 23-25, 44892 Bochum (Germany)

    2012-09-15

    Highlights: ► PCNSL are rare but highly malignant brain tumors. ► PCNSL recur in different anatomic sites compared with initial presentation. ► Non-parenchymal contrast enhancement is a frequent finding at initialdiagnosis and at relapse. -- Abstract: Purpose: Primary CNS lymphomas (PCNSL) are highly malignant non-Hodgkin's B-cell lymphoma restricted to the CNS. While MRI features of PCNSL at initial presentation have been comprehensively described, literature on MRI-characteristics at relapse is sparse. The purpose of this study was to investigate anatomic location and contrast enhancement patterns at PCNSL recurrence by cranial MRI. Methods: Sixteen immunocompetent patients (9 men, 7 women, median age 65 years) with histologically proven PCNSL and initial response to a standardized polychemotherapy, but suffering from a relapse were consecutively recorded. Native and contrast-enhanced MRI examinations carried out at initial presentation and at time of relapse were compared. Anatomical site of parenchymal enhancement, frequency and presence of non-parenchymal contrast enhancement (i.e. ventricular, superficial, subependymal) patterns at initial presentation and at relapse were recorded and compared. Results: Local recurrence was found at the site of the initial tumor presentation in four of the 16 cases. Six of 11 patients presenting a unilateral PCNSL at initial presentation had a bilateral involvement at relapse. In two cases, recurrence appeared solely on the contralateral side without involvement of the hemisphere initially affected. At both dates, subependymal enhancement was the most often found non-parenchymal pattern (six at initial presentation, and five at relapse). The number of patients with a ventricular contrast enhancement increased from one at initial presentation to four at relapse. Conclusions: PCNSL tend to recur in different parenchymal anatomic sites as compared with the site of the initial tumor presentation. Contrast-enhancing non

  3. Genetic models for CNS inflammation

    DEFF Research Database (Denmark)

    Owens, T; Wekerle, H; Antel, J

    2001-01-01

    The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily...

  4. Loss of heterozygosity at 9p and p53 immunopositivity in surgical margins predict local relapse in head and neck squamous cell carcinoma

    NARCIS (Netherlands)

    Graveland, A.P.; Golusinski, P.J.; Buijze, M.; Douma, R.; Sons, N.; Kuik, D.J.; Bloemena, E.; Leemans, C.R.; Brakenhoff, R.H.; Braakhuis, B.J.M.

    2011-01-01

    A major problem in head and neck cancer surgery is the high rate of local relapse (LR). In at least 25% of the surgically treated head and neck squamous cell carcinoma (HNSCC) patients, a genetically defined preneoplastic lesion, also known as "field," can be detected in the surgical margins. A

  5. Contrasting responses to interferon β-1b treatment in relapsing-remitting multiple sclerosis: Does baseline interleukin- 12p35 messenger RNA predict the efficacy of treatment?

    NARCIS (Netherlands)

    Boxel van-Dezaire, A.H.H.; Trigt van-Hoff, S.C.J.; Killestein, J.; Schrijver, H.M.; Houwelingen, J.C. van; Polman, C.H.; Nagelkerken, L.

    2000-01-01

    Interferon (IFN)-β treatment is effective in relapsing-remitting multiple sclerosis (RR-MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)-12 subunits p40 and p35, IL-12 receptor chains, IL-18,

  6. Prediction of relapse to frequent heroin use and the role of methadone prescription: An analysis of the Amsterdam Cohort Study among drug users

    NARCIS (Netherlands)

    Termorshuizen, Fabian; Krol, Anneke; Prins, Maria; Geskus, Ronald; van den Brink, Wim; van Ameijden, Erik J. C.

    2005-01-01

    The risk of relapse into frequent heroin use was studied among 732 participants of the Amsterdam Cohort Study (ACS) on HIV/AIDS among drug users, who experienced an episode of abstinence from or occasional use of heroin. Participants of the ACS were recruited primarily from easy access

  7. Absolute lymphocyte count predicts response to rituximab-containing salvage treatment for relapsed/refractory B-cell non-Hodgkin's lymphoma with prior rituximab exposure

    Directory of Open Access Journals (Sweden)

    Man-Hsin Hung

    2013-04-01

    Conclusion: Our study results show that for patients with relapsed/refractory B-cell NHL, rituximab-containing salvage treatment is feasible and generally tolerable. A high ALC-R value was significantly associated with a better response to this treatment.

  8. The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

    DEFF Research Database (Denmark)

    Schmiegelow, K; Donovan, Martin Heyman; Sherson, Maiken Gustafsson

    2010-01-01

    ) free survival was lower for adolescents than non-adolescents (pEFS12y:0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (rS=0.36, P=0.02), which became nonsignificant for those who relapsed (r...

  9. Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients

    DEFF Research Database (Denmark)

    Wesolowska, Agata; Borst, L.; Dalgaard, Marlene Danner

    2015-01-01

    defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates...

  10. Relapses in dogs with steroid-responsive meningitis-arteritis.

    Science.gov (United States)

    Biedermann, E; Tipold, A; Flegel, T

    2016-02-01

    To describe relapse rates in steroid-responsive meningitis-arteritis and to describe clinical and laboratory parameters in dogs with and without relapses. Seventy-four dogs with steroid-responsive meningitis-arteritis were retrospectively identified and assigned to one of three groups: (1) without relapse; (2) at least one relapse and (3) unknown relapse status. The following parameters are reported for the first two groups: sex, age, breed, body weight, nucleated cell count, total protein concentration and percentage of neutrophils on initial cerebrospinal fluid analysis, immunoglobulin A in serum and initial cerebrospinal fluid analysis, nucleated cell count on cerebrospinal fluid analysis at 3-month re-evaluation, C-reactive protein in serum and initial cerebrospinal fluid analysis and at 3-month re-evaluation. Relapses occurred in 32 · 4% of dogs (one relapse: 62 · 5%; two relapses: 25 · 0%; three relapses: 8 · 3%; four relapses: 4 · 2%), 55 · 4% were relapse-free and in 12 · 2% the relapse status was unknown. C-reactive protein in serum and cerebrospinal fluid on 3-month re-evaluation was normal in 80% and 75% of dogs with relapses, respectively. In dogs without relapse, C-reactive protein in serum and cerebrospinal fluid on 3-month re-evaluation was normal in 100% and 90% of dogs, respectively. Relapses are frequent but no reliable predictive indicator has emerged in this study. Nevertheless, elevated C-reactive protein in serum warrants continuing therapy; normal C-reactive protein in serum does not exclude future relapse. © 2015 British Small Animal Veterinary Association.

  11. The spectrum of post-vaccination inflammatory CNS demyelinating syndromes.

    Science.gov (United States)

    Karussis, Dimitrios; Petrou, Panayiota

    2014-03-01

    risk of a demyelinating CNS disease following vaccination, although non-negligible, is relatively low. The risk of onset or relapse of CNS demyelination following infections against which the vaccines are aimed to protect, is substantially higher and the benefits of vaccinations surpass the potential risks of CNS inflammation. This does not in any way exempt us from“learning” the lessons taught by the reported cases and searching new and safer ways to improve vaccination techniques and increase their safety profile.

  12. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... Relapsing-remitting MS (RRMS) Share this page Facebook Twitter Email Relapsing-remitting MS (RRMS) Relapsing-remitting MS (RRMS) Diagnosing RRMS Treating RRMS Research in RRMS Share Smaller Text Larger Text Print ...

  13. Circulating Tyrosinase and MART-1 mRNA does not Independently Predict Relapse or Survival in Patients with AJCC Stage I–II Melanoma

    DEFF Research Database (Denmark)

    Schmidt, Henrik; Sørensen, Boe S; Sjoegren, Pia

    2006-01-01

    The detection of melanoma cells in peripheral blood has been proposed to select patients with a high risk of relapse. In this study, tyrosinase and melanoma antigen recognized by T cells 1 (MART-1) mRNA expression was evaluated in serial samples obtained before definitive surgery and during follow......-up in patients with American Joint Committee on Cancer stage I-II melanoma. Serial samples (n=2,262) were collected from 236 patients from 1997 to 2002. Analyses of the RNA samples were performed with a calibrated reverse transcriptase-PCR assay. Gender, age, primary tumor site, ulceration, thickness, Clark.......07) approached significance at the 5% significance level. The serial measurements of tyrosinase and MART-1 mRNA in peripheral blood of stage I-II melanoma patients cannot be demonstrated to have independent prognostic impact on relapse-free survival....

  14. Modeling relapse in animals.

    Science.gov (United States)

    Martin-Fardon, Rémi; Weiss, Friedbert

    2013-01-01

    Alcohol addiction is a chronically relapsing disorder characterized by compulsive alcohol seeking and use. Alcohol craving and long-lasting vulnerability to relapse present a great challenge for the successful treatment of alcohol addiction. Therefore, relapse prevention has emerged as a critically important area of research, with the need for effective and valid animal models of relapse. This chapter provides an overview of the repertoire of animal models of craving and relapse presently available and employed in alcoholism research. These models include conditioned reinstatement, stress-induced reinstatement, ethanol priming-induced reinstatement, conditioned place preference, Pavlovian spontaneous recovery, the alcohol deprivation effect, and seeking-taking chained schedules. Thus, a wide array of animal models is available that permit investigation of behaviors directed at obtaining access to alcohol, as well as neurobehavioral mechanisms and genetic factors that regulate these behaviors. These models also are instrumental for identifying pharmacological treatment targets and as tools for evaluating the efficacy of potential medications for the prevention of alcohol craving and relapse.

  15. Visual working memory deterioration preceding relapse in psychosis.

    Science.gov (United States)

    Hui, C L M; Li, Y K; Li, A W Y; Lee, E H M; Chang, W C; Chan, S K W; Lam, S Y; Thornton, A E; Sham, P; Honer, W G; Chen, E Y H

    2016-08-01

    Relapse is distressingly common after the first episode of psychosis, yet it is poorly understood and difficult to predict. Investigating changes in cognitive function preceding relapse may provide new insights into the underlying mechanism of relapse in psychosis. We hypothesized that relapse in fully remitted first-episode psychosis patients was preceded by working memory deterioration. Visual memory and verbal working memory were monitored prospectively in a 1-year randomized controlled trial of remitted first-episode psychosis patients assigned to medication continuation (quetiapine 400 mg/day) or discontinuation (placebo). Relapse (recurrence of positive symptoms of psychosis), visual (Visual Patterns Test) and verbal (Letter-Number span test) working memory and stressful life events were assessed monthly. Remitted first-episode patients (n = 102) participated in the study. Relapsers (n = 53) and non-relapsers (n = 49) had similar baseline demographic and clinical profiles. Logistic regression analyses indicated relapse was associated with visual working memory deterioration 2 months before relapse [odds ratio (OR) 3.07, 95% confidence interval (CI) 1.19-7.92, P = 0.02], more stressful life events 1 month before relapse (OR 2.11, 95% CI 1.20-3.72, P = 0.01) and medication discontinuation (OR 5.52, 95% CI 2.08-14.62, P = 0.001). Visual working memory deterioration beginning 2 months before relapse in remitted first-episode psychosis patients (not baseline predictor) may reflect early brain dysfunction that heralds a psychotic relapse. The deterioration was found to be unrelated to a worsening of psychotic symptoms preceding relapse. Testable predictors offer insight into the brain processes underlying relapse in psychosis.

  16. Levels of Neural Progenitors in the Hippocampus Predict Memory Impairment and Relapse to Drug Seeking as a Function of Excessive Methamphetamine Self-Administration

    OpenAIRE

    Recinto, Patrick; Samant, Anjali Rose H; Chavez, Gustavo; Kim, Airee; Yuan, Clara J; Soleiman, Matthew; Grant, Yanabel; Edwards, Scott; Wee, Sunmee; Koob, George F.; George, Olivier; Mandyam, Chitra D.

    2011-01-01

    Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to ...

  17. Nanomedicines for the Treatment of CNS Diseases.

    Science.gov (United States)

    Reynolds, Jessica L; Mahato, Ram I

    2017-03-01

    Targeting and delivering macromolecular therapeutics to the central nervous system (CNS) has been a major challenge. The blood-brain barrier (BBB) is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Therefore, much effort has been channelled into improving transport of therapeutics across the BBB and into the CNS including the use of nanoparticles. In this thematic issue, several reviews and original research are presented that address "Nanomedicines for CNS Diseases." The articles in this issue are concentrated on either CNS-HIV disease or CNS tumors. In regards to CNS-HIV disease, there are two reviews that discuss the role of nanoparticles for improving the delivery of HIV therapeutics to the CNS. In addition, there are two original articles focusing on therapies for CNS-HIV, one of them uses nanoparticles for delivery of siRNA specific to a key protein in autophagy to microglia, and another discusses nanoparticle delivery of a soluble mediator to suppress neuroinflammation. Furthermore, a comprehensive review about gene therapy for CNS neurological diseases is also included. Finally, this issue also includes review articles on enhanced drug targeting to CNS tumors. These articles include a review on the use of nanoparticles for CNS tumors, a review on functionalization (ligands) of nanoparticles for drug targeting to the brain tumor by overcoming BBB, and the final review discusses the use of macrophages as a delivery vehicle to CNS tumors. This thematic issue provides a wealth of knowledge on using nanomedicines for CNS diseases.

  18. Evaluation of the Lactate-to-N-Acetyl-aspartate Ratio Defined With Magnetic Resonance Spectroscopic Imaging Before Radiation Therapy as a New Predictive Marker of the Site of Relapse in Patients With Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Deviers, Alexandra [Département de Radiothérapie, Institut Claudius Regaud, Toulouse (France); UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); INP (Institut National Polytechnique), ENVT (Ecole Nationale Vétérinaire de Toulouse), Unité d' Anatomie-Imagerie-Embryologie, Université de Toulouse, Toulouse (France); Ken, Soléakhéna [Département de Radiothérapie, Institut Claudius Regaud, Toulouse (France); UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); Filleron, Thomas [Bureau des Etudes Cliniques, Institut Claudius Regaud, Toulouse (France); Rowland, Benjamin; Laruelo, Andrea [Département de Radiothérapie, Institut Claudius Regaud, Toulouse (France); Catalaa, Isabelle; Lubrano, Vincent [UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); Hôpital de Rangueil, CHU (Centre Hospitalier Universitaire) de Toulouse, Toulouse (France); Celsis, Pierre [UMR (Unité Mixte de Recherche) 825, Institut National de la Santé et de la Recherche Médicale, Toulouse (France); and others

    2014-10-01

    Purpose: Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-{sup 1}H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). Methods and Materials: Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. Results: A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm{sup 3}; range: 6-49 cm{sup 3}). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). Conclusions: Pre-RT LNR-0.4 in GBM

  19. Gas Diffusion in the CNS.

    Science.gov (United States)

    Rodriguez-Grande, Beatriz; Konsman, Jan-Pieter

    2018-02-01

    Gases have been long known to have essential physiological functions in the CNS such as respiration or regulation of vascular tone. Since gases have been classically considered to freely diffuse, research in gas biology has so far focused on mechanisms of gas synthesis and gas reactivity, rather than gas diffusion and transport. However, the discovery of gas pores during the last two decades and the characterization of diverse diffusion patterns through different membranes has raised the possibility that modulation of gas diffusion is also a physiologically relevant parameter. Here we review the means of gas movement into and within the brain through "free" diffusion and gas pores, notably aquaporins, discussing the role that gas diffusion may play in the modulation of gas function. We highlight how diffusion is relevant to neuronal signaling, volume transmission, and cerebrovascular control in the case of NO, one of the most extensively studied gases. We point out how facilitated transport can be especially relevant for gases with low permeability in lipid membranes like NH3 and discuss the possible implications of NH3 -permeable channels in physiology and hyperammonemic encephalopathy. We identify novel research questions about how modulation of gas diffusion could intervene in CNS pathologies. This emerging area of research can provide novel and interesting insights in the field of gas biology. © 2017 Wiley Periodicals, Inc.

  20. Relapse of childhood acute lymphoblastic leukemia and outcomes at a reference center in Latin America: organomegaly at diagnosis is a significant clinical predictor.

    Science.gov (United States)

    Jaime-Pérez, José Carlos; Pinzón-Uresti, Mónica Andrea; Jiménez-Castillo, Raúl Alberto; Colunga-Pedraza, Julia Esther; González-Llano, Óscar; Gómez-Almaguer, David

    2018-01-01

    Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL) of childhood; it is more frequent among high-risk patients from low-middle income than from high-income countries. The frequency, sites and outcome of relapsed ALL in children of northeast Mexico over a decade was documented. A retrospective analysis of 246 children belonging to a low-income group death were estimated by the Cox regression model. Very early relapse was defined as that occurring in 36 months from diagnosis, respectively. Eighty-seven (35.4%) children relapsed. Five-year OS was 82.6% in children without relapse vs. 42% for relapsed patients. Bone marrow (BM) was the most frequent site of relapse (51.72%). Isolated central nervous system (CNS) relapses occurred in 29.9%. Five-year OS was 11.2% for BM and 15.5% for early relapse. HR of relapse for organomegaly was 3.683, 2.247 for an initial white blood cell count >50 000 × 10 9 /l and 1.169 for positive minimal residual disease status. A high rate of very early, CNS, and BM relapse with a considerably low 5-year OS requiring reassessment of therapy was documented. Organomegaly at diagnosis was a highly significant clinical predictor for relapse.

  1. Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors.

    Science.gov (United States)

    Farnedi, Anna; Rossi, Silvia; Bertani, Nicoletta; Gulli, Mariolina; Silini, Enrico Maria; Mucignat, Maria Teresa; Poli, Tito; Sesenna, Enrico; Lanfranco, Davide; Montebugnoli, Lucio; Leonardi, Elisa; Marchetti, Claudio; Cocchi, Renato; Ambrosini-Spaltro, Andrea; Foschini, Maria Pia; Perris, Roberto

    2015-05-03

    Tumour relapse is recognized to be the prime fatal burden in patients affected by head and neck squamous cell carcinoma (HNSCC), but no discrete molecular trait has yet been identified to make reliable early predictions of tumour recurrence. Expression of cell surface proteoglycans (PGs) is frequently altered in carcinomas and several of them are gradually emerging as key prognostic factors. A PG expression analysis at both mRNA and protein level, was pursued on primary lesions derived from 173 HNSCC patients from whom full clinical history and 2 years post-surgical follow-up was accessible. Gene and protein expression data were correlated with clinical traits and previously proposed tumour relapse markers to stratify high-risk patient subgroups. HNSCC lesions were indeed found to exhibit a widely aberrant PG expression pattern characterized by a variable expression of all PGs and a characteristic de novo transcription/translation of GPC2, GPC5 and NG2/CSPG4 respectively in 36%, 72% and 71% on 119 cases. Importantly, expression of NG2/CSPG4, on neoplastic cells and in the intralesional stroma (Hazard Ratio [HR], 6.76, p = 0.017) was strongly associated with loco-regional relapse, whereas stromal enrichment of SDC2 (HR, 7.652, p = 0.007) was independently tied to lymphnodal infiltration and disease-related death. Conversely, down-regulated SDC1 transcript (HR, 0.232, p = 0.013) uniquely correlated with formation of distant metastases. Altered expression of PGs significantly correlated with the above disease outcomes when either considered alone or in association with well-established predictors of poor prognosis (i.e. T classification, previous occurrence of precancerous lesions and lymphnodal metastasis). Combined alteration of all three PGs was found to be a reliable predictor of shorter survival. An unprecedented PG-based prognostic portrait is unveiled that incisively diversifies disease course in HNSCC patients beyond the currently known clinical and molecular

  2. Malignant lipogenesis defined by {sup 11}C-acetate PET/CT predicts prostate cancer-specific survival in patients with biochemical relapse after prostatectomy

    Energy Technology Data Exchange (ETDEWEB)

    Regula, Naresh [Uppsala University, Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala (Sweden); Haeggman, Michael [Uppsala University, Section of Urology, Department of Surgical Sciences, Uppsala (Sweden); Johansson, Silvia [Uppsala University, Section of Oncology, Department of Immunology, Genetics and Pathology, Uppsala (Sweden); Soerensen, Jens [Uppsala University, Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala (Sweden); PET Center Research Department, Uppsala (Sweden)

    2016-11-15

    Malignant de novo lipogenesis is strongly linked to the aggressiveness of prostate cancer (PCa) under experimental conditions. {sup 11}C-Acetate PET/CT is a potential noninvasive biomarker of malignant lipogenesis in PCa, but its prognostic value is not known. The objective of this study was to analyse {sup 11}C-acetate PET/CT image metrics in relation to survival. All patients undergoing {sup 11}C-acetate PET/CT in one university hospital from 2005 to 2011 due to PSA relapse after previous prostatectomy were retrospectively evaluated. Two groups of patients were compared: those who died from PCa and those who were censored. All previously reported findings of local recurrence, regional or distal lymph node metastases and bone metastases were counted and evaluated regarding {sup 11}C-acetate uptake intensity (SUV{sub max}) and tumour volume. Total tumour volume and total lipogenic activity (TLA, summed SUV{sub max} x TV) were calculated. Survival analysis in the entire study population was followed by Cox proportional hazards ratio (HR) analysis. A total of 121 patients were included, and 22 PCa-specific deaths were recorded. The mean PSA level at the time of PET was 2.69 ± 4.35 ng/mL. The median follow-up of the study population was 79 ± 28 months. PET identified at least one PCa lesion in 53 % of patients. Five-year PCa-specific survival after PET was 80 % and 100 % in patients with a positive and a negative PET scan, respectively (p < 0.001). Time-to-death was linearly correlated with highest SUV{sub max} (r = -0.55, p = 0.01) and nonlinearly with TLA (r = -0.75, p < 0.001). Multivariate analysis showed statistical significance for number of bone metastases (HR 1.74, p = 0.01), tertile of TLA (HR 5.63, p = 0.029) and postoperative Gleason score (HR 1.84, p = 0.045). Malignant {sup 11}C-acetate accumulation measured with PET/CT is a strong predictor of survival in the setting of PSA relapse after prostatectomy. The study provides further evidence for a

  3. Malignant lipogenesis defined by 11C-acetate PET/CT predicts prostate cancer-specific survival in patients with biochemical relapse after prostatectomy.

    Science.gov (United States)

    Regula, Naresh; Häggman, Michael; Johansson, Silvia; Sörensen, Jens

    2016-11-01

    Malignant de novo lipogenesis is strongly linked to the aggressiveness of prostate cancer (PCa) under experimental conditions. 11C-Acetate PET/CT is a potential noninvasive biomarker of malignant lipogenesis in PCa, but its prognostic value is not known. The objective of this study was to analyse 11C-acetate PET/CT image metrics in relation to survival. All patients undergoing 11C-acetate PET/CT in one university hospital from 2005 to 2011 due to PSA relapse after previous prostatectomy were retrospectively evaluated. Two groups of patients were compared: those who died from PCa and those who were censored. All previously reported findings of local recurrence, regional or distal lymph node metastases and bone metastases were counted and evaluated regarding 11C-acetate uptake intensity (SUVmax) and tumour volume. Total tumour volume and total lipogenic activity (TLA, summed SUVmax × TV) were calculated. Survival analysis in the entire study population was followed by Cox proportional hazards ratio (HR) analysis. A total of 121 patients were included, and 22 PCa-specific deaths were recorded. The mean PSA level at the time of PET was 2.69 ± 4.35 ng/mL. The median follow-up of the study population was 79 ± 28 months. PET identified at least one PCa lesion in 53 % of patients. Five-year PCa-specific survival after PET was 80 % and 100 % in patients with a positive and a negative PET scan, respectively (p novo lipogenesis and early death. 11C-Acetate PET/CT might be useful for identifying a high-risk population of relapsing patients in which therapies targeting malignant lipogenesis might be of particular benefit.

  4. Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer.

    Science.gov (United States)

    Pérez-López, María Eva; Curiel, Teresa; Gómez, Jesús García; Jorge, Mónica

    2007-06-01

    The most significant factor predicting response to second-line chemotherapy is the time interval elapsed from the end of chemotherapy to relapse occurrence. Two types of situations may be considered: patients with platinum-sensitive relapse (relapse-free interval longer than 6 months) and patients with platinum-refractory relapse (progression during treatment or relapse-free interval under 6 months). Pegylated liposomal doxorubicin is a doxorubicin formulation. Encapsulation in liposomes confers it different pharmacokinetic characteristics and a more favorable toxicity profile. The following review examines the efficacy and safety of pegylated liposomal doxorubicin for the treatment of relapsing epithelial ovarian cancer.

  5. Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen.

    Science.gov (United States)

    Kinzel, Silke; Lehmann-Horn, Klaus; Torke, Sebastian; Häusler, Darius; Winkler, Anne; Stadelmann, Christine; Payne, Natalie; Feldmann, Linda; Saiz, Albert; Reindl, Markus; Lalive, Patrice H; Bernard, Claude C; Brück, Wolfgang; Weber, Martin S

    2016-07-01

    In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.

  6. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... MS Relapsing-remitting MS (RRMS) Share this page Facebook Twitter Email Relapsing-remitting MS (RRMS) Relapsing-remitting ... Here Start Here Colophon Stay Informed Join Us Facebook Twitter LinkedIn YouTube Pinterest MS Connection About the ...

  7. Circulating tyrosinase and MART-1 mRNA does not independently predict relapse or survival in patients with AJCC stage I-II melanoma

    DEFF Research Database (Denmark)

    Schmidt, Henrik; Sørensen, Boe Sandahl; Sjøgren, Pia

    2006-01-01

    The detection of melanoma cells in peripheral blood has been proposed to       select patients with a high risk of relapse. In this study, tyrosinase and       melanoma antigen recognized by T cells 1 (MART-1) mRNA expression was       evaluated in serial samples obtained before definitive surgery...... and during       follow-up in patients with American Joint Committee on Cancer stage I-II       melanoma. Serial samples (n=2,262) were collected from 236 patients from       1997 to 2002. Analyses of the RNA samples were performed with a calibrated       reverse transcriptase-PCR assay. Gender, age, primary...... as the single independent prognostic       factor (Pmelanoma patients cannot be       demonstrated to have independent...

  8. Serum YKL-40 predicts relapse-free and overall survival in patients with American Joint Committee on Cancer stage I and II melanoma

    DEFF Research Database (Denmark)

    Schmidt, Henrik; Johansen, J. S.; Sjoegren, P.

    2006-01-01

    PURPOSE: To evaluate the novel tumor biomarker YKL-40 in serial serum       samples from patients with American Joint Committee on Cancer (AJCC) stage       I and II melanoma from the time of diagnosis and during routine follow-up.       Macrophages, neutrophils, and cancer cells secrete YKL-40......, and a high       serum level has been associated with poor prognosis in patients with       several cancer types. PATIENTS AND METHODS: Serum samples from 234       patients with stage I (n = 162) and II (n = 72) melanoma were analyzed for       YKL-40 by enzyme-linked immunosorbent assay. Serial samples...... were obtained       before definitive primary surgery and during follow-up. RESULTS: After a       median follow-up period of 66 months (range, 1 to 97 months), 41 relapses       (18%) and 39 deaths (17%) were observed. Serum YKL-40 treated as an       updated continuous covariate were analyzed...

  9. Paxillin promotes tumor progression and predicts survival and relapse in oral cavity squamous cell carcinoma by microRNA-218 targeting.

    Science.gov (United States)

    Wu, De-Wei; Chuang, Chun-Yi; Lin, Wea-Long; Sung, Wen-Wei; Cheng, Ya-Wen; Lee, Huei

    2014-08-01

    High-risk human papillomavirus (HPV) 16-infected oral cavity squamous cell carcinoma (OCSCC) differs significantly from non-HPV-infected OCSCC. However, the molecular pathogenesis of HPV-infected OCSCC remains unclear. Paxillin (PXN) has been reported to promote lung tumor progression by miR-218 targeting. In addition, expression of miR-218 has been shown to be reduced by HPV16 E6 in cervical cancer. We thus asked whether PXN can promote tumor progression by E6-reduced miR-218 in OCSCC, especially in HPV-infected OCSCC. Mechanistic studies demonstrated that PXN expression increased markedly upon E6-mediated reductions in miR-218, resulting in increased colony formation and invasion capabilities in HPV-infected OCSCC cells. Among tumor specimens, HPV16/18 infection was negatively associated with miR-218 expression and positively associated with PXN expression. Kaplan-Meier and Cox regression models demonstrated that patients with low-miR-218 tumors or high-PXN tumors exhibited shorter overall survival (OS) and relapse-free survival (RFS) than those with high-miR-218 tumors or low-PXN tumors. Interestingly, HPV-infected patients with low-miR-218, high-PXN tumors and both combinations exhibited the worst OS and RFS compared with patients in their counterparts. These observations in patients were consistent with the findings from the cell model. Therefore, we suggest that PXN might be targeted to suppress tumor progression and consequently to improve outcomes in OCSCC, especially in HPV-infected OCSCC. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Metacognitive awareness and prevention of relapse in depression: empirical evidence.

    Science.gov (United States)

    Teasdale, John D; Moore, Richard G; Hayhurst, Hazel; Pope, Marie; Williams, Susan; Segal, Zindel V

    2002-04-01

    Metacognitive awareness is a cognitive set in which negative thoughts/feelings are experienced as mental events, rather than as the self. The authors hypothesized that (a) reduced metacognitive awareness would be associated with vulnerability to depression and (b) cognitive therapy (CT) and mindfulness-based CT (MBCT) would reduce depressive relapse by increasing metacognitive awareness. They found (a) accessibility of metacognitive sets to depressive cues was less in a vulnerable group (residually depressed patients) than in nondepressed controls; (b) accessibility of metacognitive sets predicted relapse in residually depressed patients; (c) where CT reduced relapse in residually depressed patients, it increased accessibility of metacognitive sets; and (d) where MBCT reduced relapse in recovered depressed patients, it increased accessibility of metacognitive sets. CT and MBCT may reduce relapse by changing relationships to negative thoughts rather than by changing belief in thought content.

  11. Electrophoretic deposition of cellulose nanocrystals (CNs) and CNs/alginate nanocomposite coatings and free standing membranes.

    Science.gov (United States)

    Chen, Qiang; de Larraya, Uxua Pérez; Garmendia, Nere; Lasheras-Zubiate, María; Cordero-Arias, Luis; Virtanen, Sannakaisa; Boccaccini, Aldo R

    2014-06-01

    This study presents the electrophoretic deposition (EPD) of cellulose nanocrystals (CNs) and CNs-based alginate composite coatings for biomedical applications. The mechanism of anodic deposition of CNs and co-deposition of CNs/alginate composites was analyzed based on the results of zeta-potential, Fourier transform infrared spectroscopy and scanning electron microscopy (SEM) analyses. The capability of the EPD technique for manipulating the orientation of CNs and for the preparation of multilayer CNs coatings was demonstrated. The nanotopographic surface roughness and hydrophilicity of the deposited coatings were measured and discussed. Electrochemical testing demonstrated that a significant degree of corrosion protection of stainless steel could be achieved when CNs-containing coatings were present. Additionally, the one-step EPD-based processing of free-standing CNs/alginate membranes was demonstrated confirming the versatility of EPD to fabricate free-standing membrane structures compared to a layer-by-layer deposition technique. CNs and CNs/alginate nanocomposite coatings produced by EPD are potential candidates for biomedical, cell technology and drug delivery applications. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Lapse and relapse following inpatient treatment of opiate dependence.

    LENUS (Irish Health Repository)

    Smyth, B P

    2010-06-01

    We conducted a prospective follow-up study of consecutive opiate dependent patients admitted to a residential addiction treatment service for detoxification. We measured the rate of relapse following discharge, and sought to identify factors that were associated with early relapse (i.e., a return to daily opiate use). Follow-up interviews were conducted with 109 patients, of whom, 99 (91%) reported a relapse. The initial relapse occurred within one week in 64 (59%) cases. Multivariate survival analysis revealed that earlier relapse was significantly predicted by younger age, greater heroin use prior to treatment, history of injecting, and a failure to enter aftercare. Unexpectedly, those who were in a relationship with an opiate user had significantly delayed relapse. Those who completed the entire six-week inpatient treatment programme also had a significantly delayed relapse. In order to reduce relapse and the associated increased risk of fatal overdose, services providing residential opiate detoxification should prepare people for admission, strive to retain them in treatment for the full admission period and actively support their entry into planned aftercare in order to improve outcome.

  13. INS/CNS/GNSS integrated navigation technology

    CERN Document Server

    Quan, Wei; Gong, Xiaolin; Fang, Jiancheng

    2015-01-01

    This book not only introduces the principles of INS, CNS and GNSS, the related filters and semi-physical simulation, but also systematically discusses the key technologies needed for integrated navigations of INS/GNSS, INS/CNS, and INS/CNS/GNSS, respectively. INS/CNS/GNSS integrated navigation technology has established itself as an effective tool for precise positioning navigation, which can make full use of the complementary characteristics of different navigation sub-systems and greatly improve the accuracy and reliability of the integrated navigation system. The book offers a valuable reference guide for graduate students, engineers and researchers in the fields of navigation and its control. Dr. Wei Quan, Dr. Jianli Li, Dr. Xiaolin Gong and Dr. Jiancheng Fang are all researchers at the Beijing University of Aeronautics and Astronautics.

  14. Nanotechnology—novel therapeutics for CNS disorders

    Science.gov (United States)

    Srikanth, Maya; Kessler, John A.

    2013-01-01

    Research into treatments for diseases of the CNS has made impressive strides in the past few decades, but therapeutic options are limited for many patients with CNS disorders. Nanotechnology has emerged as an exciting and promising new means of treating neurological disease, with the potential to fundamentally change the way we approach CNS-targeted therapeutics. Molecules can be nanoengineered to cross the blood–brain barrier, target specific cell or signalling systems, respond to endogenous stimuli, or act as vehicles for gene delivery, or as a matrix to promote axon elongation and support cell survival. The wide variety of available nanotechnologies allows the selection of a nanoscale material with the characteristics best suited to the therapeutic challenges posed by an individual CNS disorder. In this Review, we describe recent advances in the development of nanotechnology for the treatment of neurological disorders—in particular, neurodegenerative disease and malignant brain tumours—and for the promotion of neuroregeneration. PMID:22526003

  15. Neurotrauma and Inflammation: CNS and PNS Responses

    Directory of Open Access Journals (Sweden)

    Bruno Siqueira Mietto

    2015-01-01

    Full Text Available Traumatic injury to the central nervous system (CNS or the peripheral nervous system (PNS triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity.

  16. CNS toxoplasmosis in an immunocompetent individual

    Directory of Open Access Journals (Sweden)

    Rajoo Ramachandran, MBBS, MD

    2014-01-01

    Full Text Available Toxoplasmosis is a serious and life-threatening disease in humans with a high prevalence in immunocompromised persons. The disease has a wide spectrum, depending on the immune status of the person. A CNS manifestation of toxoplasmosis in an immunocompetent person is very rare and often undetected. Our case of CNS toxoplasmosis in an immunocompetent person emphasizes the radiological diagnosis, which was further confirmed by advanced microbiology technique.

  17. Relapsing polychondritis with meningoencephalitis.

    Science.gov (United States)

    Tsai, Monica; Hu, Mengjun; Zussman, Jamie; Worswick, Scott

    2017-01-01

    Relapsing polychondritis (RP) is a rare autoimmune disease of the cartilaginous structures of the body with many systemic manifestations including meningoencephalitis (ME). We present a case of a man with RP-associated ME that was responsive to steroid treatment. An updated literature review of 7 cases of RP-associated ME also is provided. Early diagnosis of this condition may be of benefit to this select population of patients, and further research regarding the prognosis, mechanisms, and treatment of RP may be necessary in the future.

  18. Predictors of Relapse and Dropout During a 12-Week Relapse Prevention Program for Methamphetamine Users.

    Science.gov (United States)

    Chen, Yi-Chih; Chen, Chih-Ken; Wang, Liang-Jen

    2015-01-01

    In this research, the possible neuropsychological predictors of relapse and dropout of group cognitive behavioral therapy (CBT) for methamphetamine (MA) users were explored. Participants were 42 MA users sentenced by the judicial system to take part in an out-patient relapse prevention program for MA abuse and dependence that employs a CBT model once a week over the course of 12 weeks. Baseline neuropsychological functions were evaluated with the Conners' Continuous Performance Test, Wisconsin Card Sorting Test, Iowa Gambling Task, and Barratt Impulsiveness Scale. All participants had to submit to urine drug tests every week. Of the 42 participants, 69.0% had a MA positive urine screening result at least once throughout the program (relapse), while 40.5% dropped out of the treatment program prior to its completion. Short duration of MA abstinence at baseline and poor attention predicted relapse. Predictors of dropout included being unmarried and having risky decision making. Findings may be helpful for clinicians, who can screen for the aforementioned risk factors and provide strategies for high-risk patients to help prevent relapse and dropout among MA users in treatment programs.

  19. [Prodromal symptoms in schizophrenic relapse: A descriptive and comparative study].

    Science.gov (United States)

    Bouhlel, S; Jones, Y; Khelifa, E; Msolly, M; Melki, W; El-Hechmi, Z

    2012-10-01

    composed of 21 men and nine women. Their average age was 34 years and their level of education was 9.3 years. The mean number of hospitalizations was 3.8 and 73.3% of patients had interrupted their medication. The stabilized outpatients group included 25 men and five women with an average age of 40.3 years. The mean level of education was 8.3 years, the number of hospitalizations was 2.7 and 16.7% of patients had interrupted their medication. The mean time interval between the beginning of symptoms and the need for hospitalization was 160.5 days. The more frequent symptoms in the relapse group than in stabilized patients were: overinvested ideas/delusions (93.3% of relapsing patients), trouble sleeping (80%), symptoms of disorganization (80%), and excitement/mood changes (73.3%). Globally, non-specific symptoms precede specific symptoms (149.4 days vs. 94.8 days). The earlier signs were influence syndrome (113.4 days before relapse), verbal aggressions against others (108.1 days) and suicidal thoughts (94.8 days). The latest signs were physical aggression against others (37.3 days), unmotivated smiles (35.4 days), aggression against self (35 days), strange thoughts (30.7 days) and breaking things (25.3 days). The time between perception of symptoms and hospitalization in schizophrenic patients in this study was very long (approximately 6 months). Non-psychotic prodromal symptoms precede psychotic symptoms. We recommend a major focus on teaching the patient and his/her family how to recognize early signs of decompensation and what steps to take to ensure effective treatment. We also recommend further research to determine the predictive positive value of early signs of relapse. Copyright © 2011 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  20. Adhesion Molecules in CNS Disorders: Biomarker and Therapeutic Targets

    Science.gov (United States)

    Ma, Qingyi; Chen, Sheng; Klebe, Damon; Zhang, John H.; Tang, Jiping

    2015-01-01

    Mounting evidence has been provided regarding the crucial role of leukocyte extravasation and subsequent inflammatory response in several central nervous system (CNS) disorders. The infiltrated leukocytes release pro-inflammatory mediators and activate resident cells, leading to tissue injury. Leukocyte-endothelia interaction is critical for leukocyte extravasation and migration from the intravascular space into the tissue during inflammation. The basic physiology of leukocyte-endothelia interaction has been investigated extensively. Traditionally, three kinds of adhesion molecules, selectin, integrin, and immunoglobulin families, are responsible for this multiple-step interaction. Furthermore, blocking adhesion molecule function by genetic knockout, antagonizing antibodies, or inhibitory pharmacological drugs provides neuroprotection, which is associated with a reduction in leukocyte accumulation with in the tissue. Detection of the soluble form of adhesion molecules has also been proven to predict outcomes in CNS disorders. Lately, vascular adhesion protein-1 (VAP-1), a novel adhesion molecule and endothelial cell surface enzyme, has been implicated as a brake during leukocyte extravasation. In this review, we summarize the functions of traditional adhesion molecules as well as VAP-1 in the leukocyte adhesion cascade. We also discuss the diagnostic and therapeutic potential of adhesion molecules in CNS disorders. PMID:23469854

  1. Disease Type- and Status-Specific Alteration of CSF Metabolome Coordinated with Clinical Parameters in Inflammatory Demyelinating Diseases of CNS.

    Science.gov (United States)

    Park, Soo Jin; Jeong, In Hye; Kong, Byung Soo; Lee, Jung-Eun; Kim, Kyoung Heon; Lee, Do Yup; Kim, Ho Jin

    2016-01-01

    Central nervous system (CNS) inflammatory demyelinating diseases (IDDs) are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and idiopathic transverse myelitis (ITM). Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF) metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls). Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs.

  2. Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation

    DEFF Research Database (Denmark)

    Brännvall, Karin; Corell, Mikael; Forsberg-Nilsson, Karin

    2008-01-01

    Cellular origin and environmental cues regulate stem cell fate determination. Neuroepithelial stem cells form the central nervous system (CNS), whereas neural crest stem cells generate the peripheral (PNS) and enteric nervous system (ENS). CNS neural stem/progenitor cell (NSPC) fate determination...

  3. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... Types of MS Relapsing-remitting MS (RRMS) Share this page Facebook Twitter Email Relapsing-remitting MS (RRMS) ... RRMS Share Smaller Text Larger Text Print In this article Overview RRMS – the most common disease course – ...

  4. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... relapsing-remitting MS (RRMS) Learn More Learn More Research in relapsing-remitting MS (RRMS) Learn More Learn More Share Smaller Text Larger Text Print Discover More Here are a few related topics that may interest you Living with MS (.pdf) ...

  5. Relapsing Polychondritis Following Alopecia Areata

    Directory of Open Access Journals (Sweden)

    John C. Starr

    2010-01-01

    Full Text Available A case of alopecia areata followed by relapsing polychondritis is presented. Similar cases from the literature are reviewed and speculation about the relationship of these diseases is offered. Although the occurrence of these diseases together could be coincidental, an association seems immunologically plausible. Thus, relapsing polychondritis might be an unusual systemic manifestation of alopecia areata.

  6. Does improvement in maternal attachment representations predict greater maternal sensitivity, child attachment security and lower rates of relapse to substance use? A second test of Mothering from the Inside Out treatment mechanisms.

    Science.gov (United States)

    Suchman, Nancy E; DeCoste, Cindy; Borelli, Jessica L; McMahon, Thomas J

    2018-02-01

    In this study, we replicated a rigorous test of the proposed mechanisms of change associated with Mothering from the Inside out (MIO), an evidence-based parenting therapy that aims to enhance maternal reflective functioning and mental representations of caregiving in mothers enrolled in addiction treatment and caring for young children. First, using data from 84 mothers who enrolled in our second randomized controlled trial, we examined whether therapist fidelity to core MIO treatment components predicted improvement in maternal reflective functioning and mental representations of caregiving, even after taking fidelity to non-MIO components into account. Next, we examined whether improvement in directly targeted outcomes (e.g., maternal mentalizing and mental representations of caregiving) led to improvements in the indirectly targeted outcome of maternal caregiving sensitivity, even after controlling for other plausible competing mechanisms (e.g., improvement in maternal psychiatric distress and substance use). Third, we examined whether improvement in targeted parenting outcomes (e.g., maternal mentalizing, mental representations of caregiving and caregiving sensitivity) was associated in improvement in child attachment status, even after controlling for competing mechanisms (e.g., improvement in maternal psychiatric distress and substance use). Finally, we examined whether improvement in maternal mentalizing and caregiving representations was associated with a reduction in relapse to substance use. Support was found for the first three tests of mechanisms but not the fourth. Implications for future research and intervention development are discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... myelin (the layers of insulating membranes surrounding nerve fibers in the central nervous system (CNS)), as well as the nerve fibers themselves. During these inflammatory attacks, activated immune cells ...

  8. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... medications, emotional support, or other challenges to your quality of life. Please call 1-800-344-4867 ... membranes surrounding nerve fibers in the central nervous system (CNS)), as well as the nerve fibers themselves. ...

  9. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... Educational Videos Live Fully, Live Well Knowledge Is Power Everyday Matters You CAN! Webcasts DVDs Books For ... membranes surrounding nerve fibers in the central nervous system (CNS)), as well as the nerve fibers themselves. ...

  10. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... membranes surrounding nerve fibers in the central nervous system (CNS)), as well as the nerve fibers themselves. ... and problems with cognition (learning and memory or information processing). People with progressive forms of MS are ...

  11. Requirements for an Integrated UAS CNS Architecture

    Science.gov (United States)

    Templin, Fred; Jain, Raj; Sheffield, Greg; Taboso, Pedro; Ponchak, Denise

    2017-01-01

    The National Aeronautics and Space Administration (NASA) Glenn Research Center (GRC) is investigating revolutionary and advanced universal, reliable, always available, cyber secure and affordable Communication, Navigation, Surveillance (CNS) options for all altitudes of UAS operations. In Spring 2015, NASA issued a Call for Proposals under NASA Research Announcements (NRA) NNH15ZEA001N, Amendment 7 Subtopic 2.4. Boeing was selected to conduct a study with the objective to determine the most promising candidate technologies for Unmanned Air Systems (UAS) air-to-air and air-to-ground data exchange and analyze their suitability in a post-NextGen NAS environment. The overall objectives are to develop UAS CNS requirements and then develop architectures that satisfy the requirements for UAS in both controlled and uncontrolled air space. This contract is funded under NASAs Aeronautics Research Mission Directorates (ARMD) Aviation Operations and Safety Program (AOSP) Safe Autonomous Systems Operations (SASO) project and proposes technologies for the Unmanned Air Systems Traffic Management (UTM) service. Communications, Navigation and Surveillance (CNS) requirements must be developed in order to establish a CNS architecture supporting Unmanned Air Systems integration in the National Air Space (UAS in the NAS). These requirements must address cybersecurity, future communications, satellite-based navigation APNT, and scalable surveillance and situational awareness. CNS integration, consolidation and miniaturization requirements are also important to support the explosive growth in small UAS deployment. Air Traffic Management (ATM) must also be accommodated to support critical Command and Control (C2) for Air Traffic Controllers (ATC). This document therefore presents UAS CNS requirements that will guide the architecture.

  12. Acute unilateral third nerve palsy as an early manifestation of central nervous system relapse in a patient with acute myeloid leukemia.

    Science.gov (United States)

    Al-Mujaini, Abdullah S; Al-Dhuhli, Humoud H; Dennison, David J

    2009-07-01

    The reported incidence of central nervous system (CNS) involvement by acute myeloid leukemia (AML) ranges widely from less than 10-30%. Acute unilateral third nerve palsy is an unusual first manifestation of such an event. We describe a rare ophthalmologic manifestation of CNS relapse in a 25-year-old patient with AML who had undergone allogeneic stem cell transplant, and demonstrate the value of MRI in the early diagnosis.

  13. Progression of relapsing-remitting demyelinating disease does not require increased TCR affinity or epitope spread.

    Science.gov (United States)

    Kersh, Anna E; Edwards, Lindsay J; Evavold, Brian D

    2014-11-01

    In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-γ. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states. Copyright © 2014 by The American Association of Immunologists, Inc.

  14. Progressive solitary sclerosis: Gradual motor impairment from a single CNS demyelinating lesion.

    Science.gov (United States)

    Keegan, B Mark; Kaufmann, Timothy J; Weinshenker, Brian G; Kantarci, Orhun H; Schmalstieg, William F; Paz Soldan, M Mateo; Flanagan, Eoin P

    2016-10-18

    To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. © 2016 American Academy of Neurology.

  15. Does rumination mediate the relationship between mindfulness and depressive relapse?

    Science.gov (United States)

    Kearns, Nicole P; Shawyer, Frances; Brooker, Joanne E; Graham, Annette L; Enticott, Joanne C; Martin, Paul R; Meadows, Graham N

    2016-03-01

    Major depressive disorder is a significant mental illness that is highly likely to recur, particularly after three or more previous episodes. Increased mindfulness and decreased rumination have both been associated with decreased depressive relapse. The aim of this study was to investigate whether rumination mediates the relationship between mindfulness and depressive relapse. This prospective design involved a secondary data analysis for identifying causal mechanisms using mediation analysis. This study was embedded in a pragmatic randomized controlled trial of mindfulness-based cognitive therapy (MBCT) in which 203 participants (165 females, 38 males; mean age: 48 years), with a history of at least three previous episodes of depression, completed measures of mindfulness, rumination, and depressive relapse over a 2-year follow-up period. Specific components of mindfulness and rumination, being nonjudging and brooding, respectively, were also explored. While higher mindfulness scores predicted reductions in rumination and depressive relapse, the relationship between mindfulness and relapse was not found to be mediated by rumination, although there appeared to be a trend. Our results strengthen the argument that mindfulness may be important in preventing relapse but that rumination is not a significant mediator of its effects. The study was adequately powered to detect medium mediation effects, but it is possible that smaller effects were present but not detected. Mindfulness may be one of several components of MBCT contributing to prevention of depressive relapse. Although the original rationale for MBCT rested largely on a model of relapse causally linked to rumination, our findings suggest that the mechanism by which mindfulness impacts relapse is more complex than a simple effect on rumination. © 2015 The British Psychological Society.

  16. Intra and interpersonal determinants for relapse in drug addicts

    Directory of Open Access Journals (Sweden)

    Aline Cristina Zerwes Ferreira

    2016-03-01

    Full Text Available A descriptive qualitative research conducted with 20 drug addicts during treatment at a Center of Psychosocial Attention for Alcohol and other Drugs, aimed to identify intra and interpersonal determinants of relapse perceived by the drug addict. The data were collected through semi-structured interviews, submitted to Content Analysis, and organized into categories following predictive determinants for relapse. The relapse occurred by intrapersonal determinants, as self-efficacy expressed by self-confidence in interrupting the drug consumption; the result expectation by anticipation of pleasurable drug effects; the motivation by the absence of volition to interrupt the consumption; coping with the difficulty to confront daily problems; negative and positive emotional states; and craving. Interpersonal determinants expressed by social support were related to the influence of thirds. The identification of these determinants during treatment to favor relapse prevention and effective rehabilitation.

  17. Relapsing Polychondritis: A Case Report

    Directory of Open Access Journals (Sweden)

    Meltem Türkmen

    2009-09-01

    Full Text Available A 60-year-old man presented with a seven-month history of recurrent swelling, pain and warmth of bilateral ears and a four month history of coughing, tenderness over trachea. Dermatological examination revealed redness, swelling and tenderness of the cartilaginous portion of the ears. A biopsy showed perichondrial lymphocytes and neutrophilic infiltration and fibrosis. According to clinical, histological and radyologic findings, he was diagnosed as “relapsing polychondritis”. Relapsing polychondritis is a rare autoimmune disorder characterized by recurrent inflamation of articular and non-articular cartilaginous tissue. Antibodies to type II collagen in cartilage are found. Here, a case of relapsing polychondritis

  18. Immune regulation and CNS autoimmune disease

    DEFF Research Database (Denmark)

    Antel, J P; Owens, T

    1999-01-01

    The central nervous system is a demonstrated target of both clinical and experimental immune mediated disorders. Immune regulatory mechanisms operative at the levels of the systemic immune system, the blood brain barrier, and within the CNS parenchyma are important determinants of the intensity a...

  19. Acute Inflammatory Demyelination: MRI Prognostic Factors for Relapse

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-09-01

    Full Text Available Initial MRI factors predictive of a second attack and disability following a first episode of acute CNS inflammatory demyelination in a cohort of 116 children seen between 1990 and 2002 were studied at the Hopital Cochin-Saint-Vincent de Paul, Paris; Hopital Bicetre, Lille; Hopital Neurologique, Lyon, France; and McGill University, Montreal, Canada.

  20. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening . An increase in disability is confirmed when the person exhibits the same ...

  1. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... Clinically Isolated Syndrome (CIS) Relapsing-remitting MS (RRMS) Primary progressive MS (PPMS) Secondary progressive MS (SPMS) d ... these lesions contain more inflammatory cells. People with primary progressive MS (PPMS) tend to have more spinal ...

  2. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... in RRMS; however, each person's experience with RRMS will be unique. Following a relapse, the new symptoms ... and worsening, you and your MS care provider will likely want to consider a more aggressive treatment ...

  3. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... the periods of remission. At different points in time, RRMS can be further characterized as either active ( ... increase in disability over a specified period of time following a relapse) or not worsening . An increase ...

  4. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... Clinically Isolated Syndrome (CIS) Relapsing-remitting MS (RRMS) Primary progressive MS (PPMS) ... Treating MS d Comprehensive Care Developing a Healthcare Team Make the Most of ...

  5. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... of which the person is aware. What happens in RRMS? Relapsing-remitting MS is defined by inflammatory ... exactly the same symptoms. Why are modifiers used to characterize RRMS? Disease activity and progression should be ...

  6. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... Employer Matching Gifts d Gifts of Stock or Securities d Giving Circles Golden Circle Circle of Distinction ... time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI ...

  7. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... Disasters d Relationships Disclosure Family Matters Parenting Intimacy Self Advocacy in the Family Preventing Abuse d Research ... well as worsening (a confirmed increase in disability over a specified period of time following a relapse) ...

  8. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... Stimulation (FES) d Complementary & Alternative Medicines Chiropractic Therapy Marijuana Massage and Bodywork Acupuncture Low-Dose Naltrexone d ... without symptoms of which the person is aware. What happens in RRMS? Relapsing-remitting MS is defined ...

  9. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... MS Symptoms Diagnosing MS Possible MS Clinically Isolated Syndrome (CIS) Newly Diagnosed Diagnosing Tools Other Conditions to ... Sclerosis FAQs d Types of MS Clinically Isolated Syndrome (CIS) Relapsing-remitting MS (RRMS) Primary progressive MS ( ...

  10. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... disappear, resulting in an increase in disability. New lesions on MRI, as shown by the arrows, often ... as part of a relapse. However, new MRI lesions indicating MS activity may also occur without symptoms ...

  11. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... most common disease course – is characterized by clearly defined attacks of new or increasing neurologic symptoms. These ... What happens in RRMS? Relapsing-remitting MS is defined by inflammatory attacks on myelin (the layers of ...

  12. [Clinical and biological prognostic factors in relapsed acute myeloid leukemia patients].

    Science.gov (United States)

    Yébenes-Ramírez, Manuel; Serrano, Josefina; Martínez-Losada, Carmen; Sánchez-García, Joaquín

    2016-09-02

    Acute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Despite recent advances in the characterization of pathogenesis of AML, the cure rates are under 40%, being leukemia relapse the most common cause of treatment failure. Leukaemia relapse occurs due to clonal evolution or clonal escape. In this study, we aimed to analyze the clinical and biological factors influencing outcomes in patients with AML relapse. We included a total of 75 AML patients who experienced leukaemia relapse after achieving complete remission. We performed complete immunophenotyping and conventional karyotyping in bone marrow aspirates obtained at diagnosis and at leukemia relapse. Overall survival (OS) of the series was 3.7%±2.3, leukaemia progression being the most common cause of death. Patients relapsing before 12 months and those with adverse cytogenetic-molecular risk had statistically significant worse outcomes. A percentage of 52.5 of patients showed phenotypic changes and 50% cytogenetic changes at relapse. We did not find significant clinical factors predicting clonal evolution. The presence of clonal evolution at relapse did not have a significant impact on outcome. Patients with relapsed AML have a dismal prognosis, especially those with early relapse and adverse cytogenetic-molecular risk. Clonal evolution with phenotypic and cytogenetic changes occurred in half of the patients without predictive clinical factors or impact on outcome. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  13. Considerations for an Integrated UAS CNS Architecture

    Science.gov (United States)

    Templin, Fred L.; Jain, Raj; Sheffield, Greg; Taboso-Bellesteros, Pedro; Ponchak, Denise

    2017-01-01

    The National Aeronautics and Space Administration (NASA) Glenn Research Center (GRC) is investigating revolutionary and advanced universal, reliable, always available, cyber secure and affordable Communication, Navigation, Surveillance (CNS) options for all altitudes of UAS operations. In Spring 2015, NASA issued a Call for Proposals under NASA Research Announcements (NRA) NNH15ZEA001N, Amendment 7 Subtopic 2.4. Boeing was selected to conduct a study with the objective to determine the most promising candidate technologies for Unmanned Air Systems (UAS) air-to-air and air-to-ground data exchange and analyze their suitability in a post-NextGen NAS environment. The overall objectives are to develop UAS CNS requirements and then develop architectures that satisfy the requirements for UAS in both controlled and uncontrolled air space. This contract is funded under NASAs Aeronautics Research Mission Directorates (ARMD) Aviation Operations and Safety Program (AOSP) Safe Autonomous Systems Operations (SASO) project and proposes technologies for the Unmanned Air Systems Traffic Management (UTM) service.There is a need for accommodating large-scale populations of Unmanned Air Systems (UAS) in the national air space. Scale obviously impacts capacity planning for Communication, Navigation, and Surveillance (CNS) technologies. For example, can wireless communications data links provide the necessary capacity for accommodating millions of small UASs (sUAS) nationwide? Does the communications network provide sufficient Internet Protocol (IP) address space to allow air traffic control to securely address both UAS teams as a whole as well as individual UAS within each team? Can navigation and surveillance approaches assure safe route planning and safe separation of vehicles even in crowded skies?Our objective is to identify revolutionary and advanced CNS alternatives supporting UASs operating at all altitudes and in all airspace while accurately navigating in the absence of

  14. GNSS real time performance monitoring and CNS/ATM implementation

    Science.gov (United States)

    2006-07-01

    The global transition to communications, navigation, surveillance / air traffic management (CNS/ATM) technology is moving forward at an increasing pace. A critical part of the CNS/ATM concept is the ability to monitor, analyze, and distribute aeronau...

  15. Role of Microglial M1/M2 Polarization in Relapse and Remission of Psychiatric Disorders and Diseases

    Directory of Open Access Journals (Sweden)

    Yutaka Nakagawa

    2014-11-01

    Full Text Available Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed that M1/M2 polarization of macrophages plays an important role in controlling the balance between promotion and suppression in inflammation. Microglial cells share certain characteristics with macrophages and contribute to immune-surveillance in the central nervous system (CNS. In this review, we summarize immunoregulatory functions of microglia and discuss a possible role of microglial M1/M2 polarization in relapse and remission of psychiatric disorders and diseases. M1 polarized microglia can produce pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, suggesting that these molecules contribute to dysfunction of neural network in the CNS. Alternatively, M2 polarized microglia express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. Based on these aspects, we propose a possibility that M1 and M2 microglia are related to relapse and remission, respectively in psychiatric disorders and diseases. Consequently, a target molecule skewing M2 polarization of microglia may provide beneficial therapies for these disorders and diseases in the CNS.

  16. Sites of Distant Relapse and Clinical Outcomes in Patients with Metastatic Triple-Negative Breast Cancer: High Incidence of Central Nervous System Metastases

    Science.gov (United States)

    Claus, Elizabeth; Sohl, Jessica; Razzak, Abdul R.; Arnaout, Amal; Winer, Eric P.

    2008-01-01

    Purpose To characterize the outcomes of patients with metastatic triple negative breast cancers, including the risk and clinical consequences of central nervous system (CNS) relapse. Patients and Methods Using pharmacy and pathology records, a study group of 116 patients treated for metastatic triple negative breast cancer at Dana-Farber Cancer Institute from January 2000 to June 2006 was identified. Results The median survival from time of metastatic diagnosis was 13.3 months. Sixteen patients (14%) were diagnosed with CNS involvement at the time of initial metastatic diagnosis; overall, 46% of patients were diagnosed with CNS metastases prior to death. Median survival after a diagnosis of CNS metastasis was 4.9 months. The age and race-adjusted rate of death for patients whose first presentation included a CNS metastasis was 3.4 times (95%CI:1.9, 6.1) that of patients without a CNS lesion at first metastatic presentation. Of 53 patients who developed brain metastases, only 3 patients were judged to have stable or responsive systemic disease in the face of progressive CNS disease at the last follow up prior to death. Conclusion Triple negative breast cancer is associated with poor survival after recurrence. CNS relapse is common, but death as a direct consequence of CNS progression in the setting of controlled systemic disease is uncommon. Thus, it does not appear that the high rate of CNS involvement is due to a sanctuary effect, but rather to the lack of effective therapies in general for this aggressive subtype of breast cancer. New treatment strategies are needed. PMID:18833576

  17. Interneuron progenitor transplantation to treat CNS dysfunction

    Directory of Open Access Journals (Sweden)

    Muhammad O Chohan

    2016-08-01

    Full Text Available Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field.

  18. VIIP: Central Nervous System (CNS) Modeling

    Science.gov (United States)

    Vera, Jerry; Mulugeta, Lealem; Nelson, Emily; Raykin, Julia; Feola, Andrew; Gleason, Rudy; Samuels, Brian; Ethier, C. Ross; Myers, Jerry

    2015-01-01

    Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome. It has been hypothesized that the headward shift of cerebrospinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn may then induce VIIP syndrome through interaction with various biomechanical pathways. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the related IWS works submitted by Nelson et al., Feola et al. and Ethier et al.

  19. CNS adverse events associated with antimalarial agents. Fact or fiction?

    NARCIS (Netherlands)

    Phillips-Howard, P. A.; ter Kuile, F. O.

    1995-01-01

    CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too

  20. Intraventricular CNS lesions: A pictorial essay.

    Science.gov (United States)

    Watts, Jane; Yap, Kelvin K; Ou, Daniel; Tartaglia, Con; Trost, Nicholas; Sutherland, Tom

    2015-08-01

    Intraventricular lesions of the central nervous system (CNS) can present a diagnostic challenge due to a range of differential diagnoses and radiological appearances. Both CT and MRI imaging findings, in combination with location and patient's age, can help limit the differentials. This pictorial essay presents the salient radiological features, location and demographics of the more common intraventricular lesions of the brain. © 2015 The Royal Australian and New Zealand College of Radiologists.

  1. Merlin inhibits neurite outgrowth in the CNS.

    Science.gov (United States)

    Schulz, Alexander; Geissler, Katja J; Kumar, Sujeet; Leichsenring, Gregor; Morrison, Helen; Baader, Stephan L

    2010-07-28

    The neurofibromatosis type 2 gene product merlin is known to provoke gliogenic tumors as a result of its mutagenic loss. Merlin's physiological anti-mitogenic function makes it unique among its ezrin-radixin-moesin (ERM) family members. Although ERM proteins and merlin are known to be expressed in glial cells of the peripheral nervous system and CNS, the neuronal expression pattern and function of merlin have been less well investigated. We report here expression of merlin in developing and mature neurons of the murine CNS. Within cerebellar Purkinje cells (PCs), merlin was localized in the soma, sprouting dendrites and axons. Merlin expression in PCs was high during the period of initial dendrite regression and declined during later phases of dendrite elongation. Consistently, merlin expression in vivo was increased in Engrailed-2-overexpressing PCs, which are characterized by a reduced dendritic extension. Furthermore, overexpression of merlin in dissociated cerebellar cultures and in neurogenic P19 cells caused a significant decline in neurite outgrowth, while, conversely, inhibition of merlin expression increased process formation. This effect was dependent on phosphorylation of serine 518 and involved the inactivation of the growth-promoting GTPase Rac. We thus provide evidence that merlin plays a pivotal role in controlling the neuronal wiring in the developing CNS.

  2. Histamine and Immune Biomarkers in CNS Disorders

    Directory of Open Access Journals (Sweden)

    Ramón Cacabelos

    2016-01-01

    Full Text Available Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56 which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer’s disease, Parkinson’s disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer’s disease (AD. Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death.

  3. Relapse prevention for addictive behaviors

    Directory of Open Access Journals (Sweden)

    George William H

    2011-07-01

    Full Text Available Abstract The Relapse Prevention (RP model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010. Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change.

  4. Relapse prevention for addictive behaviors.

    Science.gov (United States)

    Hendershot, Christian S; Witkiewitz, Katie; George, William H; Marlatt, G Alan

    2011-07-19

    The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change.

  5. The role of craving in relapse after discontinuation of long-term benzodiazepine use.

    NARCIS (Netherlands)

    Mol, A.J.J.; Oude Voshaar, R.C.; Gorgels, W.J.M.J.; Breteler, M.H.M.; Balkom, A.J.L.M. van; Lisdonk, E.H. van de; Kan, C.C.; Zitman, F.G.

    2007-01-01

    OBJECTIVE: Craving for benzodiazepines has never been examined as a factor of relapse after successful benzodiazepine discontinuation. In this study, we examined the predictive value of craving on benzodiazepine relapse. METHOD: A stepped-care intervention trial aimed to discontinue long-term

  6. The Role of Irrational Beliefs, Self Efficacy and Social Support in Relapse of Abuse Disorder

    Directory of Open Access Journals (Sweden)

    Toraj Hashemi

    2010-05-01

    Full Text Available Aim: This study aimed to determine the role of irrational beliefs system, self efficacy and social support network in predicting of relapse/non-relapse of drug misusing, and comparison of mentioned variables between these two groups. Method: For this purpose 100 persons who had repeated relapse and 100 persons who did not have relapse were selected by available sampling of Rehabilitation Organization of Tabriz city. Albert Alic’s irrational beliefs, Sherer’s self efficacy and Wax’s social support questionnaires administered among selected samples. Results: The results showed that, there were significant differences between two relapse and non-relapse groups on irrational beliefs, self-efficacy and social support. Conclusion: The results have applied implications in addiction treatment clinics.

  7. Preclinical assessment of CNS drug action using eye movements in mice

    Science.gov (United States)

    Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

    2011-01-01

    The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development. PMID:21821912

  8. SINS/CNS Nonlinear Integrated Navigation Algorithm for Hypersonic Vehicle

    Directory of Open Access Journals (Sweden)

    Yong-jun Yu

    2015-01-01

    Full Text Available Celestial Navigation System (CNS has characteristics of accurate orientation and strong autonomy and has been widely used in Hypersonic Vehicle. Since the CNS location and orientation mainly depend upon the inertial reference that contains errors caused by gyro drifts and other error factors, traditional Strap-down Inertial Navigation System (SINS/CNS positioning algorithm setting the position error between SINS and CNS as measurement is not effective. The model of altitude azimuth, platform error angles, and horizontal position is designed, and the SINS/CNS tightly integrated algorithm is designed, in which CNS altitude azimuth is set as measurement information. GPF (Gaussian particle filter is introduced to solve the problem of nonlinear filtering. The results of simulation show that the precision of SINS/CNS algorithm which reaches 130 m using three stars is improved effectively.

  9. The movers and shapers in immune privilege of the CNS.

    Science.gov (United States)

    Engelhardt, Britta; Vajkoczy, Peter; Weller, Roy O

    2017-02-01

    Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent rediscoveries of lymphatic vessels within the dura mater surrounding the brain, made possible by modern live-cell imaging technologies, have revived this discussion. This review emphasizes the fact that understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Endothelial, epithelial and glial brain barriers establish compartments in the CNS that differ strikingly with regard to their accessibility to immune-cell subsets. There is a unique system of lymphatic drainage from the CNS to the peripheral lymph nodes. We summarize current knowledge on the cellular and molecular mechanisms involved in immune-cell trafficking and lymphatic drainage from the CNS, and we take into account differences in rodent and human CNS anatomy.

  10. Central Nervous System (CNS Disease Triggering Takotsubo Syndrome

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2016-01-01

    Full Text Available Takotsubo syndrome (TTS is usually triggered by psychological or physical stress. One of the many physical sources of stress are central nervous system (CNS disorders. CNS disorders most frequently triggering TTS include subarachnoid bleeding, epilepsy, ischemic stroke, migraine, and intracerebral bleeding. More rare CNS-triggers of TTS include posterior reversible encephalopathy syndrome (PRES, amyotrophic lateral sclerosis, encephalitis, or traumatic brain or spinal cord injury. TTS triggered by any of the CNS disorders needs to be recognized since adequate treatment of TTS may improve the general outcome from the CNS disorder as well. Neurologists need to be aware of TTS as a complication of specific CNS disorders but TTS may be triggered also by CNS disorders so far not recognised as causes of TTS.

  11. Strategies for Utilizing Neuroimaging Biomarkers in CNS Drug Discovery and Development: CINP/JSNP Working Group Report.

    Science.gov (United States)

    Suhara, Tetsuya; Chaki, Shigeyuki; Kimura, Haruhide; Furusawa, Makoto; Matsumoto, Mitsuyuki; Ogura, Hiroo; Negishi, Takaaki; Saijo, Takeaki; Higuchi, Makoto; Omura, Tomohiro; Watanabe, Rira; Miyoshi, Sosuke; Nakatani, Noriaki; Yamamoto, Noboru; Liou, Shyh-Yuh; Takado, Yuhei; Maeda, Jun; Okamoto, Yasumasa; Okubo, Yoshiaki; Yamada, Makiko; Ito, Hiroshi; Walton, Noah M; Yamawaki, Shigeto

    2017-04-01

    Despite large unmet medical needs in the field for several decades, CNS drug discovery and development has been largely unsuccessful. Biomarkers, particularly those utilizing neuroimaging, have played important roles in aiding CNS drug development, including dosing determination of investigational new drugs (INDs). A recent working group was organized jointly by CINP and Japanese Society of Neuropsychopharmacology (JSNP) to discuss the utility of biomarkers as tools to overcome issues of CNS drug development.The consensus statement from the working group aimed at creating more nuanced criteria for employing biomarkers as tools to overcome issues surrounding CNS drug development. To accomplish this, a reverse engineering approach was adopted, in which criteria for the utilization of biomarkers were created in response to current challenges in the processes of drug discovery and development for CNS disorders. Based on this analysis, we propose a new paradigm containing 5 distinct tiers to further clarify the use of biomarkers and establish new strategies for decision-making in the context of CNS drug development. Specifically, we discuss more rational ways to incorporate biomarker data to determine optimal dosing for INDs with novel mechanisms and targets, and propose additional categorization criteria to further the use of biomarkers in patient stratification and clinical efficacy prediction. Finally, we propose validation and development of new neuroimaging biomarkers through public-private partnerships to further facilitate drug discovery and development for CNS disorders. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  12. Social Resource Characteristics and Adolescent Substance Abuse Relapse.

    Science.gov (United States)

    Vik, Peter W.; And Others

    1992-01-01

    Examined social resource network characteristics of adolescent substance abusers (n=19). Perceived similarity to one's social network emerged as important moderator of whether social network provided support to remain abstinent or elevated risk for relapse. Increased perceived support predicted continued posttreatment abstinence when recovering…

  13. Mathematical Models of Tuberculosis Reactivation and Relapse

    Directory of Open Access Journals (Sweden)

    Robert Steven Wallis

    2016-05-01

    Full Text Available The natural history of human infection with Mycobacterium tuberculosis (Mtb is highly variable, as is the response to treatment of active tuberculosis. There is presently no direct means to identify individuals in whom Mtb infection has been eradicated, whether by a bactericidal immune response or sterilizing antimicrobial chemotherapy. Mathematical models can assist in such circumstances by measuring or predicting events that cannot be directly observed. The 3 models discussed in this review illustrate instances in which mathematical models were used to identify individuals with innate resistance to Mtb infection, determine the etiology of tuberculosis in patients treated with tumor necrosis factor antagonists, and predict the risk of relapse in persons undergoing tuberculosis treatment. These examples illustrate the power of various types of mathematic models to increase knowledge and thereby inform interventions in the present global tuberculosis epidemic.

  14. Superficial siderosis of the CNS. MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Uchino, Akira; Matsuo, Yoshiaki; Kato, Akira; Kudo, Sho [Saga Medical School, Nabeshima (Japan); Matsumoto, Shunichi

    1997-11-01

    Six cases of superficial siderosis of the CNS are reported here. There were 4 men and 2 women, whose ages ranged from 25 to 69 years. The clinical presentations included bilateral sensorineural hearing loss (6), cerebellar ataxia (4), and myelopathy (2). Typical hypointense rims were observed over the brain surface on T2-weighted images. Five of the 6 patients had atrophy of the superior cerebellar vermis. The spinal cord was involved in 5 of the 6 patients. On T1-weighted images, hyperintense rims were demonstrated over the brain surface in 3 of the 6 patients. This finding has not been previously reported. (author)

  15. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... Live Well Knowledge Is Power Everyday Matters You CAN! Webcasts DVDs Books For Kids: Keep S'myelin Información ... of remission. At different points in time, RRMS can be further characterized as either active (with relapses ...

  16. Relapsing-Remitting MS (RRMS)

    Medline Plus

    Full Text Available ... Us Clinical Fellows d Careers in MS Clinical Care Research Have you met? d Our Healthcare Voice Home What Is MS? Types of MS Relapsing-remitting MS (RRMS) Share this ... time helps you and your MS care provider discuss your treatment options and expected outcomes. ...

  17. Relapsing-Remitting MS (RRMS)

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    Full Text Available ... Your Life d Cognitive Health d Work, Home & Leisure Employment ... during the periods of remission. At different points in time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active , as well as worsening (a ...

  18. Borrelia hispanica Relapsing Fever, Morocco

    Science.gov (United States)

    Sarih, M’hammed; Garnier, Martine; Boudebouch, Najma; Bouattour, Ali; Rihani, Abdelaziz; Hassar, Mohammed; Gern, Lise; Postic, Danièle

    2009-01-01

    We found that 20.5% of patients with an unexplained fever in northwestern Morocco had tick-borne relapsing fever. Molecular detection specific for the 16S rRNA gene identified Borrelia hispanica. The noncoding intergenic spacer sequence domain showed high sensitivity and good resolution for this species. PMID:19861058

  19. Survival After Relapse of Medulloblastoma.

    Science.gov (United States)

    Koschmann, Carl; Bloom, Karina; Upadhyaya, Santhosh; Geyer, J Russell; Leary, Sarah E S

    2016-05-01

    Survival after recurrence of medulloblastoma has not been reported in an unselected cohort of patients in the contemporary era. We reviewed 55 patients diagnosed with medulloblastoma between 2000 and 2010, and treated at Seattle Children's Hospital to evaluate patterns of relapse treatment and survival. Fourteen of 47 patients (30%) over the age of 3 experienced recurrent or progressive medulloblastoma after standard therapy. The median time from diagnosis to recurrence was 18.0 months (range, 3.6 to 62.6 mo), and site of recurrence was metastatic in 86%. The median survival after relapse was 10.3 months (range, 1.3 to 80.5 mo); 3-year survival after relapse was 18%. There were trend associations between longer survival and having received additional chemotherapy (median survival 12.8 vs. 1.3 mo, P=0.16) and radiation therapy (15.4 vs. 5.9 mo, P=0.20). Isolated local relapse was significantly associated with shorter survival (1.3 vs. 12.8 mo, P=0.009). Recurrence of medulloblastoma is more likely to be metastatic than reported in previous eras. Within the limits of our small sample, our data suggest a potential survival benefit from retreatment with cytotoxic chemotherapy and radiation even in heavily pretreated patients. This report serves as a baseline against which to evaluate novel therapy combinations.

  20. Natural History of Non-CNS Disseminated Coccidioidomycosis

    Science.gov (United States)

    Bays, Derek; Thompson, George R; Reef, Susan; Snyder, Linda; Huppert, Milton; Salkin, David; Galgiani, John

    2017-01-01

    Abstract Background The number of patients with coccidioidomycosis continues to increase yearly. Patients with CNS disease require lifelong antifungal therapy due to the high morbidity and mortality of this disease. However, the morbidity and mortality in non-CNS disseminated disease has not been well characterized. Methods We conducted a retrospective study of 373 VA-armed forces coccidioidomycosis patients diagnosed between 1955 and 1958 and followed to 1966. Groups were identified as non-disseminated disease, non-CNS disseminated disease with and without multisite dissemination, and disseminated disease to the CNS with and without multisite dissemination. Clinical variables including demographic information, duration and severity of symptoms, coccidioidal serologies, type of infection and complications, time to disseminated disease, and mortality were abstracted from patient charts. Results Mortality attributed to coccidioidomycosis in the non-disseminated group was 0.3% (1/297) compared with the non-CNS disseminated group of 8.5% (4/47, median survival 12 months, range 12–24 months, P = 0.0002). Mortality in the CNS disseminated group was 86% (19/22, median survival of 12 months, range 12–156 months, P < 0.0001 compared with non-CNS disseminated). The single site non-CNS disseminated group had a mortality of 4.1% (1/24, survival of 12months) compared with the multiple site non-CNS disseminated group of 13% (3/23, median survival of 18 months, range of 12–24 months, P = 0.57). Conclusion This retrospective cohort study demonstrates significant mortality differences between different forms of disseminated coccidioidomycosis. CNS dissemination exhibited the highest mortality rate; however, non-CNS dissemination also exhibited an unacceptably high mortality rate. There was no significant difference in mortality between single site non-CNS disseminated disease and multiple site non-CNS disseminated disease. Disclosures All authors: No reported

  1. [Thalidomide therapy in relapsed diffuse large B-cell lymphoma in elderly patients. Three cases].

    Science.gov (United States)

    Wohner, Nikolett; Varga, Gergely; Szloboda, Péter; Farkas, Péter; Masszi, András; Horváth, Laura; Szombath, Gergely; Várkonyi, Judit; Benedek, Szabolcs; Masszi, Tamás

    2017-10-01

    Diffuse large B-cell lymphoma (DLBCL), a high-grade lymphoproliferative disease, is the most common lymphoma in adults, representing 31% of non-Hodgkin lymphomas (NHL). In elderly patients treatment is problematic because of the high toxicity of standard chemotherapy protocols, especially in relapsed cases, where high-dose chemotherapy and haematopoietic stem cell transplantation would be the best choice. More and more data is becoming available on alternative treatment of refractory/relapsed NHL, including studies on the positive effect of thalidomide and second generation IMiDs in DLBCL, which are already part of the standard treatment protocol in myeloma multiplex and myelodysplasia. The broadening use of IMiDs is due to their anti-angiogenetic, immunmodulatory and anti-inflammatory properties. In addition, a component of the E3-ubiquitin ligase complex, named cereblon, has been described in 2010 as the molecular effector of the thalidomide signal transduction pathway. We initiated thalidomide treatment in three elderly patients with relapsed DLBCL. In two cases, patients had CNS involvement, in the third case the patient had primary mediastinal disease. Patients received 100 mg thalidomide in combination with corticosteroids. Two patients showed an excellent response reaching complete remission on imaging; these patients are progression-free 12 and 20 months after the beginning of treatment. One patient with CNS involvement progressed and deceased despite therapy. According to the literature, IMiDs have significant activity in relapsed DLBCL. Our case-report presents promising results in an elderly patient population with aggressive relapsed NHL that usually has very poor outcome, as high-toxicity treatment cannot be given to these patients. Consequently, because of its efficiency, low-cost and low-toxicity, it is recommended to consider thalidomide therapy in elderly patients with high-grade DLBCL. Orv Hetil. 2017; 158(41): 1642-1648.

  2. Astrocyte scar formation aids CNS axon regeneration

    Science.gov (United States)

    Anderson, Mark A.; Burda, Joshua E.; Ren, Yilong; Ao, Yan; O’Shea, Timothy M.; Kawaguchi, Riki; Coppola, Giovanni; Khakh, Baljit S.; Deming, Timothy J.; Sofroniew, Michael V.

    2017-01-01

    Summary Transected axons fail to regrow in the mature central nervous system (CNS). Astrocyte scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or deleting chronic astrocyte scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. In striking contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocyte scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth supporting molecules. Our findings show that contrary to prevailing dogma, astrocyte scar formation aids rather than prevents CNS axon regeneration. PMID:27027288

  3. Novel agents in CNS myeloma treatment.

    Science.gov (United States)

    Gozzetti, Alessandro; Cerase, Alfonso

    2014-01-01

    Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM.Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease.

  4. Increased network centrality as markers of relapse risk in nicotine-dependent individuals treated with varenicline.

    Science.gov (United States)

    Shen, Zhujing; Huang, Peiyu; Wang, Chao; Qian, Wei; Yang, Yihong; Zhang, Minming

    2017-04-03

    Identifying smokers at high risk of relapse could improve the effectiveness of cessation therapies. Although altered regional brain function in smokers has been reported, whether the whole-brain functional organization differs smokers with relapse vulnerability from others remains unclear. Thus, the goal of this study is to investigate the baseline functional connectivity differences between relapsers and quitters. Using resting-state fMRI, we acquired images from 57 smokers prior to quitting attempts. After 12-week treatment with varenicline, smokers were divided into relapsers (n=36) and quitters (n=21) (quitter: continuously abstinent for weeks 9-12). The smoking cessation outcomes were cross-validated by self-reports and expired carbon monoxide. We then used eigenvector centrality (EC) mapping to identify the functional connectivity differences between relapsers and quitters. When compared to quitters, increased EC in the right dorsolateral prefrontal cortex (DLPFC), left middle temporal gyrus (MTG) and cerebellum anterior lobe was observed in relapsers. In addition, a logistic regression analysis of EC data (with DLPFC, MTG and cerebellum included) predicted relapse with 80.7% accuracy. These findings suggest that the DLPFC, MTG and cerebellum may be important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified before quit attempts, which could enable personalized treatment and improve smoking cessation outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Teriflunomide: a novel oral treatment for relapsing multiple sclerosis.

    Science.gov (United States)

    Sartori, Arianna; Carle, Dawn; Freedman, Mark S

    2014-05-01

    Multiple sclerosis is a disabling chronic inflammatory disease of the CNS. New emerging oral treatments can offer efficacy with higher levels of therapeutic adherence. Teriflunomide is one such oral agent that has recently been approved for the treatment of relapsing multiple sclerosis (RMS). The aim of this review is to describe the pharmacological profile of teriflunomide and review the vast clinical development program that paved the way for its approval, with emphasis on its safety and tolerability. Teriflunomide is a safe new oral medication for treating RMS. It is effective at reducing relapses, MRI activity and slowing disability progression. It is well tolerated, with mild and transitory side effects. Although teriflunomide is given a pregnancy category 'X' by the FDA and an effective contraception is needed, to date, there has been no evidence of teratogenicity in humans and a rapid washout procedure can lead to a virtually complete elimination. Its effectiveness appeared to be at least comparable to that of high-dose IFN-β-1a, and although direct comparisons with other orals are still lacking, its tolerability and encouraging safety data suggest that teriflunomide could be considered an ideal first-line medication for RMS.

  6. Sex differences in hormonal responses to stress and smoking relapse: a prospective examination.

    Science.gov (United States)

    al'Absi, Mustafa; Nakajima, Motohiro; Allen, Sharon; Lemieux, Andrine; Hatsukami, Dorothy

    2015-04-01

    Dysregulation in the hypothalamic-pituitary-adrenal axis has been shown to be associated with smoking relapse. No study has directly examined the role of sex differences in this relationship. Nicotine dependent men (n = 52) and women (n = 46) interested in cessation completed 2 laboratory stress sessions during ad libitum smoking and after 48 hr of abstinence. The laboratory session included baseline, stress, and recovery periods. Blood and saliva samples were collected at the end of each period for the measurement of cortisol and adrenocorticotropic hormone. Self-report measures of craving and withdrawal symptoms were also collected. Participants attended 4 weekly follow-up sessions for counseling where they provided biological samples and self-report measures including smoking status. Relapse was defined by smoking cigarettes for 7 consecutive days post-cessation. Results showed that 60 participants relapsed during the 4-week period. Cox regression models from the abstinence session showed that cortisol levels regardless of source were predictive of relapse but the direction of prediction was sex dependent (Sex × Hormone, all ps predicted relapse in men whereas greater cortisol levels predicted relapse in women (ps predicted early smoking relapse in men but not in women (ps predicting relapse. These findings highlight that sex differences in the hormonal response to stress and subjective craving during nicotine withdrawal are critical predictors of risk for understanding early relapse. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Microglia and CNS Interleukin-1: Beyond Immunological Concepts

    Directory of Open Access Journals (Sweden)

    Xiaoyu Liu

    2018-01-01

    Full Text Available Activation of microglia and expression of the inflammatory cytokine interleukin-1 (IL-1 in the CNS have become almost synonymous with neuroinflammation. In numerous studies, increased CNS IL-1 expression and altered microglial morphology have been used as hallmarks of CNS inflammation. A central concept of how CNS IL-1 and microglia influence functions of the nervous system was derived from the notion initially generated in the peripheral immune system: IL-1 stimulates monocyte/macrophage (the peripheral counterparts of microglia to amplify inflammation. It is increasingly clear, however, CNS IL-1 acts on other targets in the CNS and microglia participates in many neural functions that are not related to immunological activities. Further, CNS exhibits immunological privilege (although not as absolute as previously thought, rendering amplification of inflammation within CNS under stringent control. This review will analyze current literature to evaluate the contribution of immunological and non-immunological aspects of microglia/IL-1 interaction in the CNS to gain insights for how these aspects might affect health and disease in the nervous tissue.

  8. Clinical Potential of Neurosteroids for CNS Disorders

    Science.gov (United States)

    Reddy, Doodipala Samba; Estes, William A.

    2016-01-01

    Summary Neurosteroids are key endogenous molecules in the brain that affect many neural functions. Here, we describe recent advances in NIH-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus, brain injury, Fragile X syndrome, and chemical neurotoxicity. The neurosteroid field has entered a new era, as many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends. PMID:27156439

  9. Biomarkers for CNS involvement in pediatric lupus

    Science.gov (United States)

    Rubinstein, Tamar B; Putterman, Chaim; Goilav, Beatrice

    2015-01-01

    CNS disease, or central neuropsychiatric lupus erythematosus (cNPSLE), occurs frequently in pediatric lupus, leading to significant morbidity and poor long-term outcomes. Diagnosing cNPSLE is especially difficult in pediatrics; many current diagnostic tools are invasive and/or costly, and there are no current accepted screening mechanisms. The most complicated aspect of diagnosis is differentiating primary disease from other etiologies; research to discover new biomarkers is attempting to address this dilemma. With many mechanisms involved in the pathogenesis of cNPSLE, biomarker profiles across several modalities (molecular, psychometric and neuroimaging) will need to be used. For the care of children with lupus, the challenge will be to develop biomarkers that are accessible by noninvasive measures and reliable in a pediatric population. PMID:26079959

  10. Transplanting oligodendrocyte progenitors into the adult CNS

    Energy Technology Data Exchange (ETDEWEB)

    Franklin, R.J.M.; Blakemore, W.F. [Medical Research Council, Cambridge (United Kingdom)]|[Cambridge Univ. (United Kingdom). Dept. of Clinical Veterinary Medicine

    1997-01-01

    This review covers a number of aspects of the behaviour of oligodendrocyte progenitors following transplantation into the adult CNS. First, an account is given of the ability of transplanted oligodendrocyte progenitors, grown in tissue culture in the presence of PDGF and bFGF, to extensively remyelinate focal areas of persistent demyelination. Secondly, we describe how transplanted clonal cell lines of oligodendrocyte progenitors will differentiate in to astrocytes as will oligodendrocytes following transplantation into pathological environments in which both oligodendrocytes and astrocytes are absent, thereby manifesting the bipotentially demonstrable in vitro but not during development. Finally, a series of studies examining the migratory behaviour of transplanted oligodendrocyte progenitors (modelled using the oligodendrocyte progenitor cell line CG4) are described. (author).

  11. Quality of life, alcohol detoxification and relapse: is quality of life a predictor of relapse or only a secondary outcome measure?

    Science.gov (United States)

    Picci, Rocco Luigi; Oliva, Francesco; Zuffranieri, Marco; Vizzuso, Paola; Ostacoli, Luca; Sodano, Alessandro Jaretti; Furlan, Pier Maria

    2014-12-01

    To estimate variations in Overall Quality Of Life (OQOL) within 12 months following alcohol detoxification and to evaluate the predictive value of OQOL for relapse and alcohol use severity. Alcohol use disorders and four OQOL domains (physical health, psychological health, social relationships and environment) were assessed in 199 patients entering in-patient alcohol detoxification. Follow-up assessments were performed at 6 and 12 months after discharge. Cross-sectional and longitudinal analyses explored the relationship between OQOL and alcohol use severity, examining differences between abstinent and relapsed patients. The predictive value of OQOL was analyzed by logistic and linear regression. Correlation between OQOL and Alcohol Use Disorders Identification Test scores was confirmed at all stages of observation. Abstinent patients showed a significant improvement in all OQOL domains at 6 months after discharge, whereas OQOL domains did not undergo any significant change in relapsed patients. Baseline OQOL did not prove to be predictive of either relapse or alcohol use severity. Overall quality of life changed in parallel with alcohol use severity throughout the duration of the study, confirming it to be a useful and sensitive measure of secondary outcome for alcohol detoxification. Conversely, none of the OQOL baseline scores functioned as predictors of relapse within 12 months following discharge or alcohol use severity in relapsed patients.

  12. Ibrutinib Treatment of Mantle Cell Lymphoma Relapsing at Central Nervous System: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Donato Mannina

    2017-01-01

    Full Text Available Mantle cell lymphoma (MCL accounts for about 5% of all lymphomas. Its clinical and histological features are heterogeneous. After a frequently good initial response, the disease generally and repeatedly relapses and finally the outcome is poor. Particularly severe is the prognosis of the rare occurrence of CNSi (Central Nervous System involvement. Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK, has shown strong activity in relapsing patients with Chronic Lymphocytic Leukemia (CLL and MCL. Few reports are available about treatment with ibrutinib of patients presenting CNSi by lymphoproliferative diseases (LPD. In all of them, ibrutinib, at the dosage between 420 and 560 mg/day, showed an impressive effectiveness. Here we describe a case of MCL with CNS relapse showing an excellent response to ibrutinib administered at the unusual dose of 280 mg/day because of concomitant treatment of cardiological disease.

  13. Late Ebola virus relapse causing meningoencephalitis: a case report.

    Science.gov (United States)

    Jacobs, Michael; Rodger, Alison; Bell, David J; Bhagani, Sanjay; Cropley, Ian; Filipe, Ana; Gifford, Robert J; Hopkins, Susan; Hughes, Joseph; Jabeen, Farrah; Johannessen, Ingolfur; Karageorgopoulos, Drosos; Lackenby, Angie; Lester, Rebecca; Liu, Rebecca S N; MacConnachie, Alisdair; Mahungu, Tabitha; Martin, Daniel; Marshall, Neal; Mepham, Stephen; Orton, Richard; Palmarini, Massimo; Patel, Monika; Perry, Colin; Peters, S Erica; Porter, Duncan; Ritchie, David; Ritchie, Neil D; Seaton, R Andrew; Sreenu, Vattipally B; Templeton, Kate; Warren, Simon; Wilkie, Gavin S; Zambon, Maria; Gopal, Robin; Thomson, Emma C

    2016-07-30

    There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13.2). A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23.7) than plasma (31.3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors

  14. Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study.

    Science.gov (United States)

    Miller, Aaron E; Macdonell, Richard; Comi, Giancarlo; Freedman, Mark S; Kappos, Ludwig; Mäurer, Mathias; Olsson, Tomas P; Wolinsky, Jerry S; Bozzi, Sylvie; Dive-Pouletty, Catherine; O'Connor, Paul W

    2014-09-01

    Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs.

  15. The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

    Science.gov (United States)

    Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

    2016-09-01

    Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

  16. 3-D imaging of the CNS.

    Science.gov (United States)

    Runge, V M; Gelblum, D Y; Wood, M L

    1990-01-01

    3-D gradient echo techniques, and in particular FLASH, represent a significant advance in MR imaging strategy allowing thin section, high resolution imaging through a large region of interest. Anatomical areas of application include the brain, spine, and extremities, although the majority of work to date has been performed in the brain. Superior T1 contrast and thus sensitivity to the presence of GdDTPA is achieved with 3-D FLASH when compared to 2-D spin echo technique. There is marked arterial and venous enhancement following Gd DTPA administration on 3-D FLASH, a less common finding with 2-D spin echo. Enhancement of the falx and tentorium is also more prominent. From a single data acquisition, requiring less than 11 min of scan time, high resolution reformatted sagittal, coronal, and axial images can obtained in addition to sections in any arbitrary plane. Tissue segmentation techniques can be applied and lesions displayed in three dimensions. These results may lead to the replacement of 2-D spin echo with 3-D FLASH for high resolution T1-weighted MR imaging of the CNS, particularly in the study of mass lesions and structural anomalies. The application of similar T2-weighted gradient echo techniques may follow, however the signal-to-noise ratio which can be achieved remains a potential limitation.

  17. Type of residual symptom and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine.

    Science.gov (United States)

    Yang, Huaiyu; Chuzi, Sarah; Sinicropi-Yao, Lara; Johnson, Dan; Chen, Ying; Clain, Alisabet; Baer, Lee; McGrath, Patrick J; Stewart, Jonathan W; Fava, Maurizio; Papakostas, George I

    2010-03-01

    Relapse of major depressive disorder (MDD) is a common clinical problem. Identifying relapse predictors could lead to strategies that reduce relapse risk. This study is designed to determine whether residual symptoms predict relapse risk during the continuation/maintenance treatment of MDD. 570 MDD patients received open-label fluoxetine for 12 weeks. Under double blind conditions, 262 patients who responded by week 12 were randomly assigned to continue fluoxetine or switch to placebo for 52 weeks or until relapse. Residual symptoms were measured using the Symptom Checklist-90 and the Symptom Questionnaire. The relationship between residual symptom severity and relapse risk was assessed. Without adjusting for overall residual symptom severity, a greater severity of residual obsessive-compulsive and phobic anxiety symptoms predicted greater relapse risk. After adjusting for overall residual symptom severity, only severity of phobic anxiety symptoms predicted relapse risk. The predictive value of phobic anxiety symptoms with respect to relapse risk was independent of treatment assignment. The results indicated that there may be a specific pattern of residual symptoms associated with depressive relapse during antidepressant continuation/maintenance, which is unrelated to treatment assignment. Future studies are needed to further explore the relationship between residual symptoms and relapse risk in MDD. (1) It is important to treat residual symptoms among antidepressant responders/remitters in order to decrease relapse risk. (2) Clinicians should target residual phobic anxiety symptoms in order to decrease relapse risk. (3) Clinicians should target residual obsessive-compulsive symptoms in order to decrease relapse risk. (1) limited generalizability due to inclusion/exclusion criteria; (2) lack of active comparator treatment group; (3) post hoc analysis.

  18. 3rd ENRI International Workshop on ATM/CNS

    CERN Document Server

    2014-01-01

    The Electronic Navigation Research Institute (ENRI) held its third International Workshop on ATM / CNS in 2013 with the theme of "Drafting the future sky". There is worldwide activity taking place in the research and development of modern air traffic management (ATM) and its enabling technologies in Communication, Navigation and Surveillance (CNS). Pioneering work is necessary to contribute to the global harmonization of air traffic management and control. At this workshop, leading experts in  research, industry and academia from around the world met to share their ideas and approaches on ATM/CNS related topics.

  19. LINGO-1 and its role in CNS repair.

    Science.gov (United States)

    Mi, Sha; Sandrock, Alfred; Miller, Robert H

    2008-01-01

    LINGO-1 is selectively expressed in the CNS on both oligodendrocyte precursor cells (OPCs) and neurons. Its expression is developmentally regulated in the normal CNS, as well as up-regulated in human or rat models of neuropathologies. LINGO-1 functions as a negative regulator of oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration. Across diverse animal CNS disease models, targeted LINGO-1 inhibition was found to promote neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and improved functional recovery. The targeted inhibition of LINGO-1 therefore presents a novel therapeutic approach for the treatment of neurological diseases.

  20. The neurobiology of relapse in schizophrenia.

    Science.gov (United States)

    Remington, Gary; Foussias, George; Agid, Ofer; Fervaha, Gagan; Takeuchi, Hiroyoshi; Hahn, Margaret

    2014-02-01

    Dopamine's proposed role in psychosis proved a starting point in our understanding of the neurobiology of relapse, fitting given the central role positive symptoms play. This link is reflected in early work examining neurotransmitter metabolite and drug (e.g. amphetamine, methylphenidate) challenge studies as a means of better understanding relapse and predictors. Since, lines of investigation have expanded (e.g. electrophysiological, immunological, hormonal, stress), an important step forward if relapse per se is the question. Arguably, perturbations in dopamine represent the final common pathway in psychosis but it is evident that, like schizophrenia, relapse is heterogeneous and multidimensional. In understanding the neurobiology of relapse, greater gains are likely to be made if these distinctions are acknowledged; for example, efforts to identify trait markers might better be served by distinguishing primary (i.e. idiopathic) and secondary (e.g. substance abuse, medication nonadherence) forms of relapse. Similarly, it has been suggested that relapse is 'neurotoxic', yet individuals do very well on clozapine after multiple relapses and the designation of treatment resistance. An alternative explanation holds that schizophrenia is characterized by different trajectories, at least to some extent biologically and/or structurally distinguishable from the outset, with differential patterns of response and relapse. Just as with schizophrenia, it seems naïve to conceptualize the neurobiology of relapse as a singular process. We propose that it is shaped by the form of illness and in place from the outset, modified by constitutional factors like resilience, as well as treatment, and confounded by secondary forms of relapse. © 2013 Elsevier B.V. All rights reserved.

  1. Convulsant bicuculline modifies CNS muscarinic receptor affinity

    Directory of Open Access Journals (Sweden)

    Rodríguez de Lores Arnaiz Georgina

    2006-04-01

    Full Text Available Abstract Background Previous work from this laboratory has shown that the administration of the convulsant drug 3-mercaptopropionic acid (MP, a GAD inhibitor, modifies not only GABA synthesis but also binding of the antagonist [3H]-quinuclidinyl benzilate ([3H]-QNB to central muscarinic receptors, an effect due to an increase in affinity without modifications in binding site number. The cholinergic system has been implicated in several experimental epilepsy models and the ability of acetylcholine to regulate neuronal excitability in the neocortex is well known. To study the potential relationship between GABAergic and cholinergic systems with seizure activity, we analyzed the muscarinic receptor after inducing seizure by bicuculline (BIC, known to antagonize the GABA-A postsynaptic receptor subtype. Results We analyzed binding of muscarinic antagonist [3H]-QNB to rat CNS membranes after i.p. administration of BIC at subconvulsant (1.0 mg/kg and convulsant (7.5 mg/kg doses. Subconvulsant BIC dose failed to develop seizures but produced binding alteration in the cerebellum and hippocampus with roughly 40% increase and 10% decrease, respectively. After convulsant BIC dose, which invariably led to generalized tonic-clonic seizures, binding increased 36% and 15% to cerebellar and striatal membranes respectively, but decreased 12% to hippocampal membranes. Kd value was accordingly modified: with the subconvulsant dose it decreased 27% in cerebellum whereas it increased 61% in hippocampus; with the convulsant dose, Kd value decreased 33% in cerebellum but increased 85% in hippocampus. No change in receptor number site was found, and Hill number was invariably close to unity. Conclusion Results indicate dissimilar central nervous system area susceptibility of muscarinic receptor to BIC. Ligand binding was modified not only by a convulsant BIC dose but also by a subconvulsant dose, indicating that changes are not attributable to the seizure process

  2. Early CNS neurodegeneration in radiologically isolated syndrome

    Science.gov (United States)

    Overton, Eve; Khadka, Sankalpa; Buckley, Jessica; Liu, Shuang; Sampat, Mehul; Kantarci, Orhun; Lebrun Frenay, Christine; Siva, Aksel; Okuda, Darin T.; Pelletier, Daniel

    2015-01-01

    Objective: Increasing evidence indicates that the thalamus may be a location of early neurodegeneration in multiple sclerosis (MS). Our objective was to identify the presence of gray matter volume loss and thinning in patients with radiologically isolated syndrome (RIS). Methods: Sixty-three participants were included in this case-control study. Twenty-one patients with RIS were age- and sex-matched to 42 healthy controls in a 1:2 ratio. All participants underwent brain MRIs on a single 3T scanner. After lesion segmentation and inpainting, 1 mm3-isometric T1-weighted images were submitted to FreeSurfer (v5.2). Normalized cortical and deep gray matter volumes were compared between patients with RIS and controls using t tests, and thalamic volumes were correlated with white matter lesion volumes using Pearson correlation. Exploratory cortical thickness maps were created. Results: Although traditional normalized total gray and white matter volumes were not statistically different between patients with RIS and controls, normalized left (0.0046 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.006), right (0.0045 ± 0.0005 vs 0.0048 ± 0.0004, p = 0.008), and mean (0.0045 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.004) thalamic volumes were significantly lower in patients with RIS (n = 21, mean age 41.9 ± 12.7 years) than in controls (n = 42, mean age 41.4 ± 11.2 years). Thalamic volumes correlated modestly with white matter lesion volumes (range: r = −0.35 to −0.47). Conclusion: Our data provide novel evidence of thalamic atrophy in RIS and are consistent with previous reports in early MS stages. Thalamic volume loss is present early in CNS demyelinating disease and should be further investigated as a metric associated with neurodegeneration. PMID:25884012

  3. Management of relapsing Plasmodium vivax malaria.

    Science.gov (United States)

    Chu, Cindy S; White, Nicholas J

    2016-10-01

    Relapses are important contributors to illness and morbidity in Plasmodium vivax and P. ovale infections. Relapse prevention (radical cure) with primaquine is required for optimal management, control and ultimately elimination of Plasmodium vivax malaria. A review was conducted with publications in English, French, Portuguese and Spanish using the search terms 'P. vivax' and 'relapse'. Hypnozoites causing relapses may be activated weeks or months after initial infection. Incidence and temporal patterns of relapse varies geographically. Relapses derive from parasites either genetically similar or different from the primary infection indicating that some derive from previous infections. Malaria illness itself may activate relapse. Primaquine is the only widely available treatment for radical cure. However, it is often not given because of uncertainty over the risks of primaquine induced haemolysis when G6PD deficiency testing is unavailable. Recommended dosing of primaquine for radical cure in East Asia and Oceania is 0.5 mg base/kg/day and elsewhere is 0.25 mg base/kg/day. Alternative treatments are under investigation. Expert commentary: Geographic heterogeneity in relapse patterns and chloroquine susceptibility of P. vivax, and G6PD deficiency epidemiology mean that radical treatment should be given much more than it is today. G6PD testing should be made widely available so primaquine can be given more safely.

  4. Prostate-Specific Antigen Persistence After Radical Prostatectomy as a Predictive Factor of Clinical Relapse-Free Survival and Overall Survival: 10-Year Data of the ARO 96-02 Trial

    Energy Technology Data Exchange (ETDEWEB)

    Wiegel, Thomas, E-mail: thomas.wiegel@uniklinik-ulm.de [Department of Radiation Oncology, University Hospital Ulm (Germany); Bartkowiak, Detlef; Bottke, Dirk; Thamm, Reinhard [Department of Radiation Oncology, University Hospital Ulm (Germany); Hinke, Axel [WiSP, Research Institute Pharma GmbH, Langenfeld (Germany); Stöckle, Michael [Department of Urology, University Hospital Homburg/Saar (Germany); Rübe, Christian [Department of Radiation Oncology, University Hospital Homburg/Saar (Germany); Semjonow, Axel [Department of Urology, University Hospital Münster (Germany); Wirth, Manfred [Department of Urology, University Hospital Dresden (Germany); Störkel, Stephan; Golz, Reinhard [Department of Pathology, HELIOS Hospital Wuppertal (Germany); Engenhart-Cabillic, Rita [Department of Radiation Oncology, University Hospital Giessen-Marburg (Germany); Hofmann, Rainer [Department of Urology, University Hospital Giessen-Marburg (Germany); Feldmann, Horst-Jürgen [Department of Radiation Oncology, General Hospital Fulda (Germany); Kälble, Tilman [Department of Urology, General Hospital Fulda (Germany); Siegmann, Alessandra; Hinkelbein, Wolfgang [Department of Radiation Oncology, University Hospital Berlin (Germany); Steiner, Ursula; Miller, Kurt [Department of Urology, University Hospital Berlin (Germany)

    2015-02-01

    Objective: The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). Methods and Materials: For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. Results: Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm-C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score ≥8 (hazard ratio [HR] 2.8), pT ≥ 3c (HR 2.4), and extraprostatic extension ≥2 mm (HR 3.6) were unfavorable risk factors of progression. Conclusions: A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups

  5. Serum Neuroinflammatory Disease-Induced Central Nervous System Proteins Predict Clinical Onset of Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Itay Raphael

    2017-07-01

    Full Text Available There is an urgent need in multiple sclerosis (MS patients to develop biomarkers and laboratory tests to improve early diagnosis, predict clinical relapses, and optimize treatment responses. In healthy individuals, the transport of proteins across the blood–brain barrier (BBB is tightly regulated, whereas, in MS, central nervous system (CNS inflammation results in damage to neuronal tissues, disruption of BBB integrity, and potential release of neuroinflammatory disease-induced CNS proteins (NDICPs into CSF and serum. Therefore, changes in serum NDICP abundance could serve as biomarkers of MS. Here, we sought to determine if changes in serum NDICPs are detectable prior to clinical onset of experimental autoimmune encephalomyelitis (EAE and, therefore, enable prediction of disease onset. Importantly, we show in longitudinal serum specimens from individual mice with EAE that pre-onset expression waves of synapsin-2, glutamine synthetase, enolase-2, and synaptotagmin-1 enable the prediction of clinical disease with high sensitivity and specificity. Moreover, we observed differences in serum NDICPs between active and passive immunization in EAE, suggesting hitherto not appreciated differences for disease induction mechanisms. Our studies provide the first evidence for enabling the prediction of clinical disease using serum NDICPs. The results provide proof-of-concept for the development of high-confidence serum NDICP expression waves and protein biomarker candidates for MS.

  6. Diagnostic and therapeutic challenges in superficial CNS siderosis

    DEFF Research Database (Denmark)

    Kondziella, Daniel; Lindelof, M.; Haziri, Donika

    2015-01-01

    INTRODUCTION: Superficial CNS siderosis was previously almost unknown but is now diagnosed with increasing frequency owing to magnetic resonance imaging. Patients may present with sensory deafness, gait ataxia, various sensorimotor signs and, eventually, cognitive decline. They typically have a h...

  7. Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

    Directory of Open Access Journals (Sweden)

    Jacinta Nwamaka Nwogu

    2016-01-01

    Full Text Available Neurological complications associated with the human immunodeficiency virus (HIV are a matter of great concern. While antiretroviral (ARV drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity.

  8. Neuro-intensive care of patients with acute CNS infections.

    Science.gov (United States)

    Beckham, J David; Tyler, Kenneth L

    2012-01-01

    Infections in the central nervous system (CNS) are caused by a wide range of microorganisms resulting in distinct clinical syndromes including meningitis, encephalitis, and pyogenic infections, such as empyema and brain abscess. Bacterial and viral infections in the CNS can be rapidly fatal and can result in severe disability in survivors. Appropriate identification and acute management of these infections often occurs in a critical care setting and is vital to improving outcomes in this group of patients. This review of diagnosis and management of acute bacterial and viral infections in the CNS provides a general approach to patients with a suspected CNS infection and also provides a more detailed review of the diagnosis and management of patients with suspected bacterial meningitis, viral encephalitis, brain abscess, and subdural empyema.

  9. Fetal MRI in Prenatal Diagnosis of CNS Abnormalities

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-02-01

    Full Text Available The value of fetal MRI (fMRI compared to ultrasound in the prenatal detection of CNS abnormalities and impact on counseling were determined in 25 pregnant women examined at University of Dusseldorf, Germany.

  10. Treatment relapse and behavioral momentum theory.

    Science.gov (United States)

    Pritchard, Duncan; Hoerger, Marguerite; Mace, F Charles

    2014-01-01

    The relapse of problem behavior after apparently successful treatment is an enduring problem for the field of applied behavior analysis. Several theoretical accounts of treatment relapse have emerged over the years. However, one account that has received considerable recent attention is based on behavioral momentum theory (BMT). BMT has shown that behavior is more persistent in contexts that are correlated with higher rates of reinforcers after disruption of the response-reinforcer relation. Accordingly, relapse after successful treatment can be viewed as the persistence of behavior when treatment is compromised in some manner. We review basic BMT research, alternative accounts of treatment relapse, and translational research studies derived from BMT research. The implications for applied behavior analysis in practice are discussed along with potential solutions to the problem of treatment relapse. © Society for the Experimental Analysis of Behavior.

  11. CNS Anticancer Drug Discovery and Development Conference White Paper

    OpenAIRE

    Victor A Levin; Tonge, Peter J.; Gallo, James M.; Birtwistle, Marc R.; Dar, Arvin C.; Iavarone, Antonio; Paddison, Patrick J.; Heffron, Timothy P.; Elmquist, William F.; Lachowicz, Jean E.; Johnson, Ted W.; White, Forest M.; Sul, Joohee; Smith, Quentin R.; Shen, Wang

    2015-01-01

    Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. F...

  12. CNS Involvement in AML Patient Treated with 5-Azacytidine

    Directory of Open Access Journals (Sweden)

    Diamantina Vasilatou

    2014-01-01

    Full Text Available Central nervous system (CNS involvement in acute myeloid leukemia (AML is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status.

  13. Nanotechnology for CNS Delivery of Bio-Therapeutic Agents

    OpenAIRE

    Shah, Lipa; Yadav, Sunita; Amiji, Mansoor

    2013-01-01

    The current therapeutic strategies are not efficient in treating disorders related to the central nervous system (CNS) and have only shown partial alleviation of symptoms, as opposed to, disease modifying effects. With change in population demographics, the incidence of CNS disorders, especially neurodegenerative diseases, is expected to rise dramatically. Current treatment regimens are associated with severe side-effects, especially given that most of these are chronic therapies and involve ...

  14. Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections

    OpenAIRE

    Krut, JJ; Zetterberg, H.; Blennow, K.; Cinque, P.; Hagberg, L; Price, Rw; Studahl, M; Gisslén, M.

    2013-01-01

    The cerebrospinal fluid (CSF) biomarker profile in Alzheimer's disease (AD) is characterized by decreased beta amyloid (Aβ 1-42 ), increased total and hyperphosphorylated tau (t-tau and p-tau, respectively), which is a useful diagnostic tool and gives insight in the pathogenesis of AD. It is of importance to study how these biomarkers react in other CNS diseases; therefore, we decided to analyse amyloid and tau biomarkers in different CNS infections. We also included analysis of soluble amylo...

  15. Second auto-SCT for treatment of relapsed multiple myeloma.

    Science.gov (United States)

    Gonsalves, W I; Gertz, M A; Lacy, M Q; Dispenzieri, A; Hayman, S R; Buadi, F K; Dingli, D; Hogan, W J; Kumar, S K

    2013-04-01

    High-dose therapy and auto-SCT remain integral in the initial treatment of multiple myeloma (MM), and are increasingly being applied for management of relapsed disease. We examined the outcomes in 98 patients undergoing salvage auto-SCT (auto-SCT2) for relapsed MM after receiving an initial transplant (auto-SCT1) between 1994 and 2009. The median age at auto-SCT2 was 60 years (range: 35-74). The median time between auto-SCT1 and auto-SCT2 was 46 months (range: 10-130). Treatment-related mortality was seen in 4%. The median PFS from auto-SCT2 was 10.3 (95% confidence interval (CI): 7-14) months and the median OS from auto-SCT2 was 33 months (95% CI: 28-51). In a multivariable analysis, shorter time to progression (TTP) after auto-SCT1, not achieving a CR after auto-SCT2, higher number of treatment regimens before auto-SCT2 and a higher plasma cell labeling index at auto-SCT2 predicted for shorter PFS. However, only a shorter TTP after auto-SCT1 predicted for a shorter OS post auto-SCT2. Hence, auto-SCT2 is an effective and feasible therapeutic option for MM patients relapsing after other treatments, especially in patients who had a TTP of at least 12 months after their auto-SCT1.

  16. Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

    Science.gov (United States)

    Downey, Luke A.; Loftis, Jennifer M.

    2014-01-01

    Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes – increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID:24485894

  17. Electronic health record-based detection of risk factors for Clostridium difficile infection relapse.

    Science.gov (United States)

    Hebert, Courtney; Du, Hongyan; Peterson, Lance R; Robicsek, Ari

    2013-04-01

    A major challenge in treating Clostridium difficile infection (CDI) is relapse. Many new therapies are being developed to help prevent this outcome. We sought to establish risk factors for relapse and determine whether fields available in an electronic health record (EHR) could be used to identify high-risk patients for targeted relapse prevention strategies. Retrospective cohort study. Large clinical data warehouse at a 4-hospital healthcare organization. Data were gathered from January 2006 through October 2010. Subjects were all inpatient episodes of a positive C. difficile test where patients were available for 56 days of follow-up. Relapse was defined as another positive test between 15 and 56 days after the initial test. Multivariable regression was performed to identify factors independently associated with CDI relapse. Eight hundred twenty-nine episodes met eligibility criteria, and 198 resulted in relapse (23.9%). In the final multivariable analysis, risk of relapse was associated with age (odds ratio [OR], 1.02 per year [95% confidence interval (CI), 1.01-1.03]), fluoroquinolone exposure in the 90 days before diagnosis (OR, 1.58 [95% CI, 1.11-2.26]), intensive care unit stay in the 30 days before diagnosis (OR, 0.47 [95% CI, 0.30-0.75]), cephalosporin (OR, 1.80 [95% CI, 1.19-2.71]), proton pump inhibitor (PPI; OR, 1.55 [95% CI, 1.05-2.29]), and metronidazole exposure after diagnosis (OR, 2.74 [95% CI, 1.64-4.60]). A prediction model tuned to ensure a 50% probability of relapse would flag 14.6% of CDI episodes. Data from a comprehensive EHR can be used to identify patients at high risk for CDI relapse. Major risk factors include antibiotic and PPI exposure.

  18. Advances in the treatment of relapsing - Remitting multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Radu Tanasescu

    2014-04-01

    Full Text Available This article reviews and discusses the approved and emerging therapies for multiple sclerosis (MS. MS is a chronic and disabling immune-mediated disease of the central nervous system (CNS that affects mainly young adults. MS imposes a huge economic burden on healthcare systems and the society. Although the last 20 years have brought a continuous expansion in therapeutic options, there are still unmet needs in MS management. Available MS drugs have varying degrees of efficacy in reducing relapse risk. The long-term term effects of these treatments are incompletely known. New therapies, along with variations of currently available treatments, may prove more effective and tolerable than the available drugs. Treatments for MS differ with respect to the mode of administration, tolerability and likelihood of treatment adherence, side effects, and risk of major toxicity. The armamentarium of approved disease-modifying therapies in MS and those in development include: (1 the first approved, moderately effective, injectable interferon-β and glatiramer acetate; (2 oral drugs (fingolimod, laquinimod, teriflunomide, dimethyl fumarate; (3 monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab; and (4 immunosuppressive agents (e.g. mitoxantrone. The place of each drug in the therapeutic algorithm is dependent on its specific risk-benefit profile. Patients' clinical and paraclinical phenotypes and biomarker profile may help to elucidate disease subtypes and response to therapy in the future, thus allowing treatment individualization.

  19. Predicting the 5-Year Risk of Biochemical Relapse After Postprostatectomy Radiation Therapy in ≥PT2, pN0 Patients With a Comprehensive Tumor Control Probability Model

    Energy Technology Data Exchange (ETDEWEB)

    Fiorino, Claudio, E-mail: fiorino.claudio@hsr.it [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Broggi, Sara [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Fossati, Nicola [Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan (Italy); Cozzarini, Cesare [Department of Radiotherapy, IRCCS Ospedale San Raffaele, Milan (Italy); Goldner, Gregor [Klinik für Radioonkologie, Medizinische Universität Wien, Wien (Austria); Wiegel, Thomas [Department of Radiation Oncology, University Hospital Ulm, Ulm (Germany); Hinkelbein, Wolfgang [Department of Radiation Oncology, Charité Universitats Medizin, Campus Benjamin Franklin, Berlin (Germany); Karnes, R. Jeffrey; Boorjian, Stephen A. [Department of Urology, Mayo Clinic Rochester, Rochester, Minnesota (United States); Haustermans, Karin [Department of Radiotherapy, University Hospitals Leuven, Leuven (Belgium); Joniau, Steven [Department of Urology, University Hospitals Leuven, Leuven (Belgium); Palorini, Federica [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Shariat, Shahrokh [Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna (Austria); Montorsi, Francesco [Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan (Italy); Van Poppel, Hein [Department of Urology, University Hospitals Leuven, Leuven (Belgium); Di Muzio, Nadia [Department of Radiotherapy, IRCCS Ospedale San Raffaele, Milan (Italy); Calandrino, Riccardo [Department of Medical Physics, San Raffaele Scientific Institute, Milan (Italy); Briganti, Alberto [Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan (Italy)

    2016-10-01

    Purpose: To fit the individual biochemical recurrence-free survival (bRFS) data from patients treated with postprostatectomy radiation therapy (RT) with a comprehensive tumor control probability (TCP) model. Methods and Materials: Considering pre-RT prostate-specific antigen (PSA) as a surrogate of the number of clonogens, bRFS may be expressed as a function of dose-per-fraction–dependent radiosensitivity (α{sub eff}), the number of clonogens for pre-RT PSA = 1 ng/mL (C), and the fraction of patients who relapse because of clonogens outside the treated volume (K), assumed to depend (linearly or exponentially) on pre-RT PSA and Gleason score (GS). Data from 894 node-negative, ≥pT2, pN0 hormone-naive patients treated with adjuvant (n=331) or salvage (n=563) intent were available: 5-year bRFS data were fitted grouping patients according to GS (<7:392, =7:383, >7:119). Results: The median follow-up time, pre-RT PSA, and dose were 72 months, 0.25 ng/mL, and 66.6 Gy (range 59.4-77.4 Gy), respectively. The best-fit values were 0.23 to 0.26 Gy{sup −1} and 10{sup 7} for α{sub eff} and C for the model considering a linear dependence between K and PSA. Calibration plots showed good agreement between expected and observed incidences (slope: 0.90-0.93) and moderately high discriminative power (area under the curve [AUC]: 0.68-0.69). Cross-validation showed satisfactory results (average AUCs in the training/validation groups: 0.66-0.70). The resulting dose-effect curves strongly depend on pre-RT PSA and GS. bRFS rapidly decreases with PSA: the maximum obtainable bRFS (defined as 95% of the maximum) declined by about 2.7% and 4.5% for each increment of 0.1 ng/mL for GS <7 and ≥7, respectively. Conclusions: Individual data were fitted by a TCP model, and the resulting best-fit parameters were radiobiologically consistent. The model suggests that relapses frequently result from clonogens outside the irradiated volume, supporting the choice of lymph

  20. A Multi-Relational Model for Depression Relapse in Patients with Bipolar Disorder.

    Science.gov (United States)

    Salvini, Rogerio; da Silva Dias, Rodrigo; Lafer, Beny; Dutra, Inês

    2015-01-01

    Bipolar Disorder (BD) is a chronic and disabling disease that usually appears around 20 to 30 years old. Patients who suffer with BD may struggle for years to achieve a correct diagnosis, and only 50% of them generally receive adequate treatment. In this work we apply a machine learning technique called Inductive Logic Programming (ILP) in order to model relapse and no-relapse patients in a first attempt in this area to improve diagnosis and optimize psychiatrists' time spent with patients. We use ILP because it is well suited for our multi-relational dataset and because a human can easily interpret the logical rules produced. Our classifiers can predict relapse cases with 92% Recall and no-relapse cases with 73% Recall. The rules and variable theories generated by ILP reproduce some findings from the scientific literature. The generated multi-relational models can be directly interpreted by clinicians and researchers, and also open space to research biological mechanisms and interventions.

  1. [Neuropsychological sequelae in children with AML treated with or without prophylactic CNS-irradiation].

    Science.gov (United States)

    Reinhardt, D; Thiele, C; Creutzig, U

    2002-01-01

    In study AML-BFM 87 the relapse rate was lower in patients receiving cranial irradiation (CRT). However, CRT has always been associated with adverse cognitive side effects. Therefore, the impact of CRT on neuropsychological function in children with AML was retrospectively evaluated. We tested 53 children (30 boys, 23 girls) treated according to the AML-BFM-87 protocol (median age at diagnosis: 8.5 years, range 0.3 - 17.5; median time since diagnosis: 5.7 yrs, 3.8 - 10.7 yrs). To avoid any bias from additional therapy elements, patients with relapse or initial CNS involvement and transplanted patients were excluded (n=32). Our cohort was representative of the total group of 104 long term survivors of study AML-BFM 87. CNS prophylaxis consisted of ARA-C i.th., high dose ARA-C i. v. and either no CRT (n=15) or CRT (n=38) at a dose of 12 - 18 Gy depending on age. Neuropsychological function was evaluated by psychological tests of attention and concentration (test d2 by Brickenkamp) and an intelligence test (Progressive Matrices by Raven). In addition, patients and their parents were interviewed about the occurrence of learning problems, subjective deficits in concentration and physical impairment. In the total group, no significant differences were seen between irradiated and non-irradiated patients regarding the psychological tests. However, the irradiated patients scored below the non-irradiated control group in test "d2" (concentration: 41st vs. 59th percentile). In the interview, irradiated patients tended to report more learning problems (lp) (10/36 vs. 1/14; p=0.15) and subjective deficits in concentration (con). In irradiated girls (con: 6/15 vs. 0/8; p=0.06; lp: 5/15 vs. 0/8; p=0.12) and younger patients (0 - 5 years at diagnosis; con: 7/12 vs. 2/9; p=0.18; lp 3/10 vs. 1/9; p=0.18) this trend was even more pronounced. Children with AML and CRT had no significant intellectual impairment in standardized tests when compared to non-irradiated patients. However

  2. Sleep disorders in children after treatment for a CNS tumour.

    Science.gov (United States)

    Verberne, Lisa M; Maurice-Stam, Heleen; Grootenhuis, Martha A; Van Santen, Hanneke M; Schouten-Van Meeteren, Antoinette Y N

    2012-08-01

    The long-term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with clinical characteristics and daily performance (fatigue and psychosocial functioning). In a cross-sectional study at the outpatient clinic of the Emma Children's Hospital AMC (February-June 2010), sleep, fatigue and psychosocial functioning were analysed in 31 CNS tumour patients (mean age: 11.8years; 20 boys) and compared with 78 patients treated for a non-CNS malignancy (mean age: 9.7years; 41 boys) and norm data. Questionnaires applied were the Sleep Disorder Scale for Children, the Epworth Sleepiness Scale, the Pediatric Quality of Life Inventory, and the Strengths and Difficulties Questionnaire. Sleeping habits and endocrine deficiencies were assessed with a self-developed questionnaire. Increased somnolence was found in CNS tumour patients compared with those with a non-CNS malignancy (8.8±2.8 versus 7.5±2.7; P<0.05). Both patient groups reported more problems (P<0.01) than the norm with initiating and maintaining sleep. No specific risk factors were identified for a sleep disorder in CNS tumour patients, but their excessive somnolence was correlated with lower fatigue related quality of life (QoL) (r=-0.78, P<0.001) and worse psychosocial functioning (r=0.63, P<0.001). In conclusion, children treated for a CNS tumour have increased somnolence, significantly increasing fatigue and worsening daily functioning. Further investigation should focus on possibilities to improve sleep quality and diminish fatigue. © 2011 European Sleep Research Society.

  3. CNS Macrophages Control Neurovascular Development via CD95L

    Directory of Open Access Journals (Sweden)

    Si Chen

    2017-05-01

    Full Text Available The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific deletion thereof reduces both neurovascular complexity and synaptic activity in the brain. CD95L-induced neuronal and vascular growth is mediated through src-family kinase (SFK and PI3K signaling. Together, our study highlights a coordinated neurovascular development instructed by CNS macrophage-derived CD95L, and it underlines the importance of macrophages for the establishment of the neurovascular network during CNS development.

  4. CNS Macrophages Control Neurovascular Development via CD95L.

    Science.gov (United States)

    Chen, Si; Tisch, Nathalie; Kegel, Marcel; Yerbes, Rosario; Hermann, Robert; Hudalla, Hannes; Zuliani, Cecilia; Gülcüler, Gülce Sila; Zwadlo, Klara; von Engelhardt, Jakob; Ruiz de Almodóvar, Carmen; Martin-Villalba, Ana

    2017-05-16

    The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific deletion thereof reduces both neurovascular complexity and synaptic activity in the brain. CD95L-induced neuronal and vascular growth is mediated through src-family kinase (SFK) and PI3K signaling. Together, our study highlights a coordinated neurovascular development instructed by CNS macrophage-derived CD95L, and it underlines the importance of macrophages for the establishment of the neurovascular network during CNS development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. HIV-1 Induced CNS Dysfunction: Current Overview and Research Priorities.

    Science.gov (United States)

    Joseph, Jeymohan; Colosi, Deborah A; Rao, Vasudev R

    2016-01-01

    Over the past three decades, the clinical presentation of HIV infection of the Central Nervous System (CNS) has evolved. Prior to wide spread use of effective antiretroviral therapy (ART), more than a third of infected individuals exhibited a range of neurocognitive and motor deficits that frequently progressed to severe dementia and paralysis. However, the use of ART has significantly decreased the prevalence of severe forms of HIV-1 associated neurocognitive disorders (HAND). Studies of neurocognitive dysfunction have reported variable prevalence, ranging from 21% to 77.6%, defined primarily by mild to moderate neurocognitive impairment. HIV-associated chronic inflammation and associated neurotoxicity of long term ART, as well as the aging of the HIV-infected population, likely influence the pathogenesis of HAND. Despite significant research efforts directed towards a better understanding of the mechanisms underlying HIV neuropathogenesis, definitive causal pathophysiology of HAND and thus effective prevention or treatment remain elusive. Furthermore, HIV therapeutic research now includes efforts to effect a cure, by eliminating or silencing HIV within infected cells, which must include efforts to target the latently infected cells within the CNS. Prevention and treatment of the neurological complications of HIV, and eradication of persistent virus from the CNS compartment are major priorities for the HIV-CNS research. Here we give an overview of the progress of research on HIV-CNS disease, define new challenges and research areas, and highlight domestic and global priorities.

  6. The nature of relapse in schizophrenia

    National Research Council Canada - National Science Library

    Emsley, Robin; Chiliza, Bonginkosi; Asmal, Laila; Harvey, Brian H

    2013-01-01

    Multiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware...

  7. Intracranial aneurysm associated with relapsing polychondritis

    Energy Technology Data Exchange (ETDEWEB)

    Coumbaras, M.; Boulin, A.; Pierot, L. [Dept. of Neuroradiology, Hopital Foch, Suresnes (France); Piette, A.M.; Bletry, O. [Dept. of Medicine, Hopital Foch, Suresnes (France); Graveleau, P. [Dept. of Neurology, Hopital Foch, Suresnes (France)

    2001-07-01

    We describe a 50-year-old man with relapsing polychondritis (RP) involving auricular cartilage, uveitis and hearing loss, who had an aneurysm of the anterior cerebral artery. Intracranial aneurysm is a rare manifestation of RP. (orig.)

  8. Factors associated with relapse in schizophrenia

    African Journals Online (AJOL)

    Division of Psychiatry, University of the Witwatersrand,. Johannesburg ... Substance abuse is common among patients with schizophrenia16 and can lead to .... Financial. 24.6. 9.8. 13.1. 12. 9.2. 1.3. 3.9. Life stressors. Relapse. No relapses. Other. 12.3. 6.6. Fig. 1. Reasons for poor adherence in the study population. Fig. 2.

  9. Developmental models of substance abuse relapse

    OpenAIRE

    Ramo, Danielle Elizabeth

    2008-01-01

    Most models of addiction treatment outcome and relapse have been formulated on adult populations, with only modest consideration of developmental factors which are salient issues for substance use disordered (SUD) youth. The dominant cognitive behavioral model of addiction relapse (Marlatt & Gordon, 1985) has been compelling in its description of how situational context (e.g., high risk situations) interacts with cognitive factors (e.g., self-efficacy, coping resources) to elevate risk for re...

  10. Trombocytosis in childhood relapsing nephrotic syndrome

    OpenAIRE

    Ade Hafni; Danny Hilmanto; Dedi Rachmadi; Nanan Sekarwana

    2007-01-01

    Background Thrombosis is a serious complication of nephrotic syndrome (NS). Long-term steroid treatment may induce thrombocytosis in relapsing NS that may predispose to thrombosis. Most children with idiopathic NS respond to steroids; however, a substantial number of patients will relapse frequently and require repeated high dose steroid therapy, thus increase the risk of thrombocytosis. Objective To compare the occurrence of thrombocytosis between children with freque...

  11. Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

    Directory of Open Access Journals (Sweden)

    Alerie Guzman De La Fuente

    2017-08-01

    Full Text Available The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  12. How Do Meningeal Lymphatic Vessels Drain the CNS?

    Science.gov (United States)

    Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan

    2016-09-01

    The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Prospects for the development of epigenetic drugs for CNS conditions.

    Science.gov (United States)

    Szyf, Moshe

    2015-07-01

    Advances in our understanding of the epigenetic mechanisms that control gene expression in the central nervous system (CNS) and their role in neuropsychiatric disorders are paving the way for a potential new therapeutic approach that is focused on reversing the epigenetic underpinnings of neuropsychiatric conditions. In this article, the complexity of epigenetic processes and the current level of proof for their involvement in CNS disorders are discussed. The preclinical evidence for efficacy of pharmacological approaches that target epigenetics in the CNS and the particular challenges of this approach are also examined. Finally, strategies to address these challenges through the development of improved evidence-based epigenetic therapeutics and through combining pharmacological and behavioural approaches are presented.

  14. Identification of new therapeutic targets for prevention of CNS inflammation

    DEFF Research Database (Denmark)

    Owens, Trevor

    2002-01-01

    Multiple sclerosis (MS) is a disease of complex pathologies, which involves infiltration by CD4(+) and CD8(+) T cells of and response within the central nervous system. Expression in the CNS of cytokines, reactive nitrogen species and costimulator molecules have all been described in MS. Notably......, the cytokines IFN-gamma and TNF are strongly expressed. Microglial cells in the CNS express costimulator molecules and it is assumed that they play a role in directing or inducing the T cell response. Transgenic experiments have tested the effects of overexpression of these molecules in mice and have shown...

  15. Prognosis of type 1 autoimmune pancreatitis after corticosteroid therapy-induced remission in terms of relapse and diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Masaki Miyazawa

    Full Text Available Relapse and diabetes mellitus (DM are major problems for the prognosis of autoimmune pancreatitis (AIP. We examined the prognosis of type 1 AIP after corticosteroid therapy (CST-induced remission in terms of relapse and DM.The study enrolled 82 patients diagnosed with type 1 AIP who achieved remission with CST. We retrospectively evaluated the relapse rate in terms of the administration period of CST, clinical factors associated with relapse, and the temporal change in glucose tolerance.During follow-up, 32 patients (39.0% experienced relapse. There was no significant clinical factor that could predict relapse before beginning CST. AIP patients who ceased CST within 2 or 3 years experienced significantly earlier relapse than those who had the continuance of CST (p = 0.050 or p = 0.020. Of the 37 DM patients, 15 patients (40.5% had pre-existing DM, 17 (45.9% showed new-onset DM, and 5 (13.5% developed CST-induced DM. Patients with new-onset DM were significantly more likely to show improvement (p = 0.008 than those with pre-existing DM.It was difficult to predict relapse of AIP based on clinical parameters before beginning CST. Relapse was likely to occur within 3 years after the beginning of CST and maintenance of CST for at least 3 years reduced the risk of relapse. The early initiation of CST for AIP with impaired glucose tolerance is desirable because pre-existing DM is refractory to CST.

  16. Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma.

    Science.gov (United States)

    Linnebank, Michael; Moskau, Susanna; Jürgens, Annika; Simon, Matthias; Semmler, Alexander; Orlopp, Katjana; Glasmacher, Axel; Bangard, Christopher; Vogt-Schaden, Marlies; Urbach, Horst; Schmidt-Wolf, Ingo G H; Pels, Hendrik; Schlegel, Uwe

    2009-02-01

    Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.

  17. Three-dimensional analysis of condylar remodeling and skeletal relapse following bimaxillary surgery: A 2-year follow-up study.

    Science.gov (United States)

    Xi, Tong; van Luijn, Rik; Baan, Frank; Schreurs, Ruud; de Koning, Martien; Bergé, Stefaan; Maal, Thomas

    2017-08-01

    To quantify the postoperative condylar remodelling and its role in skeletal relapse after bimaxillary surgery. 50 patients with mandibular hypoplasia who underwent bimaxillary surgery were analyzed. CBCT scans were acquired preoperatively, one week postoperatively and two years postoperatively. 3D cephalometric analysis was carried out for each CBCT scan, after which the condylar volume analysis was performed. The maxilla was advanced by a mean of 2.1 mm with a corresponding mean relapse of 0.3 mm. The maxilla was impacted in 23 and extruded in 27 patients. The mean mandibular advancement was 7.8 mm. Two years after surgery a mean mandibular skeletal relapse of 1.3 mm was observed. 78% of condyles exhibited a postoperative reduction in volume of 179 mm3 (mean), equivalent to 12.5 volume%. Postoperative condylar volume loss was correlated with mandibular skeletal relapse (r = 0.42, p < 0.01), but not with maxilla relapse. Linear regression analysis identified age, gender, amount of surgical mandibular advancement and postoperative condylar volume loss as predictive factors for mandibular relapse. A significant correlation between postoperative condylar volume loss and skeletal relapse was found. Young female patients who underwent large bimaxillary advancement and postoperative reduction in condylar volume were particularly at risk for skeletal relapse. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  18. Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence.

    Science.gov (United States)

    Garbusow, Maria; Schad, Daniel J; Sebold, Miriam; Friedel, Eva; Bernhardt, Nadine; Koch, Stefan P; Steinacher, Bruno; Kathmann, Norbert; Geurts, Dirk E M; Sommer, Christian; Müller, Dirk K; Nebe, Stephan; Paul, Sören; Wittchen, Hans-Ulrich; Zimmermann, Ulrich S; Walter, Henrik; Smolka, Michael N; Sterzer, Philipp; Rapp, Michael A; Huys, Quentin J M; Schlagenhauf, Florian; Heinz, Andreas

    2016-05-01

    In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence. © 2015 Society for the Study of Addiction.

  19. Delivery of therapeutic peptides and proteins to the CNS.

    Science.gov (United States)

    Salameh, Therese S; Banks, William A

    2014-01-01

    Peptides and proteins have potent effects on the brain after their peripheral administration, suggesting that they may be good substrates for the development of CNS therapeutics. Major hurdles to such development include their relation to the blood-brain barrier (BBB) and poor pharmacokinetics. Some peptides cross the BBB by transendothelial diffusion and others cross in the blood-to-brain direction by saturable transporters. Some regulatory proteins are also transported across the BBB and antibodies can enter the CNS via the extracellular pathways. Glycoproteins and some antibody fragments can be taken up and cross the BBB by mechanisms related to adsorptive endocytosis/transcytosis. Many peptides and proteins are transported out of the CNS by saturable efflux systems and enzymatic activity in the blood, CNS, or BBB are substantial barriers to others. Both influx and efflux transporters are altered by various substances and in disease states. Strategies that manipulate these interactions between the BBB and peptides and proteins provide many opportunities for the development of therapeutics. Such strategies include increasing transendothelial diffusion of small peptides, upregulation of saturable influx transporters with allosteric regulators and other posttranslational means, use of vectors and other Trojan horse strategies, inhibition of efflux transporters including with antisense molecules, and improvement in pharmacokinetic parameters to overcome short half-lives, tissue sequestration, and enzymatic degradation. © 2014 Elsevier Inc. All rights reserved.

  20. A map of taste neuron projections in the Drosophila CNS

    Indian Academy of Sciences (India)

    We provide a map of the projections of taste neurons in the CNS of Drosophila. Using a collection of 67 GAL4 drivers representing the entire repertoire of Gr taste receptors, we systematically map the projections of neurons expressing these drivers in the thoracico-abdominal ganglion and the suboesophageal ganglion ...

  1. CNS Anticancer Drug Discovery and Development: 2016 conference insights.

    Science.gov (United States)

    Levin, Victor A; Abrey, Lauren E; Heffron, Timothy P; Tonge, Peter J; Dar, Arvin C; Weiss, William A; Gallo, James M

    2017-07-18

    CNS Anticancer Drug Discovery and Development November 2016, AZ, USA The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time- and cost-efficient clinical trials based on surrogate end points.

  2. Molecularly-Driven Doublet Therapy for Recurrent CNS Malignant Neoplasms

    Science.gov (United States)

    2018-02-20

    Anaplastic Astrocytoma; Anaplastic Ependymoma; Anaplastic Ganglioglioma; Anaplastic Meningioma; Anaplastic Oligodendroglioma; Pleomorphic Xanthoastrocytoma, Anaplastic; Atypical Teratoid/Rhabdoid Tumor; Brain Cancer; Brain Tumor; Central Nervous System Neoplasms; Choroid Plexus Carcinoma; CNS Embryonal Tumor With Rhabdoid Features; Ganglioneuroblastoma of Central Nervous System; CNS Tumor; Embryonal Tumor of CNS; Ependymoma; Glioblastoma; Glioma; Glioma, Malignant; Medulloblastoma; Medulloblastoma; Unspecified Site; Medulloepithelioma; Neuroepithelial Tumor; Neoplasms; Neoplasms, Neuroepithelial; Papillary Tumor of the Pineal Region (High-grade Only); Pediatric Brain Tumor; Pineal Parenchymal Tumor of Intermediate Differentiation (High-grade Only); Pineoblastoma; Primitive Neuroectodermal Tumor; Recurrent Medulloblastoma; Refractory Brain Tumor; Neuroblastoma. CNS; Glioblastoma, IDH-mutant; Glioblastoma, IDH-wildtype; Medulloblastoma, Group 3; Medulloblastoma, Group 4; Glioma, High Grade; Neuroepithelial Tumor, High Grade; Medulloblastoma, SHH-activated and TP53 Mutant; Medulloblastoma, SHH-activated and TP53 Wildtype; Medulloblastoma, Chromosome 9q Loss; Medulloblastoma, Non-WNT Non-SHH, NOS; Medulloblastoma, Non-WNT/Non-SHH; Medulloblastoma, PTCH1 Mutation; Medulloblastoma, WNT-activated; Ependymoma, Recurrent; Glioma, Recurrent High Grade; Glioma, Recurrent Malignant; Embryonal Tumor, NOS; Glioma, Diffuse Midline, H3K27M-mutant; Embryonal Tumor With Multilayered Rosettes (ETMR); Ependymoma, NOS, WHO Grade III; Ependymoma, NOS, WHO Grade II; Medulloblastoma, G3/G4; Ependymoma, RELA Fusion Positive

  3. Neurolymphomatosis: An International Primary CNS Lymphoma Collaborative Group report

    NARCIS (Netherlands)

    S. Grisariu (Sigal); B. Avni (Batia); T.T. Batchelor (Tracy); M.J. van den Bent (Martin); F. Bokstein (Felix); D. Schiff (David); O. Kuittinen (Outi); M.C. Chamberlain (Marc C.); P. Roth (Patrick); A. Nemets (Anatoly); E. Shalom (Edna); D. Ben-Yehuda (Dina); T. Siegal (Tali)

    2010-01-01

    textabstractNeurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%.

  4. Sleep disorders in children after treatment for a CNS tumour

    NARCIS (Netherlands)

    Verberne, Lisa M.; Maurice-Stam, Heleen; Grootenhuis, Martha A.; van Santen, Hanneke M.; Schouten-van Meeteren, Antoinette Y. N.

    2012-01-01

    The long-term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with

  5. A map of taste neuron projections in the Drosophila CNS

    Indian Academy of Sciences (India)

    2014-07-08

    Jul 8, 2014 ... Taste allows the fly to evaluate potential food sources. The presence of nutritious sugars, which taste sweet, and toxins, which taste bitter, is detected by gustatory organs. Their input is integrated in the CNS and provides a basis for feeding decisions. Drosophila is a valuable system in which to investigate ...

  6. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease.

    Science.gov (United States)

    Rajca, Sylvie; Grondin, Virginie; Louis, Edouard; Vernier-Massouille, Gwenola; Grimaud, Jean-Charle; Bouhnik, Yoram; Laharie, David; Dupas, Jean-Louis; Pillant, Helene; Picon, Laurence; Veyrac, Michel; Flamant, Mathurin; Savoye, Guillaume; Jian, Raymond; Devos, Martine; Paintaud, Gilles; Piver, Eric; Allez, Matthieu; Mary, Jean Yves; Sokol, Harry; Colombel, Jean-Frederic; Seksik, Philippe

    2014-06-01

    Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal. Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management.

  7. Myelin damage and repair in pathologic CNS: challenges and prospects

    Science.gov (United States)

    Alizadeh, Arsalan; Dyck, Scott M.; Karimi-Abdolrezaee, Soheila

    2015-01-01

    Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for

  8. PEG minocycline-liposomes ameliorate CNS autoimmune disease.

    Directory of Open Access Journals (Sweden)

    Wei Hu

    Full Text Available Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS. Minocycline, a potent inhibitor of matrix metalloproteinase (MMP-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG minocycline liposomes are effective in treating EAE.Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs, we determined that PEG minocycline-liposome preparations stabilized with CaCl(2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number.Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

  9. PEG minocycline-liposomes ameliorate CNS autoimmune disease.

    Science.gov (United States)

    Hu, Wei; Metselaar, Josbert; Ben, Li-Hong; Cravens, Petra D; Singh, Mahendra P; Frohman, Elliot M; Eagar, Todd N; Racke, Michael K; Kieseier, Bernd C; Stüve, Olaf

    2009-01-01

    Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS). Minocycline, a potent inhibitor of matrix metalloproteinase (MMP)-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG) minocycline liposomes are effective in treating EAE. Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs), we determined that PEG minocycline-liposome preparations stabilized with CaCl(2) are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number. Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

  10. Deoxyspergualin in relapsing and refractory Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Flossmann, O; Baslund, B; Bruchfeld, A

    2008-01-01

    OBJECTIVES: Conventional therapy of Wegener's granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing...... or refractory disease. METHODS: A prospective, international, multicentre, single-limb, open-label study. Entry required active Wegener's granulomatosis with a Birmingham vasculitis activity score (BVAS) > or =4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn......-threatening (> or = grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leucopaenias. CONCLUSIONS: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener's granulomatosis. Adverse events were common but rarely led...

  11. Splenosis Causing ITP Relapse: Case Report

    Directory of Open Access Journals (Sweden)

    Yavuz Koca

    2014-06-01

    Full Text Available ITP (idiopathic trombocitopenic purpura is defined as isolated thrombocytopenia which occurs even in normal bone marrow structure without any reason. Splenectomy is an efficient and permanent treatment in treatment-resistant ITP cases. Accesory spleen and splenosis, also known as auto-implantation of spleen, are rare clinical cases that need to be considered in ITP relapses. In this study, a 49 year old woman patient who had splenectomy because of ITP and had ITP relapse stemming from splenosis in postoperative 5th year is presented with literature.

  12. PARATHYROID CANCER OCCURRING IN RELAPSING SECONDARY HYPERPARATHYROIDISM

    Directory of Open Access Journals (Sweden)

    I. V. Kotova

    2016-01-01

    Full Text Available We present a clinical case of parathyroid cancer in a patient with relapsing secondary hyperparathyroidism at 4 years after subtotal parathyroidectomy. Its unique character is related to the combination of relapsing secondary hyperparathyroidism, parathyromatosis, ectopic of an adenomatous hyperplastic parathyroid gland into the thyroid gland, and parathyroid cancer. Several most complicated aspects of parathyroid surgery are disclosed, such as the choice of strategy for surgical intervention in secondary hyperparathyroidism, complexity of morphological and cytological diagnostics of this disorder.

  13. CNS immunological modulation of neural graft rejection and survival.

    Science.gov (United States)

    Borlongan, C V; Stahl, C E; Cameron, D F; Saporta, S; Freeman, T B; Cahill, D W; Sanberg, P R

    1996-08-01

    Neural transplantation therapy as a possible alternative treatment for neurological movement disorders, such as in Parkinson's disease (PD), has accentuated research interest on the immune status of the central nervous system (CNS). Most animal studies concerned with neural transplantation for the treatment of PD have utilized dopamine (DA) neurons from tissues of the embryonic ventral mesencephalon. Rat embryonic DA neurons, grafted either as solid blocks or dissociated into a cell suspension and stereotaxically injected intraparenchymally into a rat lesion model of PD, have been shown to survive and form connections with the host brain, and ameliorate the behavioral deficits of PD. Similarly, studies on nonhuman primate models of PD provide considerable support for neural transplantation of DA neurons as an experimental clinical procedure for the treatment of PD. To this end, experimental clinical trials have been centered upon transplantation of the embryonic ventral mesencephalic cells for PD patients. Although not conclusive, the findings from clinical studies have provided some evidence that most patients with marked increases in fluorodopa uptake (indicating graft survival) have been immunosuppressed. Furthermore, immune reactions have been observed in rats xenografted with human embryonic tissue. Of note, embryonic ventral mesencephalic tissues compared to adult tissues produce better morphological and long-lasting behavioral amelioration of the neurobehavioral deficits of PD, thus advocating the use of grafts from young donors (embryo) to circumvent the CNS immune rejection. The possible graft rejection due to CNS immune reactions, coupled with the social and ethical problems surrounding the use of embryonic neural tissue, and the logistical problems concerning tissue availability have prompted the development of alternative sources of DA-secreting cells. To circumvent these obstacles, several methods have been suggested including the use of

  14. Axonal regeneration in adult CNS neurons – signaling molecules and pathways

    National Research Council Canada - National Science Library

    Teng, Felicia Yu Hsuan; Tang, Bor Luen

    2006-01-01

    Failure of severed adult CNS axons to regenerate could be attributed to both a reduced intrinsic capacity to grow and an heightened susceptibility to inhibitory factors of the CNS extracellular environment...

  15. Health-Related Quality of Life in Pediatric Patients With Demyelinating Diseases: Relevance of Disability, Relapsing Presentation, and Fatigue.

    Science.gov (United States)

    Self, Mariella M; Fobian, Aaron; Cutitta, Katherine; Wallace, Arianne; Lotze, Timothy E

    2017-07-21

    Decreased health-related quality of life (HRQOL) in pediatric patients with multiple sclerosis is established, but little research has examined HRQOL in the broader pediatric demyelinating disease population, and predictors of reduced HRQOL are largely unexplored. We sought to (1) compare generic HRQOL and fatigue of pediatric patients with relapsing (i.e., multiple sclerosis and neuromyelitis optica) versus monophasic demyelinating diseases (i.e., acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, clinically isolated syndrome) and (2) examine the extent to which disability, relapsing disease, and fatigue predict HRQOL. Child and/or parent-proxy reports of generic and fatigue-related HRQOL were collected for 64 pediatric patients with demyelinating diseases. HRQOL of the sample was compared with published healthy child norms. Independent samples t -tests compared HRQOL and fatigue for children with monophasic versus relapsing diseases. Regression analyses examined disability, disease presentation, and fatigue as potential predictors of HRQOL. Compared with healthy child norms, generic HRQOL was significantly lower for the demyelinating disorder group, for both child and parent reports across multiple domains. As hypothesized, the relapsing disease group reported lower overall HRQOL and more fatigue than the monophasic group. Disability and relapsing disease predicted lower HRQOL for both parents and children, whereas fatigue was only predictive per the child perspective. Children with demyelinating diseases evidence significantly lower HRQOL than healthy peers, supporting need for intervention. Those with relapsing disease appear particularly at risk; targeting disability and fatigue may be fruitful areas for intervention.

  16. BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors.

    Science.gov (United States)

    Müller, Judit; Martins, Ana; Csábi, József; Fenyvesi, Ferenc; Könczöl, Árpád; Hunyadi, Attila; Balogh, György T

    2017-01-01

    The anticancer potential of ecdysteroids, especially their chemo-sensitizing activity has recently gained a substantial scientific interest. A comprehensive physicochemical profiling was performed for a set of natural or semi-synthetic ecdysteroids (N=37) to identify a lead compound against central nervous system (CNS) tumors. Calculated properties, such as lipophilicity (clogP), topological polar surface area (TPSA), brain-to-plasma ratio (clogBB) along with the measured blood-brain barrier specific in vitro permeability (logPe) were evaluated in parallel. Compounds with the highest CNS-availability predicted (clogBB>0.0 and logPe>-6.0) showed moderate to high lipophilicity (clogP=3.89-5.25), relatively low TPSA (94.45Å2), and shared a common apolar 2,3- and 20,22-diacetonide motif (25, 30-33). These ecdysteroids were selected for testing their capacity to sensitize SH-SY5Y neuroblastoma cells to vincristine. All of the five tested compounds exerted a remarkably strong, dose dependent chemo-sensitizing activity: at 2.5-10.0μM ecdysteroids increased the cytotoxic activity of vincristine one to three orders of magnitude in (e.g., from IC50=39.5±2.9nM to as low as 0.056±0.03nM). Moreover, analysis of the combination index (CI) revealed outstanding synergism between ecdysteroids and vincristine (CI50=0.072-0.444). Thus, based on drug-likeness, physchem character and in vitro CNS activity, compound 25 was proposed as a lead for further in vivo studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Theien, Bradley E.; Vanderlugt, Carol L.; Eagar, Todd N.; Nickerson-Nutter, Cheryl; Nazareno, Remederios; Kuchroo, Vijay K.; Miller, Stephen D.

    2001-01-01

    Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the α4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti–VLA-4 to regulate proteolipid protein (PLP) 139-151–induced R-EAE when administered either before or after disease onset. Preclinical administration of anti–VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4+ T cells in the CNS. Most significantly, anti–VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. PMID:11306603

  18. The use of the reinstatement model to study relapse to palatable food seeking during dieting.

    Science.gov (United States)

    Calu, Donna J; Chen, Yu-Wei; Kawa, Alex B; Nair, Sunila G; Shaham, Yavin

    2014-01-01

    Excessive consumption of unhealthy foods is a major public health problem. While many people attempt to control their food intake through dieting, many relapse to unhealthy eating habits within a few months. We have begun to study this clinical condition in rats by adapting the reinstatement model, which has been used extensively to study relapse to drug seeking. In our adaptation of the relapse model, reinstatement of palatable food seeking by exposure to food-pellet priming, food-associated cues, or stress is assessed in food-restricted (to mimic dieting) rats after operant food-pellet self-administration training and subsequent extinction of the food-reinforced responding. In this review, we first outline the clinical problem and discuss a recent study in which we assessed the predictive validity of the reinstatement model for studying relapse to food seeking during dieting by using the anorexigenic drug fenfluramine. Next, we summarize results from our initial studies on the role of several stress- and feeding-related peptides (corticotropin-releasing factor, hypocretin, melanin-concentrating hormone, peptide YY3-36) in reinstatement of palatable food seeking. We then present results from our studies on the role of dopamine and medial prefrontal cortex in stress-induced reinstatement of food seeking. We conclude by discussing potential clinical implications. We offer two main conclusions: (1) the food reinstatement model is a simple, reliable, and valid model to study mechanisms of relapse to palatable food seeking during dieting, and to identify medications to prevent this relapse; (2) mechanisms of relapse to food seeking are often dissociable from mechanisms of ongoing food intake. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Published by Elsevier Ltd.

  19. The role of craving in relapse after discontinuation of long-term benzodiazepine use.

    Science.gov (United States)

    Mol, Audrey J J; Oude Voshaar, Richard C; Gorgels, Wim J M J; Breteler, Marinus H M; van Balkom, Anton J L M; van de Lisdonk, Eloy H; Kan, Cornelis C; Zitman, Frans G

    2007-12-01

    Craving for benzodiazepines has never been examined as a factor of relapse after successful benzodiazepine discontinuation. In this study, we examined the predictive value of craving on benzodiazepine relapse. A stepped-care intervention trial aimed to discontinue long-term benzodiazepine use in general practice. The first step was the sending of a letter to users advising them to gradually quit their use by themselves (i.e., minimal intervention). The second step, a supervised tapering-off program, was offered to those unable to discontinue by themselves. Craving was assessed by means of the Benzodiazepine Craving Questionnaire (BCQ). Multiple Cox proportional hazards regression analyses were performed to examine the effect of craving on subsequent relapse during a 15-month follow-up period in patients who had successfully quit their benzodiazepine use by themselves after the minimal intervention (N = 79) and in those patients who had successfully quit after the supervised tapering-off program (N = 45). Data were collected from August 1998 to December 2001. Thirty-five (44%) and 24 (53%) patients had relapsed after the minimal intervention and tapering-off program, respectively. Patients able to quit by themselves experienced very little craving. In this sample, craving was not related to relapse (p = .82). In patients who needed an additional supervised tapering-off program, higher craving scores were significantly related to relapse (hazard ratio = 1.26, 95% CI = 1.02 to 1.54, p = .029), when corrected for benzodiazepine characteristics, psychopathology, and personality characteristics. Craving is an independent factor of subsequent relapse after successful benzodiazepine discontinuation in long-term benzodiazepine users who are not able to quit their usage of their own accord.

  20. Molecular and hematologic relapses in adult patients with acute promyelocytic leukemia: a cohort study.

    Science.gov (United States)

    Azevedo, Ilana de França; Magalhães, Michelline Gomes; Souto, Fernanda Ribeiro; Neves, Washington Batista das; Melo, Fárida Coeli de Barros Correia; Rego, Eduardo Magalhães; Melo, Raul Antônio Morais

    To evaluate factors predictive for relapse in a cohort of adult patients with acute promyelocytic leukemia monitored by molecular methods during consolidation and during at least one month of maintenance therapy. The charts and laboratory data of 65 adult patients with acute promyelocytic leukemia treated according to the International Consortium on Acute Promyelocytic Leukemia 2006 protocol were reviewed. The identification of the promyelocytic leukemia-retinoic acid receptor-alpha gene rearrangement at diagnosis, post-induction, post-consolidation and during maintenance treatment was performed by qualitative and quantitative reverse transcription polymerase chain reaction. Eighty-nine patients were diagnosed with acute promyelocytic leukemia over a seven-year period and of these 65 were eligible for treatment with the protocol. Among the 45 patients who received consolidation and maintenance treatment, six (13%) relapsed, three of whom presented hematologic and three presented molecular relapse. The first relapses occurred at a median of 39 months. Relapsed patients were from all risk groups (low, intermediate and high) and both morphological types (M3 and M3variant) were found. Three of these patients are alive and in molecular remission after salvage treatment. There were no statistically significant differences regarding gender, age, risk group, morphology, promyelocytic leukemia breakpoint cluster region, use of all-trans retinoic acid, development of differentiation syndrome and number of days to complete remission between the patients who relapsed and those who did not. Our results reinforce the importance of prolonged monitoring of acute promyelocytic leukemia patients using molecular methods to detect relapse early. Copyright © 2016 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.

  1. Resistance to Change and Relapse of Observing

    Science.gov (United States)

    Thrailkill, Eric A.; Shahan, Timothy A.

    2012-01-01

    Four experiments examined relapse of extinguished observing behavior of pigeons using a two-component multiple schedule of observing-response procedures. In both components, unsignaled periods of variable-interval (VI) food reinforcement alternated with extinction and observing responses produced stimuli associated with the availability of the VI…

  2. Recurrence and Relapse in Bipolar Mood Disorder

    Directory of Open Access Journals (Sweden)

    S Gh Mousavi

    2004-06-01

    Full Text Available Background: Despite the effectiveness of pharmacotherapy in acute phase of bipolar mood disorder, patients often experience relapses or recurrent episodes. Hospitalization of patients need a great deal of financial and humanistic resources which can be saved through understanding more about the rate of relapse and factors affecting this rate. Methods: In a descriptive analytical study, 380 patients with bipolar disorder who were hospitalized in psychiatric emergency ward of Noor hospital, Isfahan, Iran, were followed. Each patient was considered for; the frequency of relapse and recurrence, kind of pharmachotherapy, presence of psychotherapeutic treatments, frequency of visits by psychiatrist and the rank of present episode. Results: The overall prevalence of recurrence was 42.2%. Recurrence was lower in patients using lithium carbonate or sodium valproate or combined therapy (about 40%, compared to those using carbamazepine (80%. Recurrence was higher in patients treated with only pharmacotherapy (44.5% compared to those treated with both pharmacotherapy and psychotherapy (22.2%. Patients who were visited monthy by psychiatrist had lower rate of recurrence compared to those who had irregular visits. Conclusion: The higher rate of recurrence observed in carbamazepine therapy may be due to its adverse reactions and consequently poor compliance to this drug. Lower rates of recurrence with psychotherapy and regular visits may be related to the preventive effects of these procedures and especially to the effective management of stress. Keywords: Bipolar Mood Disorder, Recurrence, Relapse.

  3. Pharmacological interventions for alcohol relapse prevention ...

    African Journals Online (AJOL)

    Alcohol dependence is a chronic, debilitating disorder that is an important public health problem worldwide. Combined psychological and pharmacological treatment packages produce best outcomes in its management. In this paper we discuss the three NICE – approved relapse prevention medications used in treatment of ...

  4. Pharmacological interventions for alcohol relapse prevention

    African Journals Online (AJOL)

    Arun Kumar Agnihotri

    ABSTRACT: Alcohol dependence is a chronic, debilitating disorder that is an important public health problem worldwide. Combined psychological and pharmacological treatment packages produce best outcomes in its management. In this paper we discuss the three. NICE – approved relapse prevention medications used ...

  5. Normal plasma antithrombin activity in patients with relapsing-remitting and secondary progressive multiple sclerosis.

    Science.gov (United States)

    Campos-de-Magalhães, Marilza; de Almeida, Adilson José; Papaiz-Alvarenga, Regina Maria; Gadelha, Telma; Morais-de-Sá, Carlos Alberto; Alves-Leon, Soniza Vieira

    2009-06-01

    Multiple sclerosis (MS) is an inflammatory disease characterized by multifocal areas of central nervous system (CNS) demyelination. Activation of coagulation factors and fibrin deposition are observed around CNS blood vessels in experimental autoimmune encephalomyelitis, an animal model of MS. Antithrombin (AT) is a potent anticoagulant with remarkable anti-inflammatory properties, and its inhibitory effects on coagulation and inflammation may play a role in the pathogenesis and clinical course of MS. We studied the association between plasma AT activity and clinical forms of MS. A total of 69 patients, 37 with relapsing-remitting and 32 with secondary progressive MS, were included in the study. A control group (CG) of 34 normal subjects was also studied. Plasma AT activity (Stachrom ATIII) was quantified using a chromogenic activity assay with normal reference values ranging from 70% to 120% of AT activity. We found no difference between plasma AT levels in patients and those in CG. We also found no association of AT levels with activity of disease, duration of disease progression, level of neurological disability, and treatment. We found no association between plasma AT activity and RRMS or SPMS. It remains to be studied whether exists or not an association between abnormal plasma AT activity and other MS forms.

  6. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies.

    Science.gov (United States)

    Aldaz, C Marcelo; Ferguson, Brent W; Abba, Martin C

    2014-08-01

    WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers and uterine and gastric adenocarcinomas. Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer. Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism. Finally, very recently the first human pedigrees with probands carrying homozygous

  7. Sialin expression in the CNS implicates extralysosomal function in neurons.

    Science.gov (United States)

    Aula, Nina; Kopra, Outi; Jalanko, Anu; Peltonen, Leena

    2004-03-01

    SLC17A5 encodes a lysosomal membrane protein, sialin, which transports sialic acid from lysosomes. Mutations in sialin result in neurodegenerative sialic acid storage disorders, Salla disease (SD) and infantile sialic acid storage disease (ISSD). Here we analyzed sialin in mouse central nervous system (CNS) and primary cortical and hippocampal neurons and glia. In the CNS, sialin was predominantly expressed in neurons, especially in the proliferative zone of the prospective neocortex and the hippocampus in developing brain. In nonneuronal cells and primary glial cell cultures, mouse sialin was localized into lysosomes but interestingly, in primary neuronal cultures sialin was not targeted into lysosomes but rather revealed a punctate staining along the neuronal processes and was also seen in the plasma membrane. These data demonstrate a nonlysosomal localization of sialin in neurons and would imply a role for sialin in the secretory processes of neuronal cells.

  8. Positron emission tomography in CNS drug discovery and drug monitoring.

    Science.gov (United States)

    Piel, Markus; Vernaleken, Ingo; Rösch, Frank

    2014-11-26

    Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceutical's behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, the importance of appropriate tracer selection, the impact of improved radiopharmaceutical chemistry in radiotracer development, and the different roles that PET can fulfill in CNS drug research.

  9. Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Carrasco, J; Hidalgo, J

    2001-01-01

    Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein-III...

  10. Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats

    NARCIS (Netherlands)

    Adage, Tiziana; Scheurink, Anton J.W.; Boer, Sietse F. de; Vries, Koert de; Konsman, Jan Pieter; Kuipers, Folkert; Adan, Roger A.H.; Baskin, Denis G.; Schwartz, Michael W.; Dijk, Gertjan van

    2001-01-01

    The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that

  11. Leptin and the CNS Control of Glucose Metabolism

    Science.gov (United States)

    Morton, Gregory J.; Schwartz, Michael W.

    2012-01-01

    The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system (CNS) plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders. PMID:21527729

  12. 4th ENRI International Workshop on ATM/CNS

    CERN Document Server

    2017-01-01

    This book is a compilation of selected papers from the 4th ENRI International Workshop on ATM/CNS (EIWAC2015). The work focuses on novel techniques for aviation infrastructure in air traffic management (ATM) and communications, navigation, surveillance, and informatics (CNSI) domains. The contents make valuable contributions to academic researchers, engineers in the industry, and regulators of aviation authorities. As well, readers will encounter new ideas for realizing a more efficient and safer aviation system. .

  13. Hyperactivated Stat3 boosts axon regeneration in the CNS.

    Science.gov (United States)

    Mehta, Saloni T; Luo, Xueting; Park, Kevin K; Bixby, John L; Lemmon, Vance P

    2016-06-01

    Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate. Of these, signal transducer and activator of transcription 3 (STAT3), as well its downstream regeneration-associated targets, showed a significant upregulation in PNS neurons relative to CNS neurons, and a constitutively active variant of Stat3 (Stat3CA) promoted neurite growth when expressed in cerebellar neurons (Lerch et al., 2012; Smith et al., 2011). To further enhance STAT3's neurite outgrowth enhancing activity, Stat3CA was fused with a viral activation domain (VP16). VP16 hyperactivates TFs by recruiting transcriptional co-factors to the DNA binding domain (Hirai et al., 2010). Overexpression of this VP16-Stat3CA chimera in primary cortical neurons led to a significant increase of neurite outgrowth as well as Stat3 transcriptional activity in vitro. Furthermore, in vivo transduction of retinal ganglion cells (RGCs) with AAV constructs expressing VP16-Stat3CA resulted in regeneration of optic nerve axons after injury, to a greater degree than for those expressing Stat3CA alone. These findings confirm and extend the concept that overexpression of hyperactivated transcription factors identified as functioning in PNS regeneration can promote axon regeneration in the CNS. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Myelin Damage and Repair in Pathologic CNS: Challenges and Prospects

    Directory of Open Access Journals (Sweden)

    Arsalan eAlizadeh

    2015-07-01

    Full Text Available Injury to the central nervous system (CNS results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells (OPCs and neural stem/progenitor cells (NPCs contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i low levels of factors that promote oligodendrogenesis; (ii cell death among newly generated oligodendrocytes, (iii inhibitory factors in the post-injury milieu that impede remyelination, and (iv deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: 1 the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; 2 underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; 3 the endogenous mechanisms of oligodendrocyte replacement; 4 the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and 5 the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of

  15. Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections.

    Science.gov (United States)

    Krut, Jan Jessen; Zetterberg, Henrik; Blennow, Kaj; Cinque, Paola; Hagberg, Lars; Price, Richard W; Studahl, Marie; Gisslén, Magnus

    2013-02-01

    The cerebrospinal fluid (CSF) biomarker profile in Alzheimer's disease (AD) is characterized by decreased beta amyloid (Aβ(1-42)), increased total and hyperphosphorylated tau (t-tau and p-tau, respectively), which is a useful diagnostic tool and gives insight in the pathogenesis of AD. It is of importance to study how these biomarkers react in other CNS diseases; therefore, we decided to analyse amyloid and tau biomarkers in different CNS infections. We also included analysis of soluble amyloid precursor proteins (sAPPα and -β). CSF Aβ(1-42), sAPPα and -β, t-tau and p-tau were analysed in bacterial meningitis (n = 12), Lyme neuroborreliosis (n = 13), herpes simplex virus type 1 (HSV-1) encephalitis (n = 10), HIV-associated dementia (HAD) (n = 21), AD (n = 21) and healthy controls (n = 42). Concurrent with AD, Aβ(1-42) was decreased in all groups except neuroborreliosis compared to controls. HSV-1 encephalitis, bacterial meningitis and HAD showed lower concentrations of sAPPα and -β compared to AD. T-tau was increased in AD and HSV-1 encephalitis compared to all other groups. P-tau was higher in AD and HSV-1 encephalitis compared to bacterial meningitis, HAD and control. Decreased CSF Aβ(1-42), sAPPα and -β in various CNS infections imply an effect of neuroinflammation on amyloid metabolism which is similar in regard to AD concerning Aβ(1-42), but differs concerning sAPPα and -β. These results clearly indicate different pathologic pathways in AD and infectious CNS disease and may provide help in the differential biomarker diagnostics. Increased p-tau in HSV-1 encephalitis probably reflect acute neuronal damage and necrosis.

  16. Does tobacco-control mass media campaign exposure prevent relapse among recent quitters?

    Science.gov (United States)

    Wakefield, Melanie A; Bowe, Steven J; Durkin, Sarah J; Yong, Hua-Hie; Spittal, Matthew J; Simpson, Julie A; Borland, Ron

    2013-02-01

    To determine whether greater mass media campaign exposure may assist recent quitters to avoid relapse. Using date of data collection and postcode, media market estimates of televised tobacco-control advertising exposure measured by gross ratings points (GRPs) were merged with a replenished cohort study of 443 Australians who had quit in the past year. Participants' demographic and smoking characteristics prior to quitting, and advertising exposure in the period after quitting, were used to predict relapse 1 year later. In multivariate analysis, each increase in exposure of 100 GRPs (i.e., 1 anti-smoking advertisement) in the three-month period after the baseline quit was associated with a 5% increase in the odds of not smoking at follow-up (OR = 1.05, 95% CI 1.02-1.07, p exposure to tobacco-control mass media campaigns may reduce the likelihood of relapse among recent quitters.

  17. Randomized trial of oral teriflunomide for relapsing multiple sclerosis

    DEFF Research Database (Denmark)

    O'Connor, Paul; Wolinsky, Jerry S; Confavreux, Christian

    2011-01-01

    Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis.......Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis....

  18. Weight concerns, mood, and postpartum smoking relapse.

    Science.gov (United States)

    Levine, Michele D; Marcus, Marsha D; Kalarchian, Melissa A; Houck, Patricia R; Cheng, Yu

    2010-10-01

    The majority of women who quit smoking as a result of pregnancy will resume smoking during the first 6 months postpartum. Evidence suggests that changes in depressive symptoms, perceived stress, and concerns about weight may relate to postpartum smoking relapse. This study was designed to prospectively evaluate the relationship of mood and weight concerns to postpartum smoking among women who quit smoking during pregnancy. Pregnant women who had quit smoking (N=183) were recruited between February 2003 and November 2006. Women completed assessments of mood (depressive symptoms, perceived stress, positive and negative affect) and weight concerns during the third trimester of pregnancy and at 6, 12, and 24 weeks postpartum. Self-reported smoking status was verified by expired-air carbon monoxide and salivary cotinine at each assessment. Cox regression analyses in which mood and weight concerns were treated as time-dependent covariates were conducted in 2007 and 2009. By 24 weeks postpartum, 65% of women had resumed smoking. Smoking-related weight concerns increased risk of relapse, and positive affect and self-efficacy for weight management without smoking decreased risk of relapse postpartum. Moreover, after controlling for variables previously related to postpartum relapse, weight concerns remained significantly related to smoking relapse. Smoking-related weight concerns and positive affect increase the likelihood that a woman will resume smoking postpartum. Moreover, weight concerns appear to be salient even in the context of other factors shown to affect postpartum smoking. This study suggests that interventions may need to address women's weight concerns and mood to help sustain smoking abstinence after childbirth. Copyright © 2010 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Return on investment: workload, complexity and value of the CNS.

    Science.gov (United States)

    Oliver, Susan; Leary, Alison

    The rheumatology nurse specialist (RNS) has become an integral and vital part of the multidisciplinary team and is valued by patients. Yet, a number of challenges regularly face all clinical nurse specialists (CNS) in the UK. The perception that CNS are an expensive and poorly defined nursing resource results in regular threats to their sustainability, particularly that of the RNS. This study examined return on investment of the RNS. An interrelational Structured Query Language (SQL) database collected data on the day-to-day activities of the RNS based on previous models of CNS and RNS work, and qualitative narrative data were then subjected to data mining. The RNS represented an excellent return on investment, in terms of income generation activity, patient safety and efficiency. These outcomes were achieved using key principles of proactive case management using vigilance, rescue work and brokering. The mean average per whole time equivalent (WTE) RNS per annum represents £ 175,168 in terms of income/savings to an employing NHS Trust. This figure is likely to be an underestimation, as calculations on reduction in bed days in hospital have not been included.

  20. Humanized mouse models for HIV-1 infection of the CNS.

    Science.gov (United States)

    Honeycutt, Jenna B; Sheridan, Patricia A; Matsushima, Glenn K; Garcia, J Victor

    2015-06-01

    Since the onset of the HIV epidemic, there has been a shift from a deadly diagnosis to the management of a chronic disease. This shift is the result of the development of highly effective drugs that are able to suppress viral replication for years. The availability of these regimens has also shifted the neurocognitive pathology associated with infection from potentially devastating to a much milder phenotype. As the disease outcome has changed significantly with the availability of antiretroviral therapy, there is an opportunity to re-evaluate the currently available models to address the neurocognitive pathology seen in suppressed patients. In the following, we seek to summarize the current literature on humanized mouse models and their utility in understanding how HIV infection leads to changes in the central nervous system (CNS). Also, we identify some of the unanswered questions regarding HIV infection of the CNS as well as the opportunities and limitations of currently existing models to address those questions. Finally, our conclusions indicate that the earlier humanized models used to study HIV infection in the CNS provided an excellent foundation for the type of work currently being performed using novel humanized mouse models. We also indicate the potential of some humanized mouse models that have not been used as of this time for the analysis of HIV infection in the brain.

  1. "Worried about relapse": Family members' experiences and perspectives of relapse in first-episode psychosis.

    Science.gov (United States)

    Lal, Shalini; Malla, Ashok; Marandola, Gina; Thériault, Joanie; Tibbo, Phil; Manchanda, Rahul; Williams, Richard; Joober, Ridha; Banks, Nicola

    2017-05-19

    The purpose of this study was to gain an in-depth understanding on the subject of relapse from the perspectives of family members of young people receiving services for a first-episode psychosis (FEP). A qualitative descriptive approach, using focus group methods, was used to elicit experiences, understandings, and knowledge of relapse in FEP. Family members were recruited from 4 specialized early intervention programmes for psychosis in Canada. A total of 24 (6 male, 18 female) family members participated in the study. Thematic analysis was used to examine the data. The core underlying theme in all focus groups was worrying about relapse, which was often accompanied by significant levels of fear and anxiety, and was influenced by: (1) impact of an episode of psychosis; (2) limited confidence in recognizing and coping with relapse; (3) unmet needs for coping skills and emotional support and (4) unmet needs regarding frequency and continuity of communication with clinicians. Family members' unmet needs for relapse-focused education, support and communication with service providers and peers, can have a negative impact on relapse prevention. Addressing family members' education and support needs in a tailored manner (including preferences for types of peer support) can contribute positively to their confidence and ability to recognize and respond to relapse. This can help reduce fear and anxieties about relapse, and positively influence the ability to function as caregivers. Future research should focus on best approaches for providing education, sustained contact with the clinical team and family peer support. © 2017 John Wiley & Sons Australia, Ltd.

  2. Disability, body image and sports/physical activity in adult survivors of childhood CNS tumors: population-based outcomes from a cohort study

    NARCIS (Netherlands)

    Boman, Krister K.; Hörnquist, Lina; de Graaff, Lisanne; Rickardsson, Jenny; Lannering, Birgitta; Gustafsson, Göran

    2013-01-01

    Childhood CNS tumor survivors risk health and functional impairments that threaten normal psychological development and self-perception. This study investigated the extent to which health and functional ability predict adult survivors' body image (BI) and self-confidence regarding sports and

  3. Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia.

    Science.gov (United States)

    Rydström, Anna; Hallner, Alexander; Aurelius, Johan; Sander, Frida Ewald; Bernson, Elin; Kiffin, Roberta; Thoren, Fredrik Bergh; Hellstrand, Kristoffer; Martner, Anna

    2017-08-01

    Relapse of leukemia in the postchemotherapy phase contributes to the poor prognosis and survival in patients with acute myeloid leukemia (AML). In an international phase IV trial (ClinicalTrials.gov; NCT01347996), 84 patients with AML in first complete remission who had not undergone transplantation received immunotherapy with histamine dihydrochloride (HDC) and low-dose IL-2 with the aim of preventing relapse. The dynamics of myeloid cell counts and expression of activation markers was assessed before and after cycles of immunotherapy and correlated with clinical outcome in terms of relapse risk and survival. During cycles, a pronounced increase in blood eosinophil counts was observed along with a reduction in monocyte and neutrophil counts. A strong reduction of blood monocyte counts during the first HDC/IL-2 treatment cycle predicted leukemia-free survival. The HDC component of the immunotherapy exerts agonist activity at histamine type 2 receptors (H2Rs) that are expressed by myeloid cells. It was observed that the density of H2 R expression in blood monocytes increased during cycles of immunotherapy and that high monocyte H2R expression implied reduced relapse risk and improved overall survival. Several other activation markers, including HLA-DR, CD86, and CD40, were induced in monocytes and dendritic cells during immunotherapy but did not predict clinical outcome. In addition, expression of HLA-ABC increased in all myeloid populations during therapy. A low expression of HLA-ABC was associated with reduced relapse risk. These results suggest that aspects of myeloid cell biology may impact clinical benefit of relapse-preventive immunotherapy in AML. © Society for Leukocyte Biology.

  4. ANCA-Associated Glomerulonephritis : Risk Factors for Renal Relapse

    NARCIS (Netherlands)

    Goceroglu, Arda; Berden, Annelies E.; Fiocco, Marta; Flossmann, Oliver; Westman, Kerstin W.; Ferrario, Franco; Gaskin, Gill; Pusey, Charles D.; Hagen, E. Christiaan; Noel, Laure-Helene; Rasmussen, Niels; Waldherr, Ruediger; Walsh, Michael; Bruijn, Jan A.; Jayne, David R. W.; Bajema, Ingeborg M.; Stegeman, Coen

    2016-01-01

    Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors

  5. Improved outcome after relapse in children with acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Abrahamsson, Jonas; Clausen, Niels; Gustafsson, Göran

    2007-01-01

    In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were...... were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (

  6. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review.

    Science.gov (United States)

    Yanagisawa, Ryu; Nakazawa, Yozo; Sakashita, Kazuo; Saito, Shoji; Tanaka, Miyuki; Shiohara, Masaaki; Shimodaira, Shigetaka; Koike, Kenichi

    2016-01-01

    An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft-versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting. We will make further efforts to increase the efficacy.

  7. A phase I trial of flavopiridol in relapsed multiple myeloma.

    Science.gov (United States)

    Hofmeister, Craig C; Poi, Ming; Bowers, Mindy A; Zhao, Weiqiang; Phelps, Mitch A; Benson, Don M; Kraut, Eric H; Farag, Sherif; Efebera, Yvonne A; Sexton, Jennifer; Lin, Thomas S; Grever, Michael; Byrd, John C

    2014-02-01

    Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).

  8. Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Fuchs Mary

    2012-08-01

    Full Text Available Abstract Background This case report highlights the relevance of quantifying the BCR-ABL gene in cerebrospinal fluid of patients with suspected relapse of chronic myeloid leukemia in the central nervous system. Case presentation We report on a female patient with isolated central nervous system relapse of chronic myeloid leukemia (CML during peripheral remission after allogeneic hematopoietic stem cell transplantation. The patient showed a progressive cognitive decline as the main symptom. MRI revealed a hydrocephalus and an increase in cell count in the cerebrospinal fluid (CSF with around 50% immature blasts in the differential count. A highly elevated BCR-ABL/ ABL ratio was detected in the CSF, whilst the ratio for peripheral blood and bone marrow was not altered. On treatment of the malresorptive hydrocephalus with shunt surgery, the patient showed an initial cognitive improvement, followed by a secondary deterioration. At this time, the cranial MRI showed leukemic infiltration of lateral ventricles walls. Hence, intrathecal administration of cytarabine, methotrexate, and dexamethasone was initiated, which caused a significant decrease of cells in the CSF. Soon after, the patient demonstrated significant cognitive improvement with a good participation in daily activities. At a later time point, after the patient had lost the major molecular response of CML, therapy with dasatinib was initiated. In a further follow-up, the patient was neurologically and hematologically stable. Conclusions In patients with treated CML, the rare case of an isolated CNS blast crisis has to be taken into account if neurological symptoms evolve. The analysis of BCR-ABL in the CSF is a further option for the reliable detection of primary isolated relapse of CML in these patients.

  9. CNS metastasis from malignant uveal melanoma: a clinical and histopathological characterisation

    DEFF Research Database (Denmark)

    Holfort, S K; Lindegaard, J; Isager, P

    2008-01-01

    AIM: To characterise uveal melanoma that has metastasised to the central nervous system (CNS). METHODS: Review of 2365 patients constituting all patients diagnosed as having primary uveal melanoma in Denmark during the period 1943-1997. All patients with malignant uveal melanoma and metastasis...... to the CNS were identified. For each patient, clinical and histopathological data were gathered. RESULTS: Sixteen patients with CNS metastasis were identified. The median age was 58 years. The majority of CNS metastases were located in the frontal and parietal lobes. Eleven patients had widespread metastases....... Five patients had exclusively metastasis to the CNS. The average time from diagnosis of primary tumour to symptoms of CNS metastasis was 91 months. The average time from the initial CNS symptoms to death was 20 months. All tumours were composed of either mixed or spindle cells. The average largest...

  10. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries

    DEFF Research Database (Denmark)

    Oskarsson, Trausti; Söderhäll, Stefan; Arvidson, Johan

    2016-01-01

    Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic...... leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were...

  11. Mengapa Pengguna Narkoba pada Remaja Akhir Relapse?

    Directory of Open Access Journals (Sweden)

    Evi Afifah Hurriyati

    2010-10-01

    Full Text Available This research is to acknowledge causes why drug users in late adolescent, who had followed drug recovery program in drug rehabilitation centre, are relapsing at the time they came back to subject environment. This research’s background is supported with the increasing numbers of drug addictive users in Indonesia, especially in adolescent. The result of this research showed an uncondusive situation, such as conflict with parents (father when they got back to house environment, causes they are coping maladaptive, i.e. relapse. Conflict with father causes adolescent has negative perception towards social support from the father, and it effects their religious orientation and locus of control. For future research, it is suggested to do quantitative research so it can be gained measurable result statistically. 

  12. Teriflunomide in relapsing multiple sclerosis: therapeutic utility.

    Science.gov (United States)

    Freedman, Mark S

    2013-09-01

    Teriflunomide is an oral, once-daily disease-modifying therapy (DMT) approved in the USA, Australia, and Argentina for the treatment of relapsing forms of multiple sclerosis (RMS). Teriflunomide reversibly limits the expansion of activated T and B cells associated with the inflammatory process purportedly involved in multiple sclerosis pathogenesis, while preserving lymphocytes for routine immune surveillance. In an extensive clinical development program, teriflunomide demonstrated consistent benefits on both clinical and magnetic resonance imaging outcomes. In long-term studies, teriflunomide treatment was associated with low rates of relapse and disability progression for up to 8 years. The safety profile of teriflunomide has been well characterized, with adverse events generally mild to moderate in nature and infrequently leading to permanent treatment discontinuation. The evidence reviewed here indicates that teriflunomide is an effective addition to the current DMTs used to treat RMS.

  13. Predicting effects and risk of relapse into depression

    DEFF Research Database (Denmark)

    Gbyl, Krzysztof; Rosenberg, Raben; Larsson, Henrik Bo Wiberg

    Formål: Vi ønsker at undersøge hjernen hos patienter med svær depression før og efter elektrokonvulsiv terapi (ECT), samt ved en kontrol efter 6 måneder med det formål at: 1. undersøge hjernevævet så en evt. skadelig effekt af ECT-behandling kan udelukkes 2. belyse mekanismerne bag ECT for at finde...... prædiktorer for gunstige resultater, tidligt tilbagefald og for bivirkninger 3. undersøge omfanget af og baggrunden for påvirkningen af hukommelsesfunktionen Metode: I studiet planlægger vi at undersøge 60 patienter henvist til ECT på Psykiatrisk Center Glostrup, Amager og København pga. svær depression....... Desuden vha. den mest moderne MR-teknik at belyse om ECT kan skade hjernevævet. De nævnte prædiktorer vil muliggøre at behandlingen af de sværeste depressioner vil kunne forbedres og individualiseres i langt højere end i dag, hvorved sygdomsprognosen kan forbedres betydeligt. Vi forventer yderligere...

  14. The impact of residual symptoms on relapse and quality of life among Thai depressive patients

    Directory of Open Access Journals (Sweden)

    Hiranyatheb T

    2016-12-01

    Full Text Available Thanita Hiranyatheb,1 Daochompu Nakawiro,1 Tinakon Wongpakaran,2 Nahathai Wongpakaran,2 Putipong Bookkamana,3 Manee Pinyopornpanish,2 Nattha Saisavoey,4 Kamonporn Wannarit,4 Sirina Satthapisit,5 Sitthinant Tanchakvaranont6 1Department of Psychiatry, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 2Department of Psychiatry, Faculty of Medicine, 3Department of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai, 4Department of Psychiatry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 5Department of Psychiatry Khon Kaen Hospital, Khon Kaen, 6Department of Psychiatry, Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand Purpose: Residual symptoms of depressive disorder are major predictors of relapse of depression and lower quality of life. This study aims to investigate the prevalence of residual symptoms, relapse rates, and quality of life among patients with depressive disorder. Patients and methods: Data were collected during the Thai Study of Affective Disorder (THAISAD project. The Hamilton Rating Scale for Depression (HAMD was used to measure the severity and residual symptoms of depression, and EQ-5D instrument was used to measure the quality of life. Demographic and clinical data at the baseline were described by mean ± standard deviation (SD. Prevalence of residual symptoms of depression was determined and presented as percentage. Regression analysis was utilized to predict relapse and patients’ quality of life at 6 months postbaseline. Results: A total of 224 depressive disorder patients were recruited. Most of the patients (93.3% had at least one residual symptom, and the most common was anxiety symptoms (76.3%; 95% confidence interval [CI], 0.71–0.82. After 3 months postbaseline, 114 patients (50.9% were in remission and within 6 months, 44 of them (38.6% relapsed. Regression analysis showed that residual insomnia symptoms were significantly associated with these

  15. Teriflunomide in relapsing multiple sclerosis: therapeutic utility

    OpenAIRE

    Freedman, Mark S

    2013-01-01

    Teriflunomide is an oral, once-daily disease-modifying therapy (DMT) approved in the USA, Australia, and Argentina for the treatment of relapsing forms of multiple sclerosis (RMS). Teriflunomide reversibly limits the expansion of activated T and B cells associated with the inflammatory process purportedly involved in multiple sclerosis pathogenesis, while preserving lymphocytes for routine immune surveillance. In an extensive clinical development program, teriflunomide demonstrated consistent...

  16. Economic costs associated with an MS relapse

    LENUS (Irish Health Repository)

    O'Connell, K.

    2014-09-01

    This was an prospective audit composed of medical chart review and patient questionnaire. Relapses were stratified into 3 groups: low, moderate and high intensity. Age, gender, MS subtype, disease duration, expanded disability status scale (EDSS) score, disease modifying therapy (DMT) use and employment status were recorded. Direct costs included GP visits, investigations, clinic visit, consultations with medical staff, medication and admission costs. Indirect costs assessed loss of earnings, partner\\'s loss of earnings, childcare, meals and travel costs.

  17. Psychoeducational and family therapy in relapse prevention.

    Science.gov (United States)

    Goldstein, M J

    1994-01-01

    Recent shifts to briefer hospitalization and an emphasis on community care have emphasized the significance of patient-family interactions in this phase of treatment. Psychoeducational family programs designed to increase medication compliance and effectiveness in coping with stressors have been successful in reducing the risk of relapse in the first year following hospital discharge. Various models for family intervention are discussed and their strengths and weaknesses evaluated.

  18. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries

    DEFF Research Database (Denmark)

    Oskarsson, Trausti; Söderhäll, Stefan; Arvidson, Johan

    2016-01-01

    leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were......Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic...... included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5±3.4%, but 44.7±3.2% (P...

  19. Mediastinal Choriocarcinoma Masquerading as Relapsed Hodgkin Lymphoma

    Directory of Open Access Journals (Sweden)

    Selay Lam

    2011-10-01

    Full Text Available Primary mediastinal choriocarcinoma is a rare extragonadal germ cell malignancy. We describe the first case of a patient who developed mediastinal choriocarcinoma after treatment for Hodgkin lymphoma (HL. A 25-year-old man with classic HL, nodular sclerosis subtype, underwent treatment with splenectomy followed by radiation therapy. Unfortunately, his disease relapsed with a paraspinal mass, and he was subsequently treated with MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone alternating with ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine. He achieved a complete remission after 6 cycles. Ten years after treatment, the patient presented with a persistent cough, haemoptysis, right supraclavicular lymphadenopathy, and weight loss. His chest X-ray showed opacification of the lower right hemithorax with a widened mediastinum. Given unresponsiveness to several antibiotics and lack of evidence for lung volume loss, there were concerns over lung infiltration with relapsed lymphoma. Transbronchial fine needle aspiration biopsy suggested recurrence of his HL. MOPP alternating with ABVD was again given. Due to disease progression, brachytherapy as well as a cocktail of dexamethasone, cytarabine, and cisplatin were also tried. However, on a subsequent excisional lymph node biopsy, it turned out that the tumour was in fact choriocarcinoma and not relapsed HL. Unfortunately, despite aggressive therapy, the patient’s disease rapidly progressed, and he died within 2 weeks.

  20. Treatment of relapsed and refractory Hodgkin Lymphoma

    Science.gov (United States)

    von Tresckow, Bastian

    2017-01-01

    Despite the high first line cure rates in patients with Hodgkin Lymphoma (HL) still 10–20% of patients suffer from relapsed or refractory disease. High dose chemotherapy (HDCT) followed by autologous stem cell transplant (ASCT) is standard of care for suitable patients with relapsed or refractory HL and allows for cure in approximately 50%. Due to the poor prognosis of high risk patients even with HDCT and ASCT, consolidation strategies have been evaluated to improve the cure rates. For patients with recurrence after HDCT and ASCT, treatment is palliative in most cases. The anti CD30 antibody-drug conjugate brentuximab vedotin (BV) has been shown to induce high response rates in these patients; however, durable responses were reported in a small percentage of patients only. For carefully selected patients with multiple relapses, dose-reduced allogeneic transplant (RICallo) is a potentially curative option. The role of RICallo will have to be reevaluated in the era of anti-programmed death-1 (PD1) antibodies. PMID:27496309

  1. Endovascular transplantation of stem cells to the injured rat CNS

    Energy Technology Data Exchange (ETDEWEB)

    Lundberg, Johan; Soederman, Mikael; Andersson, Tommy; Holmin, Staffan [Karolinska University Hospital, Department of Clinical Neuroscience, Karolinska Institutet, Department of Neuroradiology, Stockholm (Sweden); Le Blanc, Katarina [Karolinska University Hospital, Department of Stem Cell Research, Karolinska Institutet, Department of Clinical Immunology, Stockholm (Sweden)

    2009-10-15

    Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p<0.01) and 5 days (p<0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases. (orig.)

  2. Impact of multiple sclerosis relapse: The NARCOMS participant perspective.

    Science.gov (United States)

    Nickerson, Molly; Cofield, Stacey S; Tyry, Tuula; Salter, Amber R; Cutter, Gary R; Marrie, Ruth Ann

    2015-05-01

    Acute relapses continue to be a significant aspect of multiple sclerosis (MS) on both the epidemiologic level and the individual patient level. Past work demonstrates residual disability from relapses as well as high patient-reported rates of ineffective relapse treatment. To better characterize the impact of MS relapses on the patient, a relapse-specific survey was administered through the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry to 1000 registry participants who had reported at least one relapse in the past 12 months. Thirty percent of respondents confirmed lack of relapse treatment efficacy at one month and at three months. Relapses also impacted socioeconomic measures; for individuals still going to school or working, more than half missed days and their average loss of school or work was 12.7 days. An impact on household tasks was reported by 68% of respondents. A healthcare facility such as a hospital, emergency room or urgent care center was utilized by 20.4% of respondents. The most common relapse symptoms were fatigue, weakness of the lower extremity, sensory symptoms, problems walking, and weakness of the upper extremity. Of the respondents who reported receiving corticosteroid treatment (53.3%), over half reported an adverse event. However, this was not a significant factor in dictating whether or not respondents would seek a different treatment on their next relapse, although 31% would choose a different treatment for their next relapse. Relapses continue to be an impactful experience that requires continued clinical attention. Improved follow-up from relapses and relapse treatment might be beneficial. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Phantom limb pain: a case of maladaptive CNS plasticity?

    Science.gov (United States)

    Flor, Herta; Nikolajsen, Lone; Staehelin Jensen, Troels

    2006-11-01

    Phantom pain refers to pain in a body part that has been amputated or deafferented. It has often been viewed as a type of mental disorder or has been assumed to stem from pathological alterations in the region of the amputation stump. In the past decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human studies and derive suggestions for innovative interventions aimed at alleviating phantom pain.

  4. Regenerating CNS myelin - from mechanisms to experimental medicines.

    Science.gov (United States)

    Franklin, Robin J M; Ffrench-Constant, Charles

    2017-11-16

    Although the core concept of remyelination - based on the activation, migration, proliferation and differentiation of CNS progenitors - has not changed over the past 20 years, our understanding of the detailed mechanisms that underlie this process has developed considerably. We can now decorate the central events of remyelination with a host of pathways, molecules, mediators and cells, revealing a complex and precisely orchestrated process. These advances have led to recent drug-based and cell-based clinical trials for myelin diseases and have opened up hitherto unrecognized opportunities for drug-based approaches to therapeutically enhance remyelination.

  5. Brain abscess with an unexpected finding: Actinomyces meyeri CNS infection

    DEFF Research Database (Denmark)

    Eiset, Andreas Halgreen; Thomsen, Marianne Kragh; Wejse, Christian

    Background: CNS infection caused by Actinomyces spp. is rare and the subtype Actinomyces meyeri even rarer. Risk factors include periodontal disease and alcohol overuse. We present a case report of a 54-year-old female with dental and lung foci. Case history: A female was hospitalised with tonic......-up. The source of infection was most likely periodontitis with spread to the lungs from aspiration or oropharyngeal secretion into the respiratory tract, alternatively from haematogenous spread. Conclusions: We report of the successful treatment of a cerebral abscess caused by A. meyeri with narrow spectrum...

  6. Probabilistic Approach to Generating MPOs and Its Application as a Scoring Function for CNS Drugs.

    Science.gov (United States)

    Gunaydin, Hakan

    2016-01-14

    Multiparameter optimization (MPO) scoring functions are popular tools for providing guidance on how to design desired molecules in medicinal chemistry. The utility of a new probabilistic MPO (pMPO) scoring function method and its application as a scoring function for CNS drugs are described in this letter. In this new approach, a minimal number of statistically determined empirical boundaries is combined with the probability distribution of the desired molecules to define desirability functions. This approach attempts to minimize the number of parameters that define MPO scores while maintaining a high level of predictive power. Results obtained from a test-set of orally approved drugs show that the pMPO approach described here can be used to separate desired molecules from undesired ones with accuracy comparable to a Bayesian model with the advantage of better human interpretability. The application of this pMPO approach for blood-brain barrier penetrant drugs is also described.

  7. Examining characteristics associated with quitting smoking during pregnancy and relapse postpartum.

    Science.gov (United States)

    Kia, Farnaaz; Tosun, Nicole; Carlson, Samantha; Allen, Sharon

    2017-11-10

    Smoking during pregnancy is a significant public health concern that can cause adverse health outcomes for both the mother and fetus. Studies have shown only 40% of women quit smoking during pregnancy, with more than half relapsing within 6months, and up to 90% relapsing within one year. This study investigates differences in demographics and smoking-related symptomatology between pregnant smokers and pregnant quitters, as well as factors associated with postpartum relapse. Data on pregnant smokers and pregnant quitters were obtained from two separate parent studies. Data on smoking demographics and smoking-related symptomatology were collected at screening visits. Compared to pregnant smokers, pregnant quitters had more favorable smoking characteristics (e.g., smoked fewer cigarettes per day, reported higher motivation for abstinence and less dependency). They also had more favorable relationship characteristics (e.g., were more likely to be married, less likely to have a significant other who smokes) and had less reproductive liability (e.g., fewer pregnancies, fewer children). In terms of symptomatology, pregnant quitters reported more positive affect, negative affect, physical symptoms and withdrawal but less craving. Predictors of postpartum relapse included increased maternal age, having a significant other who smokes and an increased likelihood of returning to smoking after pregnancy (self-reported prior to delivery). Several demographics and smoking-related symptomatology were significantly different between pregnant quitters and pregnant smokers. In addition, multiple factors predicting postpartum relapse were identified. This information can inform personalized interventions for high risk pregnant smokers and pregnant quitters at risk for postpartum relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Monoclonal Antibodies for Relapsing Multiple Sclerosis

    DEFF Research Database (Denmark)

    Blinkenberg, Morten; Soelberg Sørensen, Per

    2017-01-01

    leading to chronic central nervous system (CNS) demyelination, neural loss, and, finally, neurological disability. Although a number of disease-modifying treatments are available for the treatment of the inflammatory phase of MS, there is still a need for highly efficacious therapies with an acceptable...... safety profile in order to gain therapeutic control early in the disease course. Monoclonal antibodies have proven to be some of the most efficacious disease-modifying therapies in the field of MS, and recent developments in clinical research hold promise for new compounds fulfilling the need...

  9. Prediction

    CERN Document Server

    Sornette, Didier

    2010-01-01

    This chapter first presents a rather personal view of some different aspects of predictability, going in crescendo from simple linear systems to high-dimensional nonlinear systems with stochastic forcing, which exhibit emergent properties such as phase transitions and regime shifts. Then, a detailed correspondence between the phenomenology of earthquakes, financial crashes and epileptic seizures is offered. The presented statistical evidence provides the substance of a general phase diagram for understanding the many facets of the spatio-temporal organization of these systems. A key insight is to organize the evidence and mechanisms in terms of two summarizing measures: (i) amplitude of disorder or heterogeneity in the system and (ii) level of coupling or interaction strength among the system's components. On the basis of the recently identified remarkable correspondence between earthquakes and seizures, we present detailed information on a class of stochastic point processes that has been found to be particu...

  10. Residual sleep disturbance and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine

    Directory of Open Access Journals (Sweden)

    McGrath Patrick J

    2010-02-01

    Full Text Available Abstract Background Relapse of major depressive disorder (MDD is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia predict risk of relapse during the continuation and maintenance treatment of MDD. Methods A total of 570 patients with MDD were treated with open-label, flexible dose fluoxetine (range 20 to 60 mg; mean dose = 45.8 mg/day; SD = 15.1 for 12 weeks. Under double blind conditions, 262 patients who achieved clinical response were randomly assigned to continue fluoxetine or to switch to placebo for 52 weeks or until relapse. Residual sleep disturbance during the baseline visit of the double-blind phase was assessed using items 4, 5, 6 (insomnia and 22, 23, 24 (hypersomnia of the Hamilton Depression Rating Scale (HDRS. Survival analysis was utilized to determine the effect of residual sleep disturbance on risk of relapse. Results The severities of early (P > 0.05, middle (P > 0.05, late (P > 0.05, or total (P > 0.05 residual insomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Similarly, the severities of early bedtime (P > 0.05, oversleeping (P > 0.05, napping (P > 0.05, or total (P > 0.05 residual hypersomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Conclusion The present study did not identify the severity of residual sleep disturbance among fluoxetine responders to predict risk of MDD relapse. The size of our sample may have precluded us from identifying more modest effects of residual sleep disturbance on the risk of relapse in MDD patients. Future studies are needed to further explore the relationship between residual sleep disturbance and relapse in MDD. Trial Registration ClinicalTrials.gov Identifier: NCT00427128

  11. MATILDE chemotherapy regimen for primary CNS lymphoma: results at a median follow-up of 12 years.

    Science.gov (United States)

    Ferreri, Andrés J M; Ciceri, Fabio; Brandes, Alba A; Montanari, Mauro; Balzarotti, Monica; Spina, Michele; Ilariucci, Fiorella; Zaja, Francesco; Stelitano, Caterina; Bobbio, Flavio; Corazzelli, Gaetano; Baldini, Luca; Reni, Michele

    2014-04-15

    We report updated results at a median follow-up of 12 years of a phase II trial assessing first-line MATILDE chemotherapy and response-tailored radiotherapy in patients with primary CNS lymphomas (PCNSL). Forty-one HIV-negative patients (18-70 years; Eastern Cooperative Oncology Group performance status ≤3) with histologically confirmed PCNSL received 3 courses of MATILDE chemotherapy followed by whole-brain radiotherapy (WBRT). Chemotherapy activity was the primary endpoint. Overall response rate was 76% (95% confidence interval [CI] 63%-89%) after chemotherapy and 83% (95% CI 71%-95%) after chemotherapy ± radiotherapy. At a median follow-up of 144 months (range 47-153), 31 patients experienced an event: relapse in 24, progressive disease in 3, and toxic death in 4, with a 5-year progression-free survival of 24% ± 8%. Two patients experienced a late relapse (100 and 101 months). Nine patients are alive and disease-free, 8 of whom are alive at >10 years, with a 5-year overall survival of 30% ± 7%. At 10 years from diagnosis, no patient showed chronic hematologic and nonhematologic toxicities, with a Mini-Mental State Examination score of ≥29 in all cases but one. At a median follow-up of 12 years, MATILDE regimen followed by WBRT confirmed the previously reported survival plateau, which further proves its long-lasting efficacy with acceptable neurologic deficits. This study provides Class IV evidence that in patients with PCNSL, MATILDE chemotherapy followed by response-tailored radiotherapy increases the probability of disease remission at 12 years.

  12. Metallothionein Expression and Roles During Neuropathology in the CNS

    DEFF Research Database (Denmark)

    Penkowa, Milena

    2006-01-01

    /or IL-6-induced MT-I+II exert neuroprotective functions. To study MT-I+II roles in CNS, genetically modified mice with MT-I+II deficiency (MT-I+II knock-out (MT-KO) mice) or transgenic MT-I overexpression (TgMT mice) were applied along wildtype controls; as well as wildtype, and MT-KO mice receiving...... roles. Accordingly, MT-I+II reduce CNS activation of macrophages and lymphocytes including expression of proinflammatory cytokines IL-1b, IL-6, IL-12 and TNF-a. Moreover, MT-I+II are antioxidant and antiapoptotic factors counteracting reactive oxygen species (ROS)/oxidative stress, neurodegeneration...... supported by comparing various genotypes like GFAP-IL6 mice; MT-I+II deficient GFAP-IL6 (GFAP-IL6/MT-KO) mice; MT-I+II heterozygous GFAP-IL6 mice (GFAP-IL6-MT+/- mice); double-transgenic IL-6 and MT-I overexpressors (GFAP-IL6/TgMT mice); MT-KO mice; and TgMT mice. The IL-6 overexpressors are suitable...

  13. Rewiring the injured CNS: lessons from the optic nerve

    Science.gov (United States)

    Benowitz, Larry; Yin, Yuqin

    2008-01-01

    The optic nerve offers a number of advantages for investigating mechanisms that govern axon regeneration in the CNS. Although mature retinal ganglion cells (RGCs) normally show no ability to regenerate injured axons through the optic nerve, this situation can be partially reversed by inducing an inflammatory response in the eye. The secretion of a previously unknown growth factor, oncomodulin, along with co-factors, causes RGCs to undergo dramatic changes in gene expression and regenerate lengthy axons into the highly myelinated optic nerve. By themselves, strategies that counteract inhibitory signals associated with myelin and the glial scar are insufficient to promote extensive regeneration in this system. However, combinatorial treatments that activate neurons' intrinsic growth state and overcome inhibitory signals result in dramatic axon regeneration in vivo. Because of the ease of introducing trophic factors, soluble receptors, drugs, or viruses expressing any gene or small interfering RNA of interest into RGCs, this system is ideal for identifying intracellular signaling pathways, transcriptional cascades, and ligand-receptor interactions that enable axon regeneration to occur in the CNS and to develop means to augment this process. PMID:17610877

  14. Flaviviruses are neurotropic, but how do they invade the CNS?

    Science.gov (United States)

    Neal, J W

    2014-09-01

    Flaviruses (FV) are RNA viruses carried by mosquitoes. Neurological signs including acute encephalitis, meningitis and acute flaccid paralysis develop in a small percentage of infected individuals; long term sequlae are, Parkinsonism, dystonias and cognitive changes. FV neuroinfection is neurotropic involving subcortical nuclei (substantia nigra and thalamus) anterior horn neurons and neocortex. Glycosylation of the FV E envelope protein is one determinant of neuroinvasion, increasing both axonal and trans-epithelial transportation. Neutralizing antibodies against the E and NS proteins prevents FV uptake into several cell types, including axons. CD8+ T cells are vital for clearance of WNF infected cells from the CNS, whereas TLR-3 and TLR-7 mediated anti-virus response through increased serum inflammatory cytokines to disrupt the BBB providing infected leucocytes and free virus access to the CNS (so called Trojan horse) Cellular virus attachment factors, promoting FV cell entry are widely distributed and include DC-SIGN (that detects complex carbohydrate molecules); Glycosamino glycans (GAG), Heparan sulphate(HSPG) Semaphorin 7A, Low Density Lipid receptors (LDLR); these are not FV specific virus entry receptors. The FV also crosses epithelial and endothelial barriers by disrupting Tight Junction complexes to increase BBB permeability. This review describes the multiple pathways responsible for the neuroinvasive properties of the Flaviviruses. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  15. Simulation and mockup tests for developing TRR-II CNS

    Science.gov (United States)

    Lee, C. H.; Kawai, T.; Chan, Y. K.; Hong, W. T.; Lee, D. J.; Guung, T. C.; Lan, K. C.

    2002-01-01

    The Taiwan Research Reactor improvement and the utilization promotion project (TRR-II) with Cold Neutron Source (CNS) was carried out at Institute of Nuclear Energy Research. The CNS with a two-phase thermosiphon loop consists of an annular cylindrical moderator cell, a single moderator transfer tube, and a condenser. The self-regulating characteristics of a two-phase thermosiphon loop are investigated against variations of heat load. The experiments on the thermal-hydraulic characteristics have been performed using a full-scale mockup loop and a Freon-11 was used as a working fluid. Two cases were evaluated by the simulation and experiments. One case is an ORPHEE-type moderator cell in which an inner shell is open at the bottom, the other case is one with an inner cavity with no hole at the bottom but a vapor inlet opening at the uppermost part of the cavity. The flooding limitations, liquid level and void fraction in the moderator cell as a function of the initial Freon-11 inventory and the heat load are also reported.

  16. The Role of Rho GTPase Proteins in CNS Neuronal Migration

    Science.gov (United States)

    Govek, Eve-Ellen; Hatten, Mary E.; Van Aelst, Linda

    2011-01-01

    The architectonics of the mammalian brain arise from a remarkable range of directed cell migrations, which orchestrate the emergence of cortical neuronal layers and pattern brain circuitry. At different stages of cortical histogenesis, specific modes of cell motility are essential to the stepwise formation of cortical architecture. These movements range from interkinetic nuclear movements at the ventricular zone (VZ), to migrations of early-born, postmitotic polymorphic cells into the preplate, to the radial migration of precursors of cortical output neurons across the thickening cortical wall, and the vast, tangential migrations of interneurons from the basal forebrain into the emerging cortical layers. In all cases, acto-myosin motors act in concert with cell adhesion receptor systems to provide the force and traction needed for forward movement. As key regulators of actin and microtubule cytoskeletons, cell polarity, and adhesion, the Rho GTPases play a critical role in CNS neuronal migration. This review will focus on the different types of migration in the developing neocortex and cerebellar cortex, and the role of the Rho GTPases, their regulators and effectors in these CNS migrations, with particular emphasis on their involvement in radial migration. PMID:21557504

  17. The biology of CNS remyelination: the key to therapeutic advances.

    Science.gov (United States)

    Franklin, Robin J M; Kotter, Mark R

    2008-03-01

    Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets requires a detailed understanding of the cellular and molecular mechanisms of remyelination. A critical step in achieving effective remyelination is the differentiation of precursor cells into mature oligodendrocytes. In experimental models of demyelinating disease in aged animals, as well as in multiple sclerosis, such differentiation appears to be impaired. This is due, at least in part, to changes in environmental signals governing remyelination. In particular, myelin debris within lesions appears to contain powerful inhibitors of precursor cell differentiation. Efficient removal of myelin debris by macrophages may thus facilitate differentiation and permit successful remyelination of damaged axons. This may represent a promising therapeutic target for promoting remyelination in multiple sclerosis and thus limiting the accumulation of irreversible neurological disability.

  18. Risk factors for relapse to problem drinking among current and former US military personnel: a prospective study of the Millennium Cohort.

    Science.gov (United States)

    Williams, Emily C; Frasco, Melissa A; Jacobson, Isabel G; Maynard, Charles; Littman, Alyson J; Seelig, Amber D; Crum-Cianflone, Nancy F; Nagel, Anna; Boyko, Edward J

    2015-03-01

    Military service members may be prone to relapse to problem drinking after remission, given a culture of alcohol use as a coping mechanism for stressful or traumatic events associated with military duties or exposures. However, the prevalence and correlates of relapse are unknown. We sought to identify socio-demographic, military, behavioral, and health characteristics associated with relapse among current and former military members with remittent problem drinking. Participants in the longitudinal Millennium Cohort Study who reported problem drinking at baseline (2001-2003) and were remittent at first follow-up (2004-2006) were included (n=6909). Logistic regression models identified demographic, military service, behavioral, and health characteristics that predicted relapse (report of ≥1 past-year alcohol-related problem on the validated Patient Health Questionnaire) at the second follow-up (2007-2008). Sixteen percent of those with remittent problem drinking relapsed. Reserve/National Guard members compared with active-duty members (odds ratio [OR]=1.71, 95% confidence interval [CI]: 1.45-2.01), members separated from the military during follow-up (OR=1.46, 95% CI: 1.16-1.83), and deployers who reported combat exposure (OR=1.32, 95% CI: 1.07-1.62, relative to non-deployers) were significantly more likely to relapse. Those with multiple deployments were significantly less likely to relapse (OR=0.73, 95% CI: 0.58-0.92). Behavioral factors and mental health conditions also predicted relapse. Relapse was common and associated with military and non-military factors. Targeted intervention to prevent relapse may be indicated for military personnel in particular subgroups, such as Reservists, veterans, and those who deploy with combat exposure. Copyright © 2015. Published by Elsevier Ireland Ltd.

  19. Multiple Sclerosis Relapses: Epidemiology, Outcomes and Management. A Systematic Review.

    Science.gov (United States)

    Kalincik, Tomas

    2015-01-01

    Relapses (episodic exacerbations of neurological signs or symptoms) are a defining feature of relapsing-remitting multiple sclerosis (MS), the most prevalent MS phenotype. While their diagnostic value relates predominantly to the definition of clinically definite MS, their prognostic value is determined by their relatively high associated risk of incomplete remission resulting in residual disability. The mechanisms governing a relapse incidence are unknown, but numerous modifiers of relapse risk have been described, including demographic and clinical characteristics, many of which represent opportunities for improved disease management. Also relapse phenotypes have been associated with patient and disease characteristics and an individual predisposition to certain phenotypic presentations may imply individual neuroanatomical disease patterns. While immunomodulatory therapies and corticosteroids represent the mainstay of relapse prevention and acute management, respectively, their effect has only been partial and further search for more efficient relapse therapies is warranted. Other areas of research include pathophysiology and determinants of relapse incidence, recurrence and phenotypes, including the characteristics of the relapsing and non-relapsing multiple sclerosis variants and their responsiveness to therapies. © 2015 S. Karger AG, Basel.

  20. Clinical features, outcomes, and cerebrospinal fluid findings in adult patients with central nervous system (CNS) infections caused by varicella-zoster virus: comparison with enterovirus CNS infections.

    Science.gov (United States)

    Hong, Hyo-Lim; Lee, Eun Mi; Sung, Heungsup; Kang, Joong Koo; Lee, Sang-Ahm; Choi, Sang-Ho

    2014-12-01

    Varicella-zoster virus (VZV) is known to be associated with central nervous system (CNS) infections in adults. However, the clinical characteristics of VZV CNS infections are not well characterized. The aim of this study was to compare the clinical manifestations, outcomes, and cerebrospinal fluid (CSF) findings in patients with VZV CNS infections with those in patients with enterovirus (EV) CNS infections. This retrospective cohort study was performed at a 2,700-bed tertiary care hospital. Using a clinical microbiology computerized database, all adults with CSF PCR results positive for VZV or EV that were treated between January 1999 and February 2013 were identified. Thirty-eight patients with VZV CNS infection and 68 patients with EV CNS infection were included in the study. Compared with the EV group, the median age in the VZV group was higher (VZV, 35 years vs. EV, 31 years; P = 0.02), and showed a bimodal age distribution with peaks in the third and seventh decade. Encephalitis was more commonly encountered in the VZV group (VZV, 23.7% vs. EV, 4.4%; P = 0.01). The median lymphocyte percentage in the CSF (VZV, 81% vs. EV, 36%; P < 0.001) and the CSF protein level (VZV, 100 mg/dl vs. EV, 46 mg/dl; P < 0.001) were higher in the VZV group. Compared with patients with EV CNS infection, patients with VZV CNS infection developed encephalitis more often and exhibited more intense inflammatory reaction. Nevertheless, both VZV and EV CNS infections were associated with excellent long-term prognosis. © 2014 Wiley Periodicals, Inc.

  1. Callosal Disconnection Syndrome Associated with Relapsing Polychondritis.

    Science.gov (United States)

    Baba, Toru; Kanno, Shigenori; Shijo, Tomomi; Nishio, Yoshiyuki; Iizuka, Osamu; Kamimura, Naoto; Ishii, Tomonori; Mori, Etsuro

    2016-01-01

    Relapsing polychondritis (RP) is a rare inflammatory disorder of the cartilagenous structures, and it sometimes involves the central nervous system. Encephalitis associated with RP causes a wide variety of symptoms according to the affected sites. We herein report the first case of 72-year-old right-handed man who developed acute meningoencephalitis associated with RP involving the corpus callous. After immunosuppressive therapy, his symptoms dramatically improved, but difficulty in performing bimanual movements with occasional diagonistic dyspraxia in his right hand remained. Because callosal signs are easily missed, especially in acute settings, it would be useful to know that RP can sometimes cause callosal disconnection syndrome.

  2. Recent developments in animal models of drug relapse.

    Science.gov (United States)

    Marchant, Nathan J; Li, Xuan; Shaham, Yavin

    2013-08-01

    Drug craving and relapse to drug use during abstinence are defining features of addiction. Evidence indicates that drug craving and relapse in humans are often provoked by acute exposure to the self-administered drug, drug-associated cues, or stress. During the last two decades, this clinical scenario has been primarily studied at the preclinical level using the classical reinstatement model. However, a single preclinical model cannot capture the complicated nature of human drug relapse. Therefore, more recently, we and others have developed several other models to study different facets of human drug relapse. In this review, we introduce and discuss recent findings from these other relapse models, including incubation of drug craving, reacquisition and resurgence models, and punishment-based and conflict-based relapse models. Published by Elsevier Ltd.

  3. Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders

    Directory of Open Access Journals (Sweden)

    Eric eSchadt

    2014-12-01

    Full Text Available A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease (AD, and the psychiatric disorder schizophrenia (SZ, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature

  4. Expression of p-AKT characterizes adenoid cystic carcinomas of head and neck with a higher risk for tumor relapses

    Directory of Open Access Journals (Sweden)

    Müller-Hermelink Hans-Konrad

    2009-06-01

    Full Text Available Abstract Background Adenoid cystic carcinomas are rare tumors with an indolent clinical course, but frequent local relapses. The identification of tumors with a higher relapse risk seems to be interesting. Hence we investigated parameters of glucose metabolism, which were found associated with poor prognosis in other malignancies. Methods Specimen of 29 patients were investigated immunohistochemically with antibodies against p-AKT, TKTL-1 (transketolase-like 1, M2PK (M2 pyruvate kinase, and GLUT-1. Proliferation was investigated by staining with Ki67. The tumors were located at the major or minor salivary glands. Only the typical cribriform subtype was investigated. The initial tumor stage was pT1 or pT2. Results Expression of p-AKT was significantly (P = 0.036 associated with a higher relapse risk in multivariate analysis. Low expression of M2PK was non-significantly (P = 0.065 predictive for a higher risk. TKTL-1 and GLUT-1 were expressed in the majority of cases, albeit not associated with relapse risk. Conclusion Adenoid cystic carcinomas positive for p-AKT show a higher relapse risk. However, other parameters of glucose metabolism investigated here or proliferation (Ki67 were not predictive in this entity. Our findings demonstrate a possible background for therapeutic approaches targeting the inhibition of PI3K/AKT pathway.

  5. Integrity of Literature on Expressed Emotion and Relapse in Patients with Schizophrenia Verified by a p-Curve Analysis.

    Science.gov (United States)

    Weintraub, Marc J; Hall, Daniel L; Carbonella, Julia Y; Weisman de Mamani, Amy; Hooley, Jill M

    2017-06-01

    There is growing concern that much published research may have questionable validity due to phenomena such as publication bias and p-hacking. Within the psychiatric literature, the construct of expressed emotion (EE) is widely assumed to be a reliable predictor of relapse across a range of mental illnesses. EE is an index of the family climate, measuring how critical, hostile, and overinvolved a family member is toward a mentally ill patient. No study to date has examined the evidential value of this body of research as a whole. That is to say, although many studies have shown a link between EE and symptom relapse, the integrity of the literature from which this claim is derived has not been tested. In an effort to confirm the integrity of the literature of EE predicting psychiatric relapse in patients with schizophrenia, we conducted a p-curve analysis on all known studies examining EE (using the Camberwell Family Interview) to predict psychiatric relapse over a 9- to 12-month follow-up period. Results suggest that the body of literature on EE is unbiased and has integrity, as there was a significant right skew of p-values, a nonsignificant left skew of p-values, and a nonsignificant test of flatness. We conclude that EE is a robust and valuable predictor of symptom relapse in schizophrenia. © 2016 Family Process Institute.

  6. GSK-3 inhibitors: preclinical and clinical focus on CNS

    Directory of Open Access Journals (Sweden)

    Hagit eEldar-Finkelman

    2011-10-01

    Full Text Available Inhibiting glycogen synthase kinase-3 (GSK-3 activity via pharmacological intervention has become an important target for treating neurodegenerative and psychiatric disorders. The reported GSK-3 inhibitors are of diverse chemotypes and mechanisms of action that include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate-competitive inhibitors. Here we describe the variety of GSK-3 inhibitors with a specific emphasis on their biological activities in neurons and neurological disorders. We further highlight our current progress in the development of non-ATP-competitive inhibitors of GSK-3.The available data raises the hope that one or more of these drug design approaches will prove successful at stabilizing or even reversing the aberrant neuropathology and cognitive deficits of certain CNS disorders.

  7. Gene therapy for CNS diseases – Krabbe disease

    Directory of Open Access Journals (Sweden)

    Mohammad A. Rafi

    2016-06-01

    Full Text Available This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases.

  8. Resveratrol Neuroprotection in Stroke and Traumatic CNS injury

    Science.gov (United States)

    Lopez, Mary; Dempsey, Robert J; Vemuganti, Raghu

    2015-01-01

    Resveratrol, a stilbene formed in many plants in response to various stressors, elicits multiple beneficial effects in vertebrates. Particularly, resveratrol was shown to have therapeutic properties in cancer, atherosclerosis and neurodegeneration. Resveratrol-induced benefits are modulated by multiple synergistic pathways that control oxidative stress, inflammation and cell death. Despite the lack of a definitive mechanism, both in vivo and in vitro studies suggest that resveratrol can induce a neuroprotective state when administered acutely or prior to experimental injury to the CNS. In this review, we discuss the neuroprotective potential of resveratrol in stroke, traumatic brain injury and spinal cord injury, with a focus on the molecular pathways responsible for this protection. PMID:26277384

  9. A map of taste neuron projections in the Drosophila CNS

    Science.gov (United States)

    KWON, JAE YOUNG; DAHANUKAR, ANUPAMA; WEISS, LINNEA A; CARLSON, JOHN R

    2014-01-01

    We provide a map of the projections of taste neurons in the CNS of Drosophila. Using a collection of 67 GAL4 drivers representing the entire repertoire of Gr taste receptors, we systematically map the projections of neurons expressing these drivers in the thoracico-abdominal ganglion and the suboesophageal ganglion (SOG). We define 9 categories of projections in the thoracico-abdominal ganglia and 10 categories in the SOG. The projection patterns are modular, and can be interpreted as combinations of discrete pattern elements. The elements can be interpreted in terms of the taste organ from which the projections originate, the structures from which they originate, and the quality of taste information that they represent. The extensive diversity in projection patterns provides an anatomical basis for functional diversity in responses elicited by different taste stimuli. PMID:25116611

  10. Radioprotection of mouse CNS endothelial cells in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Lyubimova, N.; Coultas, P.; Martin, R. [Peter McCallum Cancer Institute, Melbourne, VIC (Australia)

    1996-12-31

    Full text: Radioprotection using the minor groove binding DNA ligand Hoechst 33342 has been demonstrated in vitro, and more recently in vivo, in mouse lung. Intravenous administration was used for the lung studies, and both endothelial and alveolar epithelial cells-showed good up-take. Radiation damage to the endothelial cell population has also been postulated as important in late developing radionecrosis of spinal cord and brain. Endothelial cell density in brain can be readily determined by a fluorescent-histochemical technique. Treatment with a monoamine oxidase inhibitor and subsequent injection with L-DOPA results in an accumulation of dopamine (DA) in CNS endothelial cells. DA is converted to a fluorophore by exposure to paraformaldehyde, and cell numbers assayed by fluorescence microscopy. Earlier studies used this technique to monitor post-irradiation changes in endothelial cell density in rodent brain and showed the loss, within 24 hours, of a sensitive subpopulation comprising about 15% of the endothelial cells. Ten minutes after intravenous injection of Hoechst 33342 (80mg/kg) the ligand is confined by its limited penetration to the endothelial cells in mouse brain. When we irradiated at this time, there was protection against early endothelial cell loss. Ablation of the sensitive subpopulation in unprotected mice takes place over a dose range of 1 to 3 Gy {gamma}-rays, but doses between 12 to 20 Gy are required in the presence of ligand. This protection equates to a very high dose modification factor of about 7 and possibly reflects a suppression of apoptosis in the sensitive endothelial subpopulation. The extent to which there is enhanced survival in the endothelial population as a whole and how the observed protection affects late CNS necrosis development has yet to be determined. However present results clearly show potential for the use of DNA-binding radioprotectors with limited penetration for investigations into the relative significance of

  11. Preliminary Results of Management for Primary CNS Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Seung Do; Chang, Hye Sook; Choi, Eun Kyong [Ulsan University College of Medicine, Seoul (Korea, Republic of)

    1993-06-15

    From October 1989 to March 1992, ten patients diagnosed as primary central nervous system(CNS) lymphoma were treated with radiation therapy at Asan Medical Center. To obtain pathologic diagnosis, five patients had stereotactic biopsy and the others underwent craniotomy and tumor removal. According to the classification by International Working Formulation, seven of 10 patients showed diffuse large cell types and the remaining 3 had diffuse mixed cell types. Computed tomographic scans of the brain disclosed solitary (6 cases) or multiple (4 cases) intracranial lesions. All patients received 4000cGy/20 fx to the whole brain followed by an additional 2000cGy/10 fx boost to the primary lesion. Six patients with initial cerebrospinal fluid (CSF) involvement were treated with whole brain irradiation and intrathecal Methotrexate(IT-MTX) chemotherapy. One of them received an additional spinal irradiation after 3 cycles of IT-MTX chemotherapy because of MTX induced arachnoiditis. One patient received 3 cycles of systemic chemotherapy prior to radiation therapy and one received 5 cycles of salvage chemotherapy for recurrence. With a median follow up time of 8 months, all patients were followed from 7 to 26 months. Radiologically seven patients showed complete remission and the remaining three showed partial remission at one month after radiotherapy. The 1 and 2 year survival rate was 86% and 69% respectively. Until now, two patients expired at 7 and 14 months. These patients developed extensive CSF seeding followed by local failure. Considering initial good response to radiation therapy and low incidence of extraneural dissemination in primary CNS lymphoma, we propose to increase total tumor dose to the primary lesion by hyperfractionated radiotherapy or stereotactic radiosurgery. For the patients with CSF involvement at diagnosis, we propose craniospinal irradiation with IT MTX chemotherapy.

  12. CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes.

    Science.gov (United States)

    Bechler, Marie E; Byrne, Lauren; Ffrench-Constant, Charles

    2015-09-21

    Since Río-Hortega's description of oligodendrocyte morphologies nearly a century ago, many studies have observed myelin sheath-length diversity between CNS regions. Myelin sheath length directly impacts axonal conduction velocity by influencing the spacing between nodes of Ranvier. Such differences likely affect neural signal coordination and synchronization. What accounts for regional differences in myelin sheath lengths is unknown; are myelin sheath lengths determined solely by axons or do intrinsic properties of different oligodendrocyte precursor cell populations affect length? The prevailing view is that axons provide molecular cues necessary for oligodendrocyte myelination and appropriate sheath lengths. This view is based upon the observation that axon diameters correlate with myelin sheath length, as well as reports that PNS axonal neuregulin-1 type III regulates the initiation and properties of Schwann cell myelin sheaths. However, in the CNS, no such instructive molecules have been shown to be required, and increasing in vitro evidence supports an oligodendrocyte-driven, neuron-independent ability to differentiate and form initial sheaths. We test this alternative signal-independent hypothesis--that variation in internode lengths reflects regional oligodendrocyte-intrinsic properties. Using microfibers, we find that oligodendrocytes have a remarkable ability to self-regulate the formation of compact, multilamellar myelin and generate sheaths of physiological length. Our results show that oligodendrocytes respond to fiber diameters and that spinal cord oligodendrocytes generate longer sheaths than cortical oligodendrocytes on fibers, co-cultures, and explants, revealing that oligodendrocytes have regional identity and generate different sheath lengths that mirror internodes in vivo. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. CNS safety pharmacology: A focus on cognitive functions.

    Science.gov (United States)

    Hernier, Anne Marie; Froger-Colléaux, Christelle; Castagné, Vincent

    2016-01-01

    The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint. The following procedures provide an index of the ability of substances to induce cognitive deficits in rodents. In the passive avoidance (PA) test, rats receiving an electric shock show on a later occasion an avoidance of the shock-associated environment. In the social recognition (SR) test, rats recognize familiar congeners. In the Morris water maze (MWM) test, rats placed into a tank containing water learn to find an invisible escape platform using extra-maze visual cues. In the delayed alternation (DA) test, rats placed in a Skinner box learn to alternate their pressing behavior between two levers in order to obtain food rewards. In the operant reversal (OR) test, rats adapt their behavior following a change of the reinforcement rule. Standard reference agents were used to confirm that the different assays were able to detect pharmacologically induced cognitive impairments. Diazepam decreased associative memory performances in the PA test. MK-801-induced memory deficits in SR. Haloperidol increased escape latencies in the MWM test. Scopolamine decreased the number of correct responses in the DA test, and nicotine decreased the number of correct responses in the OR test. The relationship between the doses administered and the effects observed was also evaluated. Cognitive assays may provide utility in determining potential undesirable effects or discharging perceived risks with novel CNS drugs under

  14. The Gut-Brain Axis, BDNF, NMDA and CNS Disorders.

    Science.gov (United States)

    Maqsood, Raeesah; Stone, Trevor W

    2016-11-01

    Gastro-intestinal (GI) microbiota and the 'gut-brain axis' are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-D-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders.

  15. Identification of 42 Genes Linked to Stage II Colorectal Cancer Metastatic Relapse

    Directory of Open Access Journals (Sweden)

    Rabeah A. Al-Temaimi

    2016-04-01

    Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer mortality. Metastasis remains the primary cause of CRC death. Predicting the possibility of metastatic relapse in early-stage CRC is of paramount importance to target therapy for patients who really need it and spare those with low-potential of metastasis. Ninety-six stage II CRC cases were stratified using high-resolution array comparative genomic hybridization (aCGH data based on a predictive survival algorithm and supervised clustering. All genes included within the resultant copy number aberrations were each interrogated independently at mRNA level using CRC expression datasets available from public repositories, which included 1820 colon cancers, and 167 normal colon tissues. Reduced mRNA expression driven by copy number losses and increased expression driven by copy number gains revealed 42 altered transcripts (29 reduced and 13 increased transcripts associated with metastatic relapse, short disease-free or overall survival, and/or epithelial to mesenchymal transition (EMT. Resultant genes were classified based on gene ontology (GO, which identified four functional enrichment groups involved in growth regulation, genomic integrity, metabolism, and signal transduction pathways. The identified 42 genes may be useful for predicting metastatic relapse in stage II CRC. Further studies are necessary to validate these findings.

  16. Improved brain uptake of peptide-based CNS drugs via alternative routes of administrations of its nanocarrier delivery systems: a promising strategy for CNS targeting delivery of peptides.

    Science.gov (United States)

    Qian, Shuai; Wang, Qianwen; Zuo, Zhong

    2014-11-01

    Recently, developing peptide-based drugs to treat CNS diseases has gained increasing attention in both academics and pharmaceutical industry. However, targeting delivery of peptides to brain is one of the most challenging problems faced in the treatment of CNS diseases. After explaining the brain barriers limiting the delivery of peptides, the current review focuses on summarizing the most promising approaches for the enhancement of peptide and brain uptake, including delivery via alternative routes of administrations or using nanocarriers or intranasal administration of nanocarriers loaded with peptide. In addition, the biopharmaceutic, pharmacokinetic and pharmacodynamic details of several successful peptide-based CNS drugs are highlighted. Although using nanocarriers or delivery via alternative routes could improve to a certain extent the brain uptake of peptides, the magnitude of changes remains moderate. Alternatively, intranasal administration of nanocarriers loaded with peptide has been demonstrated to be an effective approach for CNS-targeted delivery of peptides.

  17. Disability, body image and sports/physical activity in adult survivors of childhood CNS tumors: population-based outcomes from a cohort study.

    Science.gov (United States)

    Boman, Krister K; Hörnquist, Lina; De Graaff, Lisanne; Rickardsson, Jenny; Lannering, Birgitta; Gustafsson, Göran

    2013-03-01

    Childhood CNS tumor survivors risk health and functional impairments that threaten normal psychological development and self-perception. This study investigated the extent to which health and functional ability predict adult survivors' body image (BI) and self-confidence regarding sports and physical activity. The study cohort covered 708 eligible ≥ 18 year old CNS tumor survivors, and data from 528 (75 %) were analyzed. Disability was estimated using the Health Utilities Index™ Mark2/3, a multidimensional self-report instrument. Physical self-confidence in terms of BI and sports/physical activity-related self-confidence (SPAS) were assessed using the BI and the Sports/Athletics modules of a standardized self-report assessment scale. In adjusted regression models, global health and functional status (GHFS) predicted BI (B = 0.94, 95 % CI 0.69-1.19) and SPAS (B = 0.79, 95 % CI 0.55-1.04). Emotion and pain, and to a lesser degree cognition, speech and vision disability, were associated with poorer BI and SPAS. Gender, sub-diagnosis, and time since diagnosis influenced the relationship between health status and physical self-confidence outcomes. Females had poorer GHFS, BI and SPAS than males. Decreased health and functional ability following childhood CNS cancer intrudes on physical self-confidence, with females being at heightened risk for both disability and negative self-confidence. Identified disability and gender-related risk calls for a follow-up plan that integrates treatment of psychological sequelae in lifetime monitoring of childhood CNS tumor survivors to restore and protect self-image and self-confidence, essential mental health correlates. An expanded plan should recognize the need for such services, optimizing life-long quality of survival for CNS tumor survivors.

  18. Obesity as the initial manifestation of central nervous system relapse of acute lymphoblastic leukemia: case report and literature review.

    Science.gov (United States)

    Zhang, Li-Dan; Li, Yan-Hong; Ke, Zhi-Yong; Huang, Li-Bin; Luo, Xue-Qun

    2012-01-01

    A 6-year-old boy with acute lymphoblastic leukemia in remission experienced hyperphagia, obesity, and emotional disorders. Cytomorphologic examination of cerebral spinal fluid (CSF) and cranial MRI did not help in differentiating between central nervous system leukemia (CNSL) and other CNS diseases including tuberculosis in this boy. Flow cytometric CSF analysis on repeated lumber puncture detected lymphoblasts, while microscopic CSF examination did not definitively show relapse disease. The diagnosis of CNSL was thus made and confirmed by the response to leukemia treatment. Obesity can be the first manifestation of CNSL and the diagnosis can be challenging. A combination of CSF cytomorphology, CSF flow cytometry, and cranial MRI can be useful in the diagnosis of the disease. Two mechanisms of CNSL-related obesity are discussed based on the literature review.

  19. Obesity as the initial manifestation of central nervous system relapse of acute lymphoblastic leukemia: Case report and literature review

    Directory of Open Access Journals (Sweden)

    Li-Dan Zhang

    2012-01-01

    Full Text Available A 6-year-old boy with acute lymphoblastic leukemia in remission experienced hyperphagia, obesity, and emotional disorders. Cytomorphologic examination of cerebral spinal fluid (CSF and cranial MRI did not help in differentiating between central nervous system leukemia (CNSL and other CNS diseases including tuberculosis in this boy. Flow cytometric CSF analysis on repeated lumber puncture detected lymphoblasts, while microscopic CSF examination did not definitively show relapse disease. The diagnosis of CNSL was thus made and confirmed by the response to leukemia treatment. Obesity can be the first manifestation of CNSL and the diagnosis can be challenging. A combination of CSF cytomorphology, CSF flow cytometry, and cranial MRI can be useful in the diagnosis of the disease. Two mechanisms of CNSL-related obesity are discussed based on the literature review.

  20. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis.

    Science.gov (United States)

    Tremlett, Helen; van der Mei, Ingrid A F; Pittas, Fotini; Blizzard, Leigh; Paley, Glenys; Mesaros, Desiree; Woodbaker, Richard; Nunez, Manuel; Dwyer, Terence; Taylor, Bruce V; Ponsonby, Anne-Louise

    2008-01-01

    Monthly variation in multiple sclerosis (MS) relapses has been found. The relationship between seasonal environmental factors, infections, serum vitamin D [25(OH)D] and MS relapses is undetermined. We prospectively followed a population-based cohort of relapsing-remitting (RR) MS patients in Southern Tasmania for a mean 2.3 years (January 2002-April 2005). Associations between monthly ambient environmental factors, estimated serum 25(OH)D, upper respiratory tract (URT) infections and relapse rates were examined using weighted Pearson's correlation and linear regression. Of 199 definite MS patients, 142 had RRMS. The lowest relapse rate of 0.5 per 1,000 days (95% CI: 0.2-1.3) occurred in February (mid-late summer) versus the March-January RR of 1.1 per 1,000 days (95% CI: 0.9-1.3; p = 0.018, weighted regression). Monthly relapse rates correlated with: (1) prior erythemal ultraviolet radiation (EUV): lagged 1.5 months, r = -0.32, p = 0.046; (2) URT infection rate: no lag, r = 0.39, p = 0.014; (3) 25(OH)D: no lag, r = -0.31, p = 0.057. The association between URT infections and relapses was reduced after adjustment for monthly EUV. Relapse rates were inversely associated with EUV and serum 25(OH)D levels and positively associated with URT infections. The demonstrated lag between EUV but not 25(OH)D and relapse rates is consistent with a role for EUV-generated 25(OH)D in the alteration of relapse rates. Future work on the association between URT infections and relapses should be considered in the context of ultraviolet radiation and vitamin D. Copyright 2008 S. Karger AG, Basel.

  1. Identification of Sare0718 as an alanine-activating adenylation domain in marine actinomycete Salinispora arenicola CNS-205.

    Science.gov (United States)

    Xia, Sisi; Ma, Yanlin; Zhang, Wei; Yang, Yi; Wu, Shaowen; Zhu, Minzhe; Deng, Lingfu; Li, Bing; Liu, Zhonglai; Qi, Chao

    2012-01-01

    Amino acid adenylation domains (A domains) are critical enzymes that dictate the identity of the amino acid building blocks to be incorporated during nonribosomal peptide (NRP) biosynthesis. NRPs represent a large group of valuable natural products that are widely applied in medicine, agriculture, and biochemical research. Salinispora arenicola CNS-205 is a representative strain of the first discovered obligate marine actinomycete genus, whose genome harbors a large number of cryptic secondary metabolite gene clusters. In order to investigate cryptic NRP-related metabolites in S. arenicola CNS-205, we cloned and identified the putative gene sare0718 annotated "amino acid adenylation domain". Firstly, the general features and possible functions of sare0718 were predicted by bioinformatics analysis, which suggested that Sare0718 is a soluble protein with an AMP-binding domain contained in the sequence and its cognate substrate is L-Val. Then, a GST-tagged fusion protein was expressed and purified to further explore the exact adenylation activity of Sare0718 in vitro. By a newly mentioned nonradioactive malachite green colorimetric assay, we found that L-Ala but not L-Val is the actual activated amino acid substrate and the basic kinetic parameters of Sare0718 for it are K(m) = 0.1164±0.0159 (mM), V(max) = 3.1484±0.1278 (µM/min), k(cat) = 12.5936±0.5112 (min(-1)). By revealing the biochemical role of sare0718 gene, we identified an alanine-activating adenylation domain in marine actinomycete Salinispora arenicola CNS-205, which would provide useful information for next isolation and function elucidation of the whole cryptic nonribosomal peptide synthetase (NRPS)-related gene cluster covering Sare0718. And meanwhile, this work also enriched the biochemical data of A domain substrate specificity in newly discovered marine actinomycete NRPS system, which bioinformatics prediction will largely depend on.

  2. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma

    DEFF Research Database (Denmark)

    Andersen, Niels S; Pedersen, Lone B; Laurell, Anna

    2009-01-01

    PURPOSE: Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell...

  3. The Circulating Treg/Th17 Cell Ratio Is Correlated with Relapse and Treatment Response in Pulmonary Sarcoidosis Patients after Corticosteroid Withdrawal.

    Directory of Open Access Journals (Sweden)

    Yongzhe Liu

    Full Text Available Pulmonary sarcoidosis is an immune-mediated disease, and some patients can be effectively treated with corticosteroids. However, nearly half of all sarcoidosis patients relapse after corticosteroid withdrawal. Different subsets of CD4+ helper T cells participate in the immunopathogenesis of sarcoidosis. Thus, the aims of our study were to investigate whether the circulating subsets of CD4+ helper T cells were associated with sarcoidosis relapse and with its remission after retreatment. Additionally, we identified a useful biomarker for predicting the relapse and remission of sarcoidosis patients.Forty-two patients were enrolled in the present study who had previously been diagnosed with pulmonary sarcoidosis and treated with corticosteroids. The patients were allocated into either a stable group if they exhibited sustained remission (n = 22 or a relapse group if they experienced clinical or radiological recurrence after treatment withdrawal (n = 20. Peripheral blood cells were collected from these patients and analyzed to determine the frequencies of subsets of circulating CD4+ helper T cells by flow cytometry. The patients in the relapse group were retreated with corticosteroids and immunosuppressive agents and were then reevaluated to determine the frequencies of dynamic subsets of circulating CD4+ helper T cells after remission.The frequencies of circulating Tregs were significantly increased concomitant with a decrease in the circulating Th17 cell frequency in the relapsed patients compared with the stable patients. The Treg/Th17 ratio was negatively correlated with sarcoidosis activity and was sensitive to retreatment. In addition, the percentage of isolated CD45RO+Ki67+ Tregs was higher in the patients who were stable and in those who recovered after retreatment than in those who relapsed.An imbalance between Tregs and Th17 cells is associated with pulmonary sarcoidosis relapse after corticosteroid withdrawal. The circulating Treg/Th17

  4. Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients.

    Science.gov (United States)

    Beck, Anne; Wüstenberg, Torsten; Genauck, Alexander; Wrase, Jana; Schlagenhauf, Florian; Smolka, Michael N; Mann, Karl; Heinz, Andreas

    2012-08-01

    In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. Subsequent relapsers displayed increased brain atrophy in brain areas associated with

  5. Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption

    NARCIS (Netherlands)

    ten Kulve, Jennifer S.; Veltman, Dick J.; van Bloemendaal, Liselotte; Groot, Paul F. C.; Ruhe, Henricus G.; Barkhof, Frederik; Diamant, Michaela; Ijzerman, Richard G.

    Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using

  6. relapsing fever, a disappearing cause of fever and maternal death

    African Journals Online (AJOL)

    2013-04-01

    Apr 1, 2013 ... by various Borrelia spirochetes transmitted either by lice (epidemic relapsing fever) or ticks (endemic relapsing fever, caused by Borrelia Duttoni). Clinically, these spirochetes all produce an undulating febrile disease in humans, with signs and symptoms often indistinguishable from those of malaria (3,4) .

  7. Louseborne Relapsing Fever among East African Refugees, Italy, 2015.

    Science.gov (United States)

    Lucchini, Anna; Lipani, Filippo; Costa, Cecilia; Scarvaglieri, Mariaelisabetta; Balbiano, Rosanna; Carosella, Sinibaldo; Calcagno, Andrea; Audagnotto, Sabrina; Barbui, Anna Maria; Brossa, Silvia; Ghisetti, Valeria; Dal Conte, Ivano; Caramello, Pietro; Di Perri, Giovanni

    2016-02-01

    During June 9-September 30, 2015, five cases of louseborne relapsing fever were identified in Turin, Italy. All 5 cases were in young refugees from Somalia, 2 of whom had lived in Italy since 2011. Our report seems to confirm the possibility of local transmission of louse-borne relapsing fever.

  8. Louseborne relapsing fever among East African refugees, Italy, 2015

    OpenAIRE

    Lucchini, Anna; Lipani, Filippo; Costa, Cecilia; Scarvaglieri, Mariaelisabetta; Balbiano, Rosanna; Carosella, Sinibaldo; Calcagno, Andrea; Audagnotto, Sabrina; Barbui, Anna Maria; Brossa, Silvia; Ghisetti, Valeria; Dal Conte, Ivano; Caramello, Pietro; di Perri, Giovanni

    2016-01-01

    During June 9?September 30, 2015, five cases of louseborne relapsing fever were identified in Turin, Italy. All 5 cases were in young refugees from Somalia, 2 of whom had lived in Italy since 2011. Our report seems to confirm the possibility of local transmission of louse-borne relapsing fever.

  9. RIBOMUNYL IN PROPHYLACTICS OF RELAPSE OF STENOSING LARYNGOTRACHEITIS

    Directory of Open Access Journals (Sweden)

    S.N. Orlova

    2008-01-01

    Full Text Available The activity of ribomunyl in treatment and rehabilitation of 40 pediatric patients with relapsing stenosing laryngotracheitis, developed on the basis of acute respiratory viral infection was investigated. Treatment with ribomunyl recovers microbiocenose of nasopharynx and fauces, normalizes pulmonary ventilation and decreases liminal sensitivity of respiratory tract to the histamine.Key words: relapsing stenosing laryngotracheitis, ribomunyl, prophylactics, children.

  10. Symptomatic relapse of HIV-associated cryptococcal meningitis in ...

    African Journals Online (AJOL)

    Objectives. Cryptococcal meningitis is the most common cause of adult meningitis in southern Africa. Much of this disease burden is thought to be due to symptomatic relapse of previously treated infection. We studied the contribution of inadequate secondary fluconazole prophylaxis to symptomatic relapses of cryptococcal ...

  11. Factors associated with relapse in schizophrenia | Kazadi | South ...

    African Journals Online (AJOL)

    Aim. Early identification and prevention of relapse in patients with schizophrenia has significant therapeutic and socioeconomic implications. The aim of this study was to determine the factors, if any, that may be associated with relapse in a group of patients in Johannesburg. Method. Patients were recruited from mental ...

  12. louse-borne relapsing fever profile at jimma hospital, ethiopia

    African Journals Online (AJOL)

    dell

    ABSTRACT. Background: Louse-borne relapsing fever has been restricted to countries with poor socio economic status, the most important foci being Burundi, Rwanda and Ethiopia. Borrelia recurrentis is the etiologic agent for louse-borne relapsing fever and occurs as epidemic under conditions of overcrowding, poverty, ...

  13. Maintenance, Generalization, and Treatment Relapse: A Behavioral Momentum Analysis

    Science.gov (United States)

    Mace, F. Charles; Nevin, John A.

    2017-01-01

    Maintenance and generalization have been inconsistently defined in the behavior analytic literature. The term "treatment relapse" is used commonly in the medical and mental health literature to refer to the return of a condition that was previously considered successfully treated. Basic behavioral researchers have studied relapse related…

  14. Frequency of relapse among Nigerian children with steroid‑sensitive ...

    African Journals Online (AJOL)

    Background: The clinical course of steroid‑sensitive nephrotic syndrome (SSNS) among Nigerian children has rarely been reported; this makes prognostication difficult. Objectives: The objective was to determine the frequency of relapses including frequent relapses (FR) and steroid‑dependence (SD) in a cohort of Nigerian ...

  15. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma

    NARCIS (Netherlands)

    P.G. Richardson (Paul Gerard); P. Sonneveld (Pieter); M.W. Schuster (Michael); D. Irwin (David); E.A. Stadtmauer (Edward); T. Facon (Thierry); J-L. Harousseau (Jean-Luc); D. Ben-Yehuda (Dina); S. Lonial (Sagar); H. Goldschmidt (Hartmut); D. Reece (Donna); J.F. San Miguel (Jesús Fernando); J. Bladé (Joan); M. Boccadoro (Mario); J. Cavenagh (Jamie); W. Dalton (William); A.L. Boral (Anthony); D.-L. Esseltine (Dixie-Lee); J.B. Porter (Jane); D. Schenkein (David); K.C. Anderson (Kenneth)

    2005-01-01

    textabstractBACKGROUND: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. METHODS: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3

  16. Relapsing massive metal bezoar: a case report

    Directory of Open Access Journals (Sweden)

    Prieto-Aldape Manuel

    2009-02-01

    Full Text Available Abstract Introduction Bezoars are uncommon findings in the gastrointestinal tract and are composed of a wide variety of materials. We report a case of a relapsing metal bezoar in a man with schizophrenia. Case presentation A 34-year-old man presented with a history of sub-acute onset of mild diffuse abdominal pain and abdominal distention. Physical examination revealed dullness to percussion in the upper and lower left quadrants. Past medical history was remarkable for epilepsy, schizophrenia and previous abdominal surgery for intestinal occlusion. Plain radiographs revealed objects of metal density contained within a dilated stomach. Celiotomy was performed revealing more than 350 metal objects inside the stomach. The patient was discharged and referred to a psychiatric facility. Conclusion Intestinal occlusion in patients with psychiatric disorders can result from rare causes such as bezoars. This report alerts surgeons to rule out bezoars in the differential diagnosis of intestinal occlusion in people with mental health problems.

  17. Depression relapse prophylaxis with Mindfulness-Based Cognitive Therapy: replication and extension in the Swiss health care system.

    Science.gov (United States)

    Bondolfi, Guido; Jermann, Françoise; der Linden, Martial Van; Gex-Fabry, Marianne; Bizzini, Lucio; Rouget, Béatrice Weber; Myers-Arrazola, Lusmila; Gonzalez, Christiane; Segal, Zindel; Aubry, Jean-Michel; Bertschy, Gilles

    2010-05-01

    Mindfulness-Based Cognitive Therapy (MBCT) is a group intervention that integrates elements of Cognitive Behavioural Therapy (CBT) with components of mindfulness training to prevent depressive relapse. The efficacy of MBCT compared to Treatment As Usual (TAU), shown in two randomized controlled trials indicates a significant decrease in 1-year relapse rates for patients with at least three past depressive episodes. The present study is the first independent replication trial comparing MBCT+TAU to TAU alone across both language and culture (Swiss health care system). Sixty unmedicated patients in remission from recurrent depression (>or=3 episodes) were randomly assigned to MBCT+TAU or TAU. Relapse rate and time to relapse were measured over a 60 week observation period. The frequency of mindfulness practices during the study was also evaluated. Over a 14-month prospective follow-up period, time to relapse was significantly longer with MBCT+TAU than TAU alone (median 204 and 69 days, respectively), although both groups relapsed at similar rates. Analyses of homework adherence revealed that following treatment termination, the frequency of brief and informal mindfulness practice remained unchanged over 14 months, whereas the use of longer formal meditation decreased over time. Relapse monitoring was 14months in duration and prospective reporting of mindfulness practice would have yielded more precise frequency estimates compared to the retrospective methods we utilized. Further studies are required to determine which patient characteristics, beyond the number of past depressive episodes, may predict differential benefits from this therapeutic approach. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  18. HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

    Science.gov (United States)

    Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki

    2016-01-01

    Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries. PMID:27671118

  19. Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia

    DEFF Research Database (Denmark)

    Rohde, Christopher; Polcwiartek, Christoffer; Asztalos, Marton

    2018-01-01

    OBJECTIVE: Negative symptoms and cognitive deficits are main features of schizophrenia but with limited treatment options. Earlier studies have suggested that central nervous system (CNS) stimulants have a small effect on these domains, but with inconclusive results. As the first study to date, we...... aimed to investigate whether CNS stimulants improve naturalistic outcomes (psychiatric admissions and antipsychotic use) in patients with schizophrenia. METHODS: By using extensive health registers all patients with schizophrenia and their use of CNS stimulants in Denmark were identified. Two models...... were used to investigate the effectiveness of CNS stimulants in patients with schizophrenia between 1995 and 2014; a mirror-image model with 605 individuals, using paired t tests and Wilcoxon signed rank tests, and a follow-up study with 789 individuals, using a conditional risk-set model. RESULTS: CNS...

  20. Classification of relapse pattern in clubfoot treated with Ponseti technique.

    Science.gov (United States)

    Bhaskar, Atul; Patni, Piyush

    2013-07-01

    Relapse of clubfoot deformity following correction by Ponseti technique is not uncommon. The relapsed feet progress from flexible to rigid if left untreated and can become as severe as the initial deformity. No definitive classification exists to assess a relapsed clubfoot. Some authors have used the Pirani score to rate the relapse while others have used descriptive terms. The purpose of this study is to analyze the relapse pattern in clubfeet that have undergone treatment with the Ponseti method and propose a simple classification for relapsed clubfeet. Ninety-one children (164 feet) with idiopathic clubfeet who underwent treatment with Ponseti technique presented with relapse of the deformity. There were 68 boys and 23 girls. Mean age at presentation for casting was 10.71 days (range 7-22 days). Seventy three children (146 feet, 80%) had bilateral involvement and 18 (20%) had unilateral clubfeet. The mean Pirani Score was 5.6 and 5.5 in bilateral and unilateral groups respectively. Percutaneous heel cord tenotomy was done in 65 children (130 feet, 89%) in the bilateral group and in 12 children (66%) with unilateral clubfoot. Five relapse patterns were identified at a mean followup of 4.5 years (range 3-5 years) which forms the basis of this study. These relapse patterns were classified as: Grade IA: decrease in ankle dorsiflexion from15 degrees to neutral, Grade IB: dynamic forefoot adduction or supination, Grade IIA - rigid equinus, Grade IIB - rigid adduction of forefoot/midfoot complex and Grade III: combination of two or more deformities: Fixed equinus, varus and forefoot adduction. In the bilateral group, 21 children (38 feet, 28%) had Grade IA relapse. Twenty four children (46 feet, 34%) had dynamic intoeing (Grade IB) on walking. Thirteen children (22 feet, 16%) had true ankle equinus of varying degress (Grade IIA); eight children (13 feet, 9.7%) had fixed adduction deformity of the forefoot (Grade IIB) and seven children (14 feet, 10.7%) had two or more

  1. Circuit and Synaptic Plasticity Mechanisms of Drug Relapse.

    Science.gov (United States)

    Dong, Yan; Taylor, Jane R; Wolf, Marina E; Shaham, Yavin

    2017-11-08

    High rates of relapse to drug use during abstinence is a defining feature of human drug addiction. This clinical scenario has been studied at the preclinical level using different animal models in which relapse to drug seeking is assessed after cessation of operant drug self-administration in rodents and monkeys. In our Society for Neuroscience (SFN) session entitled "Circuit and Synaptic Plasticity Mechanisms of Drug Relapse," we will discuss new developments of our understanding of circuits and synaptic plasticity mechanisms of drug relapse from studies combining established and novel animal models with state-of-the-art cellular, electrophysiology, anatomical, chemogenetic, and optogenetic methods. We will also discuss the translational implications of these new developments. In the mini-review that introduces our SFN session, we summarize results from our laboratories on behavioral, cellular, and circuit mechanisms of drug relapse within the context of our session. Copyright © 2017 the authors 0270-6474/17/3710867-10$15.00/0.

  2. Increased multiple sclerosis relapses related to lower prevalence of pain

    Directory of Open Access Journals (Sweden)

    José Vinícius Martins da Silva

    2015-07-01

    Full Text Available Objective The study aims to investigate the presence of pain amongst multiple sclerosis (MS patients. Method One hundred MS patients responded to questionnaires evaluating neuropathic and nociceptive pain, depression and anxiety. Statistical analysis was performed using the Mann–Whitney U, Chi-Square and two-tailed Fisher’s exact tests and multivariate logistic regression. Results Women had a statistically higher prevalence of pain (p = 0.037, and chances of having pain after the age of 50 reduced. Women with pain had a statistically significant lower number of relapses (p = 0.003, restricting analysis to those patients with more than one relapse. After the second relapse, each relapse reduced the chance of having pain by 46%. Presence of pain was independent of Expanded Disability Status Scale (EDSS anxiety, and depression. Conclusion Our findings suggest a strong inverse association between relapses and pain indicating a possible protective role of focal inflammation in the control of pain.

  3. Quantitative Plasma Proteomic Profiling Identifies the Vitamin E Binding Protein Afamin as a Potential Pathogenic Factor in SIV Induced CNS Disease

    OpenAIRE

    Pendyala, Gurudutt; Trauger, Sunia A; Siuzdak, Gary; Fox, Howard S.

    2010-01-01

    Investigating, predicting, diagnosing and treating HIV-1-associated neurocognitive disorder (HAND) has been hindered by the lack of disease-related molecular markers. In this study, plasma from rhesus monkeys (n=6), before and after infection with simian immunodeficiency virus (SIV), was profiled to obtain differential fingerprints in protein expression during SIV-induced central nervous system (CNS) disease. A quantitative proteomic analysis was performed by means of isobaric tag for relativ...

  4. TIME COURSE MODIFICATIONS INDUCED BY PERINATAL ASPHYXIA IN RAT CNS

    Directory of Open Access Journals (Sweden)

    Francisco Capani

    2015-04-01

    of estradiol treatment we were able to revert some of these alterations using PI3K/Akt/GSK3. Overall these results demonstrate that synaptic dysfunction following PA might be produced by early changes in the actin organization and long-term misfolding and aggregation of proteins in the PSDs. Therefore, we hypothesize that the synaptic and neuronal cytoskeleton changes induced by PA in the rat CNS could lead to the cellular dysfunction and death in adult animals. Estradiol appears as a new therapeutic tool to slacken the damage induces by perinatal asphyxia on the CNS.

  5. Siglec-H is a microglia-specific marker that discriminates microglia from CNS-associated macrophages and CNS-infiltrating monocytes.

    Science.gov (United States)

    Konishi, Hiroyuki; Kobayashi, Masaaki; Kunisawa, Taikan; Imai, Kenta; Sayo, Akira; Malissen, Bernard; Crocker, Paul R; Sato, Katsuaki; Kiyama, Hiroshi

    2017-12-01

    Several types of myeloid cell are resident in the CNS. In the steady state, microglia are present in the CNS parenchyma, whereas macrophages reside in boundary regions of the CNS, such as perivascular spaces, the meninges and choroid plexus. In addition, monocytes infiltrate into the CNS parenchyma from circulation upon blood-brain barrier breakdown after CNS injury and inflammation. Although several markers, such as CD11b and ionized calcium-binding adapter molecule 1 (Iba1), are frequently used as microglial markers, they are also expressed by other types of myeloid cell and microglia-specific markers were not defined until recently. Previous transcriptome analyses of isolated microglia identified a transmembrane lectin, sialic acid-binding immunoglobulin-like lectin H (Siglec-H), as a molecular signature for microglia; however, this was not confirmed by histological studies in the nervous system and the reliability of Siglec-H as a microglial marker remained unclear. Here, we demonstrate that Siglec-H is an authentic marker for microglia in mice by immunohistochemistry using a Siglec-H-specific antibody. Siglec-H was expressed by parenchymal microglia from developmental stages to adulthood, and the expression was maintained in activated microglia under injury or inflammatory condition. However, Siglec-H expression was absent from CNS-associated macrophages and CNS-infiltrating monocytes, except for a minor subset of cells. We also show that the Siglech gene locus is a feasible site for specific targeting of microglia in the nervous system. In conclusion, Siglec-H is a reliable marker for microglia that will allow histological identification of microglia and microglia-specific gene manipulation in the nervous system. © 2017 Wiley Periodicals, Inc.

  6. VP-shunt dysfunction caused by malaria CNS infection.

    Science.gov (United States)

    Fehrenbach, Michael Karl; Bernhard, Matthias; Siekmeyer, Manuela; Lippmann, Norman; Kiess, Wieland; Nestler, Ulf; Meixensberger, Jürgen; Preuss, Matthias

    2016-04-01

    Malaria is a widespread mosquito-borne infectious disease with over 300 million cases and roughly 900 thousand deaths in 2013. Cerebral involvement of malaria causes 50 % of all infection-associated deaths, especially in children below the age of 5 years. Hydrocephalus is a medical condition with abnormal accumulation of cerebrospinal fluid in physiological cavities and ventricles. Standard treatment is the implantation of a cerebrospinal fluid shunt device. A common problem associated with shunt treatment especially in pediatric patients is infection and consecutive shunt dysfunction caused by bacteriae or high protein levels clogging the valve. In these cases, Staphylococcus aureus and Staphylococcus epidermidis are predominantly found in CSF cultures. We present a case of a 2-year old boy from Saudi Arabia with a ventriculoperitoneal (VP)-shunt-dependent congenital hydrocephalus who suffered from cerebral malaria and developed consecutive shunt failure. To the best of our knowledge, shunt failure caused by malaria CNS infection with Plasmodium falciparum has not yet been reported in the literature and should be considered as a rare cause of VP-shunt failure in patients with atypical VP-shunt infections living in or traveling from endemic areas.

  7. Stress preconditioning of spreading depression in the locust CNS.

    Directory of Open Access Journals (Sweden)

    Corinne I Rodgers

    Full Text Available Cortical spreading depression (CSD is closely associated with important pathologies including stroke, seizures and migraine. The mechanisms underlying SD in its various forms are still incompletely understood. Here we describe SD-like events in an invertebrate model, the ventilatory central pattern generator (CPG of locusts. Using K(+ -sensitive microelectrodes, we measured extracellular K(+ concentration ([K(+](o in the metathoracic neuropile of the CPG while monitoring CPG output electromyographically from muscle 161 in the second abdominal segment to investigate the role K(+ in failure of neural circuit operation induced by various stressors. Failure of ventilation in response to different stressors (hyperthermia, anoxia, ATP depletion, Na(+/K(+ ATPase impairment, K(+ injection was associated with a disturbance of CNS ion homeostasis that shares the characteristics of CSD and SD-like events in vertebrates. Hyperthermic failure was preconditioned by prior heat shock (3 h, 45 degrees C and induced-thermotolerance was associated with an increase in the rate of clearance of extracellular K(+ that was not linked to changes in ATP levels or total Na(+/K(+ ATPase activity. Our findings suggest that SD-like events in locusts are adaptive to terminate neural network operation and conserve energy during stress and that they can be preconditioned by experience. We propose that they share mechanisms with CSD in mammals suggesting a common evolutionary origin.

  8. Using nanotechnology to design potential therapies for CNS regeneration.

    Science.gov (United States)

    Ellis-Behnke, R G; Teather, L A; Schneider, G E; So, K-F

    2007-01-01

    The nanodelivery of therapeutics into the brain will require a step-change in thinking; overcoming the blood brain barrier is one of the major challenges to any neural therapy. The promise of nanotechnology is that the selective delivery of therapeutics can be delivered through to the brain without causing secondary damage. There are several formidable barriers that must be overcome in order to achieve axonal regeneration after injury in the CNS. The development of new biological materials, in particular biologically compatible scaffolds that can serve as permissive substrates for cell growth, differentiation and biological function is a key area for advancing medical technology. This review focuses on four areas: First, the barriers of delivering therapies to the central nervous system and how nanotechnology can potentially solve them; second, current research in neuro nanomedicine featuring brain repair, brain imaging, nanomachines, protein misfolding diseases, nanosurgery, implanted devices and nanotechnologies for crossing the blood brain barrier; third, health and safety issues and fourth, the future of neuro nanomedicine as it relates to the pharmaceutical industry.

  9. Neuronal LRP4 regulates synapse formation in the developing CNS.

    Science.gov (United States)

    Karakatsani, Andromachi; Marichal, Nicolás; Urban, Severino; Kalamakis, Georgios; Ghanem, Alexander; Schick, Anna; Zhang, Yina; Conzelmann, Karl-Klaus; Rüegg, Markus A; Berninger, Benedikt; Ruiz de Almodovar, Carmen; Gascón, Sergio; Kröger, Stephan

    2017-12-15

    The low-density lipoprotein receptor-related protein 4 (LRP4) is essential in muscle fibers for the establishment of the neuromuscular junction. Here, we show that LRP4 is also expressed by embryonic cortical and hippocampal neurons, and that downregulation of LRP4 in these neurons causes a reduction in density of synapses and number of primary dendrites. Accordingly, overexpression of LRP4 in cultured neurons had the opposite effect inducing more but shorter primary dendrites with an increased number of spines. Transsynaptic tracing mediated by rabies virus revealed a reduced number of neurons presynaptic to the cortical neurons in which LRP4 was knocked down. Moreover, neuron-specific knockdown of LRP4 by in utero electroporation of LRP4 miRNA in vivo also resulted in neurons with fewer primary dendrites and a lower density of spines in the developing cortex and hippocampus. Collectively, our results demonstrate an essential and novel role of neuronal LRP4 in dendritic development and synaptogenesis in the CNS. © 2017. Published by The Company of Biologists Ltd.

  10. Carbon monoxide and the CNS: challenges and achievements

    Science.gov (United States)

    Queiroga, Cláudia S F; Vercelli, Alessandro; Vieira, Helena L A

    2015-01-01

    Haem oxygenase (HO) and its product carbon monoxide (CO) are associated with cytoprotection and maintenance of homeostasis in several different organs and tissues. This review focuses upon the role of exogenous and endogenous CO (via HO activity and expression) in various CNS pathologies, based upon data from experimental models, as well as from some clinical data on human patients. The pathophysiological conditions reviewed are cerebral ischaemia, chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases), multiple sclerosis and pain. Among these pathophysiological conditions, a variety of cellular mechanisms and processes are considered, namely cytoprotection, cell death, inflammation, cell metabolism, cellular redox responses and vasomodulation, as well as the different targeted neural cells. Finally, novel potential methods and strategies for delivering exogenous CO as a drug are discussed, particularly approaches based upon CO-releasing molecules, their limitations and challenges. The diagnostic and prognostic value of HO expression in clinical use for brain pathologies is also addressed. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24758548

  11. Nonmyeloablative Allogeneic Stem Cell Transplantation in Relapsed/Refractory Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Khouri, Issa F.; Bassett, Roland; Poindexter, Nancy; O'Brien, Susan; Bueso-Ramos, Carlos E.; Hsu, Yvonne; Ferrajoli, Alessandra; Keating, Michael J.; Champlin, Richard; Fernandez-Vina, Marcelo

    2015-01-01

    BACKGROUND The role of nonmyeloablative allogeneic stem cell transplantation (NST) in the treatment of chronic lymphocytic leukemia (CLL) is not well established. The authors report on long-term experience with NST in relapsed/refractory CLL and define prognostic factors associated with outcome. METHODS The authors reviewed the outcome of 86 patients with relapsed/relapsed CLL enrolled in sequential NST protocols. RESULTS The median patient age was 58 years. Patients were heavily pretreated before transplantation, and 43 required immunomanipulation after NST for persistent or recurrent disease. Immunomanipulation included withdrawal of immunosuppression, rituximab, and step-wise donor lymphocyte infusions. Of 43 patients receiving immunomanipulation, 20 (47%) experienced a complete remission. Patients with human leukocyte antigen (HLA) genotype A1+/A2−/B44− were more likely to experience a complete remission (P ¼ .0009), with rates of 9%, 36%, 50%, and 91%, respectively, for 0, 1, 2, and 3 of these HLA factors. This resulted in significant improvement in progression-free-survival rates of 68.2% at 5 years for patients with all 3 HLA factors. Overall, the estimated 5-year survival rate was 51%. In a multivariate model, a CD4 count of <100/mm3 and a below normal serum immunoglobulin G level at study entry were associated with a short survival duration (P < .0001). CONCLUSIONS These results confirm the potential cure of relapsed/refractory CLL with NST and provide the first evidence that immunoglobulin G and CD4 levels are predictive of overall survival after NST in CLL and that human leukocyte antigen alleles predict response to immunomanipulation. PMID:21455998

  12. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle.

    Science.gov (United States)

    Engelhardt, Britta; Coisne, Caroline

    2011-01-18

    Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the outer walls of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the castle moat, namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the castle moat is bordered by a second wall, the glia limitans, composed of astrocytic foot processes and a parenchymal basement membrane. Inside the castle, that is the CNS parenchyma proper, the royal family of sensitive neurons resides with their servants, the glial cells. Within the CSF-drained castle moat, macrophages serve as guards collecting all the information from within the castle, which they can present to the immune-surveying T cells. If in their communication with the castle moat macrophages, T cells recognize their specific antigen and see that the royal family is in danger, they will become activated and by opening doors in the outer wall of the castle allow the entry of additional immune cells into the castle moat. From there, immune cells may breach the inner castle wall with the aim to defend the castle inhabitants by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the castle

  13. Bioavailability of dietary polyphenols: Factors contributing to their clinical application in CNS diseases.

    Science.gov (United States)

    Pandareesh, M D; Mythri, R B; Srinivas Bharath, M M

    2015-10-01

    The anatomical location of the central nervous system (CNS) renders it immunologically and pharmacologically privileged due to the blood brain barrier (BBB). Although this limits the transport of unfavorable molecules to the CNS, the ensuing privilege could be disadvantageous for therapeutic compounds. Hence, the greatest challenge in the pharmacotherapy of CNS diseases is to ensure efficient brain targeting and drug delivery. Research evidences indicate that dietary polyphenols have neuroprotective potential against CNS diseases. However, their selective permeability across BBB, poor absorption, rapid metabolism and systemic elimination limit their bioavailability and therapeutic efficacy. Consequently, the beneficial effects of these orally administered agents in the CNS still remain a subject of debate. This has also limited its clinical application either as independent or adjunctive therapy. Improving the in vivo bioavailability by novel methods could improve the therapeutic feasibility of polyphenols and assist in evolving novel drugs and their derivatives with improved efficacy in vivo. Here we review the mechanistic and pharmacological issues related to the bioavailability of polyphenols with therapeutic implications for CNS diseases. We surmise that improving the bioavailability of polyphenols entails efficient in vivo transport across BBB, biochemical stability, improved half-life and persistent neuroprotection in the CNS. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Outcome of Very Late Relapse in Patients with Hodgkin's Lymphomas

    Directory of Open Access Journals (Sweden)

    Francesco Gaudio

    2011-01-01

    Full Text Available Recurrences of Hodgkin's Lymphoma (HL 5 years after the initial therapy are rare. The aim of this study is to report a single centre experience of the clinical characteristics, outcome, and toxicity of pts who experienced very late relapses, defined as relapses that occurred 5 or more years after the achievement of first complete remission. Of 532 consecutive pts with classical HL treated at our Institute from 1985 to 1999, 452 pts (85% achieved a complete remission. Relapse occurred in 151 pts: 135 (29.8% within 5 years and 16 over 5 years (3.5%, very late relapses. Very late relapses occurred after a median disease-free interval of 7 years (range: 5–18. Salvage treatment induced complete remission in 14 pts (87.5%. At a median of 4 years after therapy for very late relapse, 10 pts (63% are still alive and free of disease and 6 (37% died (1 from progressive HL, 1 from cardiac disease, 1 from thromboembolic disease, 1 from HCV reactivation, and 2 from bacterial infection. The probability of failure-free survival at 5 years was 75%. The majority of deaths are due to treatment-related complications. Therapy regimens for very late relapse HL are warranted to minimize complications.

  15. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome.

    Science.gov (United States)

    des Portes, V; Pinard, J M; Billuart, P; Vinet, M C; Koulakoff, A; Carrié, A; Gelot, A; Dupuis, E; Motte, J; Berwald-Netter, Y; Catala, M; Kahn, A; Beldjord, C; Chelly, J

    1998-01-09

    X-SCLH/LIS syndrome is a neuronal migration disorder with disruption of the six-layered neocortex. It consists of subcortical laminar heterotopia (SCLH, band heterotopia, or double cortex) in females and lissencephaly (LIS) in males, leading to epilepsy and cognitive impairment. We report the characterization of a novel CNS gene encoding a 40 kDa predicted protein that we named Doublecortin and the identification of mutations in four unrelated X-SCLH/LIS cases. The predicted protein shares significant homology with the N-terminal segment of a protein containing a protein kinase domain at its C-terminal part. This novel gene is highly expressed during brain development, mainly in fetal neurons including precursors. The complete disorganization observed in lissencephaly and heterotopia thus seems to reflect a failure of early events associated with neuron dispersion.

  16. Delay of smoking gratification as a laboratory model of relapse: effects of incentives for not smoking, and relationship with measures of executive function.

    Science.gov (United States)

    Mueller, Eldon T; Landes, Reid D; Kowal, Benjamin P; Yi, Richard; Stitzer, Maxine L; Burnett, Cody A; Bickel, Warren K

    2009-09-01

    Nineteen nicotine-deprived cigarette smokers received monetary rewards for each minute they chose not to initiate smoking in 2-h laboratory sessions followed by a 30-min period of enforced abstinence from smoking. Reinforcer amounts were delivered according to one of three schedules: increasing, decreasing, and constant. Relapse time (time until first cigarette) was shortest in the decreasing condition, longest in the increasing condition, and intermediate in the constant condition. All differences were significant except in the constant-decreasing comparison. The relationships between a battery of baseline assessments and relapse times were examined. Relapse times were predicted by delay-discounting coefficients (k) for $10 and $1000 in money and for $1000 of cigarettes. Relapse times were also predicted by the number of cigarettes smoked daily and a Wisconsin Card Sorting Test score. Performance on the Stroop Task and the Fagerström Test for Nicotine Dependence differentiated participants dichotomized into those who relapsed 'earlier' in sessions versus those who first smoked 'later'. The variability in some scores from smoking-urges and affect questionnaires administered after smoking-room sessions was explained by measures related to in-session nicotine intake. Results are discussed as they relate to contingency-management procedures, predictors of relapse, and the competing neurobehavioral decision systems theory of addiction.

  17. Cladribine tablets for relapsing-remitting multiple sclerosis

    DEFF Research Database (Denmark)

    Rammohan, Kottil; Giovannoni, Gavin; Comi, Giancarlo

    2012-01-01

    BACKGROUND: In the phase III CLARITY study, treatment with cladribine tablets at cumulative doses of 3.5 or 5.25mg/kg over 96 weeks led to significant reductions in annualized relapse rates (ARR) versus placebo in patients with relapsing-remitting multiple sclerosis. Further post hoc analyses....../>40 years); disease duration (10 years); prior disease-modifying drug treatment (treated/naïve); relapses in the prior year (≤1/2/≥3); Expanded Disability Status Scale score (median) at baseline (all P≤0...

  18. Glioma migration: clues from the biology of neural progenitor cells and embryonic CNS cell migration.

    Science.gov (United States)

    Dirks, P B

    2001-06-01

    Neural stem cells have recently come to the forefront in neurobiology because of the possibilities for CNS repair by transplantation. Further understanding of the biology of these cells is critical for making their use in CNS repair possible. It is likely that these discoveries will also have spin-offs for neuro-oncology as primary brain tumors may arise from a CNS progenitor cell. An understanding of the normal migratory ability of these cells is also likely to have a very important impact on the knowledge of brain tumor invasion.

  19. Armies of pestilence: CNS infections as potential weapons of mass destruction.

    Science.gov (United States)

    Hart, B L; Ketai, L

    2015-06-01

    Infectious agents have been investigated, developed, and used by both governments and terrorist groups as weapons of mass destruction. CNS infections, though traditionally considered less often than respiratory diseases in this scenario, may be very important. Viruses responsible for encephalitides can be highly infectious in aerosol form. CNS involvement in anthrax is ominous but should change treatment. Brucellosis, plague, Q fever, and other bacteria can uncommonly manifest with meningoencephalitis and other findings. Emerging diseases may also pose threats. We review infectious agents of particular concern for purposes of biowarfare with respect to CNS manifestations and imaging features. © 2015 by American Journal of Neuroradiology.

  20. Do Psychiatric Disorders or Measures of Distress Moderate Response to Postpartum Relapse Prevention Interventions?

    Science.gov (United States)

    Kolko, Rachel P; Emery, Rebecca L; Cheng, Yu; Levine, Michele D

    2017-05-01

    Most women who quit smoking during pregnancy will relapse postpartum. Interventions for sustained postpartum abstinence can benefit from understanding prenatal characteristics associated with treatment response. Given that individuals with psychiatric disorders or elevated depressive symptoms have difficulty quitting smoking and that increases in depressive symptoms prenatally are common, we examined the relevance of psychiatric diagnoses, prenatal depressive symptoms, and stress to postpartum relapse prevention intervention response. Pregnant women (N = 300) who quit smoking during pregnancy received intervention (with specialized focus on mood, weight, and stress [STARTS] or a comparison [SUPPORT]) to prevent postpartum relapse. As previously published, nearly one-third and one-quarter of women achieved biochemically-confirmed sustained abstinence at 24- and 52-weeks postpartum, with no difference in abstinence rates between the interventions. Women completed psychiatric interviews and questionnaires during pregnancy. Smoking was assessed in pregnancy, and 24- and 52-weeks postpartum. Psychiatric disorders did not predict sustained abstinence or treatment response. However, treatment response was moderated by end-of-pregnancy depressive symptoms (χ2 = 9.98, p = .002) and stress (χ2 = 6.90, p = .01) at 24- and 52-weeks postpartum and remained significant after including covariates. Women with low distress achieved higher abstinence rates in SUPPORT than in STARTS (37% vs. 19% for depressive symptoms; 36% vs. 19% for stress), with no difference for women with high symptoms. Prenatal depressive symptoms and stress predicted differential treatment efficacy in women with low symptoms, not in women with high symptoms. Diagnostic history did not predict treatment differences. Future research to address prenatal distress may help tailor postpartum relapse prevention interventions. We examined prenatal history of psychiatric disorders and psychiatric distress as

  1. Radioprotection of mouse CNS endothelial cells in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Lyubimova, N.; Coultas, P.; Martin, R. [Peter MacCallum Cancer institute, Melbourne, Victoria (Australia)

    1997-03-01

    After treatments with monoamine oxidase inhibitors and L-DOPA, the blood brain barrier causes a build-up of dopamine in brain capillary endothelial cells. Conversion of the dopamine to a fluorophore provides a marker which can be used to measure endothelial cell density by fluorescence microscopy. Earlier studies used this technique to monitor post-irradiation changes in endothelial cell density in rodent brain and showed loss within 24 hours of a sub-population of about 15 % of the endothelial cells. As a first step, rather than use the later endpoints of radionecrosis it was decided to examine directly whether Hoechst 33342 could protect against this rapid initial endothelial cell loss. Ten minutes after intravenous injection of Joechst 33342, in mouse brain the ligand was confined to endothelial cells and, for irradiation at this time, there was protection against endothelial cell loss over the first 24 hours after after exposure. Ablation of the sensitive subpopulation in unprotected mice took place over a dose range of 1 to 3 Gy {gamma}-rays but doses between 12 to 20 Gy were required in the presence of the ligand. This protection equated to a high dose modification factor of approximately 7 and may reflect suppression of apoptosis in this sensitive endothelial subpopulation. The extent to which there is enhanced survival in the endothelial population as a whole, and how the observed protection affects late CNS necrosis development, has yet to be determined. However these results suggest a potential use of DNA-binding radioprotectors with limited penetration in investigations of the relative significance of endothelial and parenchymal damage in normal tissue responses to ionising radiation. (authors)

  2. Carbon monoxide inhalation increases microparticles causing vascular and CNS dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Jiajun; Yang, Ming [Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Kosterin, Paul [Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Salzberg, Brian M. [Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Milovanova, Tatyana N.; Bhopale, Veena M. [Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States); Thom, Stephen R., E-mail: sthom@smail.umaryland.edu [Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 (United States)

    2013-12-01

    We hypothesized that circulating microparticles (MPs) play a role in pro-inflammatory effects associated with carbon monoxide (CO) inhalation. Mice exposed for 1 h to 100 ppm CO or more exhibit increases in circulating MPs derived from a variety of vascular cells as well as neutrophil activation. Tissue injury was quantified as 2000 kDa dextran leakage from vessels and as neutrophil sequestration in the brain and skeletal muscle; and central nervous system nerve dysfunction was documented as broadening of the neurohypophysial action potential (AP). Indices of injury occurred following exposures to 1000 ppm for 1 h or to 1000 ppm for 40 min followed by 3000 ppm for 20 min. MPs were implicated in causing injuries because infusing the surfactant MP lytic agent, polyethylene glycol telomere B (PEGtB) abrogated elevations in MPs, vascular leak, neutrophil sequestration and AP prolongation. These manifestations of tissue injury also did not occur in mice lacking myeloperoxidase. Vascular leakage and AP prolongation were produced in naïve mice infused with MPs that had been obtained from CO poisoned mice, but this did not occur with MPs obtained from control mice. We conclude that CO poisoning triggers elevations of MPs that activate neutrophils which subsequently cause tissue injuries. - Highlights: • Circulating microparticles (MPs) increase in mice exposed to 100 ppm CO or more. • MPs are lysed by infusing the surfactant polyethylene glycol telomere B. • CO-induced MPs cause neutrophil activation, vascular leak and CNS dysfunction. • Similar tissue injuries do not arise with MPs obtained from air-exposed, control mice.

  3. Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome.

    Science.gov (United States)

    Pohl, Daniela; Alper, Gulay; Van Haren, Keith; Kornberg, Andrew J; Lucchinetti, Claudia F; Tenembaum, Silvia; Belman, Anita L

    2016-08-30

    Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti-myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurologic sequelae. This review summarizes the current knowledge on epidemiology, pathology, clinical presentation, neuroimaging features, CSF findings, differential diagnosis, therapy, and outcome, with a focus on recent advances and controversies. © 2016 American Academy of Neurology.

  4. Pemphigus erythematosus relapse associated with atorvastatin intake

    Directory of Open Access Journals (Sweden)

    Lo Schiavo A

    2014-09-01

    Full Text Available Ada Lo Schiavo,1 Rosa Valentina Puca,1 Francesca Romano,1 Roberto Cozzi2 1Department of Dermatology, Second University of Naples, Naples, Italy; 2Department of Dermatology, AORN "A Cardarelli", Naples, Italy Abstract: Statins, also known as 3-hydroxy-3-methylglutaril-CoA reductase inhibitors, are well-tolerated drugs used for prevention of atherosclerosis and cardiovascular events. Although they are generally considered safe, some serious adverse effects, such as myositis, myopathy, and rhabdomyolysis can rarely occur. Furthermore, recent data from long-term follow-up on patients who have been taking statins for a long period of time suggest that prolonged exposure to statins may trigger autoimmune reactions. The exact mechanism of statin-induced autoimmune reactions is unclear. Statins, as proapoptotic agents, release nuclear antigen into the circulation and may induce the production of pathogenic autoantibodies. Herein we report the case of a 70 year-old man who developed a relapse of pemphigus erythematosus, a syndrome with features of both lupus erythematosus and pemphigus, after atorvastatin intake. Keywords: pemphigus erythematosus, autoimmune disease, treatment, pathogenesis, statins

  5. Cognitive impairment in relapsing remitting Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Saška Roškar

    2003-06-01

    Full Text Available The purpose of the study was to identify changes in cognitive abilities that affect patients with relapsing remitting form of multiple sclerosis (MS and to find out which instrument manifests them best. The performance of MS patients was compared to a matched group of healthy people using three neuropsychological tests: Wisconsin card sorting test (WCST, Stroop color and word test and Trail making test (TMT part B. Results on all three tests indicate general cognitive impairments in the group of patients. Compared to the group of healthy people patients with MS exhibited impaired ability of abstract reasoning (WCST, impaired cognitive flexibility and less resistance to irrelevant stimuli (Stroop color and word test, slowed information processing and impaired ability of shifting attention from one symbol to another (TMT. The largest differences between groups occured in Stroop color and word test as well as in TMT. The estimation of cognitive abilities of MS patients is of high importance and sistematicaly observing of changes in those abilities should be considered.

  6. Tick-Borne Relapsing Fever in Dogs.

    Science.gov (United States)

    Piccione, J; Levine, G J; Duff, C A; Kuhlman, G M; Scott, K D; Esteve-Gassent, M D

    2016-07-01

    In the United States, Tick-Borne Relapsing Fever (TBRF) in dogs is caused by the spirochete bacteria Borrelia turicatae and Borrelia hermsii, transmitted by Ornithodoros spp. ticks. The hallmark diagnostic feature of this infection is the visualization of numerous spirochetes during standard blood smear examination. Although the course of spirochetemia has not been fully characterized in dogs, in humans infected with TBRF the episodes of spirochetemia and fever are intermittent. To describe TBRF in dogs by providing additional case reports and reviewing the disease in veterinary and human medicine. Five cases of privately-owned dogs naturally infected with TBRF in Texas are reviewed. Case series and literature review. All dogs were examined because of lethargy, inappetence, and pyrexia. Two dogs also had signs of neurologic disease. All dogs had thrombocytopenia and spirochetemia. All cases were administered tetracyclines orally. Platelet numbers improved and spirochetemia and pyrexia resolved in 4 out of 5 dogs, where follow-up information was available. TBRF is likely underdiagnosed in veterinary medicine. In areas endemic to Ornithodoros spp. ticks, TBRF should be considered in dogs with thrombocytopenia. Examination of standard blood smears can provide a rapid and specific diagnosis of TBRF when spirochetes are observed. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  7. Graves’ Ophthalmopathy Misdiagnosed as Relapsing Conjunctivitis

    Directory of Open Access Journals (Sweden)

    Irini P. Chatziralli

    2010-09-01

    Full Text Available A 59-year-old female patient presented at the outpatients’ Department of Ophthalmology with epiphora, eyelid swelling, and a foreign body feeling in the right eye. The symptoms were present for 4 months, and the patient was treated as suffering from relapsing conjunctivitis. The slit lamp examination revealed keratitis due to exposure, related with the deficient closure of the eyelids. There was a 2 mm difference in the readings with the Hertel exophthalmometry examination between the eyes. Her medical history was clear, and she was referred for computed tomography of the orbits and brain and biochemical examinations (FT3, FT4, and TSH to investigate the presence of an intraorbital mass. FT3 was significantly increased and TSH was accordingly low, indicating the diagnosis of Graves’ disease, which presented without other signs and symptoms apart from ophthalmopathy. Computed tomography scan excluded the diagnosis of an intraorbital mass. Therefore, it is important not to underestimate the ocular manifestations of systemic diseases.

  8. Ophthalmic manifestations of relapsing acute childhood leukemia.

    Science.gov (United States)

    Chocron, Isaac M; Morrison, David G; Friedman, Debra L; Desai, Neerav A; Donahue, Sean P

    2015-06-01

    Acute lymphoblastic leukemia is the most common malignancy in children. We report 3 patients who presented to their general pediatricians and pediatric oncologists with ocular complaints as the only evidence of their leukemic relapses. All patients presented with persistent conjunctival injection and were referred to an ophthalmologist for further management. Two patients were diagnosed with recurrent anterior uveitis, which after extensive workup and treatment with topical glucocorticoids was found to be a result of leukemic ocular disease. One patient had a conjunctival tumor, which was biopsied and confirmed to be leukemic infiltration. All children eventually succumbed to their recurrent disease. These cases demonstrate the need for a high index of suspicion when evaluating ocular symptoms in patients with a prior history of acute lymphoblastic leukemia. Anterior chamber paracentesis and biopsy of suspicious lesions should be considered as possible diagnostic procedures in addition to standard hematologic studies. Collaboration between a primary care physician, pediatric oncologist, and ophthalmologist is essential for optimal diagnosis and treatment. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  9. Histoplasmosis in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS): multicenter study of outcomes and factors associated with relapse.

    Science.gov (United States)

    Myint, Thein; Anderson, Albert M; Sanchez, Alejandro; Farabi, Alireza; Hage, Chadi; Baddley, John W; Jhaveri, Malhar; Greenberg, Richard N; Bamberger, David M; Rodgers, Mark; Crawford, Timothy N; Wheat, L Joseph

    2014-01-01

    Although discontinuation of suppressive antifungal therapy for acquired immunodeficiency syndrome (AIDS)-associated histoplasmosis is accepted for patients with immunologic recovery, there have been no published studies of this approach in clinical practice, and minimal characterization of individuals who relapse with this disease. We performed a multicenter retrospective cohort study to determine the outcome in AIDS patients following discontinuation of suppressive antifungal therapy for histoplasmosis. Ninety-seven patients were divided into a physician-discontinued suppressive therapy group (PD) (38 patients) and a physician-continued suppressive therapy group (PC) (59 patients). The 2 groups were not statistically different at baseline, but at discontinuation of therapy and at the most recent follow-up there were significant differences in adherence to therapy, human immunodeficiency virus (HIV) RNA, and urinary Histoplasma antigen concentration. There was no relapse or death attributed to histoplasmosis in the PD group compared with 36% relapse (p 150 cells/mL, HIV RNA <400 c/mL, Histoplasma antigenuria <2 ng/mL (equivalent to <4.0 units in second-generation method), and no CNS histoplasmosis.

  10. Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

    Science.gov (United States)

    2014-11-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Choriocarcinoma; Childhood Central Nervous System Germinoma; Childhood Central Nervous System Mixed Germ Cell Tumor; Childhood Central Nervous System Teratoma; Childhood Central Nervous System Yolk Sac Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Gonadotroph Adenoma; Pituitary Basophilic Adenoma; Pituitary Chromophobe Adenoma; Pituitary Eosinophilic Adenoma; Prolactin Secreting Adenoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Central Nervous System Embryonal Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Spinal Cord Neoplasm; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Pituitary Tumor; Recurrent/Refractory Childhood Hodgkin Lymphoma; T-cell Childhood Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; TSH Secreting Adenoma; Unspecified Childhood Solid Tumor, Protocol Specific

  11. [Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: comparisons among ASTRO and Phoenix biochemical failure definitions].

    Science.gov (United States)

    Quero, L; Mongiat-Artus, P; Ravery, V; Hennequin, V; Maylin, C; Desgrandchamps, F; Hennequin, C

    2009-07-01

    Study about the efficacy of salvage radiotherapy (RT), in terms of biochemical disease free survival (bDFS), according to ASTRO and Phoenix (nadir+2) definitions, for persistent or rising PSA after radical prostatectomy. Retrospective analysis of 59 patients who underwent RT between 1990 and 2003 for PSA recurrence after radical prostatectomy. Patients received a median of 66Gy to the prostate bed with 3D or 2D RT. The main end point was bDFS according to ASTRO and Phoenix (nadir+2) definitions. Different criterion sets were analysed to calculate bDFS and pretreatment factors that might predict biochemical relapse were sought for each. After a 38-month median follow-up, the 3-year bDFS rates were: 60 and 72% for ASTRO and Phoenix (nadir+2 ng/ml) definitions respectively. According to univariate analysis, pre-RT PSA> or =1 ng/ml and seminal vesicle involvement were associated with biochemical relapse. Multivariate analysis retained only pre-RT PSA> or =1 ng/ml as an independent predictor of biochemical relapse for the two definitions. Salvage RT is an effective treatment after radical prostatectomy according to ASTRO or Phoenix definitions. Only pre-RT PSA> or =1 ng/ml predicted relapse.

  12. Relapse in schizophrenia: Definitively not a bolt from the blue.

    Science.gov (United States)

    Spaniel, Filip; Bakstein, Eduard; Anyz, Jiri; Hlinka, Jaroslav; Sieger, Tomas; Hrdlicka, Jan; Görnerová, Natálie; Höschl, Cyril

    2016-04-22

    Detailed study of the period before schizophrenic relapse when early warning signs (EWS) are present is crucial to effective pre-emptive strategies. To investigate the temporal properties of EWS self-reported weekly via a telemedicine system. EWS history was obtained for 61 relapses resulting in hospitalization involving 51 patients with schizophrenia. Up to 20 weeks of EWS history per case were evaluated using a non-parametric bootstrap test and generalized mixed-effects model to test the significance and homogeneity of the findings. A statistically significant increase in EWS sum score was detectable 5 weeks before hospitalization. However, analysis of EWS dynamics revealed a gradual, monotonic increase in EWS score across during the 8 weeks before a relapse. The findings-in contrast to earlier studies-suggest that relapse is preceded by a lengthy period during which pathophysiological processes unfold; these changes are reflected in subjective EWS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

    Science.gov (United States)

    In this trial, patients with hairy cell leukemia who have not responded or relapsed after initial chemotherapy will be randomly assigned to receive rituximab combined with either pentostatin or bendamustine.

  14. Netrin-1 Confines Rhombic Lip-Derived Neurons to the CNS

    Directory of Open Access Journals (Sweden)

    Andrea R. Yung

    2018-02-01

    Full Text Available During brainstem development, newborn neurons originating from the rhombic lip embark on exceptionally long migrations to generate nuclei important for audition, movement, and respiration. Along the way, this highly motile population passes several cranial nerves yet remains confined to the CNS. We found that Ntn1 accumulates beneath the pial surface separating the CNS from the PNS, with gaps at nerve entry sites. In mice null for Ntn1 or its receptor DCC, hindbrain neurons enter cranial nerves and migrate into the periphery. CNS neurons also escape when Ntn1 is selectively lost from the sub-pial region (SPR, and conversely, expression of Ntn1 throughout the mutant hindbrain can prevent their departure. These findings identify a permissive role for Ntn1 in maintaining the CNS-PNS boundary. We propose that Ntn1 confines rhombic lip-derived neurons by providing a preferred substrate for tangentially migrating neurons in the SPR, preventing their entry into nerve roots.

  15. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC

    National Research Council Canada - National Science Library

    Hakan Kucukdereli; Nicola J. Allen; Anthony T. Lee; Ava Feng; M. Ilcim Ozlu; Laura M. Conatser; Chandrani Chakraborty; Gail Workman; Matthew Weaver; E. Helene Sage; Ben A. Barres; Cagla Eroglu

    2011-01-01

    Astrocytes regulate synaptic connectivity in the CNS through secreted signals. Here we identified two astrocyte-secreted proteins, hevin and SPARC, as regulators of excitatory synaptogenesis in vitro and in vivo...

  16. [11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

    DEFF Research Database (Denmark)

    Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø

    2014-01-01

    INTRODUCTION: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8......]methanolate in a Boc-protected precursor. The isolated [11C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[11C]-O-methylreboxetine ([11C]MeNER). RESULTS: The radiolabeling technique yielded [11C]NS8880 in low (... yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. CONCLUSION: Based...

  17. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

    NARCIS (Netherlands)

    Sturm, Dominik; Orr, Brent A.; Toprak, Umut H.; Hovestadt, Volker; Jones, David T. W.; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A.; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J.; Balasubramanian, Gnanaprakash; Worst, Barbara C.; Pajtler, Kristian W.; Brabetz, Sebastian; Johann, Pascal D.; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M.; Remke, Marc; Phillips, Joanna J.; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C.; Schniederjan, Matthew J.; Santi, Mariarita; Buccoliero, Anna M.; Dahiya, Sonika; Kramm, Christof M.; von Bueren, André O.; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C.; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V. Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U.; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S.; Taylor, Michael D.; Jones, Chris; Jabado, Nada; Karajannis, Matthias A.; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M.; Ellison, David W.; Korshunov, Andrey; Kool, Marcel

    2016-01-01

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally

  18. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

    NARCIS (Netherlands)

    Sturm, Dominik; Orr, Brent A.; Toprak, Umut H.; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A.; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J.; Balasubramanian, Gnanaprakash; Worst, Barbara C.; Pajtler, Kristian W.; Brabetz, Sebastian; Johann, Pascal D.; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M.; Remke, Marc; Phillips, Joanna J.; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C.; Schniederjan, Matthew J.; Santi, Mariarita; Buccoliero, Anna M.; Dahiya, Sonika; Kramm, Christof M.; Von Bueren, André O.; Von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C.; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V. Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U.; Shalaby, Tarek; Grotzer, Michael; Van Meter, Timothy; Monoranu, Camelia Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; Van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S.; Taylor, Michael D.; Jones, Chris; Jabado, Nada; Karajannis, Matthias A.; Eils, Roland; Schlesner, Matthias; Lichter, Peter; Von Deimling, Andreas; Pfister, Stefan M.; Ellison, David W.; Korshunov, Andrey; Kool, Marcel

    2016-01-01

    Summary Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of

  19. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

    DEFF Research Database (Denmark)

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H

    2016-01-01

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally dia...

  20. Domain-specific regulation of foxP2 CNS expression by lef1

    National Research Council Canada - National Science Library

    Bonkowsky, Joshua L; Wang, Xu; Fujimoto, Esther; Lee, Ji Eun; Chien, Chi-Bin; Dorsky, Richard I

    2008-01-01

    FOXP2 is a forkhead transcription factor critical for normal development of language in humans, but little is known of its broader function and regulation during central nervous system (CNS) development...

  1. Identifying relapse prevention elements during psychological treatment of depression: Development of an observer-based rating instrument.

    Science.gov (United States)

    Machmutow, Katja; Holtforth, Martin Grosse; Krieger, Tobias; Watzke, Birgit

    2017-11-06

    Although observer-rated instruments assessing therapist's adherence to relapse-preventive treatments are available, they do not adequately cover specific relapse-preventive elements that focus on implementation of strategies after terminating treatment. This study describes the development of the KERI-D (Kodierbogen zur Erfassung Rückfallprophylaktischer Interventionen bei Depression/Coding System to Assess Interventions of Relapse Prevention in Depression). The KERI-D is a new observer-based rating tool for acute or continuation/maintenance-phase sessions and assesses relapse-prevention elements including implementation into patient's daily routines. The development of the KERI-D included iterative steps referring to theoretical, clinical and empirical sources. It consists of 19 content items within four categories (self-care, early warning signs, triggering events/situations, termination of therapy) and one global item. For empirical analyses, videotaped psychotherapy sessions of 36 psychotherapies were rated by three independent observers and analyzed for their psychometric properties. Most items showed moderate to good inter-rater reliability (median ICC = .80) and retest reliability (median ICC = .93). Principal-axis factor analysis revealed three subscales, and first evidence of content validity was demonstrated. No associations with clinical follow-up data were found. Analysis was limited to a relatively small sample of selected psychotherapy sessions. Evaluation of predictive validity is a desirable next step to further examine applicability and scope of the instrument. The KERI-D is the first observer-based rating instrument measuring specific relapse-prevention strategies in psychotherapy for depression. It may help to identify elements that prove effective in reducing relapse/recurrence in the long-term and thereby help to optimize effect duration of depression treatment. Copyright © 2017. Published by Elsevier B.V.

  2. A Unique Case of Relapsing Polychondritis Presenting with Acute Pericarditis

    Directory of Open Access Journals (Sweden)

    John V. Higgins

    2013-01-01

    Full Text Available Relapsing polychondritis (RP is an inflammatory disease of the cartilaginous tissue primarily affecting the cartilaginous structures of the ear, nose, joints, and the respiratory system. Cardiovascular complications of RP are associated with high morbidity and mortality and occur most commonly as valvular disease. Pericarditis is a less common complication, occurring in 4% of patients with RP and has not previously been described at presentation. We describe a case of relapsing polychondritis with acute pericarditis at presentation.

  3. Subacute sclerosing panencephalitis. Changes on CT scan during acute relapse

    Energy Technology Data Exchange (ETDEWEB)

    Modi, G.; Bill, P. (Wentworth Hospital, Durban (South Africa). Dept. of Medicine); Campbell, H. (Wentworth Hospital, Durban (South Africa). Dept. of Radiology)

    1989-11-01

    A 19-year-old female patient presented in an acute state of akinetic mutism. Serological analysis of serum and cerebrospinal fluid demonstrated the presence of antibodies to measles virus. CT scan carried out during this acute phase of relapse demonstrated white matter enhancement affecting the cortical white matter of the frontal lobes and corpus callosum. These features indicate that active demyelination occurs during acute relapse in subacute sclerosing panencephalitis (SSPE) and suggest that immunotherapy should be considered during this acute phase. (orig.).

  4. Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.

    Science.gov (United States)

    Xu, Xiaohua; Warrington, Arthur E; Bieber, Allan J; Rodriguez, Moses

    2011-07-01

    Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes

  5. IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection

    Science.gov (United States)

    Ramos, Hilario J.; Lanteri, Marion C.; Blahnik, Gabriele; Negash, Amina; Suthar, Mehul S.; Brassil, Margaret M.; Sodhi, Khushbu; Treuting, Piper M.; Busch, Michael P.; Norris, Philip J.; Gale, Michael

    2012-01-01

    West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8+ T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons. PMID:23209411

  6. The gateway theory: bridging neural and immune interactions in the CNS

    Science.gov (United States)

    Kamimura, Daisuke; Yamada, Moe; Harada, Masaya; Sabharwal, Lavannya; Meng, Jie; Bando, Hidenori; Ogura, Hideki; Atsumi, Toru; Arima, Yasunobu; Murakami, Masaaki

    2013-01-01

    The central nervous system (CNS) is considered an immune-privileged tissue protected by a specific vessel structure, the blood-brain barrier (BBB). Upon infection or traumatic injury in the CNS, the BBB is breached, and various immune cells are recruited to the affected area. In the case of autoimmune diseases in the CNS like multiple sclerosis (MS), autoreactive T cells against some CNS-specific antigens can theoretically attack neurons throughout the CNS. The affected CNS regions in MS patients can be detected as multiple focal plaques in the cerebrum, thoracic cord, and other regions. Vision problems are often associated with the initial phase of MS, suggesting a disturbance in the optic nerves. These observations raise the possibility that there exist specific signals that direct autoreactive T cells past the BBB and into particular sites of the CNS. Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we recently defined the mechanism of the pathogenesis in which regional neural stimulations modulate the status of the blood vessel endothelium to allow the invasion of autoreactive T cells into specific sites of the CNS via the fifth lumbar cord. This gate for autoreactive T cells can be artificially manipulated by removing gravity forces on the hind legs or by electric pulses to the soleus muscles, quadriceps, and triceps of mice, resulting in an accumulation of autoreactive T cells in the intended regions via the activation of regional neurons. Gating blood vessels by regional neural stimulations, a phenomenon we call the gateway theory, has potential therapeutic value not only in preventing autoimmunity, but also in augmenting the effects of cancer immunotherapies. PMID:24194696

  7. Teriflunomide slows BVL in relapsing MS

    Science.gov (United States)

    Radue, Ernst-Wilhelm; Gaetano, Laura; Mueller-Lenke, Nicole; Cavalier, Steve; Thangavelu, Karthinathan; Panzara, Michael A.; Donaldson, Jessica E.; Woodward, Fiona M.; Wolinsky, Jerry S.; Kappos, Ludwig

    2017-01-01

    Objective: To assess, using structural image evaluation using normalization of atrophy (SIENA), the effect of teriflunomide, a once-daily oral immunomodulator, on brain volume loss (BVL) in patients with relapsing forms of MS enrolled in the phase 3 TEMSO study. Methods: TEMSO MR scans were analyzed (study personnel masked to treatment allocation) using SIENA to assess brain volume changes between baseline and years 1 and 2 in patients treated with placebo or teriflunomide. Treatment group comparisons were made via rank analysis of covariance. Results: Data from 969 patient MRI visits were included in this analysis: 808 patients had baseline and year 1 MRI; 709 patients had baseline and year 2 MRI. Median percentage BVL from baseline to year 1 and year 2 for placebo was 0.61% and 1.29%, respectively, and for teriflunomide 14 mg, 0.39% and 0.90%, respectively. BVL was lower for teriflunomide 14 mg vs placebo at year 1 (36.9% relative reduction, p = 0.0001) and year 2 (30.6% relative reduction, p = 0.0001). Teriflunomide 7 mg was also associated with significant reduction in BVL vs placebo over the 2-year study. The significant effects of teriflunomide 14 mg on BVL were observed in both patients with and without on-study disability worsening. Conclusions: The significant reduction of BVL vs placebo over 2 years achieved with teriflunomide is consistent with its effects on delaying disability worsening and suggests a neuroprotective potential. Classification of evidence: Class II evidence shows that teriflunomide treatment significantly reduces BVL over 2 years vs placebo. ClinicalTrials.gov identifier: NCT00134563. PMID:28828394

  8. Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Anindya Bhattacharya

    2018-02-01

    Full Text Available The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and in vivo effects of brain-penetrant P2X7 antagonists. Likewise, significant progress has been made around the medicinal chemistry of CNS P2X7 ligands, as antagonists for in vivo target validation in models of CNS diseases, to identification of two clinical compounds (JNJ-54175446 and JNJ-55308942 and finally, discovery of P2X7 PET ligands. This review is an attempt to bring together the current understanding of P2X7 in the CNS with a focus on P2X7 as a drug target in neuropsychiatric disorders.

  9. Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression)

    NARCIS (Netherlands)

    Appelhof, Bente C.; Huyser, Jochanan; Verweij, Mijke; Brouwer, Jantien P.; van Dyck, Richard; Fliers, Eric; Hoogendijk, Witte J. G.; Tijssen, Jan G. P.; Wiersinga, Wilmar M.; Schene, Aart H.

    2006-01-01

    BACKGROUND: Knowledge of pathogenic mechanisms and predictors of relapse in major depressive disorder is still limited. Hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation is thought to be related to the development and course of depression. METHODS: We investigated whether

  10. Health-related quality of life of significant others of patients with malignant CNS versus non-CNS tumors: a comparative study

    NARCIS (Netherlands)

    Boele, F.W.; Heimans, J.J.; Aaronson, N.K.; Taphoorn, M.J.B.; Postma, T.J.; Reijneveld, J.C.; Klein, M.

    2013-01-01

    It is often assumed that brain tumor patients’ significant others (SOs: partners, other family members or close friends) may face greater stress than those of patients with malignancies not involving the central nervous system (CNS), due to progressive changes in neurological and cognitive

  11. Prognostic factors and impact of adjuvant treatments on local and metastatic relapse of soft-tissue sarcoma patients in the competing risks setting.

    Science.gov (United States)

    Italiano, Antoine; Le Cesne, Axel; Mendiboure, Jean; Blay, Jean-Yves; Piperno-Neumann, Sophie; Chevreau, Christine; Delcambre, Corinne; Penel, Nicolas; Terrier, Philippe; Ranchere-Vince, Dominique; Lae, Marick; Le Guellec, Sophie; Michels, Jean-Jacques; Robin, Yves Marie; Bellera, Carine; Bonvalot, Sylvie

    2014-11-01

    In the medical literature many analyses of outcomes of sarcoma patients were performed without regard to the problem of "competing risks." We analyzed local relapse-free and metastasis-free survival in a population of 3255 adult patients with a primary soft-tissue sarcoma (STS) included in the French Sarcoma Group database. Cumulative incidence of local and metastatic relapse was estimated by accounting for death as a competing event. On multivariate analysis, age, tumor site, histological subtype, and grade were independent adverse prognostic factors for local relapse, whereas tumor depth and size had no influence. Histological subtype, tumor depth, tumor size, and grade were independent adverse prognostic factors for metastatic relapse. Despite a higher incidence of competing deaths in patients managed with adjuvant radiotherapy than in patients not receiving radiotherapy, adjuvant radiotherapy was associated with a significant benefit in terms of local relapse-free survival. Despite a similar cumulative incidence of competing deaths in patients with grade 2 and grade 3 disease, we found that the benefit of adjuvant chemotherapy was present only in patients with grade 3 and not in patients with grade 2 disease. In the setting of competing risks, tumor biology reflected by histological grade is a crucial predictor of local relapse, whereas tumor depth and size have poor if any influence. Grade could also predict the benefit of adjuvant chemotherapy in patients with STS. © 2014 American Cancer Society.

  12. Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial.

    Science.gov (United States)

    Mauriac, L; Keshaviah, A; Debled, M; Mouridsen, H; Forbes, J F; Thürlimann, B; Paridaens, R; Monnier, A; Láng, I; Wardley, A; Nogaret, J-M; Gelber, R D; Castiglione-Gertsch, M; Price, K N; Coates, A S; Smith, I; Viale, G; Rabaglio, M; Zabaznyi, N; Goldhirsch, A

    2007-05-01

    Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.

  13. The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking.

    Science.gov (United States)

    Nair, Sunila G; Adams-Deutsch, Tristan; Epstein, David H; Shaham, Yavin

    2009-09-01

    Relapse to old, unhealthy eating habits is a major problem in human dietary treatments. The mechanisms underlying this relapse are unknown. Surprisingly, until recently this clinical problem has not been systematically studied in animal models. Here, we review results from recent studies in which a reinstatement model (commonly used to study relapse to abused drugs) was employed to characterize the effect of pharmacological agents on relapse to food seeking induced by either food priming (non-contingent exposure to small amounts of food), cues previously associated with food, or injections of the pharmacological stressor yohimbine. We also address methodological issues related to the use of the reinstatement model to study relapse to food seeking, similarities and differences in mechanisms underlying reinstatement of food seeking versus drug seeking, and the degree to which the reinstatement procedure provides a suitable model for studying relapse in humans. We conclude by discussing implications for medication development and future research. We offer three tentative conclusions: (1)The neuronal mechanisms of food-priming- and cue-induced reinstatement are likely different from those of reinstatement induced by the pharmacological stressor yohimbine. (2)The neuronal mechanisms of reinstatement of food seeking are possibly different from those of ongoing food-reinforced operant responding. (3)The neuronal mechanisms underlying reinstatement of food seeking overlap to some degree with those of reinstatement of drug seeking.

  14. Effectiveness of Mindfulness-Based Relapse Prevention in opioid Dependence Treatment &Mental Health

    Directory of Open Access Journals (Sweden)

    2008-11-01

    Findings: therapy compliance, retention in treatment, decrease in somatic symptoms, anxiety, social dysfunction and increase in health was significantly in both combination of psychological intervention method than the Naltroxan group. Mindfulness-based on relapse prevention was more effective than CBT relapse prevention in decreasing of, social dysfunction, relapse prevention, increase of therapy compliance, and health. Results: Mindfulness based relapse prevention was superior to CBT and Naltroxan and considerably increased effectiveness of opioid relapse prevention therapy.

  15. Relapse to drug seeking following prolonged abstinence: the role of environmental stimuli

    OpenAIRE

    Fuchs, R.A.; Lasseter, H.C.; Ramirez, D.R.; Xie, X

    2008-01-01

    Successful treatment of drug addiction must involve relapse prevention informed by our understanding of the neurobiological bases of drug relapse. In humans, exposure to drug-associated environmental stimuli can elicit drug craving and relapse. Because exposure to drug-paired stimuli similarly induces drug-seeking behavior in laboratory animals, several animal models of drug relapse have been developed. Here, we review animal models of cue-induced drug relapse and critically evaluate their va...

  16. Alcohol-seeking and relapse: A focus on incentive salience and contextual conditioning.

    Science.gov (United States)

    Valyear, Milan D; Villaruel, Franz R; Chaudhri, Nadia

    2017-08-01

    Environmental stimuli that reliably accompany alcohol intake can become associated with the pharmacological effects of alcohol through classical (Pavlovian) conditioning. Of growing interest to addiction researchers is whether or not this process results in the attribution of incentive salience to alcohol-predictive cues, which could motivate alcohol-seeking behavior and relapse. To evaluate this question, we present a review of rodent behavioral studies that examined the capacity of alcohol-predictive cues to (i) support sign-tracking behavior, (ii) serve as conditioned reinforcers, and (iii) produce Pavlovian-to-instrumental transfer. A second, emerging area of research is focused on delineating the role of context in alcohol-seeking behavior and relapse. Here, we review studies showing that alcohol-associated contexts (i) support conditioned place preference, (ii) renew extinguished alcohol-seeking behavior, and (iii) modulate alcohol-seeking responses elicited by discrete alcohol-predictive cues. These behavioral effects may be mediated by unique psychological processes, and have important implications for cue-reactivity studies and neurobiological research. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Relapse to driving under the influence (DUI): a review.

    Science.gov (United States)

    Nochajski, Thomas H; Stasiewicz, Paul R

    2006-03-01

    Driving under the influence (DUI) is a major public health problem. In 2003, there were 17,401 alcohol-related crash fatalities. Although there has been a large decrease in the fatality rates over the past two decades, further progress has stalled in recent years. This plateau in the injury and death rates resulting from impaired driving has been attributed, in part, to the persistent or repeat DUI offender. Broadly defined, repeat offenders are those individuals who, following an initial DUI arrest, relapse to driving under the influence of alcohol and other drugs. In this paper, we first provide a brief overview of several models of DUI relapse. We then review the empirical literature on DUI relapse, the data describing characteristics of first-time and repeat DUI offenders, and, especially, studies that have evaluated the impact of legal sanctions and rehabilitation programs on subsequent DUI behavior. The data reveal that DUI offenders are a heterogeneous group, and that simple models relying on only one or two behavioral domains (e.g., driving characteristics, demographics) to explain DUI relapse are insufficient to account for the DUI behavior of offenders. To advance our understanding of DUI relapse, we argue for development and testing of multifactorial models focusing on the interplay of legal, social and psychological factors that describe and explain relapse among DUI offenders. By recognizing the heterogeneity within the offender population it will be easier for researchers and clinicians to identify subgroups that are at high-risk for relapse and which should be targeted by prevention and intervention programs.

  18. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies.

    Science.gov (United States)

    Nikolic, Katarina; Mavridis, Lazaros; Djikic, Teodora; Vucicevic, Jelica; Agbaba, Danica; Yelekci, Kemal; Mitchell, John B O

    2016-01-01

    HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands

  19. Large linear plasmids of Borrelia species that cause relapsing fever.

    Science.gov (United States)

    Miller, Shelley Campeau; Porcella, Stephen F; Raffel, Sandra J; Schwan, Tom G; Barbour, Alan G

    2013-08-01

    Borrelia species of relapsing fever (RF) and Lyme disease (LD) lineages have linear chromosomes and both linear and circular plasmids. Unique to RF species, and little characterized to date, are large linear plasmids of ∼160 kb, or ∼10% of the genome. By a combination of Sanger and next-generation methods, we determined the sequences of large linear plasmids of two New World species: Borrelia hermsii, to completion of its 174-kb length, and B. turicatae, partially to 114 kb of its 150 kb. These sequences were then compared to corresponding sequences of the Old World species B. duttonii and B. recurrentis and to plasmid sequences of LD Borrelia species. The large plasmids were largely colinear, except for their left ends, about 27 kb of which was inverted in New World species. Approximately 60% of the B. hermsii lp174 plasmid sequence was repetitive for 6 types of sequence, and half of its open reading frames encoded hypothetical proteins not discernibly similar to proteins in the database. The central ∼25 kb of all 4 linear plasmids was syntenic for orthologous genes for plasmid maintenance or partitioning in Borrelia species. Of all the sequenced linear and circular plasmids in Borrelia species, the large plasmid's putative partition/replication genes were most similar to those of the 54-kb linear plasmids of LD species. Further evidence for shared ancestry was the observation that two of the hypothetical proteins were predicted to be structurally similar to the LD species' CspA proteins, which are encoded on the 54-kb plasmids.

  20. Quantitative plasma proteomic profiling identifies the vitamin E binding protein afamin as a potential pathogenic factor in SIV induced CNS disease.

    Science.gov (United States)

    Pendyala, Gurudutt; Trauger, Sunia A; Siuzdak, Gary; Fox, Howard S

    2010-01-01

    Investigating, predicting, diagnosing, and treating HIV-1-associated neurocognitive disorder (HAND) has been hindered by the lack of disease-related molecular markers. In this study, plasma from rhesus monkeys (n = 6), before and after infection with simian immunodeficiency virus (SIV), was profiled to obtain differential fingerprints in protein expression during SIV-induced central nervous system (CNS) disease. A quantitative proteomic analysis was performed by means of isobaric tag for relative and absolute quantification (iTRAQ) labeling, using multidimensional liquid chromatography tandem mass spectrometry (LC-MS/MS) run on a linear ion trap mass spectrometer in an integrated mode comprising pulsed-Q-dissociation (PQD) and CID. Among a panel of proteins showing differential expression following SIV infection, we identified afamin, a member of the albumin superfamily, to be significantly down regulated after infection. Validation by Western blot confirmed this observation and, given its potential implication in neuroprotection by transport of alpha-tocopherol (alphaTocH), provides new avenues into further understanding HIV induced CNS disease. iTRAQ-based LC-MS/MS provides a valuable platform for plasma protein profiling and has important implications in identifying molecular markers relevant for the pathogenesis of neurodegenerative diseases. Using such an approach, we show its successful application in identifying differential fingerprints in SIV/HIV induced CNS disease.

  1. Histological Disease Activity as a Predictor of Clinical Relapse Among Patients With Ulcerative Colitis: Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Park, Sunhee; Abdi, Tsion; Gentry, Mark; Laine, Loren

    2016-12-01

    Endoscopic remission in ulcerative colitis (UC) is associated with improved clinical outcomes. We assessed whether histological remission predicts clinical outcomes, estimated the magnitude of effect, and determined whether histological remission provides additional prognostic utility beyond clinical or endoscopic remission. Bibliographic databases were searched for studies in inflammatory bowel disease providing baseline histological status and relation to an outcome of clinical relapse or exacerbation. Our primary analysis compared the proportion of patients with study-defined histological remission vs. the proportion with histological activity who developed clinical relapse/exacerbation. Additional analyses compared the proportion with relapse/exacerbation for the presence vs. absence of different histological features and for histological remission vs. endoscopic remission and clinical remission. A fixed-effect model was used for meta-analysis, with a random-effects model if statistical heterogeneity was present. Fifteen studies met inclusion criteria. The major methodological shortcoming was lack of blinding of the assessor of clinical relapse/exacerbation to baseline histological status in 13 of the 15 studies. Relapse/exacerbation was less frequent with baseline histological remission vs. histological activity (relative risk (RR)=0.48, 95% confidence interval (CI) 0.39-0.60) and vs. baseline clinical and endoscopic remission (RR=0.81, 95% CI 0.70-0.94). Relapse/exacerbation was also less common in the absence vs. presence of specific histological features: neutrophils in epithelium (RR=0.32, 95% CI 0.23-0.45), neutrophils in lamina propria (RR=0.43, 95% CI 0.32-0.59), crypt abscesses (RR=0.38, 95% CI 0.27-0.54), eosinophils in the lamina propria (RR=0.43, 95% CI 0.21-0.91), and chronic inflammatory cell infiltrate (RR=0.28, 95% CI 0.10-0.75). Histological remission was present in 964 (71%) of the 1360 patients with combined endoscopic and clinical remission

  2. A comparison of patients relapsing to addictive drug use with non-relapsing patients following residential addiction treatment in Antigua.

    Science.gov (United States)

    Martin, T C; Josiah-Martin, J A; Kosakoski, J; Norton, K; Sinnott, T

    2005-06-01

    The outcome of a 29-day residential addiction treatment programme for persons from Antigua and Barbuda with addiction to drugs or alcohol was assessed. All 100 patients entering the drug and alcohol treatment programme at Crossroads Centre Antigua between November 1998 and October 2002 were included. All patients were assessed with regards to drug or alcohol use or abstinence in November 2002 using telephone and mail follow-up as well as informal follow-up with families and other community contacts. Crossroads Centre Antigua is a 35 bed, 29-day residential treatment centre for drug and alcohol addiction serving patients from developed countries (85%) and from the Caribbean region (15%). Patients records were also reviewed to obtain age, gender, ethnicity, drug of choice, years of problematic use, completion of the 29 day programme, family member participation at Crossroads Centre Antigua (a four-day programme) and acceptance of halfway house placement. Of the 100 Antiguan patients admitted, 46 (46%) were abstinent (non-relapsers) at average 20.7+/-14.7 months after treatment. Abstinence did not have to be continuous. Forty-nine were known to be using drug or alcohol (49%) and five (5%) were lost to follow-up and considered to be using drugs (relapsers). Age (37.5 vs 41.1 years), gender (28% vs 22% female), ethnicity (87% vs 87% Afro-Caribbean), years of harmful use (12.7 vs 12.5 years) did not differ significantly between relapsers and non-relapsers. Crack cocaine use (67% vs 65%) and alcohol use (26% vs 31%) as primary addiction did not differ significantly between relapsers and non-relapsers. Relapsers were significantly less likely to complete the 29- day programme (81% vs 100%, p house placement (4% vs 54%, p house placement.

  3. Classification of relapse pattern in clubfoot treated with Ponseti technique

    Directory of Open Access Journals (Sweden)

    Atul Bhaskar

    2013-01-01

    In the bilateral group, 21 children (38 feet, 28% had Grade IA relapse. Twenty four children (46 feet, 34% had dynamic intoeing (Grade IB on walking. Thirteen children (22 feet, 16% had true ankle equinus of varying degress (Grade IIA; eight children (13 feet, 9.7% had fixed adduction deformity of the forefoot (Grade IIB and seven children (14 feet, 10.7% had two or more fixed deformities. In the unilateral group seven cases (38% had reduced dorsiflexion (Grade IA, six (33% had dynamic adduction (Grade IB, two (11% had fixed equinus and adduction respectively (Grade IIA and IIB and one (5% child had fixed equinus and adduction deformity (Grade III. The relapses were treated by full time splint application, re-casting, tibialis anterior transfer, posterior release, corrective lateral closing wedge osteotomy and a comprehensive subtalar release. Splint compliance was compromised in both groups. Conclusion: Relapse pattern in clubfeet can be broadly classified into three distinct subsets. Early identification of relapses and early intervention will prevent major soft tissue surgery. A universal language of relapse pattern will allow comparison of results of intervention.

  4. Relapse Prevention: An Overview of Marlatts Cognitive- Behavioral Model

    Directory of Open Access Journals (Sweden)

    2008-11-01

    Full Text Available Relapse prevention(RPis an important component of alcoholism treatment. The RP model proposed by Marlatt and Gordon suggests that both immediate determinants (e.g.,high- risk situations, coping skills, outcome expectancies, and the abstinence violation effect and covert antecedents (e.g., lifestyle factor and urges and cravings can contribute to relapse.The RP model also incorporates numerous specific and global intervention strategies that allow therapist and client to address each step of the relapse process. Specific interventions include identifying specific high-risk situations for each client and enhancing the client's skills for coping with those situations, increasing the client's self- efficacy, eliminating myths regarding alcohol's effects, managing lapses, and restructuring the client's perceptions of the relapse process. Global strategies comprise balancing the client's lifestyle and helping him or her develop positive addictions, employing stimulus control techniques and urgemanagement techniques, and developing relapse road maps. Several studies have provided theoretical and practical support for the RP model.

  5. Next generation sequencing identifies 'interactome' signatures in relapsed and refractory metastatic colorectal cancer.

    Science.gov (United States)

    Johnson, Benny; Cooke, Laurence; Mahadevan, Daruka

    2017-02-01

    In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms. Web-based bioinformatics tools (Reactome/Enrichr) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy. Pts had progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab and/or panitumumab. Most common histology was adenocarcinoma (colon N=29; rectal N=3). Of the mutations TP53 was the most common, followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average had ≥5 unique mutations. The most frequent activated signaling pathways were: HER2, fibroblast growth factor receptor (FGFR), p38 through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Dominant driver oncogene mutations do not always equate to oncogenic dependence, hence understanding pathogenic 'interactome(s)' in individual pts is key to both clinically relevant targets and in choosing the next best therapy. Mutational signatures derived from corresponding 'pathway-networks' represent a meaningful tool to (I) evaluate functional investigation in the laboratory; (II) predict response to drug therapy; and (III) guide rational drug combinations in relapsed and refractory mCRC pts.

  6. Drugs in development for relapsing multiple sclerosis.

    Science.gov (United States)

    Ali, Rehiana; Nicholas, Richard St John; Muraro, Paolo Antonio

    2013-05-01

    drugs in development, and it is likely that BG-12 will be licensed this year. This has been licensed for psoriasis so there are good safety data in humans that may also hold true in MS; however, its three times daily dosage will probably impact on patient compliance. Laquinimod has lower efficacy than BG-12 but appears safe and could find a place as a first-line agent. Teriflunomide has just been licensed by the US FDA and may challenge the current injectable first-line therapies as it has a similar efficacy but the advantage of being taken orally. However, risk of teratogenicity may caution against its use in some women of child-bearing potential. This review will examine drugs that have been recently approved as well as those that are in late phase 2 or 3 development as treatment for relapsing MS, highlighting their mechanism of action as well as the clinical trial and safety data before discussing their potential for success in an increasingly florid and complex DMT armamentarium.

  7. Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS.

    Science.gov (United States)

    Kanaan, Nicholas M; Sellnow, Rhyomi C; Boye, Sanford L; Coberly, Ben; Bennett, Antonette; Agbandje-McKenna, Mavis; Sortwell, Caryl E; Hauswirth, William W; Boye, Shannon E; Manfredsson, Fredric P

    2017-09-15

    Adeno-associated virus (AAV) is the most common vector for clinical gene therapy of the CNS. This popularity originates from a high safety record and the longevity of transgene expression in neurons. Nevertheless, clinical efficacy for CNS indications is lacking, and one reason for this is the relatively limited spread and transduction efficacy in large regions of the human brain. Using rationally designed modifications of the capsid, novel AAV capsids have been generated that improve intracellular processing and result in increased transgene expression. Here, we sought to improve AAV-mediated neuronal transduction to minimize the existing limitations of CNS gene therapy. We investigated the efficacy of CNS transduction using a variety of tyrosine and threonine capsid mutants based on AAV2, AAV5, and AAV8 capsids, as well as AAV2 mutants incapable of binding heparan sulfate (HS). We found that mutating several tyrosine residues on the AAV2 capsid significantly enhanced neuronal transduction in the striatum and hippocampus, and the ablation of HS binding also increased the volumetric spread of the vector. Interestingly, the analogous tyrosine substitutions on AAV5 and AAV8 capsids did not improve the efficacy of these serotypes. Our results demonstrate that the efficacy of CNS gene transfer can be significantly improved with minor changes to the AAV capsid and that the effect is serotype specific. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. Foxp3+ regulatory T cells control persistence of viral CNS infection.

    Directory of Open Access Journals (Sweden)

    Dajana Reuter

    Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

  9. The rostral migratory stream plays a key role in intranasal delivery of drugs into the CNS.

    Directory of Open Access Journals (Sweden)

    Robert A Scranton

    2011-04-01

    Full Text Available The blood brain barrier (BBB is impermeable to most drugs, impeding the establishment of novel neuroprotective therapies and strategies for many neurological diseases. Intranasal administration offers an alternative path for efficient drug delivery into the CNS. So far, the anatomical structures discussed to be involved in the transport of intranasally administered drugs into the CNS include the trigeminal nerve, olfactory nerve and the rostral migratory stream (RMS, but the relative contributions are debated.In the present study we demonstrate that surgical transection, and the resulting structural disruption of the RMS, in mice effectively obstructs the uptake of intranasally administered radioligands into the CNS. Furthermore, using a fluorescent cell tracer, we demonstrate that intranasal administration in mice allows agents to be distributed throughout the entire brain, including olfactory bulb, hippocampus, cortex and cerebellum.This study provides evidence of the vital role the RMS has in the CNS delivery of intranasally administered agents. The identification of the RMS as the major access path for intranasally administered drugs into the CNS may contribute to the development of treatments that are tailored for efficient transport within this structure. Research into the RMS needs to continue to elucidate its limitations, capabilities, mechanisms of transport and potential hazards before we are able to advance this technique into human research.

  10. Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Oskarsson, Trausti; Söderhäll, Stefan; Arvidson, Johan

    2017-01-01

    . PROCEDURE: In this retrospective population-based study, we described the causes of death and estimated the risk for treatment-related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL-92 and ALL-2000 trials. RESULTS: Among the 483...... patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment-related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial......, none of the 17 patients with Down syndrome died of treatment-related causes. CONCLUSIONS: Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important...

  11. Dimethyl fumarate for relapsing-remitting multiple sclerosis.

    Science.gov (United States)

    2014-09-01

    For many years the only drugs licensed for the treatment of multiple sclerosis (MS) were administered by injection (interferon beta, glatiramer and ▼natalizumab). Recently, three oral drugs have become available. We have previously reviewed the use of ▼fingolimod for highly active relapsing-remitting MS1 and ▼teriflunomide for the management of relapsing-remitting MS in adults.2 Here, we review the evidence for ▼dimethyl fumarate (Tecfidera-Biogen Idec Ltd) for the treatment of adults with relapsing-remitting MS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Relapse of Multiple Myeloma Presenting as Lower Lip Numbness

    Directory of Open Access Journals (Sweden)

    Yusra M. Al-Riyami

    2016-11-01

    Full Text Available Multiple myeloma (MM is an uncommon malignancy characterised by the proliferation of clonal plasma cells. There are few published reports describing the extramedullary presentation of MM manifesting primarily in the head and neck region. In addition, the occurrence of an isolated relapse of MM in these sites is exceedingly rare. We report a 56-year-old female who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2010 with sudden-onset numbness of the lower lip. She had a history of MM in remission following chemotherapy and a bone marrow transplant. Clinical and radiographic examinations were indicative of a possible relapse of MM, which was subsequently confirmed by bone marrow aspiration and histopathological evaluation. This unique case highlights the unusual site of relapse of a haematolymphoid malignancy.

  13. [Infectious gastroenteritis in relapses of inflammatory bowel disease. Therapeutic implications].

    Science.gov (United States)

    Baliellas, C; Xiol, X; Barenys, M; Saavedra, J; Casanovas, T; Iborra, M; Sesé, E

    1996-06-01

    The incidence and clinical importance of infectious gastroenteritis was studied in 67 consecutive relapses of inflammatory bowel disease (IBD). A stool culture was done in every case before starting treatment. Stool culture was positive in 6 relapses (8.9%): Four were exacerbations of ulcerative colitis and two of Crohn's disease (8.8% in ulcerative colitis vs 9% in Crohn's disease; NS). The microorganisms isolated were Campylobacter jejuni in three cases, Salmonella enteritidis in two and Staphylococcus aureus in one case. There were not clinical differences between patients with positive and negative stool culture. Treated with antibiotics, stool cultures became negative in all of them but only in three the disease was controlled. The other three had to be treated with corticosteroids to achieve remission. We conclude that stool culture should be practised in all relapses of IBD and in case of positivity, antibiotic therapy should be started. With this approach the use of corticosteroids can be avoided in some patients.

  14. A focus group study of predictors of relapse in electronic gaming machine problem gambling, part 1: factors that 'push' towards relapse.

    Science.gov (United States)

    Oakes, J; Pols, R; Battersby, M; Lawn, S; Pulvirenti, M; Smith, D

    2012-09-01

    This study aimed to develop an empirically based description of relapse in Electronic Gaming Machine problem gambling. In this paper the authors describe part one of a two part, linked relapse process: the 'push' towards relapse. In this two-part process, factors interact sequentially and simultaneously within the problem gambler to produce a series of mental and behavioural events that ends with relapse when the 'push' overcomes 'pull' (part one); or as described in part two, continued abstinence when 'pull' overcomes 'push'. In the second paper, the authors describe how interacting factors 'pull' the problem gambler away from relapse. This study used four focus groups comprising thirty participants who were gamblers, gamblers' significant others, therapists and counsellors. The groups were recorded, recordings were then transcribed and analysed using thematic, textual analysis. With the large number of variables considered to be related to relapse in problem gamblers, five key factors emerged that 'push' the gambler towards relapse. These were urge, erroneous cognitions about the outcomes of gambling, negative affect, dysfunctional relationships and environmental gambling triggers. Two theories emerged: (1) each relapse episode comprised a sequence of mental and behavioural events, which evolves over time and was modified by factors that 'push' this sequence towards relapse and (2) a number of gamblers develop an altered state of consciousness during relapse described as the 'zone' which prolongs the relapse.

  15. Predictors of driving in individuals with relapsing-remitting multiple sclerosis.

    Science.gov (United States)

    Akinwuntan, Abiodun Emmanuel; Devos, Hannes; Stepleman, Lara; Casillas, Rhonda; Rahn, Rebecca; Smith, Suzanne; Williams, Mitzi Joi

    2013-03-01

    We previously reported that performance on the Stroke Driver Screening Assessment (SDSA), a battery of four cognitive tests that takes less than 30 min to administer, predicted the driving performance of participants with multiple sclerosis (MS) on a road test with 86% accuracy, 80% sensitivity, and 88% specificity. In this study, we further investigated if the addition of driving-related physical and visual tests and other previously identified cognitive predictors, including performance on the Useful Field of View test, will result in a better accuracy of predicting participants' on-road driving performance. Forty-four individuals with relapsing-remitting MS (age = 46 ± 11 years, 37 females) and Expanded Disability Status Scale values between 1 and 7 were administered selected physical, visual and cognitive tests including the SDSA. The model that explained the highest variance of participants' performance on a standardized road test was identified using multiple regression analysis. A discriminant equation containing the tests included in the best model was used to predict pass or fail performance on the test. Performance on 12 cognitive and three visual tests were significantly associated with performance on the road test. Five of the tests together explained 59% of the variance and predicted the pass or fail outcome of the road test with 91% accuracy, 70% sensitivity, and 97% specificity. Participants' on-road performance was more accurately predicted by the model identified in this study than using only performance on the SDSA test battery. The five psychometric/off-road tests should be used as a screening battery, after which a follow-up road test should be conducted to finally decide the fitness to drive of individuals with relapsing-remitting MS. Future studies are needed to confirm and validate the findings in this study.

  16. Sexual dysfunction in relapsing-remitting multiple sclerosis: magnetic resonance imaging, clinical, and psychological correlates.

    Science.gov (United States)

    Barak, Y; Achiron, A; Elizur, A; Gabbay, U; Noy, S; Sarova-Pinhas, I

    1996-01-01

    The purpose of this study was to examine the sexual complaints and severity of sexual dysfunction in relapsing-remitting multiple sclerosis patients and to correlate them with psychological, neurological, and radiological variables. Frequency and characteristics of sexual disturbances were reported by 41 multiple sclerosis patients (32 females, 9 males; mean age 35.4 +/- 10.2 y). Clinical neurologic variables tested were disease duration, exacerbation rate, and disability; psychological variables tested were anxiety and depression. All patients underwent a brain magnetic resonance imaging (MRI) scan at the time of this study. The sexual dysfunction questionnaire included items based on the 3 phases of human sexual response: loss of libido, excitement (arousal difficulties, impotence, premature ejaculation), and anorgasmia. Five males (55.5%) and 16 females (50.0%) reported at least 1 sexual disturbance. The most frequent dysfunctions were loss of libido (26.8%) and arousal difficulties (19.5%). Females rated their difficulties as more severe. Sexual dysfunctions correlated with depression, (r = 0.68, P = 0.001). No correlation between MRI score and depression was found. Anorgasmia correlated with brain stem and pyramidal abnormalities (r = 0.56, P = 0.011; r = 0.56, P = 0.012, respectively). The total area of lesions (plaques) on the brain MRI scan also correlated with anorgasmia (r = 0.41, P = 0.02). Sexual dysfunctions in multiple sclerosis patients are frequent, are mild to moderate in severity, correlate with depression and in some cases central nervous system (CNS) demyelinating process, and thus may be related either to the psychological impact of this disease or to specific organic lesions in the brain. PMID:8754594

  17. Tick-Borne Relapsing Fever Spirochetes in the Americas

    Directory of Open Access Journals (Sweden)

    Job E. Lopez

    2016-08-01

    Full Text Available Relapsing fever spirochetes are tick- and louse-borne pathogens that primarily afflict those in impoverished countries. Historically the pathogens have had a significant impact on public health, yet currently they are often overlooked because of the nonspecific display of disease. In this review, we discuss aspects of relapsing fever (RF spirochete pathogenesis including the: (1 clinical manifestation of disease; (2 ability to diagnose pathogen exposure; (3 the pathogen’s life cycle in the tick and mammal; and (4 ecological factors contributing to the maintenance of RF spirochetes in nature.

  18. Late Relapses in Stage I Testicular Cancer Patients on Surveillance

    DEFF Research Database (Denmark)

    Mortensen, Mette Saksø; Lauritsen, Jakob; Kier, Maria Gry Gundgaard

    2016-01-01

    Cancer (DaTeCa) database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We estimated survival and relapse probabilities and compared the results using log-rank tests and Cox regression analyses. We compared differences in patient characteristics by using χ(2), Fisher exact, and Mann-Whitney tests...... no significant differences in patient characteristics at orchiectomy or relapse. Limitations include retrospective design and exclusion of patients who had been offered adjuvant therapy. CONCLUSIONS: The risk of VLR is minimal, and the patients carry a good prognosis. Patient characteristics of CS-1 surveillance...

  19. CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases

    DEFF Research Database (Denmark)

    Kerrn-Jespersen, B M; Lindelof, Mette; Illes, Zsolt

    2014-01-01

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appeara......Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt......-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We...... therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination...

  20. Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9.

    Science.gov (United States)

    Saraiva, Joana; Nobre, Rui Jorge; Pereira de Almeida, Luis

    2016-11-10

    Several attempts have been made to discover the ideal vector for gene therapy in central nervous system (CNS). Adeno-associated viruses (AAVs) are currently the preferred vehicle since they exhibit stable transgene expression in post-mitotic cells, neuronal tropism, low risk of insertional mutagenesis and diminished immune responses. Additionally, the discovery that a particular serotype, AAV9, bypasses the blood-brain barrier has raised the possibility of intravascular administration as a non-invasive delivery route to achieve widespread CNS gene expression. AAV9 intravenous delivery has already shown promising results for several diseases in animal models, including lysosomal storage disorders and motor neuron diseases, opening the way to the first clinical trial in the field. This review presents an overview of clinical trials for CNS disorders using AAVs and will focus on preclinical studies based on the systemic gene delivery using AAV9. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos

    DEFF Research Database (Denmark)

    Dittrich, Sabine; Rattanavong, Sayaphet; Lee, Sue J

    2015-01-01

    BACKGROUND: Scrub typhus (caused by Orientia tsutsugamushi), murine typhus (caused by Rickettsia typhi), and leptospirosis are common causes of febrile illness in Asia; meningitis and meningoencephalitis are severe complications. However, scarce data exist for the burden of these pathogens...... infections (p=0·076). INTERPRETATION: Our data suggest that R typhi/Rickettsia spp, O tsutsugamushi, and Leptospira spp infections are important causes of CNS infections in Laos. Antibiotics, such as tetracyclines, needed for the treatment of murine typhus and scrub typhus, are not routinely advised...... for empirical treatment of CNS infections. These severely neglected infections represent a potentially large proportion of treatable CNS disease burden across vast endemic areas and need more attention. FUNDING: Wellcome Trust UK....

  2. The role of the psychosocial oncology CNS in a rural cancer outreach program.

    Science.gov (United States)

    Watson, A C

    1993-09-01

    The high cancer mortality rates in rural areas of Virginia are discussed, and cancer risk factors particular to the rural population are delineated. Rural health beliefs and their relationship to delay in seeking cancer care in rural areas are examined. A rural cancer outreach program and the role of the oncology clinical nurse specialist (CNS) in the program are described in terms of Psychosocial Oncology CNS subroles, i.e., clinician, consultant-liaison, networker/linker, coach, educator, change agent, researcher, and supervisor/supervisee. Effectiveness of the role in the program is analyzed. An innovative urban-rural nurse oncology program is delineated, and recommendations for research in rural nursing cancer care and actions for fostering CNS role development are suggested.

  3. The allometry of CNS size and consequences of miniaturization in orb-weaving and cleptoparasitic spiders.

    Science.gov (United States)

    Quesada, Rosannette; Triana, Emilia; Vargas, Gloria; Douglass, John K; Seid, Marc A; Niven, Jeremy E; Eberhard, William G; Wcislo, William T

    2011-11-01

    Allometric studies of the gross neuroanatomy of adults from nine species of spiders from six web-weaving families (Orbicularia), and nymphs from six of these species, show that very small spiders resemble other small animals in having disproportionately larger central nervous systems (CNSs) relative to body mass when compared with large-bodied forms. Small spiderlings and minute adult spiders have similar relative CNS volumes. The relatively large CNS of a very small spider occupies up to 78% of the cephalothorax volume. The CNSs of very small spiders extend into their coxae, occupying as much as 26% of the profile area of the coxae of an Anapisona simoni spiderling (body mass weave prey capture webs, as do the spiderlings, beginning with second instar nymphs. Comparable allometric relations occur in adults of both orb-weaving and cleptoparasitic species, indicating that this behavioral difference is not reflected in differences in gross CNS allometry. Published by Elsevier Ltd.

  4. Test-Retest Reliability of a Computerized Concussion Test: CNS Vital Signs.

    Science.gov (United States)

    Littleton, Ashley C; Register-Mihalik, Johna K; Guskiewicz, Kevin M

    2015-01-01

    Neurocognitive testing is an important concussion evaluation tool, but for neurocognitive tests to be useful, their psychometric properties must be well established. Test-retest reliability of computerized neurocognitive tests can influence their clinical utility. The reliability for a commonly used computerized neurocognitive test, CNS Vital Signs, is not well established. The purpose of this study was to examine test-retest reliability and reliable change indices for CNS Vital Signs in a healthy, physically active college population. CNS Vital Signs yields acceptable test-retest reliability, with greater reliability between the second and third test administration compared with between the first and second administration. Cohort study. Level 3. Forty healthy, active volunteers (16 men, 24 women; mean age, 21.05 ± 2.17 years) reported to a clinical laboratory for 3 sessions, 1 week apart. At each session, participants were administered CNS Vital Signs. Outcomes included standard scores for the following CNS Vital Signs domains: verbal memory, visual memory, psychomotor speed, cognitive flexibility, complex attention, processing speed, reaction time, executive functioning, and reasoning. Participants performed significantly better on the second session and/or third session than they did on the first testing session on 6 of 9 neurocognitive domains. Pearson r test-retest correlations between sessions ranged from 0.11 to 0.87. Intraclass correlation coefficients ranged from 0.10 to 0.86. Clinicians should consider using reliable change indices to account for practice effects, identify meaningful score changes due to pathology, and inform clinical decisions. This study highlights the importance of clinicians understanding the psychometric properties of computerized neurocognitive tests when using them in the management of sport-related concussion. If CNS Vital Signs is administered twice within a small time frame (such as 1 week), athletes should be expected to

  5. Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos: a prospective study.

    Science.gov (United States)

    Dittrich, Sabine; Rattanavong, Sayaphet; Lee, Sue J; Panyanivong, Phonepasith; Craig, Scott B; Tulsiani, Suhella M; Blacksell, Stuart D; Dance, David A B; Dubot-Pérès, Audrey; Sengduangphachanh, Amphone; Phoumin, Phonelavanh; Paris, Daniel H; Newton, Paul N

    2015-02-01

    Scrub typhus (caused by Orientia tsutsugamushi), murine typhus (caused by Rickettsia typhi), and leptospirosis are common causes of febrile illness in Asia; meningitis and meningoencephalitis are severe complications. However, scarce data exist for the burden of these pathogens in patients with CNS disease in endemic countries. Laos is representative of vast economically poor rural areas in Asia with little medical information to guide public health policy. We assessed whether these pathogens are important causes of CNS infections in Laos. Between Jan 10, 2003, and Nov 25, 2011, we enrolled 1112 consecutive patients of all ages admitted with CNS symptoms or signs requiring a lumbar puncture at Mahosot Hospital, Vientiane, Laos. Microbiological examinations (culture, PCR, and serology) targeted so-called conventional bacterial infections (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, S suis) and O tsutsugamushi, Rickettsia typhi/Rickettsia spp, and Leptospira spp infections in blood or cerebrospinal fluid (CSF). We analysed and compared causes and clinical and CSF characteristics between patient groups. 1051 (95%) of 1112 patients who presented had CSF available for analysis, of whom 254 (24%) had a CNS infection attributable to a bacterial or fungal pathogen. 90 (35%) of these 254 infections were caused by O tsutsugamushi, R typhi/Rickettsia spp, or Leptospira spp. These pathogens were significantly more frequent than conventional bacterial infections (90/1051 [9%] vs 42/1051 [4%]; pLaos. Antibiotics, such as tetracyclines, needed for the treatment of murine typhus and scrub typhus, are not routinely advised for empirical treatment of CNS infections. These severely neglected infections represent a potentially large proportion of treatable CNS disease burden across vast endemic areas and need more attention. Wellcome Trust UK. Copyright © 2015 Dittrich et al. Open Access article published under the terms of CC BY. Published by .. All

  6. Clearance of an immunosuppressive virus from the CNS coincides with immune reanimation and diversification

    Directory of Open Access Journals (Sweden)

    McGavern Dorian B

    2007-06-01

    Full Text Available Abstract Once a virus infection establishes persistence in the central nervous system (CNS, it is especially difficult to eliminate from this specialized compartment. Therefore, it is of the utmost importance to fully understand scenarios during which a persisting virus is ultimately purged from the CNS by the adaptive immune system. Such a scenario can be found following infection of adult mice with an immunosuppressive variant of lymphocytic choriomeningitis virus (LCMV referred to as clone 13. In this study we demonstrate that following intravenous inoculation, clone 13 rapidly infected peripheral tissues within one week, but more slowly inundated the entire brain parenchyma over the course of a month. During the establishment of persistence, we observed that genetically tagged LCMV-specific cytotoxic T lymphocytes (CTL progressively lost function; however, the severity of this loss in the CNS was never as substantial as that observed in the periphery. One of the most impressive features of this model system is that the peripheral T cell response eventually regains functionality at ~60–80 days post-infection, and this was associated with a rapid decline in virus from the periphery. Coincident with this "reanimation phase" was a massive influx of CD4 T and B cells into the CNS and a dramatic reduction in viral distribution. In fact, olfactory bulb neurons served as the last refuge for the persisting virus, which was ultimately purged from the CNS within 200 days post-infection. These data indicate that a functionally revived immune response can prevail over a virus that establishes widespread presence both in the periphery and brain parenchyma, and that therapeutic enhancement of an existing response could serve as an effective means to thwart long term CNS persistence.

  7. Occult microlithiasis in 'idiopathic' acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy.

    Science.gov (United States)

    Ros, E; Navarro, S; Bru, C; Garcia-Pugés, A; Valderrama, R

    1991-12-01

    Gallstone pancreatitis is usually related to small stones, which may not be detected by conventional cholecystographic techniques. In the current study, it was hypothesized that some patients with acute pancreatitis of unknown cause could harbor occult microstones in the gallbladder. Therefore, evidence was sought prospectively of missed gallstones by biliary drainage and microscopic examination of centrifuged duodenal bile in 51 patients recovering from an attack of acute pancreatitis, including 24 patients with relapsing episodes. Clusters of cholesterol monohydrate crystals, calcium bilirubinate granules, and/or CaCO3 microspheroliths were found in 67% of the patients. Biliary drainage showed no abnormal findings in 12 patients convalescing from a bout of known alcoholic pancreatitis. Examination of gallbladder bile at cholecystectomy and/or serial ultrasonography of the gallbladder for up to 12 months showed that 73% of the patients with unexplained pancreatitis had biliary sludge or microlithiasis; the prior finding of biliary crystal/solid markers predicted their existence with both a sensitivity and a specificity of 86% and a predictive value of 94%. The probability of harboring occult gallstones was also associated with age (P = 0.004), prior recurrent pancreatitis (P = 0.024), and altered liver function tests results during an index episode (P = 0.003). In 13 patients with cholesterol monohydrate crystals in bile, ursodeoxycholic acid (10 mg.kg-1.day-1) eliminated gallbladder microlithiasis within 3-6 months, and subsequent maintenance treatment with a daily dose of 300 mg prevented both gallstone recurrence and further attacks of pancreatitis over a mean follow-up period of 44 months. Cholecystectomy also prevented gallstone-associated relapses in 17 of 18 patients followed up for a mean postoperative period of 36 months. This study provides firm evidence showing that in most patients with idiopathic acute pancreatitis, the disease is related to

  8. Thinking about CNS metastasis in cutaneous lymphoma: Analysis of existing data

    Directory of Open Access Journals (Sweden)

    Yi Yang

    2017-01-01

    Full Text Available To determine some of the key clinical features that help prompt clinicians to pursue additional work-up for evaluation of CNS involvement of MF, we conducted a systematic review to better define characteristics, treatments, outcomes, and mortality in these patients. Our analyses indicated that neurologic surveillance after the diagnosis of MF is crucial. Review of systems should include change in mentation, vestibular, and ocular symptoms. Progression to CNS involvement does not always occur in tandem with cutaneous disease burden. Single-agent therapies can delay disease progression and improve prognosis. Multi-agent treatment does not improve survival.

  9. Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes.

    OpenAIRE

    Braissant Olivier; Béard Elidie; Torrent Céline; Henry Hugues

    2010-01-01

    AGAT and GAMT, the two enzymes of the creatine synthesis pathway, are well expressed within CNS, suggesting autonomous brain creatine synthesis. This contradicts SLC6A8 deficiency, which causes creatine deficiency despite CNS expression of AGAT and GAMT. We hypothesized that AGAT and GAMT were not co-expressed by brain cells, and that guanidinoacetate must be transported between cells to allow creatine synthesis. We finely analyzed the cell-to-cell co-expression of AGAT, GAMT and SLC6A8 in va...

  10. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma

    Science.gov (United States)

    Xie, Wanling; Jagannath, Sundar; Jakubowiak, Andrzej; Lonial, Sagar; Raje, Noopur S.; Alsina, Melissa; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Mazumder, Amitabha; Vesole, David H.; Kaufman, Jonathan L.; Colson, Kathleen; McKenney, Mary; Lunde, Laura E.; Feather, John; Maglio, Michelle E.; Warren, Diane; Francis, Dixil; Hideshima, Teru; Knight, Robert; Esseltine, Dixie-Lee; Mitsiades, Constantine S.; Weller, Edie; Anderson, Kenneth C.

    2014-01-01

    In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m2 (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209. PMID:24429336

  11. What is the optimal value of the g-ratio for myelinated fibers in the rat CNS? A theoretical approach.

    Directory of Open Access Journals (Sweden)

    Taylor Chomiak

    2009-11-01

    Full Text Available The biological process underlying axonal myelination is complex and often prone to injury and disease. The ratio of the inner axonal diameter to the total outer diameter or g-ratio is widely utilized as a functional and structural index of optimal axonal myelination. Based on the speed of fiber conduction, Rushton was the first to derive a theoretical estimate of the optimal g-ratio of 0.6 [1]. This theoretical limit nicely explains the experimental data for myelinated axons obtained for some peripheral fibers but appears significantly lower than that found for CNS fibers. This is, however, hardly surprising given that in the CNS, axonal myelination must achieve multiple goals including reducing conduction delays, promoting conduction fidelity, lowering energy costs, and saving space.In this study we explore the notion that a balanced set-point can be achieved at a functional level as the micro-structure of individual axons becomes optimized, particularly for the central system where axons tend to be smaller and their myelin sheath thinner. We used an intuitive yet novel theoretical approach based on the fundamental biophysical properties describing axonal structure and function to show that an optimal g-ratio can be defined for the central nervous system (approximately 0.77. Furthermore, by reducing the influence of volume constraints on structural design by about 40%, this approach can also predict the g-ratio observed in some peripheral fibers (approximately 0.6.These results support the notion of optimization theory in nervous system design and construction and may also help explain why the central and peripheral systems have evolved different g-ratios as a result of volume constraints.

  12. Psychiatrist's adherence: a new factor in relapse prevention of schizophrenia. A randomized controlled study on relapse control through telemedicine system.

    Science.gov (United States)

    Spaniel, F; Novak, T; Bankovska Motlova, L; Capkova, J; Slovakova, A; Trancik, P; Matejka, M; Höschl, C

    2015-12-01

    Exposure to psychotic states has detrimental effects on the long-term outcome of schizophrenia and brain integrity. Therefore, improving relapse prevention is a key component of long-term management of schizophrenia. Previous studies using continuous monitoring of an individual's early signs of relapse and adopting preventative pharmacological interventions, when early signs are detected, showed promising clinical results in terms of relapse risk reduction. This 18-month multi-centre parallel randomized controlled, open label, trial with telemedicine relapse prevention programme ITAREPS failed to show superiority of maintenance plus prodrome-based targeted medication strategy over treatment as usual. The study, marked by low investigator's adherence, confirmed that absence of pharmacological intervention at early stage of prodrome, critically influenced the risk of relapse. This and previous randomized controlled trials with telemedicine programme ITAREPS suggested that substantial improvement in relapse prevention in schizophrenia is likely to be unattainable under current clinical settings. Future preventive strategies in schizophrenia would require rapid pharmacological intervention upon occurrence of subclinical prodromal symptoms that are undetectable under conventional outpatient practice. Studies with ITAREPS suggested that integration of telemedicine relapse prevention systems and visiting nurse service might together represent practical solution capable to address those requirements. The Information Technology Aided Relapse Prevention Programme in Schizophrenia (ITAREPS) presents a telemedicine solution for weekly monitoring and management of schizophrenia. This study aims to evaluate the effectiveness of the programme in reducing the number of hospitalizations during the 18-month multi-centre parallel randomized controlled, open label, trial. Outpatients with schizophrenia or schizoaffective disorder were randomized to the active (n = 74) or control group

  13. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients.

    Science.gov (United States)

    Le Page, Emmanuelle; Leray, Emmanuelle; Taurin, Grégory; Coustans, Marc; Chaperon, Jacques; Morrissey, Sean P; Edan, Gilles

    2008-01-01

    Mitoxantrone was approved by the French health authority (AFSAPPS) in October 2003 to treat patients with aggressive multiple sclerosis (MS). To report the long term effectiveness and safety of mitoxantrone as induction therapy in patients with aggressive relapsing-remitting MS, and to assess treatment response factors. 100 consecutive patients with aggressive relapsing-remitting MS received mitoxantrone 20 mg monthly combined with methylprednisolone 1 g for 6 months. Relapses, Expanded Disability Status Scale (EDSS) and drug safety were assessed every 6 months for up to at least 5 years. Within 6 months after induction, 73 patients received maintenance therapy (mitoxantrone every 3 months (n = 21); interferon beta (n = 25); azathioprine (n = 15); methotrexate (n = 7); glatiramer acetate (n = 5)). During the 12 months following initiation of mitoxantrone, the annual relapse rate (ARR) was reduced by 91%, 78% of patients remained relapse free, MRI activity was reduced by 89%, the mean EDSS decreased by 1.2 points (p<10(-6)) and 64% of patients improved by 1 point or more on the EDSS. In the longer term, the ARR reduction was sustained (0.29-0.42 for up to 5 years), the median time to the first relapse was 2.8 years and disability remained improved after 5 years. Younger age and lower EDSS score at the start of mitoxantrone treatment were predictive of better treatment response. Three patients presented with an asymptomatic decrease in left ventricular ejection fraction to less than 50% (one reversible). One patient was diagnosed with acute myeloid leukaemia (remission 5 years after diagnosis). Mitoxantrone monthly for 6 months as induction therapy followed by maintenance treatment showed sustained clinical benefit for up to 5 years with an acceptable adverse events profile in patients with aggressive relapsing-remitting MS.

  14. Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab.

    Science.gov (United States)

    Laursen, Julie Hejgaard; Søndergaard, Helle Bach; Sørensen, Per Soelberg; Sellebjerg, Finn; Oturai, Annette Bang

    2016-11-01

    Vitamin D insufficiency is common among multiple sclerosis patients, and hypovitaminosis D has been associated with multiple sclerosis (MS) risk and disease activity. To investigate how recommendations on vitamin D3 supplements affect 25-hydroxyvitamin D (25(OH)D) levels in patients with relapsing-remitting MS (RRMS) and to examine the clinical effects associated with changes in 25(OH)D levels. In this prospective cohort study, baseline blood samples were collected from 170 natalizumab-treated RRMS patients during winter 2009-2010 and were repeated the following winter. Vitamin D supplements were recommended according to standard clinical practice in our clinic to patients with serum 25(OH)Dvitamin D supplements in patients with vitamin D insufficiency was associated with a significant increase in serum 25(OH)D concentrations (p=5.1×10-10), which was significantly related with decreases in ARR; for each nmol/l increase in Δ25(OH)D a -0.014 (95% CI -0.026 to -0.003) decrease in ΔARR was observed, p=0.02. Correction of hypovitaminosis D in clinical practice by recommending oral D3 supplements resulted in increases in 25(OH)D levels in serum, which were associated with decreases in ARR in RRMS. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. The alternative five-factor model of personality, nicotine dependence and relapse after treatment for smoking cessation.

    Science.gov (United States)

    Nieva, Gemma; Valero, Sergi; Bruguera, Eugeni; Andión, Óscar; Trasovares, M Victoria; Gual, Antoni; Casas, Miquel

    2011-10-01

    Personality is one of several factors that have been related to the initiation, maintenance and cessation of smoking. This paper aims to analyze the relationship between the alternative five-factor model of personality (AFFM), nicotine dependence (ND), nicotine use (NU) and cessation after twelve months of a cognitive-behavioral therapy combined with medication. In this prospective study, a sample of 103 smokers who were taking part in a workplace smoking cessation intervention, answered the Zuckerman-Kuhlman Personality Questionnaire. ND and NU were measured with the Fagerström Test for the Nicotine Dependence (FTND) and the number of cigarettes smoked per day (CPD), respectively. Tobacco cessation was self-reported at twelve months follow-up and biologically confirmed. Results varied according to gender. In men, low scores on Sociability predicted high ND and large number of CPD. In addition, low scores on Sensation Seeking and high scores on Impulsivity predicted also a high smoking rate at baseline. No personality traits were found to explain ND in women, but high Impulsivity-Sensation Seeking and General Activity predicted high CPD. Predictors of cessation also differed by gender. Apart from FTND level, high levels on Impulsivity predicted relapse in males. In women, high levels on Sociability predicted relapse. This model correctly classified two thirds of abstainers and relapsers for men and three fourths for women at 12months. Furthermore an interaction between personality and gender was observed. The AFFM appears to have a substantial power for predicting cessation. Personality assessment when beginning treatment for smoking cessation could allow incorporating strategies to improve outcomes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Neural response to catecholamine depletion in remitted bulimia nervosa: Relation to depression and relapse.

    Science.gov (United States)

    Mueller, Stefanie Verena; Mihov, Yoan; Federspiel, Andrea; Wiest, Roland; Hasler, Gregor

    2017-07-01

    Bulimia nervosa has been associated with a dysregulated catecholamine system. Nevertheless, the influence of this dysregulation on bulimic symptoms, on neural activity, and on the course of the illness is not clear yet. An instructive paradigm for directly investigating the relationship between catecholaminergic functioning and bulimia nervosa has involved the behavioral and neural responses to experimental catecholamine depletion. The purpose of this study was to examine the neural substrate of catecholaminergic dysfunction in bulimia nervosa and its relationship to relapse. In a randomized, double-blind and crossover study design, catecholamine depletion was achieved by using the oral administration of alpha-methyl-paratyrosine (AMPT) over 24 h in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. In a follow-up telephone interview, bulimic relapse was assessed. Following AMPT, rBN participants revealed an increased vigor reduction and CBF decreases in the pallidum and posterior midcingulate cortex (pMCC) relative to HC participants showing no CBF changes in these regions. These results indicated that the pallidum and the pMCC are the functional neural correlates of the dysregulated catecholamine system in bulimia nervosa. Bulimic relapse was associated with increased depressive symptoms and CBF reduction in the hippocampus/parahippocampal gyrus following catecholamine depletion. AMPT-induced increased CBF in this region predicted staying in remission. These findings demonstrated the importance of depressive symptoms and the stress system in the course of bulimia nervosa. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer.

    Science.gov (United States)

    Millen, Rosemary; Malaterre, Jordane; Cross, Ryan S; Carpinteri, Sandra; Desai, Jayesh; Tran, Ben; Darcy, Phillip; Gibbs, Peter; Sieber, Oliver; Zeps, Nikolajs; Waring, Paul; Fox, Stephen; Pereira, Lloyd; Ramsay, Robert G

    2016-07-01

    The presence of tumor immune infiltrating cells (TILs), particularly CD8(+) T-cells, is a robust predictor of outcome in patients with colorectal cancer (CRC). We revisited TIL abundance specifically in patients with microsatellite stable (MSS) CRC without evidence of lymph node or metastatic spread. Examination of the density of CD8(+) T-cells in primary tumors in the context of other pro-oncogenic markers was performed to investigate potential regulators of TILs. Two independent cohorts of patients with MSS T2-4N0M0 CRC, enriched for cases with atypical relapse, were investigated. We quantified CD8(+) and CD45RO(+) -TILs, inflammatory markers, NFkBp65, pStat3, Cyclo-oxygenase-2 (COX2) and GRP78 as well as transcription factors (TF), β-catenin and MYB. High CD8(+) TILs correlated with a better relapse-free survival in both cohorts (p = 0.002) with MYB and its target gene, GRP78 being higher in the relapse group (p = 0.001); no difference in pSTAT3 and p65 was observed. A mouse CRC (CT26) model was employed to evaluate the effect of MYB on GRP78 expression as well as T-cell infiltration. MYB over-expressing in CT26 cells increased GRP78 expression and the analysis of tumor-draining lymph nodes adjacent to tumors showed reduced T-cell activation. Furthermore, MYB over-expression reduced the efficacy of anti-PD-1 to modulate CT26 tumor growth. This high MYB and GRP78 show a reciprocal relationship with CD8(+) TILs which may be useful refining the prediction of patient outcome. These data reveal a new immunomodulatory function for MYB suggesting a basis for further development of anti-GRP78 and/or anti-MYB therapies.

  18. Relapse of nephrotic syndrome triggered by Kawasaki disease.

    Science.gov (United States)

    Maeda, Ryo; Kawasaki, Yukihiko; Suzuki, Shigeo; Ohara, Shinichiro; Kazuhide, Suyama; Hosoya, Mitsuaki

    2017-11-15

    Minor infections, allergies, insect bites, and bee stings are commonly reported causes of nephrotic syndrome (NS). Herein, we report, to the best of our knowledge, the first case of NS relapse due to Kawasaki disease (KD). An 8-year-old boy presented with high fever of 4-day duration. He had developed steroid-dependent NS at the age of 4 years and remained in remission after steroid and mizonbin therapy. Renal biopsy, performed at the age of four, showed minimal change (MC) disease. Upon examination, the patient fulfilled 5 of 6 criteria for KD under the Japanese diagnostic guidelines, with positive proteinuria. He was diagnosed with NS relapse caused by KD. Proteinuria resolved after treatment with intravenous immunoglobulin and cyclosporine A. We present the case of an 8-year-old boy, whose NS relapsed due to KD. To the best of our knowledge, this is the first case report. It is necessary to recognize that KD can trigger relapse of MCNS.

  19. Germ Cell Cancer and Multiple Relapses: Toxicity and Survival

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Kier, Maria G.G.; Mortensen, Mette S.

    2015-01-01

    Purpose: A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment...

  20. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

    Science.gov (United States)

    Madan, V; Shyamsunder, P; Han, L; Mayakonda, A; Nagata, Y; Sundaresan, J; Kanojia, D; Yoshida, K; Ganesan, S; Hattori, N; Fulton, N; Tan, K-T; Alpermann, T; Kuo, M-C; Rostami, S; Matthews, J; Sanada, M; Liu, L-Z; Shiraishi, Y; Miyano, S; Chendamarai, E; Hou, H-A; Malnassy, G; Ma, T; Garg, M; Ding, L-W; Sun, Q-Y; Chien, W; Ikezoe, T; Lill, M; Biondi, A; Larson, R A; Powell, B L; Lübbert, M; Chng, W J; Tien, H-F; Heuser, M; Ganser, A; Koren-Michowitz, M; Kornblau, S M; Kantarjian, H M; Nowak, D; Hofmann, W-K; Yang, H; Stock, W; Ghavamzadeh, A; Alimoghaddam, K; Haferlach, T; Ogawa, S; Shih, L-Y; Mathews, V; Koeffler, H P

    2016-01-01

    Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential. PMID:27063598